TOWARD THE IDEAL SYNTHESIS AND TRANSFORMATIVE THERAPIES: THE ROLE OF

PL 01 / Plenary lectures
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
TOWARD THE IDEAL SYNTHESIS AND
TRANSFORMATIVE THERAPIES: THE ROLE OF
STEP ECONOMY AND FUNCTION ORIENTED
SYNTHESIS
Paul A. Wender
Departments of Chemistry and of Chemical and Systems Biology, Stanford University, Stanford, CA
USA [email protected]
Studies in our laboratory are focused on the design, synthesis and evaluation of
molecules that exhibit unique modes of action for unmet medical needs, new tools
for real time cellular and animal imaging, and novel drug delivery strategies based
on “guanidinium rich molecular transporters”. These programs all draw on the
introduction and development of new reactions and synthetic strategies that would
deliver designed or natural targets in a “step economical” if not “ideal” fashion
(Nature 2009, 197; JACS 2012, 11012). “Function oriented synthesis” is a key
concept used in achieving these combined synthetic and therapeutic goals (PNAS
2011, 6721; Accts 2008, 40). As will be presented in this lecture, representative
synthesis-driven projects are directed at as yet unachieved but hugely important
goals including the eradication of HIV/AIDS, the development of first-in-class
strategies to treat Alzheimer’s disease, and a general strategy to overcome resistant
cancer, the major cause of chemotherapy failure (Lead references include: Nature
Chemistry 2012, 705; Science 2008, 649; PNAS 2012, 13171; PNAS 2012, 13225;
Nature Chemistry 2011, 615; J. Amer. Chem. Soc. 2011, 9228; Gynecologic Oncol.
2012, 118; Nature Medicine 2000, 1253).
10
Plenary lectures / PL 02
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Transition metal catalyzed synthesis
of aromatic heterocycles
|Irina P. Beletskaya
Department of Chemistry, M.V. Lomonosov Moscow State University, Moscow, 119992, Russia
[email protected]
Several basic methods of transition metal catalysed cyclization will be considered.
1. Pd-catalysed intramolecular addition of E-H bond to triple bond
(E=element) and its intermolecular version with internal alkynes.
2. Wacker-type intramolecular addition of E-H bond to double bond.
3. Cyclisation via intramolecular Heck reactions.
4. Intramolecular and intermolecular carbon-heteroatom cross-coupling
cyclizations catalysed by Pd(0).
5. Cross-coupling via C-H activation.
6. Catalysis by Cu(I), Au(I), Au(III), Hg(II).
11
PL 03 / Plenary lectures
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
NEW advances in transition
metal-catalyzed synthesis and
functionalization of heterocycles
Vladimir Gevorgyan
Department of Chemistry, University of Illinois at Chicago
845 West Taylor Street, Chicago, Illinois 60607, USA
[email protected]
We have developed a set of new transition metal-catalyzed methodologies
for synthesis of furan, pyrrole, and N-fused heterocycles. These methods
operate via several types of novel cycloisomerizations, including migratory
cycloisomerizations, and recently discovered transannulation reaction. Lately, we
expanded the scope of these transformations, as well as performed more detailed
mechanistic studies, toward better understanding of this chemistry.
We have also developed several new two- and tri-component coupling reactions
toward synthesis of indolizines, indolines, indoles, and imidazopyridines. Some of
these methods have been applied to a synthesis of focused and mid-sized libraries
of small molecules for wide biological screening.
The scope of these and some other transformations will be demostrated and the
mechanisms will be discussed.
12
Plenary lectures / PL 04
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF PHARMACOLOGICALLY ACTIVE
HETEROCYCLIC COMPOUNDS
Hans-Joachim Knölker
Department of Chemistry, Technical University of Dresden, Bergstraße 66, 01069 Dresden, Germany
[email protected]
Natural product chemistry has always been an inspiration for the search of novel lead
structures for drug development and very often heterocyclic compounds have been in the
focus. Carbazole alkaloids represent a rich source of novel bioactive compounds.1 Using a
palladium-catalyzed oxidative cyclization, we developed a versatile route to carbazoles.1,2
Recent applications were directed towards the total synthesis of biscarbazole alkaloids.1,3
Me
Me
O
N
H
OMe
N
OMe H
OMe
Oxydimurrayaf oline
N
N
Me
N
H
N
OMe
H
Murrastifoline-A
O
O
O
HO
HO
O
HO
O
Maradolipid: Mar 18:1/19:1
O
HO
OH
MeO
MeO
OMe
Bismurrayaf oline-A
O
OH
Cl
HO
N
Cl
Crispine A
OMe
Cl
Cl
N
H
Cl
Pentachloropseudilin
We have reported the isolation of the maradolipids from the nematode C. elegans and their
synthesis.4 A silver(I)-mediated oxidative cyclization of homopropargylamines to pyrroles
was developed in our laboratories and has been applied to the synthesis of the pyrrolo[2,1-a]
isoquinoline alkaloid (±)-crispine A.5 Using a silver(I)-catalyzed cyclization process, the
total synthesis of pentachloropseudilin was achieved.6 The pentahalogenated pseudilins
represent a novel class of isoform-specific inhibitors of myosin ATPase.7
References:
1. Schmidt, A. W.; Reddy, K. R.; Knölker, H.-J. Chem. Rev. 2012, 112, 3193.
2. Gensch, T.; Rönnefahrt, M.; Bauer, I.; Knölker, H.-J.; et al. Chem. Eur. J. 2012, 18, 770.
3. Börger, C.; Kataeva, O.; Knölker, H.-J. Org. Biomol. Chem. 2012, 10, 7269.
4. Knölker, H.-J.; Kurzchalia, T. V.; et al. Angew. Chem. Int. Ed. 2010, 49, 9430.
5. Agarwal, S.; Kataeva, O.; Schmidt, U.; Knölker, H.-J. RSC Adv. 2013, 3, 1089.
6. Martin, R.; Manstein, D. J.; Knölker, H.-J.; et al. Angew. Chem. Int. Ed. 2009, 48, 8042.
7. Martin, R.; Knölker, H.-J.; Manstein, D. J.; et al. J. Med. Chem. 2011, 54, 3675.
13
PL 05 / Plenary lectures
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
The Discovery and Optimization of
Inhibitors of Hepatitis C Virus
Nicholas A. Meanwell
Department of Medicinal Chemistry, Bristol-Myers Squibb Research and Development, 5 Research
Parkway, Wallingford, CT 06492, USA
[email protected]
Hepatitis C virus (HCV) chronically infects approximately 200 million indivi­duals
worldwide and is an insidious infection that progresses slowly over the course of
decades to inflict serious liver damage. Therapy has progressed from a combination
of pegylated interferon-α and the nucleoside analogue ribavirin, neither of which
are specific antiviral agents, to include the recently launched HCV NS3 protease
inhibitors telaprevir and boceprevir. However, side effects with these drug
regimens and rates of cure are less than optimal, providing for a significant unmet
medical need for improved therapeutic options. This presenta­tion will describe two
complementary approaches to drug discovery: a structure-based approach to the
design of HCV NS3 protease inhibitors that led to the identification of asunaprevir
and the implementation of a chemical genetics strategy to identify mechanistically
novel HCV inhibitors that culminated in the discovery of the NS5A inhibitor
daclatasvir. The optimization of both asunap­revir and daclatasvir illustrate some
interesting examples of the application of bioisosterism in drug design. These two
compounds are currently being evaluated in clinical trials as combination therapy
with and without the HCV NS55 polymerase inhibitor BMS-791325 and the early
clinical results will be discussed.
OMe
MeO2CHN
N
Cl
O
O
O
NH
O
N
H
N
N
O
O
O
O O
S
N
H
H
N
N
N
N
N
H
daclatasvir
O
NHCO2M
e
asunaprevir
References:
1. Gao, M.; Nettles, R.E.; Belema, M.; Snyder, L.B.; Nguyen, V.N.; Fridell, R.A.;
Serrano-Wu, M.H.; Langley, D.R.; Sun, J.-H.; O’Boyle II, D.R.; Lemm, J.A.;
Wang, C.; Knipe, J.O.; Chien, C.; Colonno, R.J.; Grasela, D.M.; Meanwell,
N.A.; Hamann, L.G. Nature, 2010, 465, 96-100.
2. McPhee, F.; Sheaffer, A.K.; Friborg, J.; Hernandez, D.; Falk, P.; Zhai, G.;
Levine, S.; Chaniewski, S.; Yu, F.; Barry, D.; Chen, C.; Lee, M.S.; Mosure,
K.; Sun, L.-Q.; Chen, J.; Sinz, M.; Meanwell, N.A.; Colonno, R.J.; Knipe, J.;
Scola, P. Antimicrobial Agents Chemother., 2012, 56, 5387-5396.
14
Plenary lectures / PL 06
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Design and Synthesis of Ring-fused
2-Pyridones & Applications in Chemical
Biology
Fredrik Almqvist
Department of Chemistry, Umeå University, Sweden,
[email protected]
Highly substituted ring-fused 2-pyridones are excellent scaffolds for the development
of novel antibacterial agents, pilicides and curlicides, that target bacterial virulence
by inhibiting the formation of bacterial pili and curli.1,2 The heterocyclic central
fragment (1) (Fig. 1) can be synthesized via an enantioselective acyl-ketene imine
cycloaddition.3 In this reaction two substituents are independently introduced to
the scaffold (R1 and R2, Fig. 1) and methods to introduce substituents in all other
positions on the scaffold have been developed.4 In addition, we have also shown
that this synthetic platform could be directed to synthesize compounds that inhibit
the formation of functional amyloids in bacteria, curli.2,5
Figure 1. By fine-tuning the substitution pattern on the thiazolo ring-fused 2-pyridone scaffold 1,
compounds that inhibit the formation of bacterial fibers (pili and/or curli) are obtained.
References:
[1] Pinkner, J. S. et al. Proc. Natl. Acad. Sci. USA 2006, 103, (47), 17897-17902.
[2] Cegelski, L. et al. Nature Chem. Biol. 2009, 5, 913-919.
[3] Emtenäs, H.; Alderin, L.; Almqvist, F. J. Org. Chem. 2001, 66, (20), 6756-6761.
[4] e. g. (i) Chorell, E. et. al. J. Org. Chem. 2007, 72, (13), 4917-4924. (ii) Chorell,
E. et. al. J. Med Chem. 2010, 53, 5690-5695. (iii) Bengtsson, C.; Almqvist, F.
J. Org. Chem. 2010, 75, 972-975. (iv) Chorell, E. et. al. Chemistry-A European
Journal. 2012, 18 (15), 4522-4532
[5] e. g. (i) Horvath, I. et. al. J. Am. Chem. Soc. 2012, 134 (7), 3439-3444.
15
PL 07 / Plenary lectures
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Heterocycles as novel DNA Bases
Beyond Watson and Crick
T. Carell, T. Pfaffeneder, M. Wagner, B. Hackner, S. Schießer, M. Müller
Department of Chemistry, LMU Munich, Butenandtstr. 5-13, 81377 Munich,
[email protected]
I am going to discuss the latest results related to the function and distribution of the
new heterocyclic nucleobases 5-hydroxymethylcytosine (hmC), 5-formylcytosine
(fC), and 5-carboxycytosine (caC).[1] These nucleobases seem to play an important
role in epigenetic reprogramming of stem cells and some of these bases are also
detected at relatively high levels in brain tissues. I will present new synthetic
routes that enable preparation of these compounds and of the corresponding
phosphoramidites using modern metal organic chemistry. Finally I will discuss
how chemistry leads to new insights into the biology of stem cell development
processes. In particular mass spectroscopy in combination with the availability
of the isotopically labeled heterocycles allows investigation of the distribution of
these novel compounds in various tissues and during stem cell development. The
recently discovered base formylcytosine for example, is present at relatively high
levels in stem cells and its distribution varies during development in a wave like
fashion. I am going to describe the distribution of carboxylcytosine in somatic
tissues and in stem cells and will provide new quantitative data derived from a
detailed mass spectrometric analysis. In order to elucidate the function of the
nucleobases we devised a new isotope tracing experiment that enables us to unravel
the biochemistry of the heterocycles with high precision and accuracy. I will discuss
the synthesis of double [15N]-labeled hmC, fC and caC and the preparation of DNA
containing these isotopologes.[1]
Scheme 1. Depiction of the epigenetic bases hmC, fC, and caC.
1. Schiesser, B. et al. ACIE 2012, DOI: 10.1002/anie.201202583
16
Plenary lectures / PL 08
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
ENANTIOSELECTIVE SYNTHESIS OF cisDhq ALKALOIDS from chiral tricyclic
lactams
Mercedes Amat
Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine (IBUB), University
of Barcelona, 08028-Barcelona, Spain.
[email protected]
The cis-decahydroquinoline (cis-DHQ) system constitutes a key structural
framework occurring in a variety of both natural and synthetic bioactive compounds.
The most abundant source of cis-DHQ alkaloids is found in the skin secretions
of neotropical dart poison frogs. Additionally, the eight cis-DHQ members of the
lepadin family have been isolated from various marine natural sources. However,
the DHQ motif is rare in plant sources, being restricted to Lycopodium and Nitraria
species. Due to the wide range of biological activities displayed by many of these
derivatives and their ability to act as a testing ground for new synthetic methods,
DHQs have attracted considerable attention from organic chemists over the years.
Nevertheless, the number of synthetic methodologies reported in the literature
for the efficient enantio- and stereoselective construction of this azabicycle with
substituents at the carbocyclic ring is still limited.
H
H
N
H
H
H
N
H
H
cis-195A
(Pumiliotoxin C)
N
N
Myrionine
O
H
H
N
H
O
H
N
H
H
Cermizine B
H
O
OH
Lepadin A
In recent work we have explored cyclocondensation reactions between chiral
aminoalcohols and cyclohexanone- or 2-cyclohexenone derivatives having a
propionate chain at C-2, stereoselectively leading to tricyclic lactams bearing up to
four stereocenters of well-defined absolute configuration. The synthetic potential of
these chiral tricyclic lactams as precursors for the preparation of cis-DHQ alkaloids
will be discussed.
Acknowledgements
Financial support from the Ministry of Economy and Competitiveness, Spain
(project CTQ2012-35250) and the DURSI, Generalitat de Catalunya (Grant
2009SGR-1111) is gratefully acknowledged.
17
PL 09 / Plenary lectures
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
IODINE AND COINAGE METAL CATALYZED
HETEROCYCLE SYNTHESIS
Yoshinori Yamamoto
State Key Laboratory of Fine Chemicals, DLUT, Dalian 116023, China; [email protected]
WPI-AIMR, Tohoku University, Sendai 980-8577, Japan,
[email protected]
Substituted quinolines and isoquinolines are often found as structural framework
in a large number of biologically active natural products and pharmaceuticals.
Because of their importance, much attention has been paid to development of
efficient methods for the synthesis of substituted quinolines and isoquinolines. We
recently reported metal-catalyzed or non-metal-catalyzed synthesis of substituted
dihydroisoquinolines, and an entirely new method for the synthesis of substituted
isoquinolines through iodine-mediated or gold-catalyzed cyclization of 2-alkynyl
benzyl azides. 1 This method was applied to a short synthesis of norchelerythrine.
R
N
R
1
+
R
Cat. Pd or Ag
-
Nu
N
R
1
Nu
R
R
3
R
4
X
5 eq. I2, 1 eq. base, CH2Cl2, r.t.
N3
2
R
1
R
or
30 mol.. % AuCl3, 90 mol. % AgSbF6,
THF, 100°C
X = C, N
R
R
3
I
R
X
4
N
2
R
1
R
O
O
N
MeO
OMe
norchelerythrine
1. Fischer, D.; Yamamoto, Y. et. al, J. Am. Chem. Soc. 2008, 130, 15720;
Yamamoto, Y.; Gridnev, I. D.; Patil, N.; Jin, T. Chem. Comm, 2009, 5075.
18
Plenary lectures / PL 10
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
From metal-free couplings to radical
cyclization cascades: new methods for
target synthesis
David J. Procter
School of Chemistry, University of Manchester, Manchester, M13 9PL, UK
[email protected]
A nucleophilic ortho-propargylation of aryl sulfoxides exploits intermolecular
delivery of the nucleophile to sulfur followed by an intramolecular relay to carbon.1
The operationally simple, metal-free coupling is general, regiospecific with regard
to the propargyl nucleophile, and shows complete selectivity for products of orthopropargylation over allenylation.
The rerouting of carbonyl reduction through less-conventional intermediates
allows new selectivity and reactivity to be exploited. Upon treatment with SmI2–
H2O, unsaturated lactones undergo cascade processes that allow ‘one-pot’ access to
biologically-significant molecular scaffolds.2
References:
1. Eberhart, A. J.; Procter, D. J. Angew. Chem., Int. Ed. 2013, 52, 4008.
2. Parmar, D.; Matsubara, H.; Price, K.; Spain, M.; Procter, D. J. J. Am. Chem. Soc.
2012, 134, 12751.
19
INVITED LECTURE
PO
IN 01 / /Invited
Poster lectures
presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Catalysis & Complexity: From
Mechanism to FunctioN
Valery V. Fokin
The Scripps Research Institute, La Jolla, CA 92037, U.S.A.
[email protected]
Investigation of complex catalytic systems requires rigorous real-time and
global examination of the dynamics of the constantly changing environment of
a catalytic reaction, such as critically important events, such as activation and
deactivation of a catalyst, unproductive off-cycle pathways, and changes in the
nature of the dominant species. A key lesson that emerged from our work during
the last decade is highly dynamic mixtures of complexes that exist in rapid
equilibria with each other can actually serve as exquisitely selective catalysts.
A single, well-defined catalyst is not always required and may, in fact, may
be counterproductive when compatibility with many functional groups and
conditions is the goal.
This approach will be exemplified using several case studies of the catalytic
reactions of alkynes. Alkynes are among the most energetic hydrocarbons,
and transition metals enable selective and controlled manipulation of the triple
bond, opening the door to the wealth of reliable reactivity: transformations of
alkynes into heterocycles and into a variety of molecules with new carbon–
heteroatom bonds. The combination of catalytic alkyne functionalization
followed by manipulation of the resulting products allows one to proceed from
a system with high energy content to a system of lower energy in a stepwise
fashion, thereby enabling controlled introduction of new elements of diversity
in every step. Various architectures, including a range of bioactive heterocycles,
prepared using these methods are finding increased use in organic synthesis,
nano- and biotechnology, and materials science.
22
Invited lectures / IN 02
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Indirect C–H functionalization of
electron-rich heterocycles
Edgars Suna
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia
[email protected]
Development of methodologies for functionalization of heterocycles is of highest
importance both in medicinal and in process chemistry, because heterocycles are
among the most frequently encountered scaffolds in drugs and pharmaceutically
relevant substances.
Our approach is based on functionalization of aromatic and heterocyclic C–H bonds
by the in situ formation of unsymmetrical heteroaryl-l3-iodanes, followed by their
regioselective fragmentation in the presence of transition metal (Pd, Cu) catalyst.
The developed methodology effects transformation of electron-rich heterocyclic
C–H bonds into C–O bonds and C–N bonds in an operationally simple one-pot
sequential multistep process.
References:
1) Lubriks, D.; Sokolovs, I.; Suna, E. Org. Lett. 2011, 13, 4324.
2) Lubriks, D.; Sokolovs, I.; Suna, E. J. Am. Chem. Soc. 2012, 134, 15436.
23
PO
IN 03 / /Invited
Poster lectures
presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Linear Encoding of Functional Groups:
Theoretical Approach and Application
in Biomass Conversion
Valentin P. Ananikov
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow,
119991, Russia;
[email protected]
The discovery of new chemical routes to poly-substituted heterocyclic compounds
remains the area of wide research interest due to a number of natural products,
pharmaceutical substances, and material science building blocks that utilize unique
physical, chemical and biological properties of heterocyclic systems. Formation of
heterocyclic core followed by incorporation of required functional groups using a
series of substitution reactions is nowadays typical synthetic route to access polysubstituted heterocycles (Scheme 1).
Scheme 1. Routine assemble of functional groups R1 - R6 vs. linear encoding.
In our group we have predicted new intramolecular cycloaddition reactions using a
special computational approach with heteroatom scan along the linear structure of
the initial reagent (Scheme 1).[1,2] A family of novel [4+2] cycloaddition reactions
was studied to carry out efficient preparation of poly-substituted heterocyclic
compounds in a single step from linear precursors.[1,2]
Practical application of the developed approach was demonstrated on the
industrially important process of biomass conversion to platform-chemicals. A novel
conversion system was developed in ionic liquids to accomplish transformation
of carbohydrates into 5‑hydroxymethylfurfural (5-HMF).[3] The involvement of
“linear-encoded” intermediate was revealed in the reaction.
References:
[1] V. P. Ananikov, E. G. Gordeev, Chem. Sci., 2011, 2, 2332.
[2] (a) V. P. Ananikov, Chem. Heterocycl. Compd., 2012, No 1, 2.
[3] (a) E. A.Khokhlova, V. V.Kachala, V. P.Ananikov, ChemSusChem, 2012, 5, 783.
(b) V. P. Ananikov, Chem. Rev., 2011, 111, 418.
24
Invited lectures / IN 04
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
CATALYTIC OLEFINATION REACTION. NEW
APPROACH TO FLUOROORGANICS
Valentine G. Nenajdenko
Moscow State University, Department of Chemistry, Leninskie Gory, Moscow 119992, Russia
[email protected]
The importance of fluoroorganic substances is well-known, for instance, about
25% of currently used drugs contain at least one fluorine atom. A novel synthesis
of alkenes has been discovered recently by our research group. It was found that
N-unsubstituted hydrazones of carbonyl compounds can be smoothly transformed
into various substituted alkenes by treatment with polyhaloalkanes in the presence
of catalytic amounts of CuCl. This reaction was found to be a new general approach
for the construction of carbon-carbon double bonds. A number of convenient and
simple methods for the synthesis of various alkenes including fluorinated ones
were developed. Fluorinated β-halostyrenes easily synthesized by this method are
of special interest because of the possibility of their modification by nucleophilic
vinylic substitution providing simple and general pathway to useful fluorinated
building blocks. The latter compounds were successfully used in the synthesis of
various carbo- and heterocyclic compounds.
F
Ar
CN
CF3
O
Ar
CF3
MeO CN
CN
Ar
Ar
NH
N
N
F
X
X=Cl,Br
N
R
CF3
Ar
R
CF3
NHAr
2 1
NR R
R RN
Ar
2 1
NHR R X
CF3
N
Ar
2 1
CF3
CF3
N
OR
Ar
Het
Ar
R
Ar
OH
Ar
F(CF3)
CF3
CF3
Tos
Ar
CF3
N
Ar
Tos
CN
F3C
F
F
Ar
Ar
RHN
SR
CF3
Ar HN
S
CF3
Ar
Het
NR2R1
Ar
CF3
25
PO
IN 05 / /Invited
Poster lectures
presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
New Methods for Carbon-Hydrogen
Bond Functionalization
O. Daugulis
Department of Chemistry, University of Houston, Houston TX 77204
Transition-metal-catalyzed functionalization of C-H bonds is an efficient method
for the formation of carbon-carbon bonds. While significant advances have been
reported in the last decade, many challenges still remain. First, the generality of the
methods usually is not high. Second, conversion of unactivated (not benzylic or
alpha to heteroatom) sp3 C-H bonds to C-C bonds is rare. Most of such examples
involve functionalization of t-butyl groups that is inherently easy due to lack of
-hydride elimination from metalated intermediates. Third, expensive palladium,
rhodium, and ruthenium catalysts are routinely used for C-H bond conversion to
C-C bonds. Use of less exotic metals such as copper, iron, or manganese is rare.
This talk will describe our attempts to provide solutions to the problems stated
above.
26
Invited lectures / IN 06
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
TRIFLUOROMETHYLATIONs WITH
FLUOROFORM-DERIVED CuCF3
Vladimir V. Grushin
ICIQ – Institute of Chemical Research of Catalonia, Tarragona, Spain
[email protected]
Selectively fluorinated organic compounds often exhibit biological activity
and useful processing properties. Trifluoromethylated building blocks and
intermediates are in particularly high demand for the synthesis of agrochemicals,
pharmaceuticals, and specialty materials. Readily available fluoroform, CHF3, a
side-product of Teflon manufacturing, is by far the best CF3 source for various
trifluoromethylation reactions of organic compounds.1 However, the previously
developed deprotonation methodology to activate fluoroform (pKa = 27 in H2O) is
cost-prohibitive on a large scale because of the necessity to use low temperatures
in order to avoid the facile α-elimination leading to difluorocarbene.
The first reaction of direct cupration of fluoroform was discovered only recently
in our laboratories. We have found2 that CuCl reacts with 2 equiv of t-BuOM (M
= K, Na) in DMF to produce novel dialkoxycuprates [M(DMF)n]+ [Cu(OBu-t)2](X-ray) that readily metalate CHF3 at room temperature and atmospheric pressure.
The resultant CuCF3 (>90% yield) can be used for highly efficient, low-cost
trifluoromethylation reactions of a variety of organic and inorganic substrates,
including metal complexes, aryl and heteroaryl halides,2 boronic acids,3 and
α-haloketones.4
References:
1. Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475.
2. Zanardi, A; Novikov, M. A.; Martin, E.; Benet-Buchholz, J.; Grushin, V. V. J.
Am. Chem. Soc. 2011, 133, 20901.
3. Novák, P.; Lishchynskyi, A.; Grushin, V. V. Angew. Chem. Int. Ed. 2012, 51,
7767.
4. Novák, P.; Lishchynskyi, A.; Grushin, V. V. J. Am. Chem. Soc. 2012, 134, 16167.
27
PO
IN 07 / /Invited
Poster lectures
presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
TRPV1 antagonists for treatment
of pain: temperature effects, new
opportunities and recent progress
Arthur Gomtsyan
Neuroscience and Pain Research, Abbvie Inc., North Chicago, IL 60064, USA
[email protected]
TRPV1 channel is involved in the development and maintenance of pain and
participates in the regulation of core body temperature. Clinical findings from
first TRPV1 anatagonist studies raised concerns as to whether the hyperthermia
associated with TRPV1 antagonism could be overcome and led to studies to identify
anatagonists devoid of temperature effects. As a result, subseries of heteroaryl urea
compounds were identified, which did not exhibit effects on core body temperature
in preclinical models of thermoregulation.
28
Invited lectures / IN 08
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Boron-Based Drug Design: Discovery of
HIF-1α Degradation Pathway Induced by
Inhibiting HSP60 under Hypoxia
Hiroyuki Nakamura
Department of Chemistry, Faculty of Science, Gakushuin University, Tokyo, 171-8588, Japan
[email protected]
The formation of new blood vessels sprouting from existing host capillaries
(angiogenesis) is a necessary process for tumors to grow beyond a certain critical
size. Specific inhibition of this tumor-induced angiogenesis prevents growth of
many types of solid tumors and provides a novel approach for cancer treatment.
Angiogenesis factors are key growth factors in tumor angiogenesis. Hypoxiainducible factors (HIF) are heterodimeric (a/b) transcriptional factors and major
physiological stimuli for expression of angiogenesis factors. The levels of HIF1α are low under normal oxygen conditions (normoxia) but increase in response
to hypoxia. HIF-1α has been found in a wide variety of human primary tumors
compared with corresponding normal tissue, thus considered to be a potential
target for antineoplastic therapy.
We developed carborane-containing phenoxyacetanilides (1) as potent inhibitors
of HIF-1α activation under hypoxic conditions.1 Furthermore we succeeded
in the synthesis of multifunctional molecular probes of HIF-1 inhibitors (2) for
combining photoaffinity labeling and click reaction moieties in the molecules in
order to clarify the action mechanism of 1 against HIF inhibition. Using the probe
molecules (2), we identified that heat shock protein (HSP) 60 is the target protein
of 1, indicating that HSP60 might be a new molecular target for HIF inhibition.2
Photoaf finity moiety
B(OH) 2
O
O
R
O
N
H
H
OH
HIF-1a inhibitors (1)
O
O
N
H
O
Probe Molecules (2)
Click reaction
moiety
Figure 1. Structures of carborane-containing HIF-1α inhibitors and their probes
References:
1. Shimizu, K.; Maruyama, M.; Yasui, Y.; Minegishi, H.; Ban, H. S.; Nakamura,
H. Bioorg. Med. Chem. Lett. 2010, 20, 1453.
2. (a) Ban, H. S.; Shimizu, K.; Minegishi, H.; Nakamura, H. J. Am. Chem. Soc.
2010, 132, 11870. (b) Nakamura, H.; Yasui, Y.; Maruyama, M.; Minegishi, H.;
Ban, H. S.; Sato, S. Bioorg. Med. Chem. Lett. 2013, 23, 1455.
29
PO
IN 09 / /Invited
Poster lectures
presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
BiFUNCTIONAL AND DUAL CATALYSIS IN
CHEMICAL SYNTHESIS
Petri M. Pihko*
Department of Chemistry, University of Jyväskylä, P.O.B. 35, FI-40014 JYU, Jyväskylä, Finland
[email protected]
The use of more than one catalytic functionality either in the same molecule
(bifunctional catalyst) or as two separate catalytically active species (dual or
synergistic catalysis) is a very common strategy in organocatalytic reactions. In
this talk, recent examples from our research where the dual or bifunctional catalytic
strategies have proved fruitful will be discussed.1-2
Acknowledgements: Financial support from the Academy of Finland, Tekes,
Orion Pharma, Fermion, Pharmatory, Hormos, PCAS Finland, CABB and AB
Enzymes is gratefully acknowledged.
References:
a) Sahoo, G.; Rahaman, H.; Madarász, Á.; Pápai, I.*; Melarto, M.; Valkonen, A.;
Pihko, P. M. Angew. Chem. Int. Ed., 2012, 51, 13144-13148. b) Rahaman, H.;
Madarász, Á.; Pápai, I.; Pihko, P. M.*.Angew. Chem. Int. Ed. 2011, 50, 61236127.
1. a) Yip, K.-T.; Nimje, R. Y.; Leskinen, M. V.; Pihko, P. M. Chem. Eur. J. 2012,
12590-12594. b) Nimje, R. Y.; Leskinen, M. V.; Pihko, P. M. Angew. Chem.
Int. Ed.; Early View (DOI: 10.1002/anie.201300833). c) Leskinen, M. V.; Yip,
K.-T.; Pihko, P. M. J. Am. Chem. Soc. 2012, 134, 5750-5753.
30
Invited lectures / IN 10
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHETIC APPROACHES TO NOVEL ACYCLIC
NUCLEOSIDE PHOSPHONATES
Zlatko Janeba
Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Prague, Czech Republic
[email protected]
Acyclic nucleoside phosphonates (ANPs) represent a recognized class of antiviral
and anticancer agents. ANPs have originated from the successful collaboration
between Antonín Holý (Institute of Organic Chemistry and Biochemistry, Prague,
Czech Republic) and Erik De Clercq (Rega Institute for Medical Research, K.U.
Leuven, Belgium). ANPs have gradually gained recognition in the pharmaceutical
world, as 3 of them (cidofovir, adefovir, and tenofovir) have been approved by
regulatory agencies worldwide for clinical use. Tenofovir disoproxil fumarate
(TDF) has also been approved for the treatment of HIV infections in fixed-dose
combinations with other anti-HIV agents (Truvada®), Atripla®, Complera®/
Eviplera®, Stribild®). However, biological activity of ANPs is not restricted solely
to the antiviral effects. Novel types of ANPs were designed and synthesized in
our lab (e.g. compounds 1-4, Figure 1.) and some of them were shown to display
important biological properties. An overview of the most recent achievements in
the field of these nucleotide analogues will be outlined.
Figure 1. Examples of novel ANPs modified at the aliphatic moiety.
O
HN
H 2N
O
N
N
N
1
N
HN
F
H 2N
N
2
O
P(O)(OH)2
N
3
P(O)(OH)2
OH
N
HN
N
O
O
H 2N
N
O
N
OH
H 2N
N
N
N
N
HN
N
4
P(O)(OH)2
N
OH
O
O
P(O)(OH)2
Acknowledgements: This study was performed as a part of the research project
RVO: 61388963 of the Institute of Organic Chemistry and Biochemistry and was
supported by Gilead Sciences, Inc. (Foster City, CA, U.S.A.).
31
PO
IN 11 / /Invited
Poster lectures
presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
ELECTROPHILIC ACTIVATION OF
UNSATURATED SYSTEMS: APPLICATIONS
TO THE SYNTHESIS OF HETEROCYCLIC
COMPOUNDS
José M. González
Departamento de Química Orgánica e Inorgánica and Instituto Universitario de Química Organometálica
“Enrique Moles”, Universidad de Oviedo, Oviedo 33006, Spain
[email protected]
Different electrophilic transformations are now recognized as powerful synthetic
tools to accomplish the synthesis of useful heterocyclic scaffolds in an efficient and
selective manner. Thus, this presentation will address different strategies that have
been developed by our group to assist this purpose.
Thus, besides some examples touching early work on iodine-triggered
heterocyclization reactions, recent approaches to building-block elaboration based
on gold-catalyzed chemistry will be discussed. The presentation will be arranged
according to the nature of the intermediate responsible for the key cyclization step.
Eventually, differentiate procedures for the elaboration of carbo- and heterocyclic
structures from unsaturated substrates upon reaction with nucleophiles are
obtained.[1-4] Straightforward addition processes and, alternatively, “domino”
reactions, which give rise to the formation of more elaborated products from simple
precursors, are described.
Acknowledgements: Generous financial support by the Spanish MINECO and the
Principality of Asturias (Grants CTQ2010-20517-C02-01 and FC-11CO11-17) are
acknowledged.
References:
1. Suárez-Pantiga, S.; Palomas, D.; Rubio, E.; González, J. M. Angew. Chem. Int.
Ed. 2009, 48, 7857
2. Barluenga, J.; Piedrafita, M.; Ballesteros, A.; Suárez-Sobrino, A.; González, J.
M. Chem. Eur. J. 2010, 16, 11827
3. Suárez-Pantiga, S.; Hernández-Díaz, C.; Rubio, E.; González, J. M. Angew.
Chem. Int. Ed. 2012, 51, 11552
4. Suárez-Pantiga, S.; González, J. M. Pure Appl. Chem. 2013, 85, 721
32
Invited lectures / IN 12
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
How to Make Complex Molecules
from Simple Starting Material: the
Palladium, a Powerful Tool
Jean Suffert
In addition to molecular complexity, the challenge of the chemist today is also
the quest for efficiency of the synthetic route and maximization of structural
complexity. Our laboratory investigations focus for several years on the study of an
unprecedented cascade reaction involving a rare 4-exo-dig cyclocarbopalladation
followed by a terminated cross-coupling with an organometallic reagent. A 6π- or
8π-electrocyclization can occur leading to new tricyclic structures. The seminar will
show that we can offer an easy access to complex polycyclic molecules resulting
from readily available simple starting materials. Eventually, it will be possible to
propose the elaboration of a large collection of unprecedented structurally novel
molecules based on recent promising results. Below are represented several
complex structures that has been prepared through the powerful 4-exo-dig
cyclocarbopalladation. Many other extension of this method have not been so far
explored and can afford a multitude of new and original scaffolds.
33
ORAL PRESENTATION
PO 01 // Oral
OC
Poster
presentations
presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF HETEROCYCLES FUSED WITH
ENEDIYNE systems
Irina A. Balova
Department of Chemistry, Saint-Petersburg State University, Saint-Petersburg, 198504, Russia balova.
[email protected]
Heterocycles possessing an enediyne system are promising objects as analogs of
naturally occurred enediyne antibiotics, displayed strong antineoplastic activity.1
Recently we proposed a new approach towards heterocycle-fused enediyne
systems, based on the cyclization of ortho-functionalized buta-1,3-diynylarenes.2
In particular, 2-ethynyl-3-iodobenzofurans, -indoles, -benzothiophenes as direct
precursors of enediyne systems fused to a heterocyclic core are easily accessed via
electrophilic cyclization of ortho-functionalized buta-1,3-diynylarenes.3
Proposed methodology enables obtaining the asymmetrically substituted
enediyne systems with absolute regiocontrol which is very important for the
further construction of macrocycles. For the synthesis of analogs of naturally
occurring macrocyclic enediynes two approaches were developed.4 The first one
includes Richter-type cyclization of ortho-(buta-1,3-diynyl)aryltriazenes which
affords cinnoline core and the Nozaki-Hiyama-Kishi reaction for the crucial
macrocyclization step. In the second approach the electrophilic cyclization
followed by ring-closing metathesis were used for the first time as key steps in the
synthesis of a macrocyclic dienediyne fused with benzothiophenes.
Acknowledgements: Saint-Petersburg University (research grant 12.38.14.2011).
References:
1. Basak, A.; Mandal, S.; Bag, S. S.; Chem. Rev. 2003, 4077; Joshi, M. C.; Rawat,
D. S. Chem. Biodiversity, 2012, 459;
2. Vinogradova, O; Sorokoumov, V; Balova, I. Tetrahedron Lett. 2009, 6358;
3. Danilkina, N.; Bräse, S.; Balova, I. Synlett, 2011, 517.
4.Vinogradova, O.; Balova, I.; Popic, V. J. Org. Chem. 2011, 6937; Danilkina, N.;
Nieger, M.; Selivanov, S.; Bräse, S.; Balova. I. Eu. J. Org. Chem. 2012, 5660.
36
Oral presentations / OC 02
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
MICROWAVE-ASSISTED SYNTHESIS IN
P-HETEROCYCLIC CHEMISTRY
György Keglevich, Erika Bálint, Nóra Zs. Kiss, Erzsébet Jablonkai, Alajos Grün
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics,
Budapest, H-1521, Hungary
[email protected]
The microwave (MW) technique is a useful tool in synthetic organic chemistry.
We wish to show the potential of MW irradiation in the synthesis of P-heterocyclic
derivatives.1,2
MW irradiation makes possible reactions that are otherwise impossible on
conventional heating. Such reaction is the direct esterification of cyclic phosphinic
acids (1) by reaction with alcohols (1).
O
P
1
MW
~200 °C
R1OH
OH
R1=C4-C12
R2
O
P
2
OR1
(1)
Me R2
=
Me
,
Me
,
R2=H, Me
Further derivatizations, such as thioesterification and amidation may also be carried
out under MW conditions.
It is also possible that a reaction becomes simply faster and more efficient
on MW irradiation. This may be exemplified by the Diels–Alder reaction of
1,2-dihydrophisphinine oxides (3) with dialkyl acetylenedicarboxylates. In turn,
the resulted phosphabicyclo[2.2.2]octadiene derivatives (4) may be useful in
fragmentation-related phosphorylations of nucleophiles, such as phenols (2).
Cl
CO2Me
Me
O
P
3
+
Y
CO2Me
MW
110 °C
no solvent
O
Y P
Cl
R1
CO2Me
4
CO2Me
Cl
-
MW
200 °C
PhOH
Y=Ph
Me
CO2Me
O
Me P Ph
OPh
(2)
CO2Me
Other reactions, such as inverse Wittig-type reactions, Michael-additions,
transesterifications, the Arbuzov reaction and P–C couplings will also be discussed.
The third group of MW-assisted transformations embraces cases, when MW
irradiation substitutes catalysts, such as in the Kabachnik–Fields reaction, or in the
alkylation of P=O-functionalized CH acid compounds.
References:
1. Keglevich, G.; Grün, A.; Bálint, E.; Kiss, N. Zs.; Jablonkai, E. Curr. Org. Chem.
2013 (in press)
2. Keglevich, G.; Bálint, E.; Curr. Org. Synth. 2013 (in press)
37
PO 03 // Oral
OC
Poster
presentations
presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
COMBINATION OF HYDRAZINE POLYANION
STRATEGY AND RING- CLOSING METATHESIS
IN THE SYNTHESIS OF HETEROCYCLES
Svetlana TšUPOVA, Oleg LEBEDEV, Uno MÄEORG*
Institute of Chemistry, University of Tartu, Ravila 14a, 50411, Tartu, ESTONIA
[email protected]
Many of hydrazine derivatives show remarkable biological activities and were
shown to be effective for treatment of tuberculosis, Parkinsons’s disease and
hypertention [1]. Therefore, there is a need in development of new efficient
synthetic ways to hydrazine moiety containing heterocycles.
In our current work the synthesis of cyclic hydrazine derivatives using polyanion
strategy and subsequent ring-closing metathesis is described. At the first step
the alkylation of hydrazine with alkenyl bromides was performed. Then, RCM
furnished the formation of the desired 6- to 9-membered heterocyclic products [2]
.
Grubbs'
R1
Boc
Boc catalyst R1
N N
N N
R1
Boc
2 equiv BuLi
N N
H
H 1 equiv Br
n
n
R3
2 equiv BuLi
1 equiv Br
R
m
n
m
3
Grubbs'
catalyst
1 equiv
Br
n
R1 = Et, Ph, Boc
R2 = H, Me
n, m = 1-3
m
R2
R1
Boc
N N
H
n
PTC
1 equiv
Br
m
R2
R1
Boc
N N
n
m
R2
References:
[1]
U. Ragnarsson. Chem. Soc. Rev. 2001, 205-213.
[2]
S. Tšupova, O. Lebedev, U. Mäeorg. Tetrahedron, 2012, 68, 1011 - 1016.
38
Oral presentations / OC 04
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
STEREOSELECTIVE SYNTHESIS OF
BARMUMYCIN VIA A BORON ENOLATE
IRELAND-CLAISEN REARRANGEMENT
Gints Smits1, 2, Ronalds Zemrībo2
Riga Tehnical University, Azenes 14/24, Riga, Latvia
Latvian Institute of Organic Synthesis, Latvia, Riga, Aizkraukles 21
[email protected], [email protected]
1
2
Barmumycin was isolated in 20101 from an extract of the marine actinomycete
Streptomyces sp. BOSC-022A and was found to be cytotoxic against various
human tumor cell lines. Structurally Barmumycin contains one stereogenic center
and an E-ethylidene substituent at 4-position of the proline fragment. Although a
total synthesis of Barmumycien has been reported1 , efficient control of the olefin
geometry has not been achieved.
Herein we disclose an efficient, stereoselective synthesis of (S,E) ethylidene proline
derivative 2 via a boron enolate Ireland-Claisen rearrangement of 7-membered
lactone 1, and the further elaboration of this building block into Barmumycin.
References:
1. Lorente, A.; Pla, D.; Canedo, L. M.; Albericio, F.; Alvarez, M. J. Org. Chem.
2010, 75, 8508.
39
PO 05 // Oral
OC
Poster
presentations
presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Furan recyclizations aS a route to
nitrogen heterocycles
Igor Trushkov,a Alexander Butinb
Laboratory of Chemical Synthesis, Federal Research Center of Pediatric Hematology, Oncology and
Immunology, ul. Samory Mashela, 1, Moscow, 117997 Russian Federation;
b
Perm State University, Bukireva 15, Perm, 614990 Russian Federation
[email protected]
a
2-Aryl- and 2-benzylsubstituted furans bearing nucleophilic function at the orthoposition of the phenyl ring can be easily synthesized from furfural which is produced
from waste of forest and agricultural industries. An acid-induced recyclization of
2-(2-aminophenyl)- and 2-(2-aminobenzyl)furans was utilized for the synthesis of
a differently substituted indoles and quinolines:
Variation of the nucleophilic moiety and the spacer between it and the furan ring
allowed for preparation of a variety of other nitrogen heterocycles:
R
Y
N
O
O
R
N
R'
R"
N
Y
N
H
R'
O
N
Y
N
R
R'
Acknowledgements: Financial support was provided by Russian Foundation for
Basic Research (grant 13-03-00463-a) and Ministry of Education of the Perm Krai.
40
Oral presentations / OC 06
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
TOTAL SYNTHESIS OF BARINGOLIN
Xavier Just-Baringoa,b, Paolo Brunoa,b, Fernando Albericioa,b,c, Mercedes
Álvarez,a,b,d
Institute for Research in Biomedicine, Barcelona Science Park & University of Barcelona, Baldiri
Reixac 10, Barcelona; b CIBER-BBN, Networking Centre on Bioengineering Biomaterials and
Nanomedicine, Barcelona; c Department of Organic Chemistry, University of Barcelona, E-08028
Barcelona; d Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona,
Barcelona, Spain
[email protected]; [email protected]
a
Baringolin is a thiopeptide1 of marine origin extracted from Kocuria sp. cultures
which has been found to be active against Gram-positive bacteria. Although
its structure had been previously suggested,2 it needed confirmation and also
assignment of its stereochemistry. Our efforts have focused on the synthesis of
suitable enantiopure fragments3 and the development of a new synthetic strategy
to obtain baringolin in an efficient manner.
O
N
S
N
H
N
Me
O
O
O
H
N
N
H
H
N
O
O
NH2
N
S
N
N
NH
H 2N
O S
S
O
O
N
O
Me
N
HN
N
H
N
O
S
N
OH
O
Baringolin
References:
1. Bagley, M. C.; Dale, J. W.; Merritt, E.; Xiong, X. Chem. Rev. 2005, 105,
685-714.
2. Canedo Hernández, L. M.; Romero Millan, F.; Fernández Medarle, A.;
Fernández Chimeno, Rosa I.; Hidalgo Villar, Juan C. (Instituto Biomar, S.A.,
Spain). WO 2012062906, May 18, 2012.
3. Just-Baringo, X.; Bruno, P.; Albericio, F.; Álvarez, M. Tetrahedron Lett.
2011, 52, 5435.
41
PO 07 // Oral
OC
Poster
presentations
presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Asymmetric cyclopropanation of
heterocycles
Ludwig Pilsl, Beatriz López-Sánchez, Oliver Reiser*
Institute of Organic Chemistry, University of Regensburg, 93053 Regensburg, Germany
[email protected]
While the asymmetric cyclopropanation of simple olefins like styrene has been well
developed, electron-rich heterocyclic substrates like N‑protected pyrroles and furan
derivatives proved to be a challenging task.[1,2] Herein we report highly enantio- and
diastereoselective cyclopropanation reactions of aromatic, heterocyclic substrates
using diazoacetates toward multiple functionalized bicyclic compounds, which
proved to be versatile building blocks for natural product synthesis approaches,[2,3]
as well as for the development of foldamer building blocks.[4,5]
References:
1. M. Schinnerl, C. Böhm, M. Seitz, O. Reiser, Tetrahedron Asymmetry 2003, 14,
765.
2. K. Harrar, O. Reiser, Chem. Commun. 2012, 48, 3457.
3. S. Kalidindi, W. B. Jeong, A. Schall, R. Bandichhor, B. Nosse, O. Reiser, Angew.
Chem. Int. Ed. 2007, 46, 6361.
4. L. Pilsl, O. Reiser, Amino Acids 2011, 41, 709.
5. S. De Pol, C. Zorn, C. D. Klein, O. Zerbe, O. Reiser, Angew. Chem. Int. Ed.
2004, 43, 511.
42
Oral presentations / OC 08
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Recyclization of epoxyalantolactone
(het)arylethylaminoderivatives
Sergey Pukhov, Svetlana Afanasyeva, Sergey Klochkov
Laboratory of Natural Products, Institute of Physiologically Active Compounds, Chernogolovka,
142432, Russian Federation
[email protected]om
Natural sesquiterpene lactones which contain an exocyclic methylene group in the
b-position of the lactone ring react readily with N-nucleophiles to give compounds
having novel forms of biological activity when compared with the starting
compounds [1]. When the reaction was carried out with 5a-epoxyalantolactone
(1) (a secondary metabolite of the plants of the genus Inula L.) and the (het)
arylethylamines 2 we were able to show the formation of the novel heterocyclic
system, namely the hydrogenated benzo[g]furo[4,3,2-cd]indolones 3.
Me
H
Me
Me
O
H
1
O
CH2
R(CH2)nNH2
(2)
O
MeOH
20°C
H
H
Me
6
O
O
NH
R(CH2) n
7
O
n>2
8
Me
5a
9a
H
5
H
9
4a
9b
4
O
H
9c
OH
Me
N
1
R(CH2)
3
O
2a
2
n
3
2, 3 R = Ar, Hetar
Evidently the amines initially add to the activated double bond (Michael reaction)
and then the dialkylamino group attacks the sterically most available carbon atom
of the oxirane ring. The process occurs under mild conditions using an equimolar
amount of the reagents which are held at room temperature in methanol. The
reaction occurs stereospecifically to form only one spatial isomer. The structure of
the compounds 3 obtained was proved using spectroscopic methods. The complete
data for identifying the structure and the determination of the configuration of the
new C-2a asymmetric center (analysis of the IR, 1H and 13C NMR spectra including
COSY and NOESY experiments) together with the results of the X-ray structural
analysis are discussed in this report.
References:
1. Lawrence, N. J., McGown, A. T., Nduka, J., et al., Bioorg. Med. Chem. Lett.,
2001, 11, 429.
43
PO 09 // Oral
OC
Poster
presentations
presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Looking at New Inhibitors of VEGFR-2.
C. Gadais(1)*, F. Ballante (2), S. Hesse (1), R. Ragno (2), G. Kirsch (1).
(1) Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Institut Jean Barriol, FR
CNRS 2843, Université de Lorraine, 1 Boulevard Arago, 57070 Metz, France.(2) Rome Center for
Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma
“La Sapienza”, P. le A. Moro 5, 00185 Roma, Italy.
Angiogenesis is the process of new blood vessels formation, creating new capillaries
from existing vasculature. A dis-regulation of angiogenesis may be involved in
the development and progression of various diseases such as tumor growth and
metastasis.1 The vascular endothelial growth factor (VEGF) pathway provides
several opportunities by which small molecules can act as inhibitors of endothelial
proliferation and migration and thus as anticancer agents. Among VEGF receptor,
VEGFR-2 or the kinase insert domain receptor (KDR) seems to play a key role in
tumor angiogenesis. Molecular modeling based on Three-Dimensional Quantitative
Structure-Activity Relationships (3-D QSAR),2 provides crucial information
about the structure of potent inhibitors of VEGFR-2.3 A first study revealed that,
with predicted IC50 values reaching 5nM, thieno[3,2-d]pyrimidinones combined
with urea and indole moieties or equivalent aromatic rings can afford promising
VEGFR-2 inhibitors. Two synthetic strategies to access these compounds are
presented and discussed.
J. Folkman, Anti-angiogenesis: new concept for therapy of solid tumors, Ann
Surg, 175 (1972) 409-416.2 Flavio Ballante and Rino Ragno: 3-D QSAutogrid/R:
An Alternative Procedure To Build 3-D QSAR Models. Methodologies and
Applications. Journal of Chemical Information and Modeling 2012 52 (6), 16741685 3R. Ragno, VEGFR-2 Inhibitors. Ligand-Based, Structure-Based and 3-D
QSAR Studies as Tools to Design New Small Molecules, in: XXIII Congresso
Nazionale della Società Chimica Italiana, Sorrento, Italy, (2009).
1
44
Oral presentations / OC 10
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis, activity and interaction
of nitrone Functionalized Pah
Derivatives
Milan Potáček, Marian Buchlovič, Zdeněk Kříž and Ctirad Hofr
Department of Chemistry, Masaryk University, Brno, CZ – 613 37, Czech Republic
[email protected]
Polycyclic aromatic hydrocarbons (PAHs) are widely studied. Their carcinogenic
properties are well known. In a sharp contrast to those effects the functionalized
PAHs were recently identified as important candidates for cancer therapy.1
Mechanism of action is often simplified and studied at the DNA level. A lot of
discussion has been held about groups being introduced to the PAHs structure.
Novel approach to functionalized polycyclic aromatic hydrocarbons (PAHs)
is presented. According to our experience in nitrone chemistry2 the synthetic
design of new PAHs derivatives was achieved by a multicomponent reaction of
compounds 1-3.
References:
1. Banik, B. K.; Becker, F. F. Curr. Med. Chem. 2001, 8, 1513; Banik, B. K.;
Becker, F. F. Bioorg. Med. Chem. 2001, 9, 593; Rescifina, A.; Varrica, M. G.;
Carnovale, C.; Romeo, G.; Chiacchio, U. Eur. J. Med. Chem. 2012, 51, 163.
2. Buchlovič, M.; Man, S.; Potáček, M. Synthesis 2012, 973; Buchlovič, M.;
Man, S.; Potáček, M. Tetrahedron 2008, 64, 9953; Man, S.; Buchlovič, M.;
Potáček, M. Tetrahedron Lett. 2006, 47, 6961
45
PO 11 // Oral
OC
Poster
presentations
presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Heterocyclic bisaryl-methanones as
Inhibitors of flt3 and PDGFR Kinases
Bernadette Streifinger1, Andreas Sellmer1, Andrea Uecker2, Christophe
Cénac1, Emmerich Eichhorn1, Frank-D. Böhmer2, Stefan Dove1, Siavosh
Mahboobi1,*
Institute of Pharmaceutical and Medicinal Chemistry I, University of Regensburg, 93053 Regensburg,
Germany
2
Institute of Molecular Cell Biology, Jena University Hospital, 07747 Jena, Germany
[email protected]
1
FLT3 receptor tyrosine kinase is aberrantly active in many cases of acute myeloid
leukemia (AML).[1] Recently, bis(1H-indol-2-yl) methanones[2] were found to
inhibit FLT3 and PDGFR kinases. To optimize FLT3 activity and selectivity,
modeling studies were implemented.[3]
Novel derivatives of bis(1H-indol-2-yl)methanones or bisbenzofuranyl methanones
with various substituents in the 5- or 6-position of an indole ring were synthesized
and tested for inhibition of FLT3 und PDGFR autophosphorylation.
References:
1.
S. Mahboobi, et al., J. Med. Chem. 2002, 45, 1002.
2.
S. Mahboobi, et al., J. Med. Chem. 2006, 49, 3101.
3.
S. Mahboobi, et al., J. Med. Chem. 2007, 50, 4405.
46
Oral presentations / OC 12
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
RECENT TRENDS IN THE DESIGN, SYNTHESIS
AND BIOLOGICAL EXPLORATION OF
β-LACTAMS
Grigory Veinberg, Maxim Vorona, Irina Shestakova, Irina Potorochina
Latvian Institute of Organic Synthesis, 21 Aizkraukles Street, Riga, LV1006, Latvia
[email protected]
Since the discovery of penicillin, natural and synthetic β-lactams have aroused
great interest not only as sources of effective antibacterial agents but also as specific
inhibitors of proteases responsible for various non-bacterial pathological processes.
Current presentation summarises recent achievements in this area dedicated to the
design, synthesis and biological exploration of β-lactams, β-sultams, aza-β-lactams
with anti-inflammatory, antiviral, anticancer and other activities. On molecular
level these properties are based on the ability of mentioned heterocycles to form
a stable covalent conjugate with a nucleophile in the active site of specific serine
or cysteine proteases. Broad synthetic possibilities in the synthesis of variously
substituted β-lactams in combination with the availability of X-ray crystallographic
data for target enzymes and computational molecular modelling techniques create
good prerequisites for new achievements in this field of medicinal chemistry.
47
POSTER PRESENTATIONS
PO 001 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SUBSTITUTED CINNOLINES FROM
2-(2-azidoBenzyl)furans
Anastasija Plieva,a Igor Trushkov,b Alexander Butinc,d Vladimir Abaev,a
North-Ossetian State University, Vatutina 44-46, Vladikavkaz, 362025 Russian Federation
Laboratory of Chemical Synthesis, Federal Research Center of Pediatric Hematology, Oncology and
Immunology, Samory Mashela 1, Moscow, 117997 Russian Federation; [email protected]
c
Perm State University, Bukireva 15, Perm, 614990 Russian Federation; [email protected]
d
Kuban State Technological University, Moskovskaya 2, Krasnodar, 350072, Russian Federation
a
b
Azide functional group is a valuable source of nitrogen atom in the synthesis of
nitrogen-containing heterocycles. Azide nitrogen can enter into new ring through
generation of either electrophilic nitrene or nucleophilic amino-group. Within the
research project devoted to the chemistry of 2-(2-azidobenzyl)furans we elaborated
the method of synthesis of the previously unknown ortho-aminodiarylfurylmethanes
by the azide to amino-group reduction. Non-aqueous diazotization of the orthoaminodiarylfurylmethanes gave rise to cinnoline derivatives bearing acylvinyl
substituent in the 3rd position of the ring [1].
R
R
3
R
(EtO)3P
2
1
R
N3
O
se
H, OMe,
R2
R
4
O
NH2
= H, OMe, Cl,
R
2
R3 =
R
H, F,
R4
3
2
Me3SiCl
R
t-BuONO
2
1
R
1
R1 =
EtOH
3
1
R
4
R
= Me, t-Bu, p-ClC6H4,
O
N
3
N
O
R
4
N
O
Acknowledgements: Financial support was provided by the Ministry of Education
and Science of the Russian Federation (grant 3.3578.2011) and Russian Foundation
for Basic Research (grant 13-03-01048 a).
References:
V. T. Abaev, A. V. Gutnov, A. V. Butin, V. E. Zavodnik. Tetrahedron. 2000, 56,
8933-8937.
50
Poster presentations / PO 002
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Enantioseparation of
1,4-dihydropyridine6-mercaptoethanol
Ilze Adlere, Zigmars Andzans, Aivars Krauze, Gunars Duburs
Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia
[email protected]
The 1,4-dihydropyridine (1,4-DHP) nucleus serves as a scaffold for important
cardiovascular drugs possessing stereoisomers. Therefore, it’s important to develop
1,4-DHP enantioseparation methods. Previously, we reported lipase-catalyzed
hydrolysis of 6-methoxycarbonyl­methylsulfanyl-1,4-dihydropyridines1.
In this study, we describe the lipase Amano PS from Burkholderia cepacia catalyzed
kinetically controlled acylation with vinyl acetate, which proceeds with formation
of 6-acyloxyethylsulfanyl-1,4-DHP 2 in 85% enantiomeric excess and 1,4-DHP-6mercaptoethanol 3 as unreacted substrate (98% ee).
O
Ar
O
N
H
1
Vinyl acetate
CN
S
Lipase Amano PS
Organic solvent
OH
O
Ar
O
N
H
2
CN
+
S
OAc
O
Ar
O
N
H
3
CN
S
OH
Enzyme catalyzed acylation of 1,4-DHP-6-mercaptoethanol 1 by using vinyl
acetate is a new method for enantioseparation of sulfur-containing 1,4-DHPs.
References:
Andzans, Z.; Krauze, A.; Adlere, I.; Krasnova, L.; Duburs, G. Chem. Heterocycl.
Comp. 2013, in press.
Acknowledgements: study was supported by the State Research Programme
,,Biomedicine”
51
PO 003 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
NATURAL SESQUITERPENE LACTONES FROM
INULA BRITANNICA IN THE AMINATION
REACTION
A. Ermatova, S. Pukhov, S. Afanasyeva, S. Klochkov
Laboratory of Natural Products, Institute of Physiologically Active Compounds, Chernogolovka,
142432, Russian Federation
[email protected]
In recent years, amino derivatives of natural sesquiterpene lactones are considered
as prodrugs [1]. Lactones britanin (1) and inuchenolide C (2) from the plants
Inula britannica L. contain exomethylene group in lactone ring and react easily
with the N-nucleophilic reagents. We investigated the reaction of britanin (1) and
various amines 3. It was found that the direction of the reaction depends on the
structure of the reacting amine and process conditions (temperature, solvent). The
aminoderivatives (4–6) were obtained with high yield in all cases. These substances
are characterized by the presence and position of the acetyl group in the alicyclic
fragment.
AcO
H
HO H
AcO
H
HO H
O
OAc
4
Me
R1R2NH
(3)
O
OAc
Me
O
AcO
H
AcO H
1
5
AcO
HO H
6
O
NR1R2
H
Me
3
O
OH
Me
H
AcO H
O
NR1R2
AcO
2
Me
O
OH
O
O
OH
O
NR1R2
The inuchenolide C amino derivatives (5) are formed easily by the reaction of
suitable amine and compound 2.
References:
1. Woods, J.R., Mo, H., Bieberich, A.A., Alavanja, T., Colby, D.A., Med. Chem.
Commun., 2013, 4, 27.
52
Poster presentations / PO 004
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Variation in lithiation sites of various
substituted pyridines
Mohammed B. Alshammari, Gamal A. El-Hiti, Keith Smith
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK
[email protected]
Smith’s group has developed several efficient lithiation procedures for preparation
of various substituted aromatics and heteroaromatics that might be difficult to
prepare by other means.1 As part of such studies we have shown that the lithiation
and substitution of 2- and 4‑substituted N‑(pyridinylmethyl)amines provided easy
access to various side-chain (methylene) substituted derivatives in high yields.2
Variations in the site of lithiation of N-acyl-3-(aminomethyl)pyridines with
different N‑substituents using different lithiating reagents has been investigated.
Ring lithiation has been achieved by the use of t-BuLi at -78 °C followed by
reaction with various electrophiles to give the corresponding 4‑substituted products
in high yields. On the other hand, the reaction was regioselective towards the sidechain when LDA was used as the lithium reagent at -20 to 0 °C. A mixture of ring
and side-chain substitution products was obtained when n-BuLi was the lithium
reagent.
E
O
N
H
N
66-91%
O
1) 3.3 t-BuLi, THF
1) 3.3L DA,T HF
N
R
R
-20t o0 °C,6 h
-78° C, 2h
H
2)
Electrophile
2) Electrophile
N
3) aq NH4 Cl
3) aq NH4 Cl
R= NMe2 , t-Bu, t-BuO
E
O
N
H
R
N
48-75%
Acknowledgements: We thank the Saudi Government for financial support.
References
1. See for example: Smith, K.; El-Hiti, G. A.; Hegazy, A. S. Synlett 2009, 2242;
Smith, K.; El-Hiti, G. A.; Hegazy, A. S.; Fekri, A.; Kariuki, B. M. Arkivoc 2009,
xiv, 266; Smith, K.; El-Hiti, G. A.; Hegazy, A. S. Synthesis 2010, 1371; Chem.
Commun. 2010, 46, 2790; Smith, K.; El-Hiti, G. A.; Hegazy, A. S.; Fekri, A.
Heterocycles 2010, 80, 941; Smith, K.; El-Hiti, G. A.; Alshammari, M. B. Synthesis
2012, 44, 2013; J. Org. Chem. 2012, 77, 11210 and Smith, K.; El-Hiti, G. A.;
Alshammari, M. B. Synlett 2013, 24, 117.
2. Smith, K.; El-Hiti, G. A.; Fekri, A.; Alshammari, M. B. Heterocycles 2012, 86,
391.
53
PO 005 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Allylboranes in an enantioselective
synthesis of furofuran lignans
Alexander Anfimova, Sergey Erdyakova, Tamara Potapovaa and Yurii
Bubnova,b
N.D. Zelinsky Institute of Organic Chemistry RAS, 47, Leninsky prosp., 119991, Moscow, Russia
A.N. Nesmeyanov Institute of Organoelement Compounds RAS, 28, Vavilova str., Moscow, Russia
[email protected]
a
b
Allylboration now presents a classical method for new carbon-carbon bonds
formation, and a wide number of allylboranes have been used in syntheses of
natural compounds1. Compounds containing two B-allylic fragments at the same
time almost have not been studied but present promising starting materials for the
tandem allylation of carbonyl compounds.
In this work we present an efficient method for the enanthioselective synthesis
of furofuran lignans2 based on allylboration reaction of aromatic aldehydes3
with new chiral diboron derivatives
prepared from hexa‑1,5-diene and
enanthiomeric diisopinocampheyl-chloroboranes. The synthesis sequence involves
allylboration, ozonolysis (construction of 3,7‑dioxabicyclo[3.3.0]octane core) and
dehydroxylation4.
1. Bubnov Yu. N. Houben-Weyl Methods of Molecular Transformation, ed. D.S.
Matteson, D. Kaufmann, Georg Thieme Verlag, Stuttgard. 2004, 6, 945.
2. Ward R. S. Chem. Soc. Rev., 1999, 16, 75.
3. Anfimov A. N.; Erdyakov S. Yu., Gurskii M. E., Ignatenko A. V., Lyssenko K. A.
and Bubnov Yu. N. Mzendeleev Commun. 2011, 21, 1.
4. Anfimov A. N.; Erdyakov S. Yu., Gurskii M. E. and Bubnov Yu.N. Russ.Chem.
Bull., 2011, 60, 2336.
54
Poster presentations / PO 006
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
novel 2-amino-pyrrolo[1,2-a]-pyrazine1,3-dione derivatives
Maksim Voievudskyi, Valeriia Astakhina, Denis Koval, Olexander
Kharchenko
Department of Technology of organic substances and pharmaceutical preparations, Ukrainian State
University of Chemical Technology, Dnepropetrovsk, Ukraine
[email protected]
Pyrrolo[1,2-a]pyrazine is known to be a fragment of biologically active compounds
exhibiting proliferative, Vasopressin1b receptor antagonist, metabotropic glutamate
receptors modulator and other activities [1,2]. For the last years alkaloid Peramine
is of great interest too (Fig. 1) [3]. Agrochemists established that it is high effective
natural insecticide produced by endophyte.
N
H
N
HN
O
N
NH2
Fig. 1 - Alkaloid Peramine
We have managed to synthesize novel ethyl 2-amino-6,8-dimethyl-1,3-dioxo1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate and study its reactivity in
the following reactions:
H3C
H3C
O
H3C
H3C
CH3
O
NH
O
O
N
O
NH2
H3C
O
N
N
H3C
O
N
CH3
H
CH3
O
O NaNO2, H+
H3C
N
O
R
O
O
O
O
O
CH3 CH3
O
R
CH3
O
H3C
N
O
O
N
N
O
N
H
O
CH3
Scheme 1 – Reactivity of ethyl 2-amino-6,8-dimethyl-1,3-dioxo-1,2,3,4-tetra­
hydropyrrolo[1,2-a]pyrazine-7-carboxylate
References:
1. Arban, R. [et al.] Bioorg. Med. Chem. Lett., 2010, 17, 5044.
2. Rocher, J. P. [et al.] Current Topics in Medical Chemistry, 2006, 6, 680.
3. Koulman, A.; Lane, G. A.; Christensen M. J. Phytochemistry 2007, 3, 355.
55
PO 007 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
N-(HALOPYRIDYL) DERIVATIVES OF
ADAMANTANAMINES
Alexei Averin, Anton Abel, Boris Orlinson, Ivan Novakov, Irina Beletskaya
Department of Chemistry, Lomonosov Moscow State University, Moscow, 119991, Russia
[email protected]
As adamantane-containing amines and their heterocyclic derivatives are
of great interest as physiologically active compounds, we investigated the
catalytic N-heteroarylation of some amines with adamantane fragment using
dihalopyridines. We have found out that symmetrical 2,6- and 3,5-dihalopyridines
successfully produce mono- and diamino derivatives depending on the
stoichiometry of starting compounds. Generally, better results were obtained with
2,6-dichloropyridines in comparison with 2,6-dibromopyridines.
Hal
X
NH2
H
N
X
Hal
N
Hal = Cl, Br
N
Hal
X
H
N
H
N
N
X
or
Pd(dba)2/L
L = BINAP, Xantphos
N
X = CH2, CH(Ph), OCH2CH2
Br
44-95%
46-86%
X
H
N
Br
N
Br
X
H
N
H
N
X
N
or
Pd(dba)2/BINAP
59-84%
40-77%
Unsymmetrical 2,3- and 2,5-dihalopyridines did not produce corresponding
diamino derivatives even upon reacting with great excess of adamantanamines.
However, the catalytic substitution of the halogen atom at a-carbon atom was
in many cases successful, and again better results were achieved with less active
dichloropyridines. The most interesting fact is the possibility to synthesize N,Nbis(5-halopyridin-2-yl) derivatives of adamantane-containing amines in yields up
to 95% using 2,5-dihalopyridine taken in a 4-fold excess.
Hal
N
X
X
N
or
N
Hal = Cl: 87-95%
Hal = Br: 46-60%
Hal
H
N
N
X
N
Hal
Hal
Hal = Cl: 22-73%
Hal = Br: 18-66%
Hal
NH2
N
Hal
Pd(dba)2/L
Hal
X
Hal
H
N
N
Pd(dba)2/BINAP
X = CH2, CH(Ph), CH2CH(CH3), OCH2CH2
Hal = Cl: 41-94%
Hal = Br: 18-30%
L = BINAP, DavePhos
Acknowledgements: The work was supported by the RFBR grant 10-03-01108.
56
Poster presentations / PO 008
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
THe synthesis of heterocycic
aMINOPHOSPhonic AND aminophosphine
derivatives
Erika Bálint,1 Eszter Fazekas,2 Marijan Kocevar,3 György Keglevich2
Research Group of the Hungarian Academy of Sciences at the Department of Organic Chemistry and
Technology, Budapest University of Technology and Economics, Budapest, HU-1521, Hungary
2
Department of Organic Chemistry and Technology, BUTE, Budapest, HU-1521, Hungary
3
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana SI-1000, Slovenia
[email protected]
1
a-Aminophosphonates and related derivatives are in the focus these days due to
their versatile bioactivity. The most common approach to a‑aminophosphonates is
the condensation of an amine, oxo compound and dialkyl phosphite that is called the
Kabachnik–Fields (or phospha-Mannich) reaction. Continuing our research in the
field of microwave (MW)-assisted phospha-Mannich reactions,1,2 we have studied
the condensation of 3-amino-6-methyl-2H-pyran-2-ones, paraformaldehyde and
dialkyl phosphites or diphenylphosphine oxide. It was found that there is no need
for any solvent and catalyst.3
Me
R
O
O
NH2
+ (HCHO)n +
Y
Y
P
MW
T, t
no solvent
O
H
Me
R
O
O
O
NH CH2 P
Y = OMe, OEt, OBu, Ph
R= H, C(O)Me, C(O)Ph
Y
Y
We also studied the double Kabachnik-Fields reaction of primary amines,
paraformaldehyde and >P(O)H species, which provide bis(phosphonoalkyl)or bis(phosphinoxido) products.4,5 After double deoxygenation of the
bis(phosphinoxido) derivatives, we have synthesized P‑metallocycles by
complexation with Pt precursor. The ring metallocycles were tested as catalysts in
the hydroformylation of styrene.
R NH2 + 2 (HCHO)n + 2
R = nPr, nBu, cHex, Ph, Bn
Y
Y
P
O
H
MW
no solvent
R N
O
O
Y = OMe, OEt, Ph, O
O Y
CH2 P Y
1.)
SiH
CH2 P Y 2.) Pt(PhCN)2Cl2
O Y
Y=Ph
R N
CH2 P
CH2 P
Ph2
PtCl2
Ph2
,
1. Keglevich, G.; Bálint, E. Molecules, 2012, 17, 12821-12835.
2. Keglevich, G.; Szekrényi, A. Synth. Commun. 2011, 41, 2265-2272.
3. Bálint, E.; Fazekas, E.; Takács, J.; Tajti, Á.; Juranovic, A. Kocevar, M.; Keglevich, G. Phosphorus
Sulfur (in press).
4. Bálint, E.; Fazekas, E.; Pintér, G.; Szöllősy, Á.; Holczbauer, T.; Czugler, M.; Drahos, L.; Körtvélyesi,
T.;
Keglevich, G. Curr Org Chem. 2012, 16, 547-554.
5. Bálint, E.; Fazekas, E.; Pongrácz, P.; Kollár, L.; Drahol, L.; Holczbauer, T.; Czugler, M.; Keglevich,
G. J.
6. Organomet. Chem. 2012, 717, 75-82.
57
PO 009 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Enantioselective halogenation of
enamine derivatives
Meryem Benohoud, Géraldine Masson
Institut de Chimie des Substances Naturelles ICSN-CNRS
[email protected]
A highly stereoselective electrophilic α-bromination of enecarbamates allowing
to access enantioenriched vicinal bromoamines has been developped.1 Metalfree chiral phosphoric acids and chiral calcium phosphates both catalyze this
transformation and either enantiomer can be formed in good yield with excellent
diastereo- and enantioselectivity simply by switching the catalyst from the
phosphoric acid to its calcium salt.2
The generality of the reaction has been further investigated to other halogen sources
to allow the fluorination, chlorination and iodination of enamines derivatives.
Details of our study will be presented in this communication.
Cat. M = H (1 mol%)
Toluene, RT
O
R1 O
NH
Br
O
HN
O
OR1
+
N Br
O
R2
R2
Ar
O O
P
O O M
Ar
SCOPE OF
ENAMINE DERIVATIVES
Cat. M = Ca (1 mol%)
Toluene, RT
up to 98% yield
and 98% ee
O
up to 88% yield
and 96% ee
O
INFLUENCE OF
THE METAL
O
n
SCOPE OF
HALOGEN SOURCE
O
N
R1 O
Br
NH
N
R2
O
References:
1. Alix, A.; Lalli, C.; Retailleau, P.; Masson, G. J. Am. Chem. Soc. 2012,
134, 10389.
2. Recent review on halogenation of alkenes: Denmark, S. E.; Kuester, W.
E.; Burk, M. T. Angew. Chem. Int. Ed. 2012, 51, 10938.
58
Poster presentations / PO 010
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
2,6-bis-(1,2,3-triazolyl)purines in
reactions with s-nucleophiles
Ērika Bizdēna, Irina Novosjolova, Māris Turks
Faculty of Material Science and Applied Chemistry, Riga Technical University,
Riga, LV-1007, Latvia; [email protected]
Recently, we have reported the synthesis and application of 2,6-bis-(1,2,3-triazol1-yl)purine nucleosides [1]. The 1,2,3-triazolyl ring at C(6) position of purine has
been shown as good leaving group in nucleophilic aromatic substitution reactions.
In this study, we extended the range of nucleophiles with thioles. The latter produced
products with general formulas 1 and 2. Triphenylmethyl mercaptan, thiophenol,
dodecanthiol, benzylthiol, propane-1,3-dithiol, decane-1,10-dithiol were used for
the substitution. For example, S-trityl protected 2-triazolyl-6-thiopurine derivative
was obtained in reaction of 9-(2’,3’,5’-tri-O-acetyl-β-d-ribofuranosyl)-2,6-(4phenyl-1H-1,2,3-triazol-1-yl)-9H-purine with triphenyl-methyl mercaptan in good
(80%) yield. Reactions of the same substance with thiophenol and dodecanethiol
proceed equally smoothly in DMF in presence of dry K2CO3. After deprotection of
sugar moiety with MeNH2/H2O target compounds were isolated in 82% and 62%
yield.
S
N
N
R2
N
N
N
Sugar
1
S
N
N N
Sugar
N
R1
N
n
N
S
N
N N N N
N N
R1
2
N
N
N
Sugar
R1
References:
1. Kovaļovs, A.; Novosjolova, I.; Bizdēna, Ē.; Bižāne, I.; Skardziute, L.;
Kazlauskas, K.; Jursenas, S.; Turks, M. Tetrahedron Lett. 2013, 54, 850.
59
PO 011 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis of dextrorphane derivatives
Hedvig Bölcskei, Zsófia Dubrovay, Miklós Dékány, Pál Kocsis, Anikó Gere,
Mónika Vastagh, Imre Gábor
Gedeon Richter Plc., Budapest, 10, POB 27. H-1475 Hungary
[email protected]
Dextromethorphan (R1=OMe, R2=H) is a well-known coughsuppressant1, which
shows multiple activity: NMDA receptor antagonist, serotonin reuptake inhibitor
(SRI) and voltage gated sodium channel blocker (VGSCB). We wanted to increase
the SRI and VGSCB activity of dextrometorphan for the treatment of anxiolytic
diseases, e.g. obsessive compulsive disorder (OCD). New functionalities
(R2=halogen, nitro or amino groups) were built up, to introduce further building
blocks with VGSCB activity2,3 (Ar=aryl, heteroaryl, biaryl, X=O or H2 etc.) By
the Suzuki cross coupling reaction of the halogenated dextrorphan, or by alkylation
or acylation reaction of the amino group new derivatives could be synthesized.
Varying the substituents we could overcome the hERG liability. Our best compound
showed promising activity at the in vivo marble burying test.
O
Ar
R1
N
R2
X
N
Ar
O
N
N
In course of O-alkylation of dextrorphan a rearrangement reaction by opening
of the piperidine ring was observed similarly to N-methylation of N-desmethyldextromethorphan4.
References:
1. Martindale The Complete Drug Reference 36. Edition (Pharmaceutical Press,
London, Chicago) Ed. S. C. Sweetman (2009) 1555-1556.
2. I. Tarnawa, H. Bölcskei, P. Kocsis, Recent Patents on CNS Drug Discovery,
2007, 2, 57-78.
3. H. Bölcskei, I. Tarnawa, P. Kocsis, Med..Chem. Res.17 (2-7) 356-368 (2008)
4. H. Bölcskei, M. Mák, F. Dravecz, Gy. Domány, Arkivoc 2008, 182-193.
60
Poster presentations / PO 012
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis of phosphorous analogs of
cyclic aminoacids by hydrogenation of
hetarylphosphonates
Grigoriy Bondarenko, Olga Ganina, Irina Beletskaya
Department of Chemistry, Lomonosov Moscow State University, Moscow, Vorobyevy Gory, 1, 119991,
Russian Federation
[email protected]
Aminophosphonates are very interesting candidates for exhibiting a wide range of
biological activity as phosphorous analogs of naturally occurring amino acids and
can be used as antibiotics, enzyme inhibitors with antiviral agents.1,2
The new efficient method of the synthesis of diethyl 2- and 3-piperidyland 3-tetrahydroquinolyl phosphonates by hydrogenation of corresponding
hetarylphosphonates with molecular hydrogen in the presence of a palladium
catalyst has been developed.
t
)E
(O
P
H
+
N
r Pd(OAc)2/dppf
B
base
2
t
)E
(O
P
N
H2
2
Pd-catalyst
t
)E
(O
P
N
H
2
The method provides a phosphorous analogues of cyclic aminoacids in almost
quantitative yields. Hetarylphosphonates have been obtained by improved method
using Pd(OAc)2-dppf catalytic system.
Financial support was provided by Russian Foundation of Basic Research (grant
12-03-92701-IND-a).
References:
1. Maury, C.; Wang, Q.; Gharbaoui, T.; Chiadmi, M.; Tomas, A.; Royer, J.; Husson,
H.-P. Tetrahedron.1997, 53, 3627.
2. Asschel, I.; Soroka, M.; Haemersl, A.; Hooper, M; Blanot, D.; Heijenoort, J. Eur.
J. Med. Chem. 1991, 26, 505.
61
PO 013 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis of new LEVOGLUCOSAN
derivatives
Diāna Borovika, Katrina Krivenko, Pēteris Trapencieris
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia
[email protected]
Levoglucosan (1,6-anhydro-β-D-glucopyranose) as the anhydrosugar is an
important primary pyrolysis product of carbohydrates, such as starch and cellulose.
Here we report a synthesis of new substituted levoglucosan derivatives with aryl
and alkyl substituents. Procedure involves a reaction of levoglucosan with different
acyl chlorides in an excess of base. Number of reaction products depends on the
nature of acyl chloride, ratios of reagents and time of the reaction.
O
Si
Silylation
O
O
Si
O
HO
OH
O
OH
R
Cl
TMS agent: TMSCl, TMSOTf, BSA
O
Si
O
O
O
R
O
O
O
O
O
O
O
R
R = C6H5, C10H7, C5H4N et al.
R
References: Sukhova, E. V.; Dubrovskii, A. V.; Tsvetkov, Yu. E.; Nifantiev, N. E.
Russ. Chem. Bull., Int. Ed. 2007, 56, 1655.
62
Poster presentations / PO 014
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS AND CRYSTALLIZATION FEATURES
OF TIMOLOL PRECURSORS
Zemfira Bredikhina, Robert Fayzullin, Alexander Pashagin,
Dmitry Zakharychev, Aidar Gubaidullin, Alexander Bredikhin
A.E. Arbuzov Institute of Organic and Physical Chemistry, RAS, Kazan, Russia,
[email protected]
Enantiomeric (S)-timolol maleate (S)-1·(HO2CCH)2 has gained a wide acceptance
as an anti-hypertensive and anti-glaucoma remedy under a variety of trade names.
The obtaining of the enantiopure 1 is complicated by the solid solution nature of its
crystal phase. 4-[4-(Oxiran-2-ylmethoxy)-1,2,5-thiadiazol-3-yl]morpholine 2 and
3-(4-morpholino-1,2,5-thiadiazol-3-yloxy)-propane-1,2-diol 3 are valuable timolol
precursors.
O
N
O
N
S
H
N
*
O
N
CH3
CH3
H OH
N
O
CH3
O
N
S
(S)-1
N
*
N
O
O
H
N
2
S
OH
*
N
OH
3
Jacobsen kinetic hydrolytic resolution of rac-epichlorohydrin 4 was used as a
source of chirality for all the substances obtained. The oxiran (S)-2 was prepared
from (R)-4 and thiadiazolol 5, and was transformed to (S)-1:
H
Cl
S
N
N
N
HO
(R)-4
91% ee
O
5
{(S)-2 + (R)-6}
t -BuOK
N
B
+
O
O
t -BuNH2
(S)-2
S
N
N
+
Cl
O
N
H
(S)-2, 95% ee
HO
O
(1 : 5)
S
N
O
N
H
(R)-6, 91% ee
O
(S)-1, 97.5% ee
The (S)-diol 3 was obtained from (S)-3-chloropropane-1,2-diol (S)-7 and was
subsequently transformed to (S)-1 via cyclic sulfite (4R)-8:
O
HO
H
Cl
(S)-7
95.0 % ee
OH
+ 5
O
HO H
N
N
O
S
N
OH
(S)-3
SOCl 2
H
N
N
O
O
S
N
S
O
(4R)-8
O
t -BuNH 2
(S)-1
99%ee
Investigation of IR spectra, thermodynamic and X-ray characteristics has shown
that chiral molecules 2 and 3 prone to spontaneous resolution, but in the case
of 2 racemic conglomerate transforms to continuous solid solution at elevated
temperature. All the revealed crystallization properties were taken into account
during the synthesis of target enantiopure compounds 1-3.
Acknowledgements: The authors thank the Russian Fund of Basic Research for
financial support (grant number 13-03-00174).
63
PO 015 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
PYRROLO[1,2-a]PYRAZINES VIA Furan
recyclization REACTION
Tаtyana Nevolina,a Lyudmila Sorotskaya,b Natalya Samodelkina,a
Maxim Uchuskin,a Alexander Butina,b
a
b
Perm State University, Bukireva 15, Perm, 614990 Russian Federation; [email protected]
Kuban State Technological University, Moskovskaya st. 2, Krasnodar, 350072, Russian Federation
Within the research project towards synthesis of annulated pyrroles through
intramolecular Paal-Knorr-like reaction employing furans as 1,4-diketone
equivalents [1,2], we proposed a new approach to pyrrolo[1,2-a]pyrazines 4 via
recyclization of 2-amino-N-(furan-2-ylmethyl)acetamides 2.
R
3
R
R
N
O
R
HCl
AcOH
O
2
3
N2H4.H2O
N
O
1
1
EtOH
O
O
R
R
1
O
N
3
R
O
3
NH2
R
2
R
R
N
O
R
2
NH2
1
O
R
2 88-94%
R
1) NaHCO3
2) AcOH, reflux
R
O
2
N
1
N
R
3
R
4 15-74%
R = Me, Et, t-Bu; R1 = H, Me, Ph; R2 = H, Me;
R3 = o-FC6H4, p-ClC6H4, p-FC6H4, p-OMeC6H4, p-CF3C6H4, p-MeC6H4
Acknowledgements: Financial support was provided by Russian Foundation for
Basic Research (grant 13-03-96024) and the Council of President of the Russian
Federation (grant MK-442.2013.3).
se
References:
1. Butin, A. V.; Nevolina, T. A.; Shcherbinin, V. A.; Trushkov, I. V.; Cheshkov, D.
A.; Krapivin, G. D. Org. Biomol. Chem. 2010, 8, 3316.
2. Nevolina, T. A.; Shcherbinin, V. A.; Serdyuk, O. V.; Butin, A. V. Synthesis 2011,
3547.
64
Poster presentations / PO 016
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF 4-SUBSTITUTED
1,2-BENZOXATHiine-2,2-dioxides
Inga Cauņa, Aiga Grandāne, Raivis Žalubovskis
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia
[email protected]
Carbonic anhydrases (CA) are zinc containing enzymes which catalyze reversible
hydration and transport of carbon dioxide and provide pH regulation in cells.
In a search for new inhibitors of tumor associated CA IX, good inhibitory activities
were demonstrated for coumarin derivatives [1, 2]. Therefore we were interested in
synthesis of derivatives of 1,2-benzoxathiine 2,2-dioxide (2) which is consider to
be the bioisostere of coumarin (1) and potential CA IX inhibitor.
O
1
O
O
S
O
O
2
In a search for new inhibitors we developed a synthesis of 4-substituted
1,2-benzoxathiine 2,2-dioxides 3 from salicylaldehyde (4) and Gringard reagent
with following oxidation, mesylation and cyclization in presence of strong organic
base.
O
R
H
4
OH
3
O
S
O
O
References:
1. Maresca, A.; Temperini, C.; Vu, H.; Pham, N. B.; Poulsen, S. A.;
Scozzafava, A.; Quinn, J.; Supuran, C. T. J. Am. Chem. Soc. 2009, 131,
3057–3062.
2. Maresca, A.; Temperini, C.; Pochet, L.; Masereel, B.; Scozzafava, A.;
Supuran, C. T. J. Med. Chem. 2010, 53, 335–344.
65
PO 017 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Direct Trifluoromethylation of
1,3-dimethyluracil and consecutive c-H
Arylation
Miroslava Čerňová, Michal Hocek
Department of Organic and Nuclear Chemistry, Faculty of Science, Charles University in Prague,
Hlavova 8, 12843 Prague 2, Czech Republic
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead
Sciences & IOCB Research Center, Flemingovo nam. 2, 16610 Prague 6, Czech Republic
[email protected]
The introduction of fluorine containing groups into molecules plays an important
role in organic chemistry because of the changes of molecular properties of
modified compounds. The trifluoromethyl group is an important structural moiety
present in diverse classes of pharmaceuticals, agrochemicals, liquid crystals, dyes,
and polymers1. Therefore, we decided to introduce the trifluoromethyl group to
1,3-dimethyluracil as a model compound for pyrimidine nucleobases and then to
apply C-H arylation to the next position.
O
H3C
O
N
N
CH3
O
O
H3C
O
CF3
N
N
CH3
H3C
O
N
CF3
Ar
N
CH3
Acknowledgements:
This work was supported by the Academy of Sciences of the Czech Republic
(RVO: 61388963), by the institutional support of the Charles University, by the
Czech Science Foundation (P207/12/0205), and by Gilead Sciences, Inc.
References:
Examples: (a) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886.
(b) Purser, S.; Moore, P. R.; Swallow, S. & Gouverneur, V. Chem. Soc. Rev. 2008,
37, 320–330. (c) Jeschke, P. ChemBioChem 2004, 5, 570–589.
66
Poster presentations / PO 018
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Towards synthesis of heterocyclic
fused dienediynes
Natalia Danilkina1,2, Alexander Khlebnikov1, Stefan Bräse2, Irina Balova1
Department of Organic chemistry, Saint-Petersburg State University, Saint-Petersburg, Russia
[email protected]
2
Institute of Organic chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany
[email protected]
1
Enediyne antibiotics are one of the most active classes of natural products possessing
antineoplastic activity [1]. Recently we have demonstrated that electrophilic
cyclization of o-functionalized diacetylenic arenes is a useful tool for the synthesis
of acyclic [2] and 12-membered cyclic [3] enediynes fused to heterocyles. In order
to obtain highly active synthetic analogs of enedyne antibiotics, 10- (1, 2) and 11membered (3) dienediynes were chosen as targets.
m
m
Grubbs I or II or
Hoveyda-Grubbs
S Me
2
R
R = (CH 2) n or TMS
S
n
n = m =1, 5 steps, 12%
n = 0, m = 2, 6 steps, 40%
n = 1, m = 2, 5 steps, 7%
n
S
n = m =1 (1)
n = 0, m = 2 (2)
n = 1, m = 2 (3)
The synthetic strategy towards these macrocycles involved electrophilic cyclization
(EC) and ring closing metathesis (RCM) as two key steps. In that way using of EC
on initial steps allowed to obtain substrates for RCM in rather good overall yields.
Unfortunately, the final step – RCM – did not proceed regardless of the nature
of catalyst and reaction conditions, while the same reaction for the formation of
the 12-membered dienediyne proceeded smoothly [3]. The found reactivity was
explained in terms of the isodesmic reaction approach based on DFT calculations
at the B3LYP/6-31++G(d,p) level.
Acknowledgements:
N.D. is thankful to SPbSU (12.38.14.2011) and to the CFN.
References:
1. Joshi M. C., Rawat D. S. Chem. Biodiversity 2012, 9, 459–498. 2. Danilkina
N. A., Bräse S., Balova I. A., Synlett 2011, 517–520. 3. Danilkina N., Nieger M.,
Selivanov S., Bräse S., Balova I. Eur. J. Org. Chem. 2012, 5660-5664.
67
PO 019 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis of ISOXAZOLES with
Photochromic label
Olga Demina, Nikolay Belikov, Sergey Varfolomeev, Andrey Khodonov
N.M. Emanuel Institute of Biochemical Physics RAS, Moscow, 119334, Russia
[email protected]
The development of new pathways for the modification of various bioobjects by the
photochromic ligands led to the creation of the effective way for the photocontrol
of their biological activity. Nowadays the modified spiropyran derivatives are the
attractive photochromic probes for the labeling of different biological targets. It has
been shown by us that 3,5-substituted isoxazoles are potent inhibitors of the human
platelets aggregation process. For the purpose of the ligand-receptor binding
investigation of these compounds we synthesized new 3,5-substituted isoxazole
analogs with photochromic label – a spiropyran moiety at the 3- or 5-position of
the isoxazole ring. We proposed several variants for direct modification of the
spiropyran core at the C5′-position of the indoline cycle to introduce biospecific
tag fragments. The key reaction involved a [3+2]cycloaddition of nitrile oxides
with alkynes or alkenes. Spectral-kinetic properties of synthesized compounds
were investigated in two solvents – ethanol and toluene. The specific binding of
these compounds with human platelets was studied.
R
O N
N O
R=CH2OH
R=C6H5
NO2
O
N
O N
N
O2N
Acknowledgements: This work was partly supported by RFBR Grant for young
scientists (project № 12-04-31190) and the Grant of President of the Russian
Federation for Young Ph.D. Scientists (project No. МК-6901.2013.4).
68
Poster presentations / PO 020
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
synthesis of salts of guareschi imides
Elena A. Chigorina and Victor V. Dotsenko
Chemical Diversity Research Institute, 2a-1 Rabochaya St., Khimki, Moscow region, 141400 Russia
[email protected]
Guareschi imides (2,6-dioxopiperidine-3,5-dicarbonitriles) are well known to
exhibit anticonvulsive, sedative and analgesic activities [1-7]. The common
approach to Guareschi imides is based on the reaction of NH3, ethyl cyanoacetate
and carbonyl compounds. As it was shown [6], the success in the synthesis of
Guareschi imides strongly depends on the nature of carbonyl components – the
reaction proceeds smoothly with unbranched ketоnes up to C3–C4 substituents.
However, it fails when attempting to use arylalkyl ketones, branched ketones
or aldehydes. In the case of aldehydes, the initially formed Guareschi products
1 undergo oxidation under reaction conditions to give pyridine-2-ones 2, and
4-monosubstituted Guareschi imides cannot be obtained by this way.
NH3
O
NC
OEt
R
N
N
+
[O]
R
N
N
2
1
RCHO
O
N
H
O
O
N
H
OH
To overcome the disadvantages of the classic approach, we had to develop a
new method to the synthesis of Guareschi imides. We found that treatment of
cyanoacrylamides 3 with 1-cyanoacetyl-3,5-dimethylpyrazole 4 in the presence
of excessive Et3N in cold acetone leads to triethylammonium salts 5. The free
Guareschi imides 1 could be obtained after reaction with aq. HCl.
CN
Ar
O
3
NH2
O
+
Et3N
(CH3)2CO
H3C
N
NC
4
N
CH3
55-98%
Ar
N
N
Et3NH+
O
N
H
5
O
References:
1. Shaw, F. H.; Simon, S. R.; Cass, N.; Shulman, A. et al. Nature 1954, 174, 402.
2. Shulman, A.; Shaw, F. H.; Cass, N.; Whyte, N. M. Brit. Med. J. 1955, 1955 (I), 1238.
3. Somers, T. C. Nature 1956, 178, 996.
4. Tagmann, E.; Sury, E.; Hoffman, K. Helv. Chim. Acta 1952, 35, 1235.
5. Tagmann, E.; Sury, E.; Hoffman, K. Helv. Chim. Acta 1952, 35, 1541.
6. Handley, G. J.; Nelson, E. R.; Somers, T. C. Austr. J. Chem. 1960, 13, 129.
7. El Batran, S. A.; Osman, A. E. N. et al. Inflammopharmacology 2006, 14, 62.
69
PO 021 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SOME NUCLEOPHILIC REACTIONS WITH
4-HYDROXY-1-METHYL-3-[(2-OXO-2HCHROMENE-3-YL)-CARBONYL]QUINOLIN2(1H)-ONE
El-Hossain A Mohamed, Mohamed Abass, and Aisha S. Mayas
Department of Chemistry, Faculty of Education, Ain Shams University
[email protected]
The reactivity of 4-hydroxy-1-methyl-3-[(2-oxo-2H-chromen-3-yl)carbonyl]quinolin-2(1H)-one (1), as a new asymmetric diheterocyclic ketone, towards
different nucleophilic reagents, was examined. The reaction of the ketone 1 with
hydrazine led to pyrazolinone 2, and excess of hydrazine pyrazolinopyrazole 3
was obtained. Treatment of the ketone 1 with 2,2-dimethoxyethanamine gave
pyrrolocoumarin 4, while cyanoguanidine afforded pyrimidinone 5. Under PTC
conditions, the ketone 1 was reacted with chloroacetonitrile, diethyl malonate, ethyl
cyanoacetate, malononitrile, and cyanoacetamide to give coumarinyl furoquinoline
6, pyranoquinolines 7, 8, 9, and benzonaphthyridine 10, respectively.
OH
O
N
O
O
O
CH3
N2 H4 .H2 O
1:1
OH
N
excess
N2 H4 .H2 O
1
NH
OH
O
NH
N
NH
NH
O
CH3
2
OCH3
OH
NH
3
HO
N
NH2
CH(OCH3)2
H2N
Toluene
Heat
4
N
CH3
O O
O
N
CH3
O Ar
Ar=2HOC6 H4
Ar
NH2
O
OH
NH
KOH/EtOH
R'
N
R
K2 CO3 /TBAB DMF
R
O
X
70
CN
CH3
O
6-10
N
O
CH3
R = CN, COOEt
x = O-C=O, NH-C=O, O-C=NH, O
O
N
N
5
CN
Ar=2-HOC6 H4
Poster presentations / PO 022
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
A NEW RECYCLIZATION OF 2‑SUBSTITUTED
4-OXO-PYRIMIDINES
Victor Markov, Oleg Farat, Ekaterina Velikaya, Svetlana Varenichenko
Ukrainian State University of Chemical Engineering, 49005 Dnepropetrovsk, Ukraine.
[email protected]
2-Substituted 4-oxo-pyrimidines are known for a number of unusual rearrangements
catalyzed by acid agents. Upon treatment with strong acids (pTSA or polyphosphoric
acid) at the temperatures of 220° or 135°C respectively, pyrimidine 1 produces
octahydrophenanthridone 2. When boiled in toluene with 8 to 10-fold excess of
POCl3 for a long time (10 to 24 h), it produces 10-aminooctahydroacridine 3.
NH2
H
N
POCl3
N
+
H
NH
O 1
3
N
H
O
2
In our study, we established a new rearrangement of 2-substituted 4-oxo-pyrimidines
by the formylation during soft conditions.
CN
H
N
POCl3+DMF
NH
O 1
CN
6
CHO
N
H
NH
NH
+
N
4
N
8
NH
NC
O
NH2
POCl3+DMF
N
O
CHO
7
O
H
N
O
+
N
9
O
POCl3+DMF
N
5
NC
CN
10
Unexpected reaction occurred at fomylation of thio-analog 11.
N
H
N
NH
S
11
POCl3+DMF
S
N
N
12
Some another model compounds were used at this formylation.
71
PO 023 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Cyclic peptides with biaryl and
triazolyl amino acids
Iteng Ng-Choi, Sílvia Vilà, Cristina Rosés, Marta Planas, Lidia Feliu
LIPPSO, Department of Chemistry, University of Girona, Girona, E-17071, Spain
[email protected]
Unnatural amino acids play an important role in the structure of many natural
peptides. In particular, biaryl amino acids are present in a wide range of naturally
occurring peptides that display significant biological activity (1). Among them,
5-arylhistidines have been shown to be the central structures of cytotoxic and
antifungal marine peptides (2). Moreover, the incorporation of unnatural amino
acids into natural or synthetic sequences has led to peptides with comparable or
improved biological profile. In this context, our research group has reported the
synthesis of linear peptidotriazoles and linear biaryl peptides with potent activity
against plant pathogenic bacteria and fungi, and low hemolysis (3,4).
In this work, we have extended our previous studies on the synthesis of linear
peptides containing biaryl and triazolyl amino acids to the preparation of cyclic
sequences incorporating these unnatural amino acids. The key step for the synthesis
of the cyclic biaryl peptides was the formation of an aryl-aryl bond between the
side-chain of two aromatic amino acids through a Suzuki-Miyaura cross-coupling.
Cyclic peptidotriazoles incorporated a 1,2,3-triazole at the side-chain of a selected
residue. This heterocycle was prepared through a copper-catalyzed azide alkyne
cycloaddition. The structure of both families of cyclic peptides as well as their
solid-phase synthesis will be presented.
1. Feliu, L.; Planas, M. Int. J. Pept. Res. Ther. 2005, 11, 53.
2. Faulkner, D. J. et al. Gazz. Chim. Ital. 1993, 123, 301.
3. Güell, I. et al. Peptides 2012, 33, 9.
4. Ng-Choi, I. et al. Eur. J. Org. Chem. 2012, 4321.
72
Poster presentations / PO 024
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Novel Highly functionalized cyclic
amino acids
Ferenc Fülöp,1 Melinda Nonn,1 Loránd Kiss,1 Reijo Sillanpää2
Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary,
Department of Chemistry, University of Jyväskylä, FIN-40014, Jyväskylä, Finland
1
2
Dipolar cycloaddition of nitrile-oxides to an olefinic bond, followed by reduction
of the formed isoxazoline ring represent a powerful selective synthetic strategy
for the access of many highly functionalized cyclic amino acid derivatives such
as Peramivir and other analogues with important biological properties [1]. Novel
highly functionalized cyclopentane amino acid derivatives have been synthetized
starting from bicyclic β- and γ-lactams by nitrile-oxide cycloadditions to the C-C
double bond of the corresponding cyclopentane amino esters, followed by reductive
isoxazoline opening. Synthetic aspects of the cycloaddition and isoxazoline
opening related to their selectivity will be discussed [2].
N
NHBoc
O
CO2Et
CO2Et BocHN
CO2Et
CO2Et
O
N
N
NHBoc
O
NHBoc
N
O
BocHN
CO2Et
N
O
O
N
O
NHBoc
HN
O
O
NHBoc
HO
BocHN
N
BocHN
NH
CO2Et
BocHN
CO2Et
R
CO2Et
H
BocHN
CO2Et
HO
CO2Et BocHN
BocHN
R
O
N
HO
BocHN
H
N
CO2Et
H
R
CO2Et
NHBoc
O
References:
1. Kiss, L.; Nonn, M.; Fülöp, F: Synthesis 2012, 44, 1951.
2. a) Nonn, M.; Kiss, L.; Hänninen, M. M.; Sillanpää, R.; Fülöp, F: Chem. Biodiv.
2012, 9, 2571. b) Nonn, M.; Kiss, L.; Sillanpää, R.; Fülöp, F: Tetrahedron 2012,
68, 9942.
73
PO 025 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
caged proton sponges
in base-catalyzed reactions
Juraj Galeta, Milan Potáček
Department of Chemistry, Faculty of Science, Masaryk University, Kotlářšká 2, 611 37 Brno, Czech
Republic
[email protected]; [email protected]
We reported a suitable synthetic approach to the preparation of compounds 1 with
four fused five-membered rings1 and their acid-catalyzed rearrangement leading to
bidentate caged secondary amines 2 in quantitative yields.2,3 Following alkylation
reactions under basic conditions led to air nonsensitive highly stable substituted
diazatetracyclo[4.4.0.13,10.15,8]dodecanes (DTDs) 3 with properties of proton
sponges.3 Their pKBH+ values were determined by 1H NMR transprotonation
experiments with known reference base. The molecular structures of free base and
its conjugated acid 4 have been proved by X-ray structure analysis. Recently we
performed several types of base-catalyzed reactions with one selected DTD (pKBH+
(CD3CN) = 21.7±0.1). Knoevenagel condensation and Pudovik reaction are two
chosen candidates where we discovered good to excellent kinetic activity of our
system in particular.
R
N N
HAc
NaBH3CN
MeOH
R
1
O
O
P
EtO
OEt
R
phospha-Brook
rearrangement
R
N
H
R
R
2
O
P
EtO
DCM
N
H
v ik
do on
Pu ac ti
re
OH
OEt
R
R
R
NaH, R1X
R
NH4ClO4
N
R1
3
N
R1
MeCN
N
N ClO
4
R1 H R1
4
Kn
co oev
nd en
en a
sa g el
tio
n
Y
R
X
Acknowledgements:
This work was financially supported by the Grant Agency of the Czech Republic
(grant No. 203/09/1345).
References:
1. Zachová, H.; Man, S.; Nečas M.; Potáček M. Eur. J. Org. Chem. 2005, 2548.
2. Zachová, H.; Marek, R.; Man, S.; Taraba, J.; Potáček, M. Tetrahedron Lett.
2006, 47, 8157.
3. Galeta, J.; Potáček, M. J. Org. Chem. 2012, 77, 1010.
74
Poster presentations / PO 026
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SIMPLE ROUTE TO FURFURYLARYLGLIOXALS
Oksana Gataeva,a Aleksey Boumber,b Marina Tskhovrebova,a
Vladimir Abaeva
North-Ossetian State University, Vatutina 44-46, Vladikavkaz, 362025 Russian Federation
Southern Federal University, Institute of Physical and Organic Chemistry, Stachki 194/2, Rostov-onDon, 344090, Russian Federation
a
b
Simple furan derivatives are valuable synthons in the heterocyclic syntheses due
to furan ring ability to serve as a 1,4-diketone equivalent. From this point of view
carbonyl furan derivatives can be considered as hidden polyketones and can provide
rich possibilities for recyclization reactions. Earlier we proposed a new method for
the synthesis of phenacylfurans [1]. Now we wish to report the two-stage simple
approach to the corresponding furan containing α-diketones [2].
O
R
O
R = H, Me
O
N3
R
R1
EtOH
1
R
O
O
O
R
2a
1
1
HO
R
R
O
= H, F, Cl, Br, OMe, NO2
(Et3O)3P
EtOH
HCl
N3
AcOH.C5H11N
+
O
1
R
R
O
2b
1
O
Acknowledgements: Financial support was provided by the Ministry of Education
and Science of the Russian Federation (grant 3.3578.2011) and Russian Foundation
for Basic Research (grant 13-03-01048 a).
se
References:
1. Abaev, V.T.; Bosikova K.V.; Serdyuk, O.V.; Butin, A.V. Chem. Heterocyclic
Comp. 2009, 45, 611-612.
2. Knittel D.; Hemetsberger H.; Wiedmann H. Monatsh. Chem. 1970, 101, 157160.
75
PO 027 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
1,2-DIHYDROXYINDOLIZIDINES:
A NEW APPROACH FROM
1-(2-PYRIDYL)-2-PROPEN-1-OL
Donatella Giomi, Renzo Alfini, Alessandra Micoli, Elisa Calamai, Elisa
Bindini, Alberto Brandi
Dipartimento di Chimica“Ugo Schiff”, Università di Firenze, 50019 Sesto Fiorentino (FI), ITALY.
[email protected]
The significant biological activities of polyhydroxylated indolizidine alkaloids
promoted an intense synthetic work to afford these natural products and their
nonnatural analogues. In particular, natural (+)-lentiginosine, isolated in 1990
from the leaves of Astragalus lentiginosus, was found to be a potent and selective
inhibitor of the fungal a-glucosidase, amyloglucosidase, while recent results
showed that the nonnatural enantiomer (–)-lentiginosine acts as an apoptosis
inducer on tumor cells of a different origin.1
H OH
N
N
OH
H OH
OH or
rac-lentiginosine
N
OH
rac-8a-epi-lentiginosine
1-(2-Pyridyl)-2-propen-1-ol, obtained by vinylation of commercially available
picolinaldehyde, behaved as a good starting material for the synthesis of the
indolizidine skeleton. A simple process involving bromination, reduction, and onepot nucleophilic substitution (via elimination/addition) afforded (±)–lentiginosine,
in ca. 27% overall yield, as well as the nonnatural diastereomer with inverted
configuration at C-8a.2 Synthetic and mechanistic aspects of this new approach,
able to afford variously functionalized indolizidines even in optically pure form,
will be discussed.
1. (a) Cardona, F.; Goti, A.; Brandi, A. Eur. J. Org. Chem. 2007, 1551-1565. (b)
Macchi, B.; Minutolo, A.; Grelli, S.; Cardona, F.; Cordero, F. M.; Mastino, A.;
Brandi, A. Glycobiology 2010, 20, 500-506.
2. Giomi, D.; Alfini, R.; Micoli, A.; Calamai, E.; Faggi, C.; Brandi, A. J. Org.
Chem. 2011, 76, 9536-9541.
76
Poster presentations / PO 028
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
NOVEL stereoselective route to SYN and
ANTI AMINO ALCOHOLS
Liene Grigorjeva, Aigars Jirgensons
Latvian Institute of Organic Synthesis; Aizkraukles 21, Riga, Latvia
[email protected]
Amino alcohols are valuable constituents of a wide range of biologically active
natural products and pharmacologically important compounds. Besides, they serve
as a versatile precursors for other building blocks, such as β-hydroxy-α-amino
acids, 2-hydroxyalkyl piperidines, 2-amino 1,3-diols, etc.
Vinyloxazolines 2 are versatile amino alcohol precursors. Herein, we present an
investigation of regioselectivity and diastereoselectivity in Lewis acid catalysed
cyclization of bis-trichloroacetimidates 1 to the corresponding cis- and trans-Eoxazolines 2.
It was found that the double bond configuration of substrate determines the reaction
diastereoselectivity. In the case of E-bis-imidates 1 the major reaction product
was cis-E-oxazoline 2, while Z-bis-imidates 1 gave trans-E-oxazoline 2. It is
demonstrated, that regioisomeric ratio varies depending on substrate used, as well
as Lewis acid catalyst.
77
PO 029 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS AND PROPERTIES OF NOVEL
HETEROCYCLIC DERIVATIVES OF
BENZANTHRONE
Ivanova I.D.a, Orlova N.V.a, Puchkin A.I.b, Kirilova E.M.b
Faculty of Chemistry, University of Latvia, 48, Kr. Valdemara str., LV-1013, Riga, Latvia
Department of Natural Sciences and Mathematics, Daugavpils University, 13, Vienibas str., LV 5401,
Daugavpils, Latvia
[email protected]
a
b
The design of new fluorescent molecules is of continuing interest for many
applications in research and industry. Especially donor–acceptor p-conjugated
organic materials have attracted considerable interests owing to their potential
wide applications for development of photoactive materials. Many derivatives of
benzo[de]anthracene-7-one are known as effective luminescent dyes with emission
in the spectral region from green to red-purple, depending on the structure [1].
Target benzanthrone derivatives are synthesized by condensation reaction of
3-amino¬benzanthrone with appropriate heterocyclic aldehydes with following
reduction of obtained imines by NaBH4 in DMF solution:
R:
NH2
O
1
O
R
N
H
R
H
N
NaBH4, DMF
O
2a-g
R
N
N
N
O
3a-g
O
N
N
S
References:
1. B.M. Krasovitskii, B.M. Bolotin, Organic luminescent materials. - VCH
Publishers, 1988.
78
Poster presentations / PO 030
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis and Asymmetric Catalytic
Activity of 4-Phenylquinazolines
Idris KARAKAYAa,b, Semistan KARABUGAc Ramazan ALTUNDASb, Sabri
ULUKANLIa
a) Faculty of Arts and Science, Department of Chemistry, Osmaniye Korkut Ata University,
Karacaoglan Campus, 80000 Osmaniye, [email protected]
b) Faculty of Arts and Science, Department of Chemistry, Atatürk University, 25240 Erzurum
c) Faculty of Arts and Science, Department of Chemistry, Kahramanmaras Sütcü Imam University,
46100 Kahramanmaras
The of addition of phenyl acetylenes to aldehydes, particularly asymmetric version
has been quite important study in the area of C-C-bond formation reactions in the
past decade due to the synthesis of propargylic alcohols.1
Quinazolinones (QH) (1a-e) were synthesised from α-hydroxy acids or α-amino
acids in 4-5 steps in high yields without a need of chromatography, following with
the literature procedure.2 Subsequently, QH’s were converted into enantiopure
4-phenylquinazolines (2a-e) in additional 2 steps. After successfully synthesis of
PhQ’s, were tested in catalytic enantioselective propargylic alcohol synthesis..
Under the optimised reaction conditions, propargylic alcohols were then
successfully accomplished by reaching up to %91 ee and up to 98% product yield.
R
OH
O
O
N
NH
OH
N
X
C4
R
R
N
OH
X= NH2
OH
QH (1a-e)
O
Ar
H
+
Ph
PhQ (2a-e)
OH
L*(2a) 10mol%
Ti(OPri)4 25 mol%
Et2Zn, THF, -10 oC
2a:Me,
2b:iPr,
R= 2c:tBu,
2d:Ph,
2e:Bn
Ar
up to 91 ee
Ph
References:
[1] M. Yamaguchi, A. Hayashi, T. Minami, J. Org. Chem. 56 (1991) 4091–4092.
[2] M. Catir, M. Cakici, S. Karabuga, S. Ulukanli, E. Sahin, H. Kilic, Tetrahedron:
Asymmetry, 20 (2009) 2845-2853
79
PO 031 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
novel racemic and optically active
1-alkyl-3-phospholene platinum(II)
complexes
György Keglevich, Péter Bagi, Tamara Kovács, Elemér Fogassy
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics,
Budapest, H-1521, Hungary
[email protected]
Chiral transition metal-phosphine complexes form an important group within the
organophosphorous compounds, as they may be used as enantioselective catalysts
in homogenous catalytic reactions, such as hydrogenation and hydroformylation.1
As an extension of a resolution method developed by our research group,2
the resolution of 1-alkyl-3-phospholene 1-oxides (1) was accomplished using
TADDOL derivatives (2-3) and Ca2+ salts of dibezoyl- and di-p-toluyl-tartaric acid
(4) as resolving agents.
R1 R2
Me
O
P
O
Y
O
H
Ca2+ ArC(O)O
HOOC
OH HO
1
Y=aryl, alkyl, alkoxi
R1, R2 = Me, Me
(-)-(R,R)-2
(-)-(R,R)-3
R 1, R 2 =
O(O)CAr
H
COO-
2
(R,R)-4
Ar=Ph (a)
p-MePh (b)
The racemic and optically active 1-alkyl-3-phospholenes 1-oxides (1a-e) were
converted to the corresponding novel racemic and optically active platinum(II)complexes (6a-e), and they were tested in the hydroformylation reaction of
styrene. Unexpectedly high regioselectivities towards the branched aldehyde were
observed, and the enantioselectivities were significantly higher than in case of the
phenyl-substituted derivative.3
Me
P
R
O
0 -> 26 °C
Cl3SiH
PhH
1
Me
P
R
5
26 °C
PtCl2(PhCN)2
PhH
Me
Me
P
R
Cl
Pt
6
P
Cl
R
R= Et (a), nPr (b), nBu (c),
iBu d iPent e Ph f
( ),
( ),
()
References:
1. Kollár, L.; Keglevich, G. Chem. Rev. 2010, 110, 4257.
2. Novák, T.; Ujj, V.; Schindler, J.; Czugler, M.; Kubinyi, M.; Mayer, Z. A.;
Fogassy, E.; Keglevich, G. Tetrahedron: Asymmetry 2007, 18, 2965.
3. Pongrácz , P.; Kollár, L.; Kerényi, A.; Kovács , V.; Ujj, V.; Keglevich, G. J.
Organomet. Chem. 2011, 696, 2234.
80
Poster presentations / PO 032
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
functionalized tetrahydro-indolizines
as building blocks for medicinal
chemistry
Andrei R. Khairulin
Department of synthesis, Institute of pharmacology and toxicology, Kiev, 030057, Ukraine
[email protected]
New synthetic strategies for the construction of functionally diverse
tatrahydroindolizines scaffolds are of importance to many areas of pharmaceutical
and academic research.1 Natural products featuring the tetrahydroindolizine
framework often exhibit desirable pharmacological activities such as antibacterial,
antihelmintic, and other properties. Rhazinilam 1 have attracted considerable
attention in both the biological and synthetic communities.2 Similar to taxol
and vincristine, rhazinilam was found to interfere with tubulin polymerization
dynamics, making it a promising starting point for the development of anticancer
agents. Our laboratory has developed a new, multicomponent procedure for the
synthesis of highly functionalized 5,6,7,8-tetrahydroindolizines rings through a
selective hydrohenation of the indolizine nucleus. Starting indolizines synthesized
under the Thorpe reaction conditions.3
References:
1. Baudoin, O.; Gue´nard, D.; Gue´ritte, F. Mini-Rev. Org. Chem. 2004, 1, 333.
2. Barbe, G.; Pelletier, G.; Charette, A. B. Org. Lett. 2009, 11, 3398−3401.
3. Baron, H.; Remfry, F. G. P.; Thorpe, Y. F. J. Chem. Soc. 1904, 85, 1726.
81
PO 033 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
DESIGN OF CHIRAL PYRIDINES AS
ORGANOCATALYSTS FOR ASYMMETRIC
CYCLOPROPANATION REACTION
Artis Kinens, Edgars Suna, Edwin Vedejs
Latvian Institute of Organic Synthesis, Aizkraukles str. 21, Riga, LV-1006, Latvia
[email protected]
Pyridine derivatives are widely used as organocatalysts and as ligands in transition
metal catalysis. Herein we report synthesis and application of chiral pyridine
organocatalysts in cyclopropanation reaction.
To find suitable conditions for pyridine 4a-c catalyzed cyclopropanation a
range of solvents and bases was screened. It was found that the desired reaction
proceeds smoothly without non-catalyzed background cyclopropanation reaction
if K2HPO4·3H2O or KOAc were used as base in dichloromethane.
Further investigation on pyridine derivative 4a-c structure showed that electron
donating groups in para-position accelerate cyclopropanation. Notably,
4-methoxypyridine (4a) and N-pyridin-4-ylacetamide (4b) showed the best yields
(80% and 78%, respectively), whereas 4-dimethylaminopyridine (4c) gave only
trace amounts of cyclopropane 3.
R1
O
Ph
Br + Ph
1
Br
5
N
4a-c
NC CN
Ph
DCM, K2HPO4.3H2O
O
or KOAc
3
R1 = a) MeO-, b) AcNH-, c) Me2N-
CN
2
O
N
CN
1) t-BuLi, THF -78oC
O
2)
HN
R3
(S )-6
O
N
O
Ph
R2
HN
R3
(S ,S )-7aa'-cc'
R2 = a) Ac, b) Bz, c) Piv
R3 = a') Bz, b') Piv, c') Ts
Chiral organocatalysts (S,S)-7aa’-cc’ were synthesized by ortho-lithiation of
pyridine 5 followed by quenching with aldehydes (S)-6a’-c’.
When catalysts (S,S)-7aa’-cc’ were employed in cyclopropanation reaction best
enantioselectivities (48.8% ee) were achieved with sterically large substiruent R3
(Piv and Ts).
82
Poster presentations / PO 034
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
MICROWAVE-ASSISTED direct
esterification and amidation of cyclic
phosphinic acids
Nóra Zs. Kiss, Zoltán Mucsi, Tamás Körtvélyesi, György Keglevich
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics,
Budapest, H-1521, Hungary
[email protected]
Phosphinic acids do not undergo direct esterification and other related derivatizations.
The conventional methods for the synthesis of phosphinates involve P-chlorides
that are not environmentally friendly.
Therefore, we wished to study the MW-assisted direct esterification of cyclic
phosphinic acids (1), such as 1-hydroxy-3-phospholene 1-oxides, 1-hydroxyphospholane 1-oxides and a 1-hydroxy-1,2,3,4,5,6-hexahydrophosphinine 1-oxide,
resulting in the formation of the appropriate phosphinates (3). To our surprise, the
esterifications did take place that may be due to the beneficial effect of the MW
irradiation.1,2
The energetics and mechanism of the direct esterifications were evaluated by
B3LYP/6-31++G(d,p) calculations.3
Encouraged by the above results, we also studied the MW-assisted direct
thioesterification and amidation of the cyclic phosphinic acids.
However, these reactions could be performed in only lower conversions. This
experience is the consequence of the thermodinamics of the reactions as suggested
by high level calculations.
References:
1. Keglevich, G.; Bálint, E.; Kiss, N. Zs.; Jablonkai, E.; Hegedűs, L.; Grün, A.;
Greiner I. Curr Org Chem 2011, 15, 2802.
2. Keglevich, G.; Kiss, N. Zs.; Mucsi, Z.; Körtvélyesi, T. Org. Biomol. Chem. 2012,
10, 2011.
3. Keglevich, G.; Kiss, N. Zs.; Drahos, L.; Körtvélyesi, T. Tetrahedron Lett. 2013,
54, 466.
83
PO 035 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
The synthesis and use of
1-alkoxy- and 1-amino-3‑phospholene
1-oxides
Nóra Zs. Kiss, Róbert Örkényi, Zita Rádai, György Keglevich
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics,
Budapest, H-1521, Hungary
[email protected]
Various 3-phospholene 1-oxides, such as 1-alkoxy and 1-amino derivatives that
are available by the McCormack reaction and subsequent direct functionalizations,
form a representative group of P-heterocycles. 1,2
1-Alkoxi-3-phospholene 1-oxides (1), obtained directly from the corresponding
phosphinic acids by MW-assisted direct esterification, can be used in ring
enlargement involving the addition of dichlorocarbene on the double-bond of the
phospholene oxide (1) followed by the thermal opening of the cyclopropane ring
of the dichlorocarbene adduct (2) so formed.
ClTEBA
NaOH/H2O
O
P
1
OR
Cl
CHCl3
Cl
Cl
TEA
O
P
2
OR PhMe
O
R = C8-C12 alkyl
P
OR
3
We have found that higher carbon atom chain alkoxy groups promote the
dichlorocarbene addition reaction.
The synthesis of 1-amino-3-phospholene 1-oxides (5) involves the reaction of
the corresponding phosphinic chloride (4) with amines. However, the reaction
results in a mixture containing the expected amino-phospholene oxide (5) and,
surprisingly, its N-phosphinoyl derivative (6) as a by-product.
RNH2
O
P
Cl
4
Me
Me
Me
O
P
5
+
NHR
O
P
N
6 R
Me
P
R = alkyl, aryl, aralkyl
O
It was found, that the product composition could be influenced (fine-tuned) and
thus, either phosphinic amide 5 or the corresponding bis product (6) can be obtained
selectively, and in high yields.
References:
1. Keglevich, G.; Grün, A.; Bálint, E.; Kiss, N. Zs.; Jablonkai, E. Curr. Org. Chem.
2013 (in press).
2. Keglevich, G.; Kiss, N. Zs.; Körtvélyesi, T.; Heteroatom Chem. 2013 (in press).
3. Kiss, N. Zs.; Simon, A.; Drahos, L.; Huben, K.; Jankowski, S.; Keglevich, G.
Synthesis, 2013, 45, 199.
84
Poster presentations / PO 036
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Direct C-H sulfenylation of
7‑deazapurines
Martin Klečka,a,b Michal Hoceka,b*
Dept. of Organic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 8, CZ-12843
Prague 2, Czech Republic
b
Institute of Organic Chemistry and Biochemistry, v.v.i., Academy of Sciences of the Czech Republic;
Gilead Sciences & IOCB Research Center, Prague, Czech Republic;
[email protected], [email protected]
a
Purines1 and their analogues show a great variety of biological activities.
7-Deazapurines (pyrrolo[2,3-d]pyrimidines) have been much less thoroughly
studied but some examples display antibiotic2, antiviral3 and cytostatic4 effects.
In our previous study, we have reported synthetic approach to 8-modified
7-deazapurines via a “one pot“ C-H borylation followed by Suzuki coupling.5
An analogy to C-H sulfenylation of indoles,6 we report here on sulfenylation
of 7-deazapurines to position 7 by diverse disulfides using Cu catalysis in air.
Optimized conditions (Scheme 1) allowed the synthesis of the target 7-alkyl- or
-arylsulfanyl derivatives in nearly quantitative yields.
X
N
N
N
H
X=Ph, Cl, NH2
RS-SR
cat. Cu
solvent
110°C
a ir
X
SR
N
N
N
H
R=Me, Ph, 4-MeOPh, 4-NO2Ph
Scheme 1
Acknowledgement
This work is part of a research project by Czech Science Foundation (P207/12/0205)
and by Gilead Sciences, Inc. (Foster City, CA, U.S.A.).
References
1) 2)
3)
4)
5)
6)
Review: Legraverend, M.; Grierson, D.S. Bioorg. Med. Chem. 2006, 14, 3987-4006
Anzai, K. J. Antibiotics 1957, 10, 201-204
Wu, R.; Smidansky, E.D.; Oh, H.S.; Takhampunya, R.; Padmanabhan, R.; Cameron, C.E.;
Peterson, B.R. J. Med. Chem. 2010, 53, 7958-7966
a) Nauš, P.; Pohl, R.; Votruba, I.; Džubák, P.; Hajdúch, M.; Ameral, R.; Birkus, G.; Wang, T.;
Ray, A.S.; Mackman, R.; Cihlar, T.; Hocek, M. J. Med. Chem. 2010 , 53, 460–470
b) Spáčilová, P.; Nauš, P.; Pohl, R.; Votruba, I.; Snášel, J.; Zábranská, H.; Pichová, I.; Ameral, R.;
Birkuš, G.; Cihlář, T.; Hocek, M. ChemMedChem 2010, 5, 1386–1396
Klečka, M.; Pohl, R.; Klepetářová, B.; Hocek, M. Org. Biomol. Chem. 2009, 7, 866-868
a) Li, Z.; Hong, J.; Zhou, X. Tetrahedron ,2011, 67, 3690-3697
b) La Regina, G.; Gatti, V.; Famiglini, V.; Piscitelli, F.; Silvestri, R. ACS Comb. Sci., 2012, 14,
258–262
85
PO 037 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
a convenient SYNTHESIS OF IMIDAZO[1,2-C]
quinazolines
Edward E. Korshin,a Leila A. Sabirova,b Yakov A. Levinb
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
Institute of Organic and Physical Chemistry, Kazan, Russia.
[email protected]
a
b
Variously hydrogenated 5-alkyl- and 5-arylimidazo[1,2-c]quinazolines have
shown attractive pharmacological activities and insecticidal properties. However,
the previous methods for synthesis of this tricyclic ring system were very limited
and mostly relied on assembling of imidazole heterocycle onto quinazoline frame.
In this communication we report a convenient approach to synthesis of 5-substituted imidazo[1,2-c]quinazolines 3-5 which based on a quinazoline ring closure.
N
N
RCHO
3
N
CN
1
NH2
EDA
2
N
H
NH2
N
H
R
N
N
RC(OMe)3
or
RC(NH)OMe
N
5
N
4
N
N
R
R
Thus, anthranilonitrile (1) smoothly reacted with EDA in the presence of P2S5 (0.02
equiv) to give aminoimidazoline 2 (93%). Acid-free condensation of the latter
with aromatic and aliphatic aldehydes led to 2,3,5,6-tetrahydroimidazo[1,2-c]
quinazolines 3 in high yield. Condensation of 2 with orthoesters or with iminoesters
afforded 5,6-dihydroimidazo[1,2-c]quinazolines 4. Derivatives 3 were selectively
dehydrogenated to 4 with KMnO4/SiO2 (1 equiv), while applying 2 equiv of the
same reagent led to exhaustive dehydrogenations to 5. Additional variants of the
ring closure and dehydrogenations will be also discussed.
86
Poster presentations / PO 038
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Catalytic approach to steroids bearing
heterocyclic moiety
Yuri Kotovshchikov, Gennadij Latyshev, Nikolai Lukashev, Irina Beletskaya
Department of Chemistry, Lomonosov Moscow State University, Moscow, 119991, Russia
[email protected]
Development of new catalytic tools for modification of biologically active natural
molecules is one of the most important challenges of modern organic chemistry.
Vinyl iodides obtained from readily available ketosteroids have been involved
in copper-catalyzed cross-coupling reactions. An efficient protocol for C-N bond
formation between steroid fragment and various azoles have been developed.
R
R
H
H
+
H
I
CuI, DPM, K2CO3
DMSO, 100 °C
X
H
H
N
H
H
N
X
R = OH;
Another type of hetaryl substituents have been introduced by means of Pd-free
Sonogashira reaction followed by cyclization step.
I
H
H
H
1. CuI, Ph3P, TMEDA
K2CO3, DMSO, 100 °C
+
2. Cyclization
HX
O
X
H
H
H
O
Copper-catalyzed 1,3-dipolar cycloaddition reaction of azidosteroids with
iodoacetylenes has afforded 5-iodotriazoles which can be converted to different
functionalities by diverse cross-coupling methodologies.
OH O
N3
H
H
O
OH O
H
R
+
I
CuI, TTTA
H
H
THF
O
H
N N
N
R
I
Valuable substrate f or
Cross-coupling reactions
We are grateful to RFBR (grant № 11-03-00265-а) for financial support.
87
PO 039 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
REACTIONS OF TETRACYANOETHYLENE WITH
N’-ARYLBENZAMIDINES: A SHORT ROUTE TO
2-PHENYL-3H-IMIDAZO[4,5-b]­QUINOLINE-9CARBONITRILES
Panayiotis A. Koutentis, Maria Manoli and Styliana I. Mirallai
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus
[email protected]
Tetracyanoethylene (TCNE) is the simplest of the percyano alkenes (cyano­
carbons).1 It is highly electron-deficient and therefore strongly electrophilic.2
TCNE reacts with a variety of bis-amino-nucleophiles to give after the initial
addition to the double bond intramolecular cyclisations typically on the vicinal
nitrile that lead to various heterocyclic systems.3 Here we report our comple­
mentary study on the reaction of tetracyanoethylene (TCNE) with the readily
available N'-arylbenzamidines 14 which affords 2-[1-aryl-5-imino-2-phenyl-1Himidazol-4(5H)-ylidene]malononitriles 2 in good yield. Dimroth rearrangement5
of which, affords the isomeric (Z)-2-[4-(arylimino)-2-phenyl-1H-imidazol-5(4H)ylidene]malononitriles 3 in near quantitative yield. Subsequent thermolysis in
biphenyl ether yielded 2-phenyl-3H-imidazo[4,5-b]quinoline-9-carbonitriles 4
again in near quantitative yields. Single crystal X-ray structures for 2-[5-imino1,2-di­phenyl-1H-imidazol-4(5H)-ylidene]malononitrile 2 (Ar = Ph) and (Z)-2-[2phenyl-4-(phenylimino)-1H-imidazol-5(4H)-ylidene]malononitrile 3 (Ar = Ph) are
presented.
NC
Ar
NH2 NC
N
Ph
1
CN
TCNE
CN
CN
N
CN NC
HN
2
N
Ar
Ph
Dimroth NC
N
Ar
H
N
N
3
CN
Ph
Thermolysis
N
Ar
N
N
H
Ph
4
References:
1. Heckert, R. E.; Little, E. L. Jr. US Pat. 2,794,824 (1957).
2. Freeman, F. Chem. Rev. 1980, 80, 329-350; Fatiadi, A. J. Synthesis 1986, 249.
3. Hecht, S. M.; Werner, D.; Traficante, D. D. J. Org. Chem. 1975, 40, 1815.
4. Koutentis, P. A.; Mirallai, S. Tetrahedron 2010, 66, 5134.
5. L’Abbe, G. J. Het. Chem. 1984, 21, 627.
88
Poster presentations / PO 040
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Control formation of 3,3’- and
3,4’-pyrazolinylpyrazoles
on the base of unsaturated
oxiranylketones
Tatyana A. Koval’chuk, Nina M. Kuz’menok, Sergey G. Mikhalyonok
Department of Organic Chemistry, Belarusian State Technological University, Minsk, Belarus
[email protected]
New bipyrazoles heterocycles have been synthesized due to their complex-forming
ability. Unsaturated oxyranylketones 1 were used as starting substances owing to
convenient polyfunctionality. The diazole cycle formation has been obtained by
variation in the sequence of 1,3-dipolar diazomethane cycloaddition to double
bond and hydrazines cyclocondensation with oxyranylketone moiety. These two
routes allowed to realise target synthesis of pyrazolinylpyrazoles with heterocyclic
rings bonded in 3,3'- and 3,4'-positions.
R'
R
O
Ar
1
O
TsNHNH2
route 1
Ar
R
R'
N
Ts
route 2 CH N
2 2
R'
O
R
Ar
N
O
R
R'
HN N
NH
R'
N
N NH
Ts
R
O
R
R
HN N
OH Ar
3
N HN
N +
N
N N
Ts
N N
6
Ts
R
H
N N
Ar
7
N N
+
N
NH
Ar
R'
Ts
N N
MeOHaq/OH-
R
Ar H
R
N
NH
R'
N N
H
R'
Ar
R'
N
NH
N2H4
R'
Ar H
H
R
Ar
O
N2H4
OH Ar
2
1. TsCl;
2. CH3ONa
CH2N2 R'
R'
N NH
4
MeOHaq/OH-
R
N N
H
Ar
5
N NH
R = H, CH3; R' = H, CH3, Ph; Ar = Ph, 4-NO2-C6H4, 3-NO2-C6H4, 4-Br-C6H4, 4-CH3O-C6H4
Bipyrazoles with 3,3’-coupled rings 2-5 can be obtained by both synthetic routes.
While the synthesis of 3,4’-coupled pyrazolinylpyrazoles 6,7 can only be achieved
by the route 2 and the regioselectivity of the 1,3-dipolar cycloaddition stage in this
case is controlled by the introduction of electron-withdrawing substituent in the
styryl moiety.
89
PO 041 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
reaction of 6-halogeno­pyrimidine
carboxylates
with n-, o-, s-nucleophiles
Iryna O. Lebedyeva, Mykhaylo V. Povstyanoy
Department of Organic and Biochemical Synthesis, Kherson National Technical University, Kherson,
325008, Ukraine
[email protected]
Dihydropyrimidines, obtained via a three-component Biginelli reaction are thoroughly
studied these days due to the wide spectrum of their biological activity. Over the
years various synthetic approaches towards Biginelli compounds were developed.1
However, there was a lack of study on the reactivity of Biginelli reaction products
towards various nucleophiles. In present work we developed synthetic approaches
towards 6-methyl substituted pyrimidine carboxylates 2 where the substituents at C6
are N-, O-, S-nucleophiles that were introduced into the dihydropyrimidine molecule
via reaction of 1 with biologically active nucleophilic reagents. Therefore, we were
able to link the residues of substituted amines, sulfanilamides, aminoacids, phenols,
thiophenol and 2-mercaptobenzimidazole to the pyrimidine core of 2.
Ar
HN
O
O
X R
N
H
3
X
R
Ar
R = Alk, Ar, Het HN
X = N, O, S
N
O
H
1
X
O
O
Hal
Ar
R
R = Alk, Ar, Het HN
X = N, O, S
O
N
H
O
O
X R
2
Synthesis of products 3 where X = N, O, S has been provided by the change of both
the reaction conditions and reagents. The reaction products of both types 2 and 3
were isolated with the yields of 38-94 % depending on the nature of the substituent
introduced into the pyrimidine molecule.
1. Kappe, C. O. Acc. Chem. Res. 2000, 33, 879.
90
Poster presentations / PO 042
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS AND THERMOLYSIS OF
4-(2-THIENYLCARBONYL)-5(TRIFLUOROMETHYL)-2,3-FURANDIONE
Natalya Lisovenko, Anton Merkushev, Alexsandr Rubzov
Department of Chemistry, Perm State National Research University, Perm, 614990, Russian
[email protected]
4H-pyran-4-one derivatives constitute an useful class of heterocyclic compounds
which are widely distributed in nature. These compounds display diverse biological
activities [1-3]. On the other hand, polyfluoroalkyl- substituted heterocyclic
compounds are of particular interest owing to their biological activity, specific
properties and chemical reactivity [4]. Therefore, there is a need for development
of available and convenient methods of synthesis polyfluoroalkyl-substituted
4H-pyran-4-one.
We showed for the first time that the reaction of 4,4,4-trifluoro-1-(2-thienyl)1,3-butanedione 1 with oxalyl chloride give to 4-(2-thienylcarbonyl)-5(trifluoromethyl)-2,3-furandione 2, whose thermolysis leads to 3,5-bis(2thienylcarbonyl)-2,6-bis(trifluoromethyl)-4H-pyran-4-one 3.
O
O
O
S
CF3
(COCl)2
-2HCl
1
O
S
CF3
O
O -CO; -CO2
S
O
O
O
CF3
O
CF3
2
S
3
The structure of compound 3 was established by elemental analysis, IR,
13
C-NMR, 19F-NMR and single-crystal X-ray diffraction ..
H-NMR,
1
References:
1. Morris, J.; Kalamazoo, M., U.S. Patent 5,252,735, 1993.
2. Clark, B. P.; Ross, W. J.; Todd, A. U.S. Patent 4,471,129, 1984.
3. Clark, B. P.; Ross, W. J.; Todd, A. U.S. Patent 4,364,956, 1981.
4. Welch, J.T. Tetrahedron 1987, 43, 3123.
The work was carried out with financial support from the Ministry of Education of
Perm Region (project MIG).
91
PO 043 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
isoxazole-linked oligosaccharides
Jevgeņija Lugiņina, Vitālijs Rjabovs, Māris Turks
Faculty of Material Science and Applied Chemistry, Riga Technical University,
14/24 Āzenes Str., Riga, LV-1007, Latvia,
[email protected]
Modification of C(3) and C(5) position in glucose leads to discovery of new
previously unknown conjugates. Here we report a novel approach for synthesis
of sugar clusters which is based on Michael addition/1,3-dipolar cycloaddition
reaction sequence. We have identified glucose-derived nitroalkene 1 as a suitable
structural motif which is capable to link a molecule possessing nucleophilic center
and a molecule possessing terminal alkyne.1 Using different O-, S-, N- sugar
nucleophiles it is possible to build carbohydrate cluster of type 2 and 3.
Acknowledgements: The authors thank JSC Olainfarm for kind donation of
diacetone-d-glucose and for scholarship.
References:
1. Lugiņina, J.; Rjabovs, V.; Belyakov, S.; Turks, M. Carbohydr. Res. 2012, 350,
86.
92
Poster presentations / PO 044
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
1,3-dipolar cycloaddition of nitrones
to substituted allenes
Julia Malinina, Alexander Molchanov
Department of Chemistry, Saint Petersburg State University, Saint-Petersburg, 199034, Russia
[email protected]
1,3-Dipolar cycloaddition is known as one of the most powerful tools to create
N,O–five-membered heterocycles. In particular, dipolar cycloaddition of nitrones
to carbon-carbon double bonds of different alkenes allows access to a variety of
isoxazolidines. These cycloadducts attracted considerable attention due to their potential biological activities. Isoxazolidines have also been used as precursors of
such natural products as b-lactam antibiotics and alkaloids. In this work reactions
of arylallenes with C-carbamoyl- and C,C-bis(methoxycarbonyl)nitrones were investigated and regio- and stereoselectivity of the reaction was shown. It was found
that in some cases initial products undergo the further transformations.
Ar
R1
C
+
N
R2
Ar
O
H
R3
R3
R2
Ar
N
R1
O
+
R3
R2
R1=
Ar, Me;
R2=
Ar
O
O
R2
N
H
R3
C(O)NHAr, R3=H; R2= R3 = COOMe
O
Ar
R2
+
N
H
N
R1
O
R3
+
R3
R2
N
R1
Ar
The structure of obtained products was established by spectral and X-ray methods.
The mechanism of the reactions is discussed. So, the reaction of allenes with nitrones afford isoxazolidines with additional functionalities, that may be transformed
in some new heterocyclic systems.
93
PO 045 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
A Convenient ROUTe To 4-aryl-3,4dihydro-1H-QUINOLIN-2-ONES
Agnese Stikute, Inese Mierina, Mara Jure
Faculty of Material Science and Applied Chemistry, Riga Technical University
Azenes Str. 14/24, Riga, LV-1048.
[email protected]
3,4-Dihydro-1H-quinolin-2-ones containing hydroxyl group in benzene ring are
starting compounds for synthesis of phosphodiesterase inhibitor Cilostazol and
atypical antipsychotic and antidepressant Aripiprazole. Our studies were devoted
to synthesis of 4-aryl-3,4-dihydro-1H-quinolin-2-ones 1, mainly substituted with
methoxy groups in both aromatic rings. It is well known that compounds 1 can be
obtained by internal cyclization of cinnamoyl anilines.1 We found out that anilides
2 also can be successfully used for synthesis of target compounds 1. Taking this
into account, we developed a new convenient method: one pot direct preparation
of quinolinones 1 by heating of malonanilic acids 3 and aromatic aldehydes in
trifluoroacetic acid without isolation of cinnamoyl anilines 2. The crude products
of this procedure contained up to 90% of 1H-quinolin-2-ones 1. The antiradical
properties of obtained compounds 1 have been tested.
Ar
OH
R
N
H
O
Ar-CHO
O TFA
reflux
OH
R
Ar
O
R
N
H
O
N
H
O
1
2
Acknowledgements. Authors thank JSC Olainfarm for scholarship to A. Stikute.
References
1. (a) Koltunov, K. Y.; Walspurger, S.; Sommer, J. Chem. Comm. 2004, 15, 1754.
(b) Kraus, J. M.; Tatipaka, H. B.; McGuffin, S. A.; et al. J. Med. Chem. 2010, 53,
3887.
3
94
Poster presentations / PO 046
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF ACYCLIC AND MACROCYCLIC
MULTIURACILS
Anton Nikolaev, Lilya Saifina, Vyacheslav Semenov, Vladimir Reznik
A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan, Russian Federation
[email protected]
Earlier we’ve shown that pyrimidine containing macrocycles (pyrimidinophanes)
possess high antimicrobial activity. We suggested that a compound, consisting
of several “monomeric” pyrimidinophanes linked together in some way, can
demonstrate higher activity and/or selectivity. We used azide-alkyne cycloaddition
and coupling of acetylenes with copper acetate to obtain nanosized structures
containing pyrimidinophanes.
O
X
Cu(OAc)2
O
N
O
N
R
N
N
N
O
O
X
X
O
X
N3 X N3
O
N
N
N
N X N
N
N
O
N
N
N
N
O
O
X
We also synthesized a series of acyclic analogues of macrocyclic multiuracils.
Among them we consider uracil containing dendrimers to be the most promising.
We managed to synthesize several uracil containing dendrimers, including the 3rd
generation dendrimers, which consists of 15 uracil units.
Br
N
N
N
N
N
O
N
O
Br
Br
N
O
Br
O
O
N N
N
Br
N
N
N
N
N
O
N
N
O
O
N N
N
N
N
N
N
N
N
N
O
N
N
O
O
N
N
N
N
O
N
O
N
N
N
N
N
N N
O
N
N
N O
Br
O
N N
N
O
O
N
Br
N
N
O
Br
N
N
N
Br
N
N
N
Br
O
O
O
N
O
N
N
N
O
N
N
O
N
N
N
O
N
N
N
Br
Br
Br
O
O
Br
N
N
N
N
O
Br
O
Br
Acknowledgements: Financial support of the Russian Foundation for Basic
Research (projects #13-03-00709 and 12-03-31862) and the President’s grant
(project MK-5936.2012.3) is acknowledged
95
PO 047 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
synthesis of n6-substituted-2‑triazolyladenine derivatives
Irina Novosjolova, Ērika Bizdēna, Sergey Belyakov, Māris Turks
Faculty of Material Science and Applied Chemistry, Riga Technical University,
Riga, LV-1007, Latvia;
[email protected]
A novel class of 2,6-bis-triazolylpurine nucleosides 2 were obtained from
2,6-diazido precursors 1 via copper (I) catalyzed azide-alkyne 1,3-dipolar
cycloaddition reaction. These intermediates appeared to be very reactive towards
N-nucleophiles and thus selectively gave C(6)-substituted analogs 3 with triazolyl
moiety at C(2)-position. Thereby, 1,2,3-triazoles act as good leaving groups in
regioselective nucleophilic aromatic substitution reactions [1].
Photophysical properties of the obtained products have been studied. Products 3
exhibit interesting fluorescence properties.
References:
1. Kovaļovs, A.; Novosjolova, I.; Bizdēna, Ē.; Bižāne, I.; Skardziute, L.;
Kazlauskas, K.; Jursenas, S.; Turks, M. Tetrahedron Lett. 2013, 54, 850.
96
Poster presentations / PO 048
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
DIASTEREOSELECTIVE SYNTHESIS OF
1,2-DIHYDROARENOFURANS
Dmitry Osipov, Vitaly Osyanin, Yuri Klimochkin
Department of Organic Chemistry, Samara State Technical University, Samara, 443100, Russia
[email protected]
The dihydroarenofurans belong to an important class of heterocycles, principally
because this ring-system constituents the core skeleton of an increasing number
of biologically active natural products and pharmaceuticals. We have developed
a simple, general route to the 1,2-dihydroarenofurans, subsituted in position 2
by an acyl or aryl group, starting from phenolic Mannich bases, 2-acetoxybenzyl
acetates or quaternary ammonium salts and the carbonyl-stabilised pyridinium
ylides generated in situ from pyridinium salts. The mechanism of the reaction is
believed to involve the formation of the o-quinone methide intermediate, Michaeltype addition of the ylide to the o-quinone methide followed by intramolecular
nucleophilic substitution.
This method can be also widespread on N-benzylpyridinium salts. The advantages
of this approach include the use of readily available starting materials, simple
experimental steps and product isolation, and chromatographic purification is not
usually required.
97
PO 049 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
NOVEL METHOD FOR SYNTHESIS
OF 2‑NITROARENOFURANS
Vitaly Osyanin, Dmitry Osipov, Maxim Demidov, Yuri Klimochkin
Department of Organic Chemistry, Samara State Technical University, Samara, 443100, Russia
[email protected]
Synthesis of 2-nitroarenofurans has drawn extensive and enduring attention because
of their varied biological activities. Many of these compounds exhibit antibacterial,
antiparasitic and mutagenic properties. Besides, 2-nitrobenzofurans are useful
intermediates for the preparation of 2-halogenobenzofurans, dibenzofurans and
benzofuro[2,3-c]pyrroles. Herein, we report a simple, efficient, TEA catalyzed
method for the synthesis of 2-nitroarenofurans from quaternary ammonium
salts, phenolic Mannich bases or 2-acetoxybenzyl acetates and potassium
trinitromethanide in moderate-to-good yields using acetonitrile or ethanol as the
reaction medium.
O
R
NO2
13 examples
NMe2
O2N
O
N
H
NH
N
H
O
-
+
+
Me2N
OAc
NO2
Me2N
CO2Et
HO
CO2Et
O
N
COMe
O
R
O
O2N
N
Me
OAc
OH
-
NMe3I HO
+KC(NO2)3
NMe3I
O
OH
R
NH
HO
O2N
COMe
O
R
O
R = H, Br
NO2
O
In some cases, trinitromethyl derivatives and 2,2-dinitro-2,3-dihydrobenzofurans
were isolated.
R
Cl
OH
+KC(NO2)3
R
C(NO2)3
OH
DMSO
R
O
NO2
NO2
R = NO2, COMe
The mechanisms of these reactions are believed to involve the formation of the
o‑quinone methide intermediate.
98
Poster presentations / PO 050
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF FLUORINATED 3,4‑DIHYDRO­
PYRIDINES
Francisco Palacios, Ana Mª Ochoa de Retana, Guillermo Fernández de
Trocóniz, Sergio Pascual, Ander Vélez del Burgo
Departamento de Química Orgánica I, Facultad de Farmacia, Universidad del País Vasco-Euskal
Herriko Unibertsitatea (UPV/EHU), Vitoria-Gasteiz, Spain
[email protected]
Fluorine emerged as a “magic element” in Drug Discovery and the develop of
synthetic methods for the preparation of fluorinated building blocks with biological
activity have attracted a great deal of attention in recent years [1]. Furthermore,
α,β-unsaturated imines are a versatile family of compounds with a wide range of
applications in preparative organic chemistry. We described the preparation of the
first stable N-unsubstituted α,β-unsaturated imines [2]. These fluorinated imines
are used as intermediates for synthesis of vinylogous fluoro­alkylated amino nitrile
derivatives (3) and for the regioselective synthesis of fluorine containing trans3,4-dihydropyridin-2-ones [3]. Continuing with our interest in the design of new
fluoroalkyl substituted building blocks, we report here a simple and regioselective
synthesis of fluorine containing 3,4-dihydro­pyridines (2) by conjugate addition
(1,4) of nitriles to α,β-unsaturated imines (1).
NH2
1
R
2
R
RF
CN
TMSCN
(1,2-Ad)
NH
1
R
2
R
RF
3
R
CN R3
(1,4-Ad)
1
R
NH2
N
RF
Acknowledgements:
The authors thank, The Education and Research Department from Gobierno Vasco
(GV, Vitoria, IT-422-10) and the Dirección General de Investigación del Ministerio
de Ciencia y Tecnología (MICIN, Madrid DGI, CTQ2009-12156) for supporting
this work. G.F.T. thanks the University of the Basque Country for a formation
contract.
References:
[1] Müller, K.; Faeh, C.; Diederich, F. Science. 2007, 317, 1881-1886.
[2] Palacios, F.; Ochoa de Retana, A.M.; Oyarzabal, J.; Pascual, S.; Fernandez
de Troconiz, G. J. Org. Chem. 2008, 73, 4568-4574.
[3] Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal, J.; Pascual, S.; Fernandez de Troconiz G. and Ezpeleta J. Eur. J. Org. Chem. 2010, 34, 6618-6626.
99
PO 051 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF 10-METHYL-8,10DIAZABICYCLO[4.3.1]DECANE RING SYSTEM
Osvaldas Paliulisa, Dan Petersb, Wofgang Holzerc and Algirdas Šačkusa
a
Kaunas University of Technology, Institute of Synthetic Chemistry,
Radvilėnų pl. 19, LT-50254 Kaunas, Lithuania
b
DanPET AB, Rosenstigen 7, 216 19 Malmö, Sweden
c
Department of Drug and Natural Product Synthesis, Faculty of Life Sciences, University of Vienna
Althanstrasse 14, A-1090 Vienna, Austria
[email protected]
A convenient method for the synthesis of 10-methyl-8,10-diazabicyclo[4.3.1]
decane 6 as a new important synthetic organic chemistry scaffold was developed
using octanedioic acid as a starting material. The key transformation in the
5-step synthesis sequence involved a chemoselective reaction of dimethyl
2,7-dibromooctanoate 2 with methylamine, which resulted in the formation of cisdimethyl 1-methylazepan-2,7-dicarboxylate 3. The latter was further transformed
into bicyclic 8-benzyl-10-methyl-8,10-diazabicyclo[4.3.1]decane-7,9-dione 4
under heating with benzylamine. Reduction of the formed bicyclic dione with
LiAlH4 resulted in 8-benzyl-10-methyl-8,10-diazabicyclo[4.3.1]decane 5, and
hydrogenolysis efficiently yielded the target product.
OH
O
O
OH
1. SOCl2, 40 °C;
2. Br2, 90 °C, hν;
3. MeOH
1
OMe
S*
R*
OMe
Br
O
MeNH2, THF,
120 °C, 2 h
MeOOC
2 (84%)
1. BnNH2, xylene,
reflux, 72 h;
2. 205 °C, 24 h
O
LiAlH4, dioxane,
reflux, 20 h
Me
N
N
Bn
O
4 (42%)
100
Br
O
Me
N
H2, Pd/C, 50 bar,ethanol, Me
N
100 °C, 40 h
N
Bn
5 (68%)
NH
6 (79%)
N
Me
COOMe
3 (30 %)
Poster presentations / PO 052
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis of adamantyl-substituted
isoxazoles
Anastasia Panfilova, Oksana Bondarenko, Yurii Klimochkin, Nikolai Zyk
Department of Chemistry, Moscow State University, Moscow, 119991, Russia
[email protected]
Isoxazole derivatives are of interest as objects for pharmacology. They are active
principle of some drugs differ in their functions. On the other hand, the introduction
of lipophilic adamantyl radical to some molecules provides a significant increase
in the pharmacological activity of the compound. It seems promising to modify the
biological activity of isoxazoles with adamantyl radical.
A simple method for the synthesis of adamantyl-substituted 5-chloroisoxazoles has
been proposed via heterocyclization reaction of 1,1-dichlorocyclopropanes with
NOCl•2SO3 under nitrosation conditions affording a mixture of regioisomers and
their monochlorinated derivatives. The yield and the ratio of the products depend
on the reaction conditions.
Cl
N
NOCl * 2SO3 (2 eq)
CH2Cl2, 20 h
Cl
+
Cl
B
A
Cl
N
O
O
Cl
NOCl * 2SO3 (2 eq)
CH2Cl2, 3 d
A
+
B
N
N
O
O
+
+
Cl
Cl
Cl
In the case of 2-adamantyl-1,1-dichloro-3-methylcyclopropane only chlorination
of the adamantly fragment was observed obviously due to the steric hindrance.
This work was supported by the RFBR (pr. no. 11-03-00707-a) and the program of the Presidium of the
RAS ‘Development of Methods for Synthesizing Chemical Compounds and Creating New Materials’.
101
PO 053 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Selectivity in the crosscoupling reactions of 6-bromo7‑triflyloxychromoneS
Tamás Patonaya, Imran Malika,b, Krisztina Kónyaa, Peter Langerb
Department of Chemistry, University of Debrecen, H-4032 Debrecen, Hungary
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, D-18059 Rostock, Germany
a
b
[email protected]
In continuation of our work in the cross-coupling reactions of chromones
and flavone[1] we have investigated the Suzuki-Miyaura and/or Sonogashira
transformations of 6-bromo-7-triflyloxychromones.
C-arylation/alkynylation of 6-bromo-7-triflyloxychromone performed exclusively
in position 7 due to the electronic effect. This selectivity allowed the synthesis of
unsymmetrically substituted products. bis-Arylated or alkylated products have also
been prepared. These reactions allow the synthesis of various hitherto unknown
derivatives including compounds available from natural sources.
6-Bromo-8-methyl-7-triflyloxychromone was completely unreactive under these
conditions.
Ar
O
Br
O
TfO
O
Ar
Br
O
O
Ar1
Br
O
Ar
O
O
Ar
O
Ar
O
Ar
O
Ar
Ar
O
Ar1
O
O
References:
1.(a) Patonay, T.; Vasas, A.; Kiss-Szikszai, A.; Silva, A. M. S.; Cavaleiro, J. A.
S. Aust. J. Chem. 2010, 63, 1582. (b) Vasas, A.; Patonay, T.; Kónya, K.; Silva,
A. M. S.; Cavaleiro, J. A. S. Aust. J. Chem. 2011, 64, 647. (c) Fekete, Sz.;
Patonay, T.; Silva, A. M. S.; Cavaleiro, J. A. S. ARKIVOC 2012(v), 210. (d)
Patonay, T.; Pazurik, I.; Ábrahám, A. Aust. J. Chem. 2013, in press; (e) Hassan,
Z.; Patonay, T.; Langer, P. Synlett 2013, in press.
102
Poster presentations / PO 054
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF 2,6-DIAZA-BICYCLO[2.2.2]
OCTANE 3,5-DIONES
Jānis Pelšs, Raivis Žalubovskis
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia
[email protected]
Zinc containing enzymes (ZCE), such as histone deacetylase (HDAC) and
matrix metalloproteinases (MMP), play a major role in both cancer initiation and
progression. It has been shown that some of these enzymes can be inhibited by
cyclic amides as zinc-binding groups [1], therefore bicyclic diamides 2,6-diazabi­
cyclo[2.2.2]octane 3,5-diones could be used for ZCE inhibition. A simple one-pot
three-component method for synthesis of these compounds has been previously
reported [2], but the scope of this reaction hasn’t been investigated. 2,6-Diaza­bi­
cyclo[2.2.2]octane 3,5-diones are synthesized in a reaction between an aromatic
aldehyde 1, a ketone 2 and malonic diamide 3 in presence of base.
We have discovered, that assymetric methylketones, both aliphatic and aromatic,
could be used in a regioselective reaction to form only 1,8-disubstituted 2,6-di­aza­
bicyclo[2.2.2]octane 3,5-diones. Aromatic aldehydes with both electron donating
groups, as well as weak electron withdrawing groups, were successfully used,
however aldehydes with strong electron withdrawing substituents did not afford
the bicyclic product. We achieved yields up to 85% in the regioelective reactions.
O
R1
HN
Ar
R2
N
H
5
Ar
O
O
Ar
1
+
O
2
R2
R1
+
O
O
O
H2N
NH2
3
O
HN
R1
4
N
H
R2
References:
1. Mai A., Altucci L., Brosch G., et al. J. Med. Chem. 2006, 49, 6046.
2. Žalubovskis R., Kalme Z., Duburs G. Chem. Heterocycl. Compd. (Engl.
Ed.) 1998, 34, 503.
103
PO 055 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis of GABA derivatives from
chiral pool
Viktors Pozņaks, Māris Turks
Faculty of Material Science and Applied Chemistry, Riga Technical University, Azenes Str 14/24, Riga,
LV-1007, Latvia
[email protected]
We present an approach to synthesis of enantiomerically enriched 3-substituted
γ-aminobutyric acid derivatives. This class of compounds includes well-known
CNS drugs baclofen, phenibut and pregabalin.
baclof en: R = -C6H4-p-Cl
phenibut: R = Ph
H2N
pregabalin: R = i -Bu
R
.
ux
.a
ch
R
O
.
ux
.a
ch
OH
NH2
OH
O
O
O
The proposed key reaction is diastereoselective Michael addition on
α,β-unsaturated lactone 2 which contains sugar moiety as chiral auxiliary. The latter
is obtained in a three-step synthesis from diacetone-d-glucose 1, an inexpensive
and commercially available compound.
O
O
O
O
O
O
O
HO
O
O
NH3
O
O
O
R
O
O
OH
O
NH2
4
1. TFA
2. NaIO4
O
[RM]
O
O
R1
O
O
1
3a
O
O
R2
O
O
O
3a: R1 = alkyl, aryl; R2 = H
1
2
3b: R = H; R = alkyl, aryl
2
O
OH
PIFA
OH
R
R
H2N
O
O
5
H2N
6
Diastereoselectivity of the reaction 2 → 3a+3b and its optimization will be
discussed.
104
Poster presentations / PO 056
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF 1-(3-NITROPHENYL)5,6‑DIHYDRO-4H-[1,2,4]TRIAZOLO[4,3-a]-[1,5]
BENZODIAZEPINES
Vida Ragaleviciene, Lidija Kosychova, Antanas Karalius, Daiva Podeniene
Institute of Biochemistry, Vilnius University, Vilnius, LT-08662, Lithuania
[email protected]
Through the various molecules designed and synthesized in recent years, active
research has been initiated on heterocycles and the chemistry of 1,2,4-triazoles has
received considerable attention owing to their wide range of biological activities.
Benzodiazepines and their polycyclic derivatives also exhibit a broad spectrum
of useful properties. It was therefore of interest to prepare tricyclic 1,2,4-triazolo
derivatives as the combination of different pharmacophores frame which may lead
to compounds with interesting biological profiles.
H
N
S
N
R
N
R2
R1
1
S
N
R
N
R2
R1
N
R2
O
H
N N
H
R
NO2
R1
3
2
NO2
R = H, CH3
R1 = H, CH3
R2 = CH2C6H5. CONHC6H5
N
N
N
R
N
R2
R1
4
Thionation of the corresponding cyclic lactams with P2S5 afforded thiolactams
1. The alkylation of less reactive thioamides 1 led to the desired imidothioethers
2 which were converted to N’-(2,3-dihydro-1H-1,5-benzodiazepin-4-yl)-3nitrobenzohydrazide derivatives 3. The tricyclic 1-(3-nitrophenyl)-5,6-dihydro4H-[1,2,4]triazolo[4,3-a]benzodiazepines 4 were prepared by the thermal
cyclization of compounds 3. Compounds 4 were obtained in 65-81 % yield. The
IR, 1H, 13C NMR spectral data of new compounds correspond to their structure.
1. Upmanyu, N.; Kumar, S.; Kharya, M.-D.; Shah, K.; Mishra, P. Acta Poloniae
Pharmaceutica. Drug Research 2011, 68, 2, 213-221.
105
PO 057 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Stereoselective synthesis of
2-vinylserinol derivatives
Dace Rasina, Kristine Klimovica, Aigars Jirgensons
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia
[email protected]
2-Vinylserinol derivatives 1 are structural elements of a number of biologically
active natural products including isoleucyl tRNA synthetase inhibitor SB203207,
20S proteasome inhibitor omuralide, and sphingolipid mycestericin E.
O
O O
S
NH2
N
SB203207
O
O
H
NH
CO2H
O
NH
OH
O
Omuralide
OH
O
H
CONH2
OR
OR
R
OH
R
NH2
1
NH
O
HN
CCl3
O
1
1
OH OH
CCl3
2
Mycestericin E
cat. Lewis acid:
BF3.OEt2, FeCl3, Fe(OTf)3, 1
R
TMSOTf, AlCl3, Al(OTf)3
CO H
NH2 2
OR
O
N
3
CCl3
Herein we report novel stereoselective synthesis of protected 2-vinylserinols –
oxazolines 3 by Lewis acid catalyzed cyclization of chiral bis-trichloroacetimidates 2.
The best diastereoselectivity (d.r. 99:1) for oxazoline 3 formation was achieved
with O-TBS protected substrate (R1=iPr) and AlCl3 as a catalyst.
106
Poster presentations / PO 058
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
sugar based spirooxazolidinones
Evija Rolava, Vitalijs Rodins, Jevgeņija Lugiņina, Māris Turks
Faculty of Material Science and Applied Chemistry, Riga Technical University
14/24 Āzenes Str., Riga, LV-1007, Latvia
N-Acyl-oxazolidinones have found extensive applications in the asymmetric
synthesis as chiral auxiliaries. Present work describes an optimized protocol for
the synthesis of carbohydrate derived spirooxazolidinones (1).1 Commercially
available diacetone-d-glucose was chosen as a convenient starting material2 for
the preparation of spirooxazolidinones in seven steps with a combined yield of
36% on a 10 g scale. The method of N-acylation with acylchlorides for both types
of spirooxazolidinones was developed to study the diastereoselective alkylation
at α-position. To explore the scope and reactivity of the obtained compounds, a
small combinatorial library of novel N-alkyl-spirooxazolidinones derivatives was
generated with individual product yields reaching up to 88%.
O
O
O
RN
O
O
O
1a
O
O
O
O
RN
O
O
O
O
1b
Acknowledgements: The authors thank JSC Olainfarm for kind donation of
diacetone-d-glucose and for scholarship.
References:
1. Gasch, C.; Illangua, J. M.; Merino-Montiel, P.; Fuentes, J.Tetrahedron 2009,
65, 4149-4155.
2. Ostrovskis, P.; Mackeviča, J.; Kumpiņš, V.; López, O.; Turks, M. Large Scale
Synthesis
of
1,2:5,6-Di-O-isopropylidene-α-d-ribo-3-hexofuranose-3-ulose
by Oxidation of Diacetone-α-d-Glucose. In Carbohydrate Chemistry: Proven
Synthetic Methods; van der Marel, D., Codee, J., Eds.; 2013, Vol 2, in press.
107
PO 059 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF NEW FUNCTIONALIZED
PYRAZOL-5-ONE DERIVATIVES
Sergey V. Ruban, Sergey V. Baranin, Vladimir A. Dorokhov
N.D.Zelinsky Institute of Organic Chemistry Russian Academy of Sciences, 47 Leninsky prosp.,
Moscow 119991 Russian Federation
[email protected]
The derivatives of pyrazol-5-one exhibit various biological activities which in
fact depend on the nature of functional groups and its position in the molecule.
Here we present the synthetic route to diaminomethylidene derivatives of 1-aryl-3methylpyrazol-5-one based on the chelate assisted methodology developed in our
group [1].
O
O
Me
N
PhC(O)NHCN
N
Ar
NH
Ph
Me
O Ni(OAc)2, DMF, D
N
NH2
N
Ar
* 0.5Ni
O
NH
Ph
HCl, EtOH, D Me
N
NH2
N
Ar
O
1. MeONa, MeOH, D
2. AcOH
Me
N
H2N
N
Ar
NH2
O
Ar = Ph, 4-ClC6H4, 4-MeC6H4
Such an approach makes it possible to construct biheterocyclic systems connected
by C-C bond. Thus, compounds 1 were further used as N,N-dinucleophyles in the
heterocyclisation reactions, and the new corresponding pyrazolon-5 derivatives 2
and 3 with N-containing heterocyclic substituent in position 4 were obtained.
R1
Me
N
N
N
N OH
Ar
2
R2
R3
Me
H2N
N
N
Ar
1
OH
NH2
O
Me
N
N
N
Ph
Ph
N OH
Ar
3
Ar = Ph, 4-ClC6H4, 4-MeC6H4; R1 = Me, R2 = H, R3 = OH; R1 = H, R2 = CN, R3 = NH2.
Acknowledgements: This work was financially supported by the Russian Academy
of Sciences (Program for Basic Research of the Presidium of the Russian Academy
of Sciences “Development of a Methodology of Organic Synthesis and Creation of
Compounds with Valuable Applied Properties).
References:
1. Prezent, M. A.; Bogdanov, V. S.; Dorokhov, V. A. Russ. Chem. Bull., 1996, 45,
2671.
108
Poster presentations / PO 060
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis of Macrocyclic Systems
Derived from di-(2-indolyl)
heteroarenes
Ibrahim F. Sengul1, Naresh. Kumar 2, David. StC. Black.2
Department of chemistry, Osmaniye Korkut Ata University, 80000, Osmaniye, Turkey
Deparment of chemistry, The University of New South Wales, NSW 2052, Sydney, Australia
1
2
Indoles are an important class of heterocyclic compounds whose derivatives occur
widely as natural products in plants, fungi and marine organism. More complex
indoles, such as bis-indoles are very important biologically active scaffolds as they
are found in many pharmacologically active alkaloids. Bis-indole alkaloids are
heterocyclic compounds, which consist of two indoles connected to each other
via linking units. In our current synthetic study, a novel range of bis-indoles
2,2’-linked with heterocyclic units such as carbazole and dibenzofuran have
been prepared. Imine cyclic systems were subsequently produced from these
precursors via condensation of the corresponding of dialdehydes with various
diamines (Figure 1). In particular, the desired indole macrocyclic systems were
successfully produced from aliphatic diamino compounds such 1,4-diaminobutane
and 1,6-diaminohexane.
N
N
N
N
NH
HN
NH
HN
X
X
X= O, NH, NMe
Figure 1: Macrocyclic bis-indole systems
109
PO 061 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis of 2-ethynyl glycinols by
lewis acids catalyzed cyclization of
bistrichloroacetimidates
Jekaterina Sirotkina, Aigars Jirgensons
Latvian Institute of Organic Synthesis, Aizkraukles str. 21, LV-1006, Riga, Latvia
[email protected]
2-Ethynyl glycinol derivatives belong to the class of β-aminoalcohols which are
important building blocks for the synthesis of natural products and pharmaceuticals.
NH
OH
HO
1
CCl3CN
cat. DBU
R
O
Cl3C
O
NH
2
Cl3C
CCl3
R
cat. LA
O
N
3
H3O+
R
HO
NH2
4
R
R = Me, inversion of configuration
R = Ph, racemization
Herein we report novel method for the synthesis of ethynyl glycinols 4 from
butyne-1,2-diols 1. The synthetic route involves transformation of diol 1 to bistrichloroacetimidate 2 which undergoes cyclization in the presence of Lewis
acids to give oxazolines 3 as precursors of ethynyl glycinols 4. Cyclization of
bistrichloroacetimidates 2 is regioselective leading to 3 as major product. In the
case R = Me cyclization of 2 proceeds with complete inversion of configuration at
the chiral center suggesting SN2 mechanism of the reaction. In the case of R = Ph,
cyclization of 2 proceeds with racemization indicating SN1 mechanism in the case
of carbenium ion stabilizing substituent.
110
Poster presentations / PO 062
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
β-exomethylene δ–amino alcohols by
intramolecular amination of nonclassical cyclopropyl methyl cation
Marija Skvorcova, Liene Grigorjeva, Aigars Jirgensons
Latvian Institute of Organic Synthesis, Aizkraukles str. 21, LV-1006, Riga, Latvia
[email protected]
β-Exomethylene δ-amino alcohols 4 are multifunctional building blocks that can be
transformed to amino acids, γ-butyrolactams, pyrrolidine derivatives etc.
NH
Cl3C
NH
NH
O
CCl3
O
1
cat. LA
O
+
CH2
R
R
1) 6M HCl, EtOH, reflux
2) sat. NaHCO3, Boc2O,
EtOAc
R
HO
Cl3C
NHBoc
4
R = carbocation stabilizing group
HN
+
R
CCl3
2
O
N
R
Cl3C 3
yield up to 85%
Herein we present Lewis acid catalysed intramolecular amination of nonclassical cyclopropyl methyl cation as a novel, late transition metal-free route to
β-exomethylene δ-amino alcohols 4. We have demonstrated that bis-imidates 1 give
6-methylene oxazepines 3 in moderate to good yield, if R is carbocation stabilizing
group. In addition, we have shown that oxazepines 3 can be readily transformed to
N-protected β-exomethylene δ-amino alcohols 4.
111
PO 063 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis of New Type of Bicyclic
Nitrosoacetals by Formal
[3+3]-Cycloaddition of Nitronates with
cyclopropanes
Andrey Tabolin, Evgenia Gorbacheva, Roman Novikov, Yulia Nelyubina,
Sema Ioffe
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47,
Moscow 119991, Russian Federation
[email protected]
Cyclic nitronates 1 are well-known 1,3-dipoles in [3+2]-cycloaddition chemistry
and their reactions with olefins have been intensively investigated. Here we report
formal [3+3]-cycloaddition and the first synthesis of bicyclic nitrosoacetals 3,
possessing two annelated 6‑membered rings.
The transformation utilizes donor-acceptor cyclopropanes (DAC) 2 as 1,3-dipole
equivalents under Lewis acid (Yb(OTf)3, Sc(OTf)3) catalysis. For 3-unsubstituted
nitronates (R5 = H) good yields with good to excellent diastereoselectivity are
achieved, while 3-substituted (R5 = Me) ones failed to react. The conformational
preferability of adducts 3 is also discussed.
R1
R5
R2
R3
R4
O
1
N
O
E
E
+
R6
2
E = CO2Me
Yb(OTf )3, MS 4Å,
CH2Cl2, rt, 3 d
R1
R2
R3
R4
O
H
N
E E
O
R6
f or R5 = H;
61-92%,
dr = 2:1 - single isomer
3
Acknowledgements: The work was supported by RFBR (grant №12-03-00278).
References:
1. Ioffe, S. L. Nitrile oxides, nitrones, and nitronates in organic synthesis, 2nd ed.;
Feuer, H., Ed.; John Wiley & Sons: Hoboken, New Jersey, 2008, 541.
2. Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137.
3. Young, I. S.; Kerr, M. A. Angew. Chem. Int. Ed. 2003, 42, 3023.
112
Poster presentations / PO 064
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
dihydropyrrolo[1,2-b]PYRAZOLES WITH
POTENTiAL BIOLOGICAL ACTIVITY
Lukáš Tenora, Juraj Galeta and Milan Potáček
Department of Chemistry, Faculty of Science, Masaryk University,
Kotlářská 2, 611 37 Brno, Czech Republic.
[email protected]
Many compounds with dihydropyrrolo[1,2-b]pyrazole skeleton appeared as very
interesting for their biological activity. Beside alkaloid withasomnine, known
since 1966,[1] there are some recently published papers where compounds with this
skeleton act as inhibitors of TβR-I or p38 MAPK kinases.[2]
Herein, we report a synthesis of dihydropyrrolo[1,2-b]pyrazoles starting either
from g-butyrolactone or ethyl-4-chlorobutyrate. Our target compounds have
various substitution R on the pyrazole ring (phenyl, 4-pyridyl, 5-isochinolinyl, etc.)
and another amino or alkoxy substitution at the position 4 of the pyrrole ring.
O
EtO
N N
Cl
O
O
O
Cl
N N
Br
N N
Br
O
N N
´
NR
H
R
OH
R
N N
O
N
O
R
References:
1. Schröter, H.-B.; Neumann, D.; Katritzky, A. R. et al. Tetrahedron, 1966, 22,
2895.
2. (a) Sawyer, J. S.; Beight, D. W.; Britt, K. S. et al. Bioorg. Med. Chem. Lett. 2004,
14, 3581. (b) Li, H.; Wang, Y.; Campbell, R. M. et al. Bioorg. Med. Chem. Lett.
2004, 14, 3585.
113
PO 065 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
UNUSUAL FURAN RECYCLIZATION IN THE
INDOLE SYNTHESIS
Maxim Uchuskin,a Natalia Molodtsova, a Igor Trushkov,b Alexander Butina
Perm State University, Bukireva 15, Perm, 614990 Russian Federation; [email protected]
Laboratory of Chemical Synthesis, Federal Research Center of Pediatric Hematology, Oncology and
Immunology, Samora Mashel st. 1, Moscow, 117997 Russian Federation
a
b
Earlier, we reported an acid-catalyzed reaction of 2-(tosylamino)benzyl alcohols
with N-tosylfurfurylamine affording 2-(2-acylvinyl)indoles 1 [1]. Indoles are
formally formed through the oxidative furan ring opening despite the absence of
any oxidant. Effect of “oxidation” is achieved due to the elimination of tosylamine
under acidic conditions.
O
N
Ts
NH
Y
OH
3
Y
R
MeO
+
R
Ts
N
O
O
Ts
N
MeO
H+
O
H
N Ts
Ts
NH
H+
Y
Ts
NH
O
+
Y
O
2
O
NPht
R
H
N Ts
O
H+
R
-TsNH2
R
1
In this report, we present the results of our careful investigations of this reaction,
namely, the effect of the reaction conditions and the nature of the leaving
group on the recyclization process. In particular, we found that the reaction of
N-furfurylphthalimide with benzhydryl alcohols 3 produces indoles 2 via a
protolytic furan ring opening.
Acknowledgements: Financial support was provided by Russian Foundation for
Basic Research (grant 13-03-00463-a) and Ministry of Education of the Perm Krai.
References:
1. Butin, A. V., Smirnov, S. K. Tetrahedron Lett. 2005, 46, 8443–8445.
114
Poster presentations / PO 066
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Facile Synthesis of Triazoles and
Benzotriazole Deriva­tives Using
Nanoparticles of Organosilane-based
Nitrite Ionic Liquid Immobilized on
Silica dicationic Nitrite Ionic Liquids
Hassan Valizadeh, Hamid Gholipour
Department of Chemistry, Faculty of Sciences, Azarbaijan Shahid Madani University, Tabriz, Iran.
[email protected]
Nanoparticles of organosilane-based nitrite ionic liquid immobilized on silica,
1-butyl-3-methylimidazolium
nitrite
and
1-(3-Trimethoxysilyl­propyl)-3methylimidazolium nitrite, were used as effective reagents for the preparation of
benzotriazole derivatives from the 1,2-diaminobenzenes at room temperature under
mild solvent-free conditions. 1,5-Bis(3-methyl­imidazolium-1-yl)pentane nitrite
and azide was used as dicationic task-specific ionic liquid (DTSIL) for the efficient,
fast, straightforward and one-pot synthesis of 1,2,3-triazoles under mild conditions.
115
PO 067 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Enaminones boron chelates in
the synthesis of N-containing
heterocycles
Leonid S. Vasil`ev, Sergey V. Baranin, Vladimir A. Dorokhov
N.D.Zelinsky Institute of Organic Chemistry Russian Academy of Sciences, 47 Leninsky prosp.,
Moscow 119991 Russian Federation
[email protected]
Enaminones (1) easy form stable in air and under heating diphenyl boron
complexes 2 and 3. The latter were used for the synthesis of new CF3-containing
heterocyclic compounds: 4-amino(4-hydroxy)pyridines and 1,6-naphtyridin-4ones. Interaction of 2 with primary amines results in yield 4-amino(alkylamino)-3trifluoroacetimidoylpent-3-en-2-one – new building blocks for the construction of
N-containing heterocycles. Several ones, synthesized on the base of chelates 2 and
3, are presented on the scheme.
F3C
NH2
H
N
F3C
a
O
Y
O
Y
1
Me
c,d
b
OH
F3C
Y
CF3
CF3
Ac
Me
R
N
N
Y
c
CF3
NH
=H
c
Me2NHC=HC
N
CF3
O
Me
CF3
N
N
Me
f
N
Me F3C
CF3
N
N
N
N
4 (R = H)
e, f (R = H)
N
4 R
CF3
Ac
N
N
NHR
Y g
Me 3
Me
c
NHR
c, d
BPh2
NR
Me 2
Ac
N
H
N
F3C
b
BPh2
h
D
N
R`
N
N
H
Regents and conditions: a: Ph2BOBu; b: RNH2; c: Me2NCH(OMe)2; d: BuOH; e: CH(OEt)3; f: NH3 / MeOH; g: MeONa / MeOH; h:
H2O, ROH, RNH2, NH2NH2
Y = H, Ac, CO2Me, COPh
R = H, Alk, PhCH2,
O
CH2 , S
CH2
R` = OH, OAlk, NHAlk, NHNH2
References:
1. Vasil`ev, L.S.; Baranin, S.V., Ignatenko, A.V., Nelyubina, Yu.V., Dorokhov, V.A.
Russ. Chem. Bull., 2010, 59, 1403.
116
Poster presentations / PO 068
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
The bromination of 4-phenyl2‑pyrrolidone derivatives
N. Orlova, M. Vorona, J. Kuznecovs, E. Liepinsh, S. Belyakov, A. Mishnev,
G. Veinberg
Latvian Institute of Organic Synthesis, 21 Aizkraukles Street, Riga, LV1006, Latvia
[email protected]
During past decade there was observed steady interest in the structure activity
relationship (SAR) investigations aimed at the search of new agents for the
treatment of central nervous system (CNS) disorders: impairment of cognition/
memory, epilepsy and seizure, neurodegenerative diseases, stroke/ischaemia,
stress and anxiety. At present the key role in their treatment belong to drugs sharing
pyrrolidin-2-one pharmacophore 1a-d. That is why in the frame of synthetic studies
aimed at the targeted preparation of new biologically active pyrrolidin-2-one
derivatives by regioselective formation of new C-C bonds we have developed new
methodology for the insertion of bromine in various derivatives of this heterocycle.
R
X
Ar
O
1
R
NR
1a-d
a) R = CH2CONH2; X = H Piracetam
b) R = CH(Et)CONH2; X = H Levetiracetam
c) R = CH2CONH2; X = OH Oxiracetam
d) R = CH2CONH2; X = C6H5 Phenotropil
O
NAc
-HBr
O
Ar
R2
2a-e
Br
Ar
O
1
R
NAc
R2
3a-e
R
R
Ar
R
NBS
AIBN or hν
NAc
H
4a-c
Br
O
NAc
Br
5a,c
Ar
O
NAc
Br
Br
6d
a) Ar=Ph, R=R1=R2=H; b) Ar=Ph, R=CO2Et, R1=R2=H;
c) Ar=4-ClC6H4, R=R1=R2=H;
d) Ar=Ph, R=R2=H, R1=Me; e) Ar=Ph, R=H, R1=R2=Me
It was unexpectedly found that 1-acetyl-4-phenylpyrrolidin-2-on 2a and its
variosly substituted derivatives 2b-e could be easily converted into appropriate
1-acetyl-penyl-pyrrolin-2-ones 3a-e by radical bromination using NBS in the
presence of AIBN catalyst or UV-irradiation, which was accompanied by the
spontaneous dehidrobromination of unstable halogenated intermediate. In the case
of the excess of brominating agent there was observed allylic bromination in the
position 5 of pyrrolin-2-ones 3a-d with the formation of 5-brom and 5,5-dibrom
substituted heterocycles 4a-d and 5a,c. Specifically dibrominated compound 6d,
which structure was confirmed by X-ray analysis, was isolated after analogous
treatment of 3d with the excess of brominated agent.
117
PO 069 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF PYRROLOPYRIMIDINE
DERIVATIVE
Anatoly Velikorodov, Olga Titova, Nagezhda Stepkina
Department of Organic & Pharm. Chemistry, Astrakhan State University, Astrakhan, 414000, Russia
[email protected]
We earlier investigate interaction of methyl N-{4(3)-[2-(2-oxo-1,2-dihydro-3Нindol-3-ylidene)acetyl]phenyl}carbamates with ethyl-3-aminocrotonate upon
heating in mixture of toluene - ethanol, 2:1 resulting to formation of 3-pyrrol-3′yloxindoles with carbamate function [1]. It is found, that heating of chalcone (I) and
6-amino-2-(methylthio)pyrimidin-4(3H)-one (II) in [bmim]Br during 1 h results in
formation of methyl N-{4-[2-(methylsulfanyl)-4-oxo-5-(2-oxo-2,3-dihydro-1Нindol-3-yl)-4,7-dihydro-3Н-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl} carbamate (III)
in 69% yield.
O
NHCO 2Me
MeS
O
MeS
HN
N
NH 2
II
N
H
O
[bmim]Br, D
NHCO2Me
H
N
N
HN
O
O
N
H
I
III
The structure of compound (III) has been confirmed by IR, H, C NMR spectra.
Acknowledgements:
The authors thank the professor of Voronezh State University Kh.S. Shikhaliev,
who provided sample of enamine for research.
1
13
References:
1. Velikorodov, A.V.; Kuanchalieva, A. K.; Ionova, V.A. Russ. J. Org. Chem. 2011,
47, 1715.
118
Poster presentations / PO 070
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
THE PREPARATION AND BIOLOGICAL
INVESTIGATION OF STEREOISOMERIC
2-(5-METHYL-4-PHENYL-2-OXO­PYRROLIDIN-1YL)-ACETAMIDES
M. Vorona, N. Orlova, J. Kuznecovs, G. Veinberg, E. Vavers, L. Zvejniece,
M. Dambrova
Department of Chemistry, Riga Technical University, Riga, LV-1001, Latvia
[email protected]
Individual enantiomers of 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide
5a-d were synthesized using following chemical scheme. Diastereoisomeric
mixtures of diethyl (1R)- and (1S)-2-(2-nitro-1-phenylpropyl)-malonates 1a,b
were prepared by asymmetric Michael addition of diethyl malonate to 2-nitro­prop1-enylbenzene in the presence of (3aR,3'aR,8aS,8'aS)-2,2'-cyclopropyli­de­nebis[3a,8a]-dihydro-8H-indeno-[1,2-d]-oxazole or its optical antipode.
Me
NO2
Me
COOEt
R 1
R
R
NO2
R1
COOMe
chromatographic
separation
COOEt
2a,b
1a,b
a R=Ph, R1=H; b R=H, R1=Ph
R2
R3
R
NO2
COOMe
R1
3a-d
R1
R
R2
N
R3 H
4a-d
O
R1
R
R2
N
O
R3
CONH2
5a-d
a R=Ph, R1=H, R2=Me, R3=H; b R=Ph, R1=H, R2=H, R3=Me;
c R=H, R1=Ph, R2=H, R3=Me; d R=H, R1=Ph, R2=Me, R3=H
Obtained compounds were converted into methyl (3R)- and (3S)-4-nitro-3‑pheny­
lpentanoates 2a,b and separated by chromatography on silica gel, affording four
erythro- and threo isomers 3a-d. Each enantiomer was transformed into individual
5-methyl-4-phenylpyrrolidin-2-one 4a-d by reductive cyclisation and afterward
into target compound 5a-d by the attachment of the acetamide group to the
heterocyclic nitrogen in 4a-d.
119
PO 071 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF TRIAZOLYL DERIVA­TIVES OF
2-SULFONAMIDO THIOPHENE
Agnese Sprūdža, Igor Vozny, Aiga Grandāne, Raivis Žalubovskis
Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006, Latvia
[email protected]
Zinc-containing enzymes Carbonic anhydrases (CA) are playing an important role
in metabolic processes of bicarbonate and carbon dioxide. Presently are known 16
α-CA isoforms with various physiological functions. Among inhibitors of CA drugs
with clinical applications as diuretics, antiglaucoma, antiobesity and antitumor are
found.1 Acetazolamide (AAZ), a common antiglaucoma drug and CA inhibitor,
contains [1,3,4]thiadiazole scaffold. Driven by medicinal chemistry needs we were
interested to replace thiadiazole ring with thiophene to obtain structures 3.
Here we report synthesis of thiophene-2-sulfonamide triazolyl derivatives 3. Since
bromide 1 with free sulfonamide group did not participate in Sonogashira reaction,
we have developed synthetic pathway where as a core intermediate role plays
protected sulfonamide 2. In subsequent Sonogashira and click-reactions desired
compounds 3 were synthesized.
Br
S
1
O
S NH
2
O
Br
S
2
O
S N
O
N
N
N
N
R
S
O
S NH
2
O
3
Acknowledgements: This project was financed by European Social Fund
(No. 2009/0203/1DP/1.1.1.2.0/09/APIA/VIAA/023).
1. Alterio, V.; Di Fiore, A.; D’Ambrosio, K.; Supuran, C. T.; De Simone, G.
Chem. Rev. 2012, 112, 4421–4468.
120
Poster presentations / PO 072
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF PYRROLO[1,2-α]- QUINAZOLINE
DERIVATIVES
Daina Zicane, Zenta Tetere, Irisa Ravina, Maris Turks
Faculty of Material Sciences and Applied Chemistry, Riga Technical University,
Riga, LV-1007, Latvia
[email protected]
Fused quinazoline derivatives such as pyrrolo[1,2-a]quinazolinones can be found
both in natural and in synthetic pharmaceutically active substances.
One approach to the pyrrolo[1,2-a]quinazolinone synthesis is reactions of
aminobenzoic acid (anthranilic acid) amides with a-ketoacids.
We present here anthranilic acid hydrazides (3a-j) prepared from isatoic anhydride
(1) and aromatic (2a-e) or cyclohexene dicarboxylic acid hydrazides (2f-j) that are
useful instead of amides.
O
O
O
1
N
H
O
O
+
R
N
H
NH2
N
H
NH2
O
H
N
R
O
O
COOH
4, 5
R
H
N
N
R2 O
N
6, 7 O
3
2
R2
R1
2, 3, 6, 7 R= a)
; b)
; c)
HO
Br
R1= f) H; g) F; h) Cl; i) Br; j) NO2
; d)
N
; e)
N ; f-j
CH3
4, 6 R2= COOH; 5, 7 R2= CH3
121
PO 073 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
New selenium substituted imidazolyl
imines and their complexes with
copper(II)
Nikolai Zyk, Elena Beloglazkina, Alexander Majouga, Roman Antipin, Anna
Moiseeva, Kseniya Myannik
Department of Chemistry, Moscow State University, Moscow, 119991, Russia
[email protected]
High biological activity made selenium-containing organic compounds an
attractive class of ligands for studying of coordination properties in the reactions
with transition metals. Such complexes can be used as cytostatic agents [1]. In
view of the recent increased interest in effects of selenium rapid expansion of our
understanding of the roles of this trace element in biology can be expected [2]. We
have obtained the novel selenium containing organic ligands N-(ω-phenylseleno)
ethyl)-N-(imidazolylmethylene)amines, and their complexes with copper(II)
chloride:
R
( )n
CHO
N
N
+
H2N
( )n
EtOH
SePh
CHO
R
NH
N
+
H2N
( )n
SePh
R = H, CH3
L
3-10
.
+ CuCl2 2H2O
R
t oC
EtOH
t oC
n = 1,2
EtOH/CH2Cl2
N
NH
LCuCl2
11-26
References:
1. G. Mugesh et al., Chem.Rev. 2001, 101, 2125.
2. T. C. Stadtman, J. Biol. Chem. 1991, 266, 16257.
SePh
N
N
R
The X-ray analysis of copper complex with
2-(phenylseleno)ethyl)-N-(imidazol-4-ylmethylene)
amine revealed that the copper(II) ion assumes a
tetracoordinated square–planar geometry with an
N2Cl2 donor set. Cyclic voltammetry experiments
showed a quasi-reversible behavior of the CuII/CuI
redox couple.
122
N
N
( )n
SePh
Poster presentations / PO 074
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
[(4Z)-2-tioxo-4-[(pyridine-2-yl)methylene]-1-(2-azidoethyl)-imidazol5(4H)-ohe and its copper complex
Nikolai Zyk, Elena Beloglazkina, Alexander Majouga, Olga Krasnovskaya,
Vasiliy Gerasimov
Department of Chemistry, Moscow State University, Moscow, 119991, Russia
[email protected]
In this work, 2-thiohydantoins containing 2-azidosubstituted alkyl fragment, was
synthesized by the three-step reaction sequence shown below. The treatment of
the ligand 3 with copper(II) chloride dihydrate led to the formation of a binuclear
copper complex with a [Cu+1.5Cu+1.5] redox states:
S
H3N
Cl
Cl
1) NaN3, H2O
2) NaOH
N3
H2N
EtOOC
NCS
EtO
Et2O
O
1, 93%
1) KOH, EtOH
2) 2-Py-CHO
3) HCl
O
NH
2, 61%
N3
N3
N
N3
N
H
N
H
S
.
CuCl2 2H2O
CH2Cl2/MeOH
N
3, 57%
O
N
S
Cl
Cu
N
N
N
Cu
S
4, 50%
N
N
O
N3
The copper complex 4 was characterized
by X-Ray analysis. Both copper atoms of
the binuclear cluster have almost equivalent
metal coordination geometries and are located
in a tetrahedral environment (disregarding the
neighboring Cu atom) bound by one bridging
chlorine atom. Apparently, methanol acts as
a reducing agent in the process of complex 4
formation.
123
PO 075 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis and biological activity of
1,5-naphthyridines
Concepción Alonso, María Fuertes, María González, Gloria Rubiales,
Francisco Palacios*
Department of Organic Chemistry I, University of Basque Country (UPV/EHU), Paseo de la
Universidad nº 7, 01006 Vitoria-Gasteiz, Spain.
[email protected]
Nitrogen-containing heterocycles are important compounds widely employed in
the fields of biochemistry, pharmaceuticals, and materials science.1 Consequently,
reactions, including hetero-Diels-Alder reactions of azadienes have attracted special
interest because of its utility on the synthesis of nitrogen containing heterocycles,
both chemo- and stereoselectively.
Recently, we have reported the synthesis of nitrogen-containing heterocyclic
compounds, as 1,5-naphthyridines, in a regio- and stereoselective way by a cyclo­
addition reaction (see Scheme).2 Several different derivatives have been obtained
by this strategy modulating both aldehyde and dienophile nature. Moreover,
in some cases, oxidation of methylene groups of polycyclic compounds 4 has
yielded corresponding carbonyl derivatives 5. Biological activity of all obtained
heterocyclic compounds has been studied in order to inhibit COLON cancer cells
proliferation as inhibitors of Topoisomerase I. The docking studies have also
indicated the intercalation of these heterocycles in the TOP I/ADN complex.
Scheme
Acknowledgements: Financial support from the UPV/EHU (UPV, UFI-QOSYC
11/12), GV/EJ (IT-422–10) and the Spanish MICINN (Madrid DGI, CTQ200912156) is gratefully acknowledged. M. G. thanks Basque Government for a
formation contract. UPV/EHU-SGIker technical support (MICINN, GV/EJ,
European Social Fund) is gratefully acknowledged.
References:
1. a) Schreiber, S. L. Science 2000, 287, 1964. b) Teague, S. J.; Davis, A. M.;
Leeson, P. D.; Oprea, T. Angew. Chem., Int. Ed. 1999, 38, 3743.
2. Palacios, F.; Alonso, C.; Arrieta, A.; Cossío, F. P.; Ezpeleta, J. M.; Fuertes, M.;
Rubiales, G. Eur. J. Org. Chem. 2010, 2091.
124
Poster presentations / PO 076
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
PYRROLO[2,3-a]CARBAZOLES AS PIM
KINASE INHIBITORS
Fabrice Anizon, Francis Giraud, Rufine Akué-Gédu, Lionel Nauton, Vincent
Théry, Pascale Moreau.
CNRS, UMR 6296, ICCF, Clermont Université, Université Blaise Pascal, BP 80026, 63171 Aubière,
France
[email protected]
The Pim family of protein kinases is composed of three isoforms (Pim-1, Pim-2 and
Pim-3) involved in survival pathways in cancer cells. These recent findings gave
rise to a growing interest in the development of Pim kinase inhibitors as antitumor
agents. We recently reported pyrrolo[2,3-a]carbazole-3-carbaldehydes, such as
compound 1, as potent Pim inhibitors.1 As part of our ongoing studies aiming at
developing new inhibitors of these kinases, we carried on our structure-activity
relationship studies by the synthesis of novel substituted pyrrolo[2,3-a]­carbazoles.2
The synthesis of these new analogues will be presented, as well as their evaluation
toward Pim kinases. Molecular modeling studies identifying interactions between
newly synthesized compounds and their biological target will also be discussed.
References:
1) (a) Akué-Gédu, R.; Rossignol, E.; Azzaro, S.; Knapp, S.; Filippakopoulos, P.;
Bullock, A.N.; Bain, J.; Cohen, P.; Prudhomme, M.; Anizon, F.; Moreau, P. J. Med.
Chem. 2009, 52, 6369–6381, (b) Akué-Gédu, R.; Nauton, L.; Théry, V.; Bain, J.;
Cohen, P.; Anizon, F.; Moreau, P. Bioorg. Med. Chem. 2010, 18, 6865–6873, (c)
Akué-Gédu, R.; Letribot, B.; Saugues, E.; Debiton, E.; Anizon, F.; Moreau, P.
Bioorg. Med. Chem. Lett. 2012, 22, 3807–3809
2) Giraud, F.; Akué-Gédu, R.; Nauton, L.; Candelon, N.; Debiton, E.; Théry, V.;
Anizon, F.; Moreau P. Eur. J. Med Chem. 2012, 56, 225–236
125
PO 077 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Microwave-Assisted Synthesis of Pyridines, Pyrazoles,
Pterins and the P38 MAPK Inhibitor RO3201195
Mohammed A. Baashen, Mark C. Bagley
Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, East
Sussex, BN1 9QJ, UK
[email protected]
The Bohlman–Rahtz synthesis of various substituted pyridines has been modified
to be simple, involves mild conditions and high yielding. We have shown
that substituted pyridines could be synthesis efficiently and high yields under
microwave condition for a relatively short reaction time. The process was also
successful for the production of a range of fused heterocycles containing pyridine
moiety in high yields (e.g. pyrido[2,3-d]pyrimidin-4(3H)-ones and pyrido[2,3-d]
pyrimidine-2,4(1H,3H)-diones) (Structure 1).
The synthesis of chemotherapeutic agent RO3201195, has been investigated in a
highly selective inhibitor of P38α, in seven steps under microwave conditions. The
procedure provides high yield of the desired product and all other intermediate
involved in all steps compared with conventional heat methods (Structure 2).
R1
O
HN
H 2N
N
NH 2
O
R2
R1
N
N
HN
AcOH
+
O
30 min, 120 °C
H 2N
R2
R 1 = H, Ph
R 2 = Me, Ph
Structure 1
O
NHNH3 Cl
O
CN
+
NHPh
F
Structure 2
126
OMe
EtOH, Et 3N
microwaves
MeO
H 2N
N
140 °C, 60 min
(86%)
F
N
RO3201195
Poster presentations / PO 078
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
1,4-dihydropyridines possessing antiviral efficacy
Gunars Duburs, Egils Bisenieks, Ilze Jansone, Brigita Vigante,
Janis Poikans, Imanta Bruvere, Imants Bisenieks, Ilmars Stonans
Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia
JSC Grindeks, Riga, LV-1057, Latvia
[email protected]
Most of the anti-viral compounds known in the art are nucleoside derivatives.
In turn, 1,4-dihydropyridines (1,4-DHP) are well known as a class of calcium
channel blockers, but there are only few patent data on the anti-viral action of
1,4‑DHP related compounds. Recently we have found that disodium 2,6-dimethyl1,4-dihydropyridine-3,5-bis-carbonyloxyacetate (carbatone) possesses anti-herpes
activity [1]. In this report the results of the study of anti-viral activities of new type
of water-soluble 1,4-DHP – analogues of carbatone – are presented.
O
NaO
O
O
O
ONa
O
N
H
O
Carbatone
R
O
2
R
O
1
O
O
R
3
N
H
All the synthesized 1,4-DHP were evaluated in in vitro experiments as potential
anti-viral compounds using virus infected mammalian cell lines. The research was
performed with various groups of viruses – group V: (-)ssRNA viruses (influenza
A(H3N2) virus), group IV: (+)ssRNA viruses (Dengue virus type 2) and group
I: dsDNA viruses (HSV2). These investigations have confirmed the anti-herpes
activity of carbatone and have revealed several perspective lead compounds
possessing remarkable activity concerning influenza A(H3N2) virus.
Acknowledgement:
The study was partially supported by the State Research Programme “Biomedicine”
References:
1. Bisenieks, E., Chapenko, S., Kozireva, A., Murovska, M., Duburs, G., Tirzitis,
G., Uldrikis, J. 6th International Conference on HHV-6 & 7, June 19-22, 2008,
Baltimore, Marylend, USA. Program Book. 2008, 71.
127
PO 079 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis and bioactivity of
1,2-dihydroxyindolizidines
Franca M. Cordero, Bhushan B. Khairnar, Carolina Vurchio, Alberto Brandi
Department of Chemistry“Ugo Schiff”, Università di Firenze, 50019 Sesto Fiorentino (FI), ITALY.
[email protected]
H
HO
OH
N
HO
OH
(+)-lentiginosine
natural iminosugar
amyloglucosidase inhibitor
Hsp90 inhibitor
H
N
(-)-lentiginosine
non-natural
proapoptotic agent
(+)-Lentiginosine, a hydroxyindo­lizi­
dine alkaloid found in the leaves of Astragalus lentiginosus, is a selective inhibitor
of amylogluco­sidases and a potent inhibitor of Heat shock protein 90 (Hsp90) a
therapeutic target for some diseases including cancer.1
Non-natural (–)-lentiginosine is a caspase-dependent apoptosis inducer on different
strains of human cancer cells, but with very low cytotoxicity.2
The interesting biological profile of lentiginosine in both its enantiomeric forms
encourages the collection of variously functionalised derivatives to modulate
bioactivity and study the interaction of 1,2-dihydroxyindolizidines with
bioreceptors.
X
H OH
Y
1
7
5
N
X
OH
H OH
N
H OH
OH
N
OH
In this communication,
some aspects of the stereoselective synthesis of 7-substituted and benzo-fused
lentiginosine derivatives such as 1-3 and the effect of the structural modifications
on bioactivity will be presented.
1
2
3
1. Dal Piaz, F.; Vassallo, A.; Chini, M. G.; Cordero, F. M.; Cardona, F.; Pisano, C.; Bifulco, G.; De
Tommasi, N.; Brandi, A. PLoS One 2012, 7, e43316.
2. Macchi, B.; Minutolo, A.; Grelli, S.; Cardona, F.; Cordero, F. M.; Mastino, A.; Brandi A. Glycobiology
2010, 20, 500.
128
Poster presentations / PO 080
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS AND ANTICANCER ACTIVITY OF
3-(2,4-DICHLOROPHENOXYMETHYL)-6-ARYL-7Н-[1,2,4]
TRIAZOLO[3,4-B][1,3,4]THIADIAZINES DERIVATIVES
Demchenko D.A., Yanchenko V.A., Grynevych A.I.
State Centre of Innovation Biotechnologies. 30 Donetska str., Kyiv, Ukraine
[email protected]
It is known that condensed 4-aminotriazoles exhibit a wide spectrum of
biological activity. A range of 7Н-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 4 was
obtained in high overall yields.
O
Cl
O
O
OEt
NH2NH2
Cl
O
CS2 KOH
NH2NH2
Cl
Cl
NHNH2
ArCOCH2Br
2
N
S
N
N
3
N
O
Cl
SH
N
NH2
Cl
Cl
1
N N
O
R
4
Cl
R = F, OMe, OCHF2
Anticancer activity for these compounds was studied at the United States
National Cancer Institute (NCI, Bethesda, Maryland, USA). Results obtained show
that these compounds are promising for creating of a new drug for the treatment of
melanoma on their basis. It was found that anticancer properties of compounds 4
increase with increasing of electron-donor properties of the substituent in the para
position. Thus, compound 4 (R = F) inhibits the development of melanoma cells
LOX IMVI to 36.73% better than 5-fluorouracil, 4 (R = OCHF2) - to 80.29%, and
4 (R = OCH3) - to 90.79%, respectively. This trend is observed in all 8 varieties of
cancerous melanoma cells.
129
PO 081 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis of New 2-Benzazepino­
naphthalene Derivatives
via 1,7‑Electrocyclisation
T. Novák, Z. Mucsi, B. Balázs, L. Keresztély, G. Blaskó, M. Nyerges
Servier Research Institute of Medicinal Chemistry, H-1031 Budapest Záhony u. 7, Hungary
[email protected]
For many years 1,3-dipoles have been used extensively for the construction of fivemembered heterocyclic rings via their cycloadditions with suitable dipolarophiles
and by the 1,5-electrocyclization reactions of a,β-unsaturated 1,3-dipoles. More
recently, the electrocyclization of diene-conjugated 1,3-dipolar intermediates has
provided a powerful general synthetic route to seven-membered heterocyclic ring
systems. As a continuation of these studies our aim was to show the generality of
these methods as useful tools for the annelation of benzazepine ring to different
napthtaline derivatives in a single step.1 In this communication we describe the
synthesis of some unknown 2-benzazepino[4,5-a]naphthalene derivatives (1, 2, 3
and 4) via 1,7-electrocyclization of nonstabilized azomethine ylides. The starting
material 3,4-dihydro-aryl-napthtalenes derivatives 5 were prepared in two steps
starting from the corresponding a-tetralone 6, through intermediate 7 and 8. Our
studies applied the generation of non-stabilised azomethine ylides from various
amimo acids 9 and 10 by the decarboxylation method.1 In some cases, surprisingly,
pyrrole derivs. were isolated. A mechanism for the formation of the pyrrole 11
byproduct is proposed.
R
CH2O
Ph
H
N
CO2H
N CH2Ph
9
R
R
MeO
O
1
Br
CHO
PBr3/DMF
MeO
MeO
7
6
CHO
B(OH)2
Pd cat.
HO2C
5
R = OMe
R = CO2Me
CO2Me
R
CH2O
MeO
NH
NH
H
10
MeO
2
Pd cat.
MeO2C
CO2Me
CH2O
NH
HO2C
MeO
3
MeO2C
H
NH
10
N Me
CHO
MeO
MeO
8
R
N
MeO2C
+
MeO
4
11
References:
1
Novak, Tibor; Mucsi, Zoltan; Balazs, Barbara; Keresztely, Laszlo; Blasko, Gabor;
Nyerges, Miklos Synlett 2010, 16, 2411-2414.
130
Poster presentations / PO 082
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
synthesis of glycosylated porphyrinoligothiophene conjugates
Katriann Arja, Mathias Elgland, Peter Konradsson, Peter Nilsson
Department of Physics, Chemistry and Biology, Linköping University, SE-581 83 Linköping, Sweden.
[email protected], [email protected]
Porphyrins and porphyrin-based compounds are of great interest in a vast variety of
scientific areas due to their unique photophysical and biochemical properties. We
have recently reported a porphyrin-oligothiophene conjugate that selectively binds
to amyloid fibrils associated with Alzheimer’s disease which shows enhanced
fluorescent properties as compared to the previously used probes.1 A prerequisite
to use these conjugates for intracellular applications, e.g., real time imaging and
photodynamic therapy, is that the cellular uptake of the conjugates is adequate.
Glycosylation offers the means to meet this requirement.2 We herein present the
synthesis of novel glycosylated porphyrin-oligothiophene conjugates for the
improved water-solubility and cellular uptake.
References:
Arja, Sjölander et al. In Press. Macromolecular Rapid Communications
2
Hirohara et al. Bioconjug. Chem. 2012, 23 (9), 1881-1890
1
131
PO 083 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
NITROGEN HETEROCYCLES CONTAINING
1,2-BENZOXATHIINE 2,2-DIOXIDES
Aiga Grandāne, Raivis Žalubovskis
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia
[email protected]
Carbonic anhydrases (CA) are zinc containing enzymes which catalyze reversible
hydration and transport of carbon dioxide and provide pH regulation in cells.
In a search for new inhibitors of tumor associated CA IX, good inhibitory activities
were demonstrated for coumarin derivatives [1, 2]. Therefore we were interested in
synthesis of derivatives of 1,2-benzoxathiine 2,2-dioxide (2) which is consider to
be the bioisostere of coumarin (1) and potential CA IX inhibitor.
O
O
1
O
S
O
O
2
After a primary CA inhibition screening of several previously synthesized
1,2‑benzoxathiine 2,2-dioxides it was observed, that higher selectivity towards CA
IX exhibit 6-substituted 1,2‑benzoxathiine 2,2-dioxides. Therefore it was of our
interest to develop synthesis of 6-substituted 1,2-benzoxathiine 2,2-dioxides 3 and
4 containing triazole and tetrazole cycles.
N N
N
R
O
3
S O
O
N N
N
N
R
O
S
O
O
4
Acknowledgements: This project was financed by European Social Fund
(No. 2009/0203/1DP/1.1.1.2.0/09/APIA/VIAA/023)
References:
1. Maresca, A.; Temperini, C.; Vu, H.; Pham, N. B.; Poulsen, S. A.; Scozzafava,
A.; Quinn, J.; Supuran, C. T. J. Am. Chem. Soc. 2009, 131, 3057–3062.
2. Maresca, A.; Temperini, C.; Pochet, L.; Masereel, B.; Scozzafava, A.;
Supuran, C. T. J. Med. Chem. 2010, 53, 335–344.
132
Poster presentations / PO 084
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
2-THIENYLAMINOPROPYLGERMA-CYCLES
Luba Ignatovich, Velta Muravenko, Ilze Sleiksha, Irina Shestakova
Latvian Institute of Organic Synthesis, 21 Aizkraukles, Riga LV 1006, Latvia
e-mail: [email protected]
Highly cytotoxic amino derivatives of 2-thienylgermacyclanes (LC50 1-6 mg/ml)
have been prepared by hydrogermylation reaction of heterocyclic N-allylamines
with corresponding hydrogermane in the presence of platinum catalysts. The effects
of the amines and the germacycle were examined to establish structure-activity
relationships. The starting 2-thienylhydrogermanes 3 have been synthesized
from the 2-bromothiophene by two consecutive Grignard syntheses followed by
conversion of bromo derivatives 1 into ethoxy derivatives 2 by alcoholysis and
subsequent reduction by LiAlH4 under phase transfer catalysis conditions. Next,
Pt-catalyzed hydrogermylation of different allylamines with hydrogermanes 3
allowed for efficient preparation of a series of 2-thienyl-aminopropylgermacycles:
EtO
Br
S
Br
a)
S
GeCl3
b)
S
1
c)
Ge
S
(CH2) n
R = NEt2,
-N
Ge
(CH2) n
2
, -N
, -N
O , -N
R
H
d)
S
e)
Ge
3
(CH2) n
S
Ge
(CH2) n
4
NMe ; n = 0, 1
a) Mg/Et2O/GeCl4, b) BrMg(CH2)5-nMgBr/Et2O/THF, c) EtOH/Et3N/hexane, d) LiAlH4/18-crown-6/hexane, e)
R
/H2PtCl6.6H2O
In order to reveal the effect of heterocyclic amino group and size of germanium
cycle in compounds 4 on their antitumor activity we have studied their cytotoxicity
(IC50) on two cell tumour lines: HT-1080 (human fibrosarcoma) and MG-22A
(mouse hepatoma). The investigations showed that most of germacyclohexyl
derivatives (n = 1) exhibited high antitumor activity against mouse hepatoma MG22A (IC50 1-4 mg/ml) and less cytotoxicity for normal fibroblasts NIH 3T3 (IC50
19-37 mg/ml). All of the studied compounds possessed moderate toxicity; lethal
doses for them are in the range 338-782 mg/kg.
133
PO 085 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
novel derivatives of 5-ethynyl-2’deoxyuridine and their biological
investigations
A. Ilinovaa, V. Bregadzea, I. Lobanovaa, A. Semioshkina, E. Paradowskab,
M. Studzińskab, A. Jabłońskab and Z. J. Lesnikowskib
a
A.N.Nesmeyanov Institute of Organoelement Compounds, RAS, Moscow, RUSSIA, bLaboratory of
Molecular Virology and Biological Chemistry, Institute of Medical Biology, PAS, Lodz, POLAND
[email protected]
Nucleosides are basic building blocks of ribonucleic (RNA) and deoxyribonucleic
(DNA) acids. They also play many important functions as themselves or in
phosphorylated form (nucleotides) in conjugation with other biomolecules.
Because of their crucial role in many metabolic pathways their derivatives and
analogues are often used as chemotherapeutics, mainly as antiviral and anticancer
agents1. Among the vast number of nucleoside derivatives, boronated nucleosides
constitute an attractive subfamily. Boron containing nucleosides are considered
to be potential boron carriers for the boron neutron capture therapy (BNCT) of
tumors2.
N
O
O
NH
Si
O
1
B
O
O
Si
N
O
X
N+
X X=CH2
1.
, X=O
CH3CN,reflux
O
O
NH
B O+
O
n-
B
HO
O
N
O
2. NBu4F/THF
-
= C2B9H11CoC2B9H10 or B12H11
2-
OH
Now we would like to present synthesis of novel derivatives of 5-ethynyl2’‑deoxyuridine with closo-dodecaborate and cobalt-bis-dicarbollide. At the first
step of our investigation new 5-ethynyl-2’-deoxyuridine modification (1) was
effectively synthesized. Then, desired conjugates were prepared by the reaction
of 1 with a range of cyclic oxonium adducts of closo-dodecaborate and cobalt-bisdicarbollide boron clusters. Cytotoxicity of these new conjugates in several cell
lines was examined. These compounds can be used as potential boron delivering
drugs for the boron neutron capture therapy (BNCT) of tumors.
Authors thank grants RFBR 12-03-31146 and POIG.01.01.02-10-107/09.
1. De Clercq, E. Nature Rev. Drug Discov. 2002, 1, 13–25.
2. Yinghuai, Z.; Yan, K.C.; Maguire, J.A.; Hosmane, N.S. Curr. Chem. Biol. 2007,
1, 141–149.
134
Poster presentations / PO 086
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
synthesis of 2-aryl-6-sulfamoyl­
saccharin derivatives
Jekaterīna Ivanova, Pēteris Trapencieris, Raivis Žalubovskis
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia
[email protected]
The aim of this project was to develop a method of synthesis of 2-aryl6‑sulfamoylsaccharin derivatives.
In a search for new zinc binding groups as potential inhibitors of zinc containing
enzymes carbonic anhydrases (CAs), we focused our attention on saccharin
derivatives because of saccharin’s promising ability to inhibit tumor associated
isoform of carbonic anhydrase CA IX.1
During our investigation we concluded that it’s impossible to arylate
6‑sulfamoylsaccharin using Cu, Fe and Ni catalysts.
O
H2 N
S
O
O
H2N
S
O
O
O
S
NH
O
O
O
S
N Ar
O
Here we report successful 5 step synthesis of 2-aryl-6-sulfamoylsaccharins starting
with 2‑amino-4-nitrobenzoic acid.
O
O
OH
O2N
O
H2N
S
O
NH2
O
O
S
N Ar
O
O2N
O
Cl
S
O
N
H
NH2
Ar
O2N
O
O
S
N Ar
O
O
O
S
N Ar
O
H2N
O
O
S
N Ar
O
References:
1. Rami, M.; Winum, J.-Y.; Innocenti, A.; Montero, J.-L.; Scozzafava, A.; Supuran,
C. T. Bioorg. Med. Chem. Lett. 2008, 18, 836-841.
135
PO 087 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
PEPTIDIC α-KETOAMIDES with glutamine P1
side chain
Samir Kher, Kristaps Jaudzems, Aigars Jirgensons
Latvian Institute of Organic synthesis, Riga, LV-1006, Latvia
[email protected]
As a part of the program for design & synthesis of malarial protease PfSUB1
inhibitors, α-ketoamides based on the substrate nonprime sequence KITAQ were
targeted [1]. Ketoamide containing protected glutamine side chain 1 was prepared
as a model compound and subjected to deprotection conditions. Formation of
cyclic tautomer 3 was observed as a major product while expected compound 2
was present in a trace amount (ca 5 %). This was obviously due to strong electron
withdrawing α-keto group in ketoamide 2.
H
N
O
H
N
O
O
H
N
*
O
X
O
H
N
O
OH
O
O
O
O
50 vol% TFA
O
NH2
OH
2
DCM. r.t., 2 h
O
O
*
O
N
H
HO
H
N *
O
1
HN
*
NH
O
O
1H
O
3
NMR, HMBC, TOCSY, LC/MS
These results suggest that biosteric replacements for the glutamine side chain are
necessary to prepare analogues of α-ketoamides based on KITAQ sequence.
References:
1. Withers-Martinez, C., Blackman, M.J. Int. J. Parasitol. 2012, 42, 597.
136
Poster presentations / PO 088
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
NEW BIOACTIVE SULFONYLAMIDE
DERIVATIVES OF AZOLES
Vladimir Postnov, Ludmila Shumilova, Mikhail Korsakov, Mikhail Dorogov
Yaroslavl State Pedagogical University named after K.D. Ushinsky,
Respublikanskay str. 108, Yaroslavl, 150000, Russian Federation
[email protected]
The high bioactive potential and combinations sulfonyl amide pharmacophore
with a low-molecular structural core causes interest to search new sulfonyl amide
derivatives of azoles.
We have elaborated the synthesis consisting in creation azole-containing
biheterocyclic systems on the basis of various acetylthiophene or acetylfuran and
the subsequent introduction of sulfonyl amide component in a molecule.
CH3
Het
O
R2
N
R3
O
Het
S
O
N
O
R2
N
O
R1
R3
O
Het
S
N
O
Y
z
R4
O
R2
N
R3
O
Het
S
N
O
O
R2
R4
N
R1
O
Het
N
R3
R5
S
O
Het
O
N
R5
O
N
O
S
Het =
*
,
H3C
S
*
S
O
,
,
*
.
*
The resulting combinatorial series of structural analogs were tested for cytotoxicity
to cancer cells of different origin (MDA-MB-231, Du145) and normal liver cells to
assess the prospects of these substances and their impact on the safety of the human
liver. Based on these results, we have selected the most promising compounds in
the search for new anticancer drugs.
137
PO 089 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS AND BIOCONVERSION OF NEW
1,5-BENZODIAZEPINE OXIMES
Lidija Kosychova, Regina Vidziunaite, Irina Bratkovskaja,
Jonita Stankeviciute, Vida Ragaleviciene, Daiva Podeniene
Institute of Biochemistry, Vilnius University, Mokslininkų 12, Vilnius LT-08662, Lithuania. Lidija.
[email protected]
Recent studies on the degradation of some benzodiazepines catalyzed
by laccase in the presence of mediator in aqueous solution prompted us to
investigate the ability of Polyporus pinsitus laccase (rPpL) to oxidize new
1,3,4,5-tetrahydro-2H-1,5-benzodiazepine oxime derivatives without mediator.
The new 1,3,4,5-tetrahydro-2H-1,5-benzodiazepine oximes (IIa-c) were obtained
by refluxing 1,5‑benzodiazepinthiones (Ia-c), hydroxylamine hydrochloride and
sodium acetate in anhydrous ethanol.
H
N
S
R2
N
H
NH2OH.HCl, CH3COONa,
C2H5OH
H
N
N
OH
R2
N
H
R1
Ia-c
R1
IIa-c
Ia, IIa
Ib, IIb
Ic, IIc
R1
R2
H
CH3
H
H
H
CH3
Synthesized derivatives have similar absorbance spectra in UV region with a
maximum at 290 nm. (Fig. 1a). Oxidation potentials and pKa of the derivatives of
these compounds were determined.
a
0.8
0.4
0
280
IIa
IIb
IIc
300
320
340
Wavelength, nm
360
b
1.6
Absorbance
Absorbance
1.2
1.2
0.8
0.4
0
300
400
500
600
700
Wavelength, nm
Fig. 1. IIa-c absorbance spectra (a) and IIc absorbance spectra change during
oxidation catalyzed by rPpL laccase (b).
During the oxidation process the increase of absorbance was observed in all 280700 nm region (Fig. 1b). The absorbance increased at 290 nm and new absorbance
maxima at 360 and 550 nm were observed. Absorbance increasing as well as
reaction rate depended on laccase and derivatives concentrations, structure and
buffer solution pH. During the biocatalytic process derivatives were completely
converted according to the LC-MS analysis.
138
Poster presentations / PO 090
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF NEW WATER SOLUBLE
PHTHALOCYANINES
Tatjana Kriviča, Modris Roze
Riga Technical Unversity, Department of Chemistry, 14/24 Azenes Str., Riga, LV-1048, Latvia
[email protected]
Phthalocyanines are an important class of non-natural organic pigments which
find applications in different technological areas (e.g., photodynamic therapy (PDT)
and organic photovoltaics). Last decades uses of phthalocyanines for therapy and
diagnosis of cancer and some other diseases are intensively studied [1]. According
to, photophysical and photochemical characteristics such as solubility in water,
photostability under light irradiation, quantum yield lifetime, phthalocyanines are
candidate for further investigation for application in photodynamic therapy [2, 3].
Here we present the synthesis of new water soluble phthalocyanines. As starting
material we chose 4-nitrophthalodinitrile, which in reactions with 3-pyridinemethanol
and 3-pyridinepropanol gave 4-(3-pyridylmetoxy)- and 4-(3-pyridylpropoxy)phthalodinitriles. Synthesis of phthalocyanines was accomplished in penthanol in
the presence of strong base DBU. Synthesis of pyridinium salts was accomplished
with methyl iodide in DMF. Tetrakis-[3-(N-methyl)pyridylmethoxy]phthalocyanato
tetraiodide and tetrakis-[3-(N-methyl)pyridylpropoxy]phthalocyanato tetraiodide
are soluble in water, and show good photostability under light irradiation. Physical
and physicochemical properties of new phthalocyanines were investigated.
O
X
N
I
N
+
N
N
X
O
HN
NH
N
N
N
+
I
O
X
N
+
I
N
X = -CH2-; -CH2CH2CH2-
+
N I
X
O
References:
[1]. Vyklicky, V., Dedic, R., Curkaniuk, N., Hala, J., J. Lumines., 2011, 10, 1016.
[2] Canlica, M., Nyokong, T., Polyhedron, 2012, 31, 704 – 709.
[3] Sekkat, N., Bergh, H., Nyokong, T., Lange, N., Molecules, 2012, 17, 98-144.
139
PO 091 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
The new building-blocks on the basis of
4,4,4-trifluorocrotono­nitrile, indole
and pyrrole derivatives
Natalia Labodnevaa, Andrey Volkonskiib,
Andrey Siganb, Nikolai Chkanikovb
a
D. Mendeleyev University of Chemical Technology of Russia, Miusskaya Str. 9, Moscow 125047,
Russia
b
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28
Vavilov Str., Moscow 119991, Russia
[email protected] The new method of choice for selective functionalizatione of indoles and pyrroles
using 4,4,4-trifluorocrotononitrile in the presence Lewis acids is proposed. The
compounds obtained are successfully converted to the valuable building-blocks for
construction more complicated structures with useful properties.
F3C
COOH
R1
N
CF3
R1
R = H, R1 = H
N
R
R = H, R1 = Me
R
COOH
R = Me, R1 = H
F3C
CN
indoles
pyrroles
F3C
CN
R1
R1
CF3
N
R
N
NC
R
F3C
NH2
R1
R1
CF3
N
R
N
R
NH2
Synthetic utility of the new compounds and their biological activity are discussed.
140
Poster presentations / PO 092
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Diastereomeric atropisomers
of 1,4-dihydroPyridines
Anna Lielpētere, Baiba Turovska, Inguna Goba
Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga, LV-1006, Latvia
[email protected]
Potentially biologically active diastereomeric 1,4-dihydropyridine (1,4-DHP)
atropisomers are synthesized and investigated by spectroscopic and electrochemical
methods at variable temperatures.
O
NC
H
R3
N
R2
H
R3 = CN (1), COCH3 (2), COOCH3 (3)
R2 = CH3 (a), C5H4N (b)
H 3C
Rotation barrier of the C(4)-C(1’) bond between naphthyl and 1,4-DHP ring
are compared for symmetrically (1a) and unsymmetrically substituted dihydropyridine derivatives (1b, 2a, 3a). Obtained results are compaired with the 4-aryl3,5-dicyano-2,6-dimethyl-1,4-dihydropyridine whose the rotation of C(4)-C(1’)
bond has been ′′frozen-out′′ already at room temperature [1].
In aprotic media electrochemical oxidation of the 1,4-DHP (4-6) proceeds in
one irreversible step, while 1,4-DHP (1a-3a, 1b) undergo two step irreversible
oxidation (Table 1). During the anodic oxidation of 1,4-DHP (4-6) dimethoxymethyl group is eliminated, while the 4-(3-ethoxy-naphthalen-2-yl) substituted
pyridine derivatives were the products of the first oxidation step of 1,4-DHP (1a3a). Mechanism and products of anodic oxidation have been studied.
Cpd
1a
1b
2a
3a
4
5
6
E1ox, V
+1.09
+1.19
+1.44
+1.03
+1.12
+1.17
+1.05
+1.09
E2ox, V
+1.68
+1.74
+1.67
+1.68
-
Table 1.
Cyclic voltammperogram:
CH3CN / 0.1 M NaClO 4,
working electrode – glassy carbon,
counter electrode – Pt wire,
reference electrode – Ag/Ag+.
1. Palmer, R. B.; Andersen, N. H. Tetrahedron 1996, 52, 29, 9665.
141
PO 093 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Towards the synthesis of THFcontaining marine polyketides
Adriana Lorente,a Fernando Albericioa,b and Mercedes Álvareza,c
Institute for Research in Biomedicine, Barcelona Science Park-University of Barcelona, Spain.
Department of Organic Chemistry, UB, cLaboratory of Organic Chemistry, Faculty of Pharmacy,
UB, Spain.
[email protected] a
b
Marine organisms produce structurally diverse secondary metabolites with important
biological activities, providing excellent candidates for the investigation of new
bioactive molecules. Polyketide macrolides containing tetrahydropyran (THP) or/
and tetrahydrofuran (THF) units have shown interesting pharmacological profile,
some of them reaching the clinical trial stage or the market.1 The determination of
full bioactivity, mechanism of action, and further medical application are usually
unfeasible because their isolation from natural sources furnishes small sample
amounts. Thus, synthesis is a must for further development of these macrolides as
pharmacological leads in terms of their supply and for structural and stereochemical
assignments.2
The synthesis of the THF-containing macrolactone of a new group of secondary
metabolites with important cytotoxic activity against various human tumour cell
lines will be discussed. Our efforts towards a strategy based on a RCM to form
a trisubstituted double bond provided only small amount of product. Finally, a
strategy based on a Julia-Kocienski olefination led to the desired macrocycle.
References:
1. Lorente, A.; Lamariano, J.; Albercio, F.; Álvarez, M. Chem. Rev. 2013, Accepted.
2. (a) Nicolaou, K. C.; Snyder, S. A. Ang. Chem. Int. Ed. , 2005, 44, 1012. (b) Lorente, A.;
Pla, D.; Cañedo, L. M.; Albericio, F.; Álvarez, M. J. Org. Chem. 2010, 75, 8508.
142
Poster presentations / PO 094
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
pyrrolediones recyclizations in
Bioheterocyclic chemistry
Andrei Maslivetc, Pavel Silaichev, Ekaterina Denislamova, Maksim Dmitriev
Department of Organic Chemistry, Perm State University, Perm, 614990, Russia
[email protected]
Recyclizations of 1H-pyrrole-2,3-diones via their interaction with bifunctional
nucleophiles represent a convenient construction method towards previously
inaccessible or hardly accessible heterocyclic systems of condensed, bridge
and spiro-types. The interactions described here present rare examples of the
regioselective synthesis of spiro heterocyclic systems embedding different
functional substituents in both heterocyclic fragments. Structurally all the products
are the polycarbonyl compounds suitable for further elaboration. High yields,
simplicity of reaction and purification procedures are the key advantages of this
synthetic approach. The structures of compounds were confirmed by X-ray analysis.
O
CONHAr
ArCO
N
N
RCO
HN
Me
N
Me
N
O
Ph Ar
Me
NHAr
O
Ar
O Ar
N
O
R
Me
N
Me
O
N
R
N
N
N
O
OH
NHAr
O
O
COR Me
Me
OH
O
O R
OH
O
Me
H
N
COAr
N
H
Me
R
O
O
COR Ar
N H
O
OH
N
Ar
O
COAr
N
R
N
O
Ph
Ar
Ar
Me
HO
RCO
O
COAr
N
O
Ar
NHAr
OH O
N
Ar
NHR
Ar
COAr
N
COAr
O
Ar
RCO
O
O
O
O
NH2
S
N
N
Ar O
Multicomponent reactions of 1H-pyrrole-2,3-diones is an effective technique for
creation of spiroheterocyclic systems by upbuilding of the pyrroledione cycle.
Me
H
N
Me
Me
RCO
Ar
N
R
O
O
O
O
O
RCO
Ar
N
R
Me
O
NH2
O
CN RCO
O
Ar
H
N
Ar
N
NH2
RCO
N
R
CN
O
Ar
N
R
OO
O
RCO
Ar
N
OO
R
Thus, the new synthetic strategy to produce biologically active heterocycles has
been developed and it will be discussed.
Acknowledgements: The study was financially supported by the RFBR (Grants
12-03-00696 and 12-03-31157), the Ministry of Education and Science of Russian
Federation, the Ministry of Education of Perm Region.
143
PO 095 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF TRIARYL PYRROLES
AS CANNABINOID RECEPTOR LIGANDS
Sergei G. Mikhalyonoka, Nina M. Kuz’menoka, Alexander M. Zvonokb
Department of Organic Chemistry, Belarusian State Technological University, Minsk, Belarus
Center for Drug Discovery, Bouve College of Health Sciences, Northeastern University, Boston, MA,
United States
[email protected]
a
b
Cannabinoid receptor ligands show clinical efficacy in the treatment of obesity and
obesity-related disorders and improved cardiovascular and metabolic risk factors.
The present study is devoted to the synthesis of new aryl pyrrole derivatives, which
are analogues of known CB1 receptor antagonist – Rimonabant (SR141716), and
their binding affinity and selectivity towards CB1 and CB2 cannabinoid receptors
were evaluated. Triaryl substituted epoxy alkanoyl dihydropyrroles 1a–f were
obtained as individual diastereomers by cycloaddition nitrile ylide 2 to epoxy
enones 3a–f reaction.
O
O
+ p-O2NC6H4
C6H4X-p
Me
3a-f
C
H
N
+
C
2
a X = H, b X = Cl, c X = Br, d X = Me, e X = OMe, f X = OEt
Ph
CH2Cl2
O
O
Me
p-O2NC6H4
C6H4X-p
Ph
N
1a-f
Among these compounds, dihydropyrrole 3f exhibited similar values of binding
affinity towards both subtypes of cannabinoid receptors (Кi СВ1 = 0,54 mM, Кi
СВ2 = 0,27 mM). Dihydropyrrole 3c displayed high CB2 receptor selectivity, in
contrast to the CB1 ligand Rimonabant. Compound 3c showed slightly lower CB2
activity value (Кi СВ1 > 10 mМ, Кi СВ2 = 0,061 mМ) as compared with the natural
cannabinoid (-)-D9-ТНС (Кi СВ2 = 0,036 mМ). The results of this research indicate
the expediency of further investigation of selective CB1 and CB2 ligands in series
of triaryl substituted pyrroles and confirm the fact that minor structural changes
in the analogs of known ligands can substantially to respond to the specificity and
efficiency of their interactions at the receptor level.
144
Poster presentations / PO 096
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis of polyquinolines: new Bcl-2
family protein modulators
Pascale Moreau, Emmanuelle Saugues, Anne-Laure Debaud,
Fabrice Anizon, Nathalie Bonnefoy
Clermont Université, UBP, CNRS-UMR 6296, BP 10448, 63000 Clermont-Ferrand, France
[email protected]
Bcl-2 family members are important regulators of apoptosis that are divided in
three groups comprising anti- and pro-apoptotic members. Overcoming altered
apoptosis leading to resistance of tumor cells to conventional chemotherapy is
an attractive therapeutic approach that could be achieved by modulation of the
Bcl-2 family protein-protein interactions (PPI). Thus, the development of small
molecules able to mimic the a-helix of pro-apoptotic proteins that interact with
the hydrophobic groove of their anti-apoptotic counterparts has lately attracted
great interest. Consequently, we recently developed a research program concerning
the synthesis and biological evaluation of quinolines that mimic the helicoidal
structures involved in PPI regulating cellular apoptosis.
N
N
N
OEt
OEt
OEt
The synthetic work and the results of the structure-activity relationship studies
performed in the series will be described.
References:
E. Saugues, A.-L. Debaud, F. Anizon, N. Bonnefoy, P. Moreau. Eur. J. Med. Chem.
2012, 57, 112-125 and references therein.
145
PO 097 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS and Biological evaluation
of aziridin-1-yl oximes as potential
antitumor agents
Anna Nikitjuka, Aigars Jirgensons
Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006, Riga
[email protected]
In our effort to discover and develop potential anticancer agents, we synthesized
a series of aziridin-1-yl oximes 1 derivatives. A preliminary study of SAR of 1
suggested that substitution on p-position of aniline core increases the cytotoxic
activity.
N
HO
linker
NH
N
R
O
1
For this reason and also in order to obtain SAR of p-substitution at aniline core we
have extended the range of analogues of 1 and evaluated their cytotoxic activity on
several cancer cell lines.
The results obtained allowed us to provide a hypothesis for further structure
optimization of aziridin-1-yl oximes 1.
146
Poster presentations / PO 098
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Obtain new diarylquinolines
derivatives
Anton Omelkov, Vadim Ilin, Vladimir Fedorov
ZAO «Pharm-Sintez», Moscow, h. Enthusiasts, 38, Russia
[email protected], [email protected]
Tuberculosis is a major health problem worldwide. In 2008, there were an
estimated 8.9–9.9 million incident cases of TB, 9.6–13.3 million prevalent cases
of TB, 1.1–1.7 million deaths from TB among HIV-negative people and an
additional 0.45–0.62 million TB deaths among HIV-positive people (classified as
HIV deaths in the International Statistical Classification of Diseases), with best
estimates of 9.4 million, 11.1 million, 1.3 million and 0.52 million, respectively
[1]. The development of effective chemotherapy for the treatment of tuberculosis
began in the 1940s and has been reinvigorated recently due to concern regarding
the emergence of highly drug-resistant TB strains [2]. Today, procedures being
at the stage of clinical trials or preclinical development several compounds such
as diarylquinolines (TMC207). They show promising activities against sensitive
and resistant Mycobacterium tuberculosis strains [3]. We applied lithiation method
with some modification using cerium chloride (III) to chemical sythesis of some
derivatives of diarylquinolines. The results of our studies of this reaction are
reported.
CH3
R1
R1
R2
R3
O
i-Pr2NLi
N
N
HLi
C
R2
+
Cl
R3
R3
N
CH3
HClaq.
Cl
R2
R1
CH3
N
Cl
OH
* *
+
NHClCH3
References:
[1]. Organization W. H. Global tuberculosis control: WHO report 2010.
[2]. Elliott R. L. Third World Diseases / Ed. by Springer. 2011.
[3]. Baptiste V. et al. European Journal of Med. Chem., 2012, 51, 1 - 16
147
PO 099 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
selenium analogues of raloxifene:
synthesis and activity
Edgars Paegle, Pavel Arsenyan
Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia
[email protected]
Raloxifene is selective estrogen receptor modulator (SERM) already used for
treatment of osteoporosis and reduction of invasive breast cancer incidence in
postmenopausal women. On the other hand, selenium has attracted a great interest
as an essential element and certain diseases have been eradicated by dietary
supplementation of this element. Furthermore, selenophene–based derivatives
exhibit potent in vitro and in vivo antitumoral activity which involves DNA damage.
With the aim to develop new drugs for treatment of estrogen dependant cancers
we have elaborated convenient synthetic pathway for preparation of selenium
analogues of Raloxifene as a key step using cyclization of diarylalkyne under two–
phase selenobromination conditions.
N
R
N
R
O
.
HCl
R
.
O
HO
S
Raloxifene
N
R
O
HCl
O
.
OH
HO
Se
HCl
O
O
OH
F
Se
F
A series of selenium analogues have been obtained and characterized. Structure
and cytotoxic activity relationship on various cancer cell lines including estrogenpositive and estrogen-negative will be discussed.
148
Poster presentations / PO 100
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS AND STUDIES OF AMPHIPHILIC 1,4DHP DERIVATIVES with STYRYLPYRIDINIUM
MOIETIES
Karlis Pajuste, Arkady Sobolev, Klavs Pajuste, Martins Rucins,
Marina Gosteva, Ilona Domracheva, Irina Shestakova, Aiva Plotniece
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia
[email protected]
1,4-Dihydropyridine (1,4-DHP) derivatives possess a wide variety of pharmacolo­
gical activities. According to Triggle, 1,4-DHP nucleus is a privileged structure
which is intrinsic characteristic for many pharmacologically active compounds
and commercial drugs. Polyfunctional pyridinium amphiphiles based on 1,4-DHP
structures possess self-assembling properties and some of them are very efficient
in gene delivery experiments into many cell lines in vitro.
The aim of our work - synthesis of new cationic amphiphilic 1,4-DHP derivatives
containing styrylpyridinium moieties, studies of self-assembling, fluorescent and
antioxidant properties.
N+
N
O
R
R
O
O
Br
O
R'
R"
R"
O
R
O
R"
NH
NH
O
Br N+
Br
R'
O
O
R
N+
R"
Br-
Establishing of structure-activity relationships for polyfunctional pyridinium
1,4‑DHP derivatives is a promising tool for design and developing of more potent
and efficient physiologically active compounds. Obtained styrylpyridine 1,4-DHP
derivatives could be promising fluorescent probes with specific biological activities
for biochemical experiments.
Acknowledgements: EURONANOMED Project “ChemTherDel”
149
PO 101 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
NEW 2-OXINDOLE CONTAINING
ANTIPROFILERATIVE AGENTS
Boris V. Paponova, Sergey V. Lvova, Ekaterina V. Ichetovkinaa,
Alexander V. Shyshova, Valiantsin N. Dudnikb, Raman V. Dudnikb
a
Kharkov V.N. Karazin National University, Kharkov 61077, Ukraine.
[email protected]
b
“Kedr” Company LTD, Gomel 246050, Belarus.
[email protected]
Two new basic molecules containing 2-oxindole fragments as potential inhibitors of
the ATP-binding sites of GSK-3β/CDK kinases family have been designed. QSAR
and molecular docking methods were used for this. Evidently that ErlenmeyerPlöchl reaction is optimal for the synthesis of compounds designated as 3 and 6.
The above mentioned reactions were carried out successfully using the activation
by ultrasonic irradiation. This procedure is the first successful application of
ultrasound supporting for Erlenmeyer-Plöchl reaction 1.
O
N
H
1
NH
O
2 a-g
N
Ac2O,
US,
r.t.
Ar
HN
O
O
O
Ar
O
HO
O
N
H
HO
O
NH2
3 a-g
NH
NH2
O
- ArCONH2
N
H
4
O
O
OH
NH
N
H
5
O
O
Ac2O, US, r.t.
HN
O
2 a-g
Ar
N
H 6 ag
O
Ar
a Ar = C6H5; b Ar = 4-FC6H4; с Ar = 4-ClC6H4; d Ar = 3-BrC6H4;
e Ar = 2-CH3C6H4; f Ar = 4-CH3C6H4; g Ar = 4-tert-butylC6H4.
The compound 4 inhibits proliferation of human lymphoma cell culture Jurcat cells
and non-toxic to human fibroblasts in concentrations of 10-50 mmol/l.
1. Boris V. Paponov, Sergey V. Lvov, Ekaterina V. Ichetovkina, Ilya A. Panasenko,
Stepan G. Stepanian. Mendeleev Communications. 2012, 22, 273.
150
Poster presentations / PO 102
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
preparation and cytotoxicity of
Selenolothiophenes
Alla Petrenko, Pavel Arsenyan
Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia
[email protected]
In the last years, fused heterocyclic systems have attracted considerable attention
both from a theoretical standpoint and in view of their various practical applications.
This interest is evidenced by a sharply increasing number of publications devoted
to various aspects of the chemistry of fused thiophenes. However, much less is
known about selenolothiophenes. Motivated by the importance of developing
direct and facile methods for the preparation of various selenolothiophenes we
examined interaction of 2- and 3-ethynylthiophenes with various selenium (I), (II)
and (IV) chlorides and bromides in aprotic solvents as well in aqueous media.
X
R
N R'
S
Se
SenXm
S
N R'
X
R
or
S
Se
N R
R'
SenXm = SeCl4, SeOCl2, SeCl2, Se2Cl2, SeBr4, SeBr2, Se2Br2
As a result desired aminomethylselenolo[2,3-b]- and -[3,2-b]thiophenes
were obtained in good to almost quantitative yields. Molecular structures of
selenolothiophenes have been unambiguously confirmed by X-ray analysis.
Structure and cytotoxic activity relationship on HT-1080 (human fibrosarcoma),
MG-22A (mouse hepatoma), and NIH 3T3 (normal mouse fibroblasts) will be
discussed.
151
PO 103 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Molecular modeling, synthesis and
biological evaluation of new potent
pyrazolo[1,5-a]-pyrimidine inhibitors
of cDK2
Michaela Petrůjová,a Lenka Musilová,a Radek Jorda,b,c Vladimír Kryštof,c
Pathik Brahmkshatriya,d Pavel Hobzad and Kamil Parucha,e
Department of Chemistry, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
Masaryk Memorial Cancer Institute, Regional Centre for Applied Molecular Oncology, 656 53
Brno, Czech Republic
c
Laboratory of Growth Regulators, Faculty of Science, Palacký University & Institute of Experimental
Botany, Šlechtitelů 11, 783 71 Olomouc, Czech Republic
d
Institute of Organic Chemistry and Biochemistry, v.v.i. and Gilead Sciences and IOCB Research
Center, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Prague 6, Czech
Republic
e
International Clinical Research Center, St. Anne’s University Hospital Brno, Pekařská 53, 656 91
Brno, Czech Republic
[email protected]
a
b
Despite the fact that the structures of many protein kinases have been characterized
by X-ray crystallography, molecular modeling of new kinase inhibitors remains
a significant challenge. Recently, we successfully applied a refined quantum
mechanics-based scoring protocol to reproduce the binding affinities of known
pyrazolo[1,5-a]pyrimidine inhibitors of CDK2 kinase and their bioisosteres.1
Utilizing the same scoring function, we have modeled new, previously unknown
inhibitors bearing properly substituted biphenyls at the 5-postion of the
pyrazolo[1,5-a]pyrimidine core. The predictive power of the in silico methodology
has been verified by subsequent synthesis and biological evaluation of the
compounds. The most potent compounds in this series exhibit activity against
CDK2 kinase in the single-digit nanomolar range.
References:
1. Brahmkshatriya, P.; Dobes, P.; Prenosil, O.; Fanfrlik, J.; Rezac, J.; Paruch, K.; Lepsik, M.; Hobza,
P. Curr. Comput.-Aid. Drug. 2013, 9, in press
152
Poster presentations / PO 104
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF novel triazoleQUINAZOLINoNE DERIVATIVES
Irisa Ravina, Inese Rijkure, Daina Zicane, Maris Turks
Faculty of Material Sciences and Applied Chemistry, Riga Technical University, Riga, LV-1007, Latvia
[email protected]
Quinazolines play important role in the field of drug discovery. Coupling
quinazolines to biologically active molecules like triazoles might be a way for the
synthesis of novel and significant derivatives.
Considering our research interests related to the synthesis of new quinazolinone
derivatives with potential antioxidant application, we now report the synthesis of
novel triazole-quinazolinone derivatives.
O
OH
O
O
HC(OEt)3
H2NC2H4OH
OH
N
NH2
N
TsCl
N
N
O
O
NaN3
N3
N
R
Cu(I)
R= Ph-;
;
;
OH
OH ;
N
N
N
N
OTs
N
N
R
;
OH ;
OH
;
;
153
PO 105 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
STABILITY AND DEHYDRATION KINETICS OF
PEMETREXED HYDRATES
Toms Rēķis, Agris Bērziņš, Andris Actiņš
Department of Chemistry, University of Latvia, Kr. Valdemāra iela 48, Riga, LV-1013, Latvia
[email protected]
Pemetrexed disodium (Fig. 1.) is a heterocyclic compound containing pyrrolo[2,3-d]
pyrimidine bicyclic core and is used in chemotherapy mainly for lung cancer
treatment.
Figure 1. The structure of pemetrexed disodium
It is highly water-solube white crystalline solid that may form two hydrates and
metastable amorphous form [1].
Preparation conditions of hemipentahydrate, heptahydrate and amorphous form
were clarified and obtained solid phases were investigated with powder X-ray
diffraction. The stability of pemetrexed hydrates over controlled relative humidities
and temperature was studied. Thermogravimetric and differential thermal analysis
showed that dehydration of heptahydrate occurs at 60 °C and proceeds stepwise
by forming hemipentahydrate followed by further dehydration. Dehydration
kinetic parameters and most appropriate kinetic model for hemipentahydrate was
calculated.
References:
1. Chelius, E.; Reutzel-Eden, S.; Snorek, S.Eli Lilly and Company (2003), Novel
Crystalline of N-[3-[2[)2-amino-4,7-dihydro-4oxo-3H-pyrrolo[2,3-d]pyrimidin5-yl)ethyl]-benzoyl]-L-glutamic Acid and Process Therefor, U.S. Pat. PCT/
US01/01229
154
Poster presentations / PO 106
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS AND CYTOTOXIC ACTIVITY OF
FURYLSILYLAMINES
Vitalijs Romanovs, Luba Ignatovich, Jana Spura, Irina Shestakova
Latvian Institute of Organic Synthesis, 21 Aizkraukles, Riga LV 1006, Latvi
[email protected]
The heterocyclic amines are important building blocks for the creation of
anticancer drugs1. To further extension of our investigations on the biologically
active organosilicon compounds we have prepared new 2,5-bis(3-aminopropyldimethylsilyl)furans. The starting furylhydrosilanes 1, 2 have been synthesized from
the furan by consecutive metallation and hydrosilylation reactions:
Me
SiH
O
Me
a)
O
Me
Si(CH2)3R
Me
b)
Me
Me
HSi
Me
1
O
Si(CH2)3R
Me
c)
8 R = -N
, R' = -N
O ; 5 R =-N
NMe ; 9 R = -N
O , R' = -N
, R' = -N
O ; 6 R = -N
NMe ; 10 R = -N
O
Si(CH2)3R
Me
3 -11
2
3 R = R' = NEt2; 4 R = NEt2 , R' = -N
Me
Me
R'(H2C)3Si
Me
, R' = -N
S , R' = -N
O; 7 R = -N
NMe ; 11 R = -N
, R' = -N
NMe , R = -N
NMe ;
NMe
_____________
a)
R /H PtCl 6H O b n-BuLi/Me
2
2
6
)
2SiHCl c)
R'/H PtCl 6H O
2
2
6
The transformation afforded a series of silylamines 3-11 containing two or three
different heterocycles in good yield (51-59%). The cytotoxicity of amines on
tumour cells HT-1080, MG-22A and normal mouse fibroblasts 3T3 have been
investigated in vitro. All studied compounds exhibited high cytotoxic activity
(IC50 0,3-3 μg/ml). Compound 8 with piperidine and N-methylpiperazine rings in
one molecule is the most promising compound in this series of amines: moderate
toxicity (LD50 380 mg/kg), high cytotoxicity on both cancer lines (IC50 0,3-2 μg/ml)
and lower cytotoxicity on normal fibroblasts (IC50 11 μg/ml).
___________
1
Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances.
Thieme: Stuttgart-New York, 2009; pp 1332.
155
PO 107 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
­ YNTHESIS AND STUDIES OF NOVEL
S
1,4-DIHYDROPYRIDINE DERIVATIVES
Martins Rucins1, Karlis Pajuste1, Linda Klimaviciusa2, Klavs Pajuste1, Iveta
Kanepe-Lapsa2, Baiba Jansone2, Irina Sestakova2, Brigita Cekavicus1, Vija
Klusa2, Marina Gosteva1, Arkadij Sobolev1, Ruta Muceniece2, Aiva Plotniece1
Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga, LV-1006, Latvia;
University of Latvia, Faculty of Medicine, 1A Sarlotes St., Riga, LV-1001, Latvia
[email protected]
1
2
Introduction. 1,4-Dihydropyridine (1,4-DHP) derivatives are compounds which
play an important role in synthetic, medicinal and bioorganic chemistry [1].
The aim of work. New N-propargyl and/or cationic pyridine moieties-containing
1,4-DHP’s and their structure-related parent compounds were synthesized to
study: 1).structure-activity relationships in cell viability test in SH-SY5Y human
neuroblastoma cells in the absence/presence of mitochondrial toxin (MPP+); 2).
1,4-DHP’s influence on calcium overload in SH-SY5Y and A7R5 rat aorta smooth
muscle cells; 3). total antioxidant activity using phosphomolybdenum method.
Results. Novel N-propargyl substituted and N-unsubstituted 1,4-DHP’s have been
synthesised according to Scheme.
X
O
O
O
O
O
N
R
O
R1 Br+
N
N
O
O
O O
[N]
O
O
O
O
O
O
N
R
-
O
O
O
N
R
N+
O
O
O
O
O
O
N
R
Tested 1,4-DHP’s possessed moderate antioxidant activity. Analyses of structureactivity relationships shows that addition of N-propargyl substituent to 1,4-DHP
cycle did not affect any protective activity in MPP+ cytotoxicity model in SHSY5Y cells, however slightly increased the Ca2+ channel blocking activity in SHSY5Y cells, but not in A7R5 cells.
Acknowledgements: EURONANOMED Project “ChemTherDel” and ESF Project
Nr. 2009/0217/1DP/1.1.1.2.0/09/APIA/VIAA/031.
References: 1. Triggle, D.J. Biochem. Pharmacol. 2007, 74, 1.
156
Poster presentations / PO 108
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Stability of isoniazid–carboxylic acid
cocrystals
Inese Sarcevica, Liana Orola, Sergey Belyakov, Mikelis V.Veidis
Department of Chemistry, University of Latvia, Riga, LV-1013, Latvia
[email protected]
Isoniazid is an anti-tubercular drug used to treat the Mycobacterium tuberculosis
bacterial infection. Isoniazid tablet formulations are known to undergo degradation.
Possible solutions for the stability problem are alternative crystal forms of isoniazid.
For instance, cocrystals are crystalline single phase materials composed of different
molecular compounds. New isoniazid cocrystals with selected carboxylic acids
have been prepared and their properties have been investigated to explain stability
of these cocrystals.
The melting points of isoniazid–dicarboxylic acid 2:1 cocrystals decrease with an
increasing length of the acid chain. However, conformation change of compounds
introduces instability to the system.
Isoniazid–dicarboxylic acid cocrystal solubility tends to increase with an increasing
solubility of the coformer. The solubility may be influenced by the stability of a
cocrystal.
The stability of isoniazid–carboxylic acid cocrystals was evaluated at accelerated
climatic conditions (30 °C, 75% RH). Decomposition of isoniazid–benzoic acid
and isoniazid–malonic acid cocrystals was observed after 2-4 week storage. The
poor stability of isoniazid–benzoic acid cocrystal is explained by similar hydrogen
bonding motifs in crystalline isoniazid and isoniazid–benzoic acid cocrystal.
Acknowledgements: This work has been supported by the European Social Fund
within the project “Support for Doctoral Studies at University of Latvia”.
157
PO 109 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Targeted Conjugate of Isoniazid with
Magnetic Nanoparticles
Miloš Sedlák, Dattatry Bhosale and Aleš Imramovský
Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of
Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic
[email protected]
At present, isoniazid (isonicotinoyl hydrazide, INH) represents a medical drug of
first choice to be used for prevention and treatment of tuberculosis.1 This serious
infectious disease represents a considerable threat to humankind and affects up to
one third of world population, however, mostly people with decreased immunity
(e.g., HIV).1 The present article describes preparation and characterization of
isoniazid conjugate (INH) with magnetic nanoparticles (~ 60 nm) with a core-shell
structure ([email protected]).2 The isoniazid molecules were attached to the surface of
the nanoparticles [email protected] by means of covalent pH-sensitive amidine bond.
tO
E
tO
E
H
O
i
S
H
N
2
tO
E
O
O S
i
tO
E
H
O
H
N
O
H
O
[email protected]
[email protected]–NH2
O
O S
i
O
N
H
H
C
N
H
N
C
N
2
H
N
C
O
+
N
N
O
.
The conjugate was characterized by means of microanalysis, IR spectroscopy,
powder X-ray diffraction, TEM and dynamic light scattering. The release of INH
from the carrier was monitored under the in vitro conditions with the use of UV-Vis
spectroscopy. In a solution of 1·10–2 mol·1–1 HCl at the temperature of 37 °C, INH
is released from the carrier with the half-time t1/2 = 65 s. In a model medium with the
pH value equal to 5.3, which is characteristic of a pathological tissue, isoniazid is
released with the half-time t1/2 = 115 s (phosphate buffer 2·10–2 mol·1–1; 37 °C). The
synthesized potential slow-acting1 conjugate of INH with biocompatible magnetic
nanoparticles [email protected] enables a targeted effect of isoniazid in the affected
tissue by application of external magnetic field.2
[email protected]–INH
Acknowledgements: The authors wish to acknowledge the financial support Grant
Agency of the Czech Republic (Grant No. P106/11/0058).
References:
1. Imramovský, A.; Grusová, L.; Beneš, L.; Pejchal, V.; Sedlák, M. Bioorg. Med.
Chem. Lett. 2012, 22, 5952.
2. Arora, V. S. Int. J. Nanomedicine 2012, 7, 3445.
158
Poster presentations / PO 110
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Synthesis, structure and biological
properties of 1-(thiazol-2-yl)- and
1-(benzo thiazol-2-yl)pyrrolidin-2-ones
Izolda Segal, Alla Zablotskaya, Tatiana Eremkina, Juris Popelis, Irina
Shestakova, Vizma Nikolajeva
Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia
University of Latvia, Biological Faculty, Riga LV-1586, Latvia
[email protected]
Novel effective synthetic pathway has been developed for the preparation of
N-hetaryl substituted 2-oxo-pyrrolidine based structures through intramolecular
alkylation of 4-chloro-N-(hetaryl)butanamides. To adjust the bis-cyclic products
formation in presence of K2CO3, NaOH, NaI, amines or silica gel in different
solvents, acetone, ethanol and toluene, in order to assess the possibility of thermal
induced cyclization of 4-chloro-N-(1,3-thiazol-2-yl)butanamide and 4-chloroN-(1,3-benzothiazol-2-yl)butanamide, the reaction process was controlled by
HPLC-MS method. The reaction products have been identified using various
physico-chemical methods, including HSQC and HMBC two-dimensional NMR
spectroscopy. We found that in contrast to literature data for similar compounds,
regiospecific alkylation took place not at the endocyclic, but at the exocyclic
nitrogen atom and proceeded with the formation of 1-[(benzo)thiazol-2-yl]
pyrrolidin-2-ones. The optimal conditions for the regioselective alkylation have
been proposed and tested for the analogous intramolecular cyclization of 3-chloroN-(1,3-thiazol-2-yl)propanamide.
N
O
Het
N
Het :
S
N
,
S
It had been established that the synthesized compounds were non-toxic substances
and exhibited selective inhibitory activity against the test gram-positive bacterial
(Staphylococcus aureus and Bacillus cereus) and fungal (Candida albicans and
Aspergillus niger) strains. 1-(Benzothiazol-2-yl)pyrrolidin-2-one displayed a
specificity of the cytotoxic effect towards mouse hepatoma cell line MG-22A in
microgram range. The nootropic activity of the synthesized N-substituted 2-oxopyrrolidines has been examined.
Acknowledgement: We thank the Latvian Council of Science (Joint Project
10.0030) for financial support.
159
PO 111 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
novel Antimicrobial
tetrahydroisoquinolines: synthesis
and immobilization on the surface of
magnetic nanocarriers
Izolda Segal, Alla Zablotskaya, Galina Kazachenok, Anatoly Mishnev,
Mikhail Maiorov, Elmars Blums, Vizma Nikolajeva
Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia,
Institute of Physics, University of Latvia, LV-2169, Latvia,
University of Latvia, Biological Faculty, Riga LV-1586, Latvia
[email protected]
A series of new N,O-alkyl derivatives of N-(2-hydroxyethyl)-1,2,3,4-tetra­
hydroisoquinoline has been synthesized under PTC conditions and subsequent
N‑alkylation. Various PTC systems and catalysts have been examined in order
to investigate the reaction regioselectivity. The synthesized compounds revealed
good inhibitory activity concerning Gram-positive and Gram-negative bacterial
strains and fungi with MIC and MBC of 0.5–32 μg/ml for the most active ones,
which were recommended for further investigation on enzymes involved in process
of DNA replication.
R2
X-
+
N
OR1
R1 = H, Alk, SiR’R’’R’’’; R2 = Alk
Some of the obtained compounds of different structure were selected for the
synthesis of iron oxide/oleic acid based nanoparticles to evaluate their efficacy
as antimicrobial agents. Superparamagnetic nanoparticles with iron oxide
core diameter of 6.4–10.5 nm were synthesized using our earlier developed
methodology [1]. To explore the possibility of extending the range of biologically
active compounds used for synthetic magnetosomes preparation, the procedure
for their synthesis was improved. XRD analysis, DLS measurements, method
of magnetogranulometry and some others have been employed to determine the
structure and size and investigate the properties of the nanoparticles synthesized.
Acknowledgement: We thank the Latvian Council of Science (Gr.09.1321 and
Joint Project 10.0030) and EU COST Action CM 0902 for financial support.
References:
1.Zablotskaya, A.; Segal, I.; Lukevics, E. Appl. Organomet. Chem. 2010, 24, 150.
160
Poster presentations / PO 112
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
heterocyclophanes based on uracil
derivatives
Vyacheslav E. Semenov, Anatoly S. Mikhailov, Rashit Kh. Giniyatullin,
Evgeniya S. Krylova, Anton E. Nikolaev, Vladimir S. Reznik
A.E. Arbuzov Institute of Organic and Physical Chemistry of RAS, Kazan, Russia
[email protected]
Herein a method for preparating of heterocyclophanes which consist of uracil
derivatives and five- and six-membered heterocycles bridged to each other with
polymethylene chains is reported. The starting material for the introduction
of uracilic constituents were 1,3-bis(ω-bromoalkyl)-5(6)-substituted uracils 1.
Reactions of the dibromides with 2-mercaptobenzimidazole afforded macrocyclic
isomers 2a,b and heterocyclophane 3. Substitution of Br in 1 with NH2Et followed by the reaction with cyanuric chloride gave heterocyclophanes 4. Macrocycles 5 have been prepared by click-chemistry method. Acyclic counter-parts
of the heterocyclophanes have been synthesized with the same approach.
(CH 2) nBr
O
N
R1
N
H 3C
O
R2
(CH2 )n Br
R1 ,R2 =Br, H, CH3 , n=3-5 1
O
Br
(CH 2)n
N
N
S
O
S
3
N
N
N
N
(CH 2) n
N
N
O
O
N
O
S
S
N
O
H 3C
N
N
(CH2 )n
N
2b
O
N
(CH2 )n
N
4
CH 3
N
N
CH3
N
N
(CH 2) n
2a
O
(CH 2 )n
N
(CH 2) n
H 3C
(CH 2 )n
O
Cl
H 3C
N
N
(CH2 )n
N
N
N
O
O
(CH2 )n
5
N
N
N
O
N
Some of the acyclic and macrocyclic compounds showed activity towards grampositive bacteria and yeast fungus.
Acknowledgements: RFBR (projects ##12-03-31862 and 13-03-00709), Federal
goal-oriented program (contract #8432)
References:
1. Semenov, V. E.; Krylova, E. S.; Galyametdinova, I. V.; etc. Tetrahedron. 2011,
38, 7370.
2. Semenov, V. E.; Nikolaev, A. E.; Krylova, E. S.; etc. Russ. J. Org. Chem. 2012,
48, 582.
161
PO 113 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
DESIGN AND SYNTHESIS OF
metal-binding peptides
Marta Soler,a,b Lidia Feliu,a Marta Planas,a Xavi Ribas,b Miquel Costasb
a) QBIS b) LIPPSO, Department of Chemistry, University of Girona, Girona 17071 Spain
[email protected]
A promising approach for the design of novel potential antitumor agents consists
on the conjugation of a metal complex to a peptide sequence in an effort to improve
its activity and bioavailability. Active research has been focused on the use of
complexes of non-toxic metals such as Fe, Cu or Mn. In fact, complexes of these
metals containing the tetradentate ligand Me2PyTACN have been described
as excellent oxidation catalysts on a wide range of substrates (1-3). Moreover,
these N4 ligands are emerging as versatile catalysts for oxidative processes with
biomedical applications. These properties prompted us to study the conjugation
of a Me2PyTACN ligand to the undecapeptide BP16 (4). This sequence has been
identified from a library of antimicrobial peptides and has been shown to exhibit
excellent cell-penetrating properties.
Herein we report a useful methodology for the solid-phase synthesis of peptides
bearing a Me2PyTACN ligand either at the N-terminus or at the Ne-amino group of
a Lys residue. The strategy involves the preparation of a peptide sequence followed
by incorporation of a pyridine derivative as the anchor binding point. Next, the
corresponding secondary amine ligand is attached affording the metal-binding
peptide. The solid-phase synthesis of a range of metal-binding peptides will be
described and discussed.
1. Company, A. et al. Chem. Eur. J. 2008, 14, 5727.
2. Company, A. et al. Chem. Eur. J. 2009, 15, 3359.
3. Gómez, L. et al. Angew. Chem. Int. Ed. 2009, 48, 5720.
4. Badosa, E. et al. Peptides 2007, 28, 2276.
162
Poster presentations / PO 114
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
THIOL-FREE PROCEDURE FOR THE SYNHTESIS
OF THIOETHERS
Agnese Sprūdža, Nadežda Černova, Raivis Žalubovskis
Latvian Institute of organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia
[email protected]
Zinc-containing enzymes Carbonic anhydrases (CA) are playing an important role
in metabolic processes of bicarbonate and carbon dioxide. From presently known
16 CA isoforms, the highest attention is paid to tumor associated CA IX. The waste
majority of known CA inhibitors contain sulfonamide moiety as Zn‑binding group.
Expanding research on new anti-cancer agents we paid our attention to derivatives
of thiophene-2-sulfonamide.
Here we report thiol-free procedure for the synthesis of thiophene-2-sulfonamide
thioethers 2 based on derivatives of thiouronium salt 1.
S
R
Hal
or
R
OH
H2N
Br
NH2
R
S
+
NH2
S
NH2
1
Base
O
S
O
NH2
R
S
S
O
S
O
NH2
2
163
PO 115 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS AND CYTOTOXICITY OF NEW
6,6-DIMETHYL-2-OXO-4‑{2‑[5‑ALKYL­
SILYL(GERMYL)]­HETARYL-2‑YL}VINYL-5,6DIHYDRO-2H-PYRAN-3‑CARBONITRILES
Luba Ignatovich, Velta Muravenko, Jana Spura,
Sergey Belyakov, Irina Shestakova
Latvian Institute of Organic Synthesis, 21 Aizkraukles, Riga LV 1006, Latvia
[email protected]
New 6,6-dimethyl-2-oxo-4-{2-[5-alkylsilyl(germyl)]thiophen-2-yl}-5,6-dihydro2H-pyran-3-carbonitriles have been prepared by condensation of corresponding
silicon(germanium) containing furyl(thienyl)-2-carbaldehydes with 3-cyano4,6,6-trimethyl-5,6-dihydropyran-2-one using pyridine acetate as the catalysts:
O
+
H
O
O
X
R
NH, CH3COOH
C6H6
N
R = Me3Si, Et3Si, Me3Ge, Et3Ge, Me2BuSi, Me2PhSi,
C11
C4
O
O
C2'
X
R
C10
1
N
Si Me , X = O, S; n = 1,2
(CH2) n
The structure of 6,6-dimethyl-2-oxo-4-[2-(5-trimethylsilyl)thiophen-2-yl]-5,6di­hydro-2H-pyran-3-carbonitrile (1a) was studied by X-Ray diffraction method.
The molecule of 1a is characterized by E-conformation: the torsion angle of C4C10-C11-C2’ is equal 178.4(2)°. The effects of the heterocycle and the substituent
at the heterocyclic ring on the cytotoxicity (two tumour cell lines HT-1080, MG22A and normal mouse fibroblasts NIH 3T3) of the compounds have been studied
in vitro. Introduction of the certain triethylsilyl(germyl) group at the thiophene
ring improves the cytotoxicity against cancer cells MG-22A (IC50 = 2-6 mg/ml)
and suitably decreases cytotoxicity to normal cells NIH 3T3 (IC50 = 201-362 mg/
ml). Furthermore, these groups greatly reduce the toxicity of new compounds
(LD50 = 1296-1569 mg/kg).
164
Poster presentations / PO 116
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS, STRUCTURE AND MOLECULAR
MODELING OF 2’-{[(E)-ANDROST-5-EN-17YLIDENE]-METHYL}OXAZOLINES
Sergey V. Stulova, Roman A. Novikovb, Irina V. Fedyushkinaa,
Alexander Yu. Misharina
a
Orekhovich Institute of Biomedical Chemistry RAMS, 119121 Moscow, Russian Federation,
Engelghardt Institute of Molecular Biology RAS, 119991 Moscow, Russian Federation
[email protected]
b
Three step synthesis of 2’-{[(E)-androst-5-en-17-ylidene]-methyl}oxazolines
3 – new probes for investigation target macromolecules and key compounds for
development of potential therapeutics is presented. Interaction of 20-ketosteroid17,21-dihalide 1 with amines led to Favorsky type rearrangement [2]; cyclization of
obtained amides 2, followed by removal of protective groups and/or transformations
of substituents in oxazoline ring results in target 17(20)E-oxazolines 3, particularly
to compounds with C4’ chiral atom[2,3]. Oxazolines 3f and 3g were successfully
docked to ligand-binding site of nuclear receptor LXRβ.
I
O
O
O
Br
AcO
1
X
N
H
2
N
Y
OH
HO
3
X
Y
a, X=Y=H
b, X=Y=CH
c, X-C4'-Y=cyclohexyl
d, X=COOCH3; Y=H
e, X=H; Y=COOCH3
f , X=CH2OH; Y=H
g, X=H; Y=CH2OH
Acknowledgement: This study was supported by RFBR (grant 12-04-31075 mol_а).
References: 1. Stulov S.V. et al., Bioorg. Med. Chem. Lett. 2010, 20, 5495.
2. Stulov, S.V. et al, Steroids 2012, 77, 77.
3. Stulov, S.V. et al, Steroids 2013, Ms-STEROIDS-D-12-00309
(accepted)
165
PO 117 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SYNTHESIS OF SUBSTITUTED PYRIMIDO[4,5-b]
INDOLE RIBONUCLEOSIDES
Michal Tichý, Michal Hocek
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead
Sciences & IOCB Research Center, Flemingovo nám. 2, CZ-16610 Prague 6, Czech Republic
[email protected]
Some 7-hetaryl-7-deazaadenosines showed cytostatic activity against multiple
cell lines in nanomolar concentrations.1 Based on these results, the goal of this
work was to synthesise a series of 4-amino-5(6)hetaryl as well as 4-substituted
pyrimido[4,5-b]indole ribonucleosides to investigate their biological acitivities.
Synthesis started from previously prepared benzoylated 4‑chloro nucleosides2
which were converted to free 4‑aminopyrimido[4,5-b]indole nucleosides or directly
to 4-substituted derivatives. (Het)aryl substituents were introduced into positions 5
or 6 by Pd-catalysed Suzuki or Stille cross-coupling reactions using X-Phos ligand
in DMF. Target nucleosides were tested for biological activities.
c
Cl
R1
N
N
BzO
N
O
OBz OBz
R 1 = H; R2 = H;
R 1 = H; R2 = Cl
R 1 = Cl; R2 = H
R2
NH2
R1
N
a
N
HO
N
O
R2
R3
R2
N
b
N
HO
OH OH
R 1 = H; R 2 = Cl;
R 1 = Cl; R 2 = H;
R 1 = H; R 2 = H;
R1
N
O
OH OH
R 1 = H; R 2 = H; R3 = alkyl,(alkyl)amino
R 1 = heteroaryl; R 2 = H; R 3 = NH 2
R 1 = H; R 2 = heteroaryl; R 3 = NH 2
Scheme 1: a: NH 3 (aq), dioxane; b: Suzuki or Stille coupling; c: i) nucl. subst., Negishi coupling or Pd-catalysed
alkylation; ii) MeONa, MeOH
A
c
k
n
o
w
l
e
d
g
e
m
e
n
t
s
:
This work was supported by the Academy of Sciences of the Czech Republic, Czech
Science Foundation (P207/11/0344) and by Gilead Sciences, Inc.
References:
1) Bourderioux, A. et al. J. Med. Chem. 2011, 54, 5498.
2) Tichy, M. et al. Bioorg. Med. Chem. 2012, 20, 6123.
166
Poster presentations / PO 118
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
SynTHeSIS of NoveL BIOACTIVE
ANTHRA[2,3-b]FURAN-5,10-DIONES
Alexander Tikhomirov, Andrey Shchekotikhin
Gause Institute of New Antibiotics, Moscow, 119021, Russia
[email protected]
Heterocyclic derivatives of anthraquinone are promising compounds to search for
the new anticancer drugs. Previously, we have reported the method of synthesis
of 2-methylanthra[2,3-b]furan-5,10-diones and shown that some of them are
able to inhibit topoisomerase I and have a high anti-proliferative activity [1]. For
further structure-activity studies, we have developed a scheme for the synthesis
of anthra[2,3-b]furan-5,10-diones with carboxamide group at the position 2.
Anthra[2,3-b]furan-5,10-dione-2-carboxamide was obtained from 4,11-di­
methoxy-5,10-dioxoanthra[2,3-b]furan-2-carboxylic acid 1 [2]. Nucleophilic
substitution of methoxy groups by ethylenediamine and the following intro­duction
of the guanidino-residues at side chains produce the final compound 2. Biotesting
established that 4,11-bisguanidine derivative 2 selectively inhibits a growth of
prostate tumor cells (DU-145) and shows a high activity against telomerase and
topoisomerase I –potential targets of cancer therapy. Moreover, the novel derivative
2 has an antiviral activity against Coxsackie B4 virus and resistant Herpes simplex
virus-1.
OMe
O
O HN
O
OMe
O
1
H
N
CO2H
NH
O
N
NH
O
O
HN
2
NH2
N
H
NMe
NH2
References:
1. Shchekotikhin, A. E. et. al. J. Eur. Med. Chem. 2011, 46, 423.
2. Tikhomirov, A. S. et. al. Chem. Heterocyc. Compd. 2012, 47 (10), 1206.
167
PO 119 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
dihydroquercetin metal Complexes:
synthesis, structure and properties
Natalya Trofimova1, Elena Stolpovskaya1, Vasily Babkin1, Roman Zhitov2
1
A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
664033, Russia, Irkutsk, 1 Favorskogo str.
2
Irkutsk State University, Chemical Faculty, 664033, Russia, Irkutsk, Lermontova 126.
[email protected]
Flavonoids, arilbenzo-[b]-pyrans, are large and widespread group of natural
compounds, which have an unusually wide range of biological activity.
Dihydroquercetin (1) - trans-2R3R-2,3-dihydro-2-(3,4-dihydroxyphenyl)
-3,5,7-trihydroxy-4H-1-​​benzopyran-4-on (C15H12O7, M 304) is one of the
representatives of this group. The oxygen atoms can coordinate metal ions to form
aquacomplexes of dihydroquercetin of various types.
We report here the synthesis and properties of new stable mono- and biligand zinc
(2), copper (3) and calcium (4) aquacomplexes, shown in the figure below:
OH
3'
HO
O
7
3
5
OH
O
OH
4'
OH
Zn
1. ÄÊÂ=L
Cu
2+
2. ZnL2(H2O)2, Ñ30H26O16Zn, M 707
2+
2+
3. CuLH2O, Ñ15H13O8Cu, M 385
Ca
4. CaLH2O, Ñ15H13O8Ca, M 361
Physical methods (NMR, IR, UV-vis, EPR, RSEDMA) were used to establishing
the structure and properties of new complex compounds. Results indicate that the
chelation sites are different for zinc, copper and calcium compounds.
The content of bound water in the zinc, copper and calcium complexes of
dihydroquercetin was established by differential scanning calorimetry and
thermogravimetry. It is described; there are two types of bound water in the zinc
complex: weakly and strongly bound. There is only one kind of bound water in
copper and calcium complexes.
The study of the biological activity of the new compounds showed their potential
as candidate molecules for development of medicines.
168
Poster presentations / PO 120
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
POLYMORPHISM OF THE NEW QUINOLONE
DIURETIC CARBOQUINOL
Igor Ukrainets, Nikolai Golik
Department of Pharmaceutical Chemistry, National University of Pharmacy, Kharkiv, 61002,
Ukraine, [email protected]
Since polymorphism of drugs can greatly affect their biological characteristics [1],
any serious pharmaceutical manufacturer can not ignore this problem at present.
By the same reason the government regulatory agencies pay attention to the
issues of obtaining, identification, description, purity and properties of crystalline
forms of products used in pharmacy. As a result, nowadays the registration of a
new medicinal substance became impossible without such information in many
countries of the world. Taking into account these circumstances we have studied
crystal modifications of 6-hydroxy-N-(4-meth­oxy­phenyl)-4-oxo-1,2-dihydro4Н-pyrrolo[3,2,1-ij]quinoline-5-carboxamide (1) proposed under the name of
Carboquinol as a new diuretic.
OH
OMe
O
N
H
N
O
1
Thus, it has been found that depending on the solvent used for crystallization
anilide 1 can actually form some polymorphic modifications, which are different
by their diuretic properties. The conditions, which according to the data of X-ray
powder and single-crystal X-ray structural analysis, NMR 1Н and 13С spectroscopy
in solution, solid-state 13C NMR-spectroscopy, as well as high performance liquid
chromatography allow to obtain the crystal modification of Carboquinol required
with a high chemical and polymorphic purity, have been suggested.
References:
1. Bernshtein, J. Polymorphism in molecular crystals. Oxford: Clarendon Press,
2002.
169
PO 121 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
2,1-BENZOTHIAZINE-3-CARBOXAMIDES AS
POTENTIAL NEW ANALGESICS
Igor Ukrainets, Sergei Dzyubenko, Amjad Abu Sharkh
Department of Pharmaceutical Chemistry, National University of Pharmacy, Kharkiv, 61002,
Ukraine
[email protected]
oxicams are an integral part of the range of modern non-steroidal anti-inflammatory
drugs [1]. piroxicam (1, R = 2-Py) became the first commercially successful drug of
this group. Later its more effective analogs – Isoxicam, Meloxicam, etc., appeared
at the pharmaceutical market. Today they are widely used by practical medicine in
treating numerous rheumatic and autoimmune human diseases under the common
name of selective inhibitors of cyclo­oxy­genase-2. it is interesting that isomeric
oxicams of 4-hydroxy-1-R-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides (2),
which are different only by reverse mutual arrangement of atoms of nitrogen and
sulfur in the thiazine cycle, remain completely unstudied at present. The cause of
the existing situation is known – it is the absence of preparative methods for the
synthesis of compounds of this chemical group.
OH
O
OH
S
O
O
1
Me
O
OAlk
NH-Ar (Ht)
NHR
N
OH
O
N
R
2
S
O
O
N
R
S
O
O
3
We have developed a simple and effective method for obtaining of alkyl 4-hyd­
roxy-1-R-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates (3, R = H, Alk,
All, Ph); on their basis a large series of anilides and hetarylamides 2 have been
synthesized. To confirm their structure NMR spectroscopy (1Н and 13С), mass
spectrometry and X-ray structural analysis have been used. According to the results
of pharmacological trials the substances, which exceed significantly the known
drugs of the oxicam series by their analgesic properties and are of interest for
further profound research, have been found among amides 2 synthesized.
References:
1. Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances:
Syntheses, Patents, Applications of the most relevant APIs, 5th ed., Stuttgart:
Thieme, 2008.
170
Poster presentations / PO 122
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
COUMARIN DERIVATIVES WITH POTENTIAL
ANTICANCER ACTIVITY
Ineta Vendiņa, Anete Parkova, Pēteris Trapencieris
Latvian Institute of Organic synthesis, Riga, Latvia
[email protected]
The carbonic anhydrases (CA) are metalloenzymes, containing zinc ion in the
active site of enzyme. These enzymes catalyze a very simple reaction – inter
conversion of carbon dioxide and the bicarbonate ion­. Many of CA isozymes are
important targets for the design of inhibitors with the clinical applications. Two
main classes of carbonic anhydrase inhibitors are known: the metal complexing
anions and unsubstitued sulfonamides, which bind to the Zn2+ ion of the enzyme.
Coumarin derivatives were shown to constitute a totally new class of inhibitors of
the zinc metalloenzyme carbonic anhydrase­1.
H2NO2S
R2NO2S
R
R
Y
3
O
OH
O
Y=O, NH
1
2
O
O
R=OMe, Me
In our work, we synthesized coumarin sulfonamides 2 via Pechman condensation
and coumarin sulfonylation. Tricylic coumarins 3 were synthesized from ethyl2‑oxocylopentanecarboxylate and phenols 1.
Inhibition of hCA with coumarins were shown.
Acknowledgements: This project was partially financed by European Social Fund
(No. 2009/0203/1DP/1.1.1.2.0/09/APIA/VIAA/023).
References:
1. Temperini, C.; Innocenti, A.; Scozzafava, A.; Parkkila, S.; Supuran, C. T. J. Med.
Chem. 2010, 53, 850-854.
171
PO 123 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
REDOX LABELLING OF NUCLEIC ACIDS FOR
ANALYZING NUCLEOTIDE SEQUENCES
Jana Balintová, Michal Hocek
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead
Sciences & IOCB Research Center, Flemingovo nam. 2, 16610 Prague, Czech Republic
[email protected]
Nucleobase labelling of DNA for electrochemical sensing was attained through
enzymatic incorporation of nucleotide conjugates with redox-active moieties
(anthraquinone1, benzofurazane and azidophenyl) using labelled deoxynucleoside
triphosphates. An efficient two-step methodology for construction of basemodified DNA2 was developed based on aqueous-phase cross-coupling reactions of
halogenated nucleoside triphosphates (dNTPs) with arylboronic acids (the SuzukiMiyaura reaction) or terminal acetylenes (the Sonogashira reaction) followed by
polymerase incorporation. 5-Substituted pyrimidine dNTPs and 7-substituted
7-deazapurine dNTPs are good substrates for some DNA polymerases and can be
incorporated into DNA by primer extension which is suitable for construction of
short DNAs with a few modifications in one strand.
Acknowledgements:
This work was supported by the Academy of Sciences of the Czech republic (RVO:
61388963), Grant Agency of the Academy of Sciences of the Czech Republic
(IAA400040901), Czech Science Foundation (203/09/0317 and P206/12/G151)
and by Gilead Sciences, Inc. (Foster City, CA, U. S. A.).
References:
1. Balintová, J.; Pohl, R.; Horáková, P.; Vidláková, P.; Havran, L.; Fojta, M.;
Hocek, M. Chem. Eur. J. 2011, 17, 14063-14073.
2. Review: Hocek, M.; Fojta, M. Chem. Soc. Rev. 2011, 40, 5802-5814.
172
Poster presentations / PO 124
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Optimization of the lead md77
Daniela Barlocco, Daniela Masciocchi, Stefania Villa, Arianna Gelain,
Fiorella Meneghetti, Byoung-Mog Kwon
Department of Medicinal Chemistry, Università degli Studi di Milano, Italy
[email protected] KRIBB, Daejeon 305 – 333, South Korea
The investigation which led to the identification of our lead MD771 began from
a screening (dual-luciferase assay system) of chemical libraries, performed in
collaboration with our colleagues of the Korean Research Institute of Bioscience
and Biotechnology (KRIBB). MD77 exerted positive results in the dual-luciferase
assay, showing 20% inhibition at 5 μM. It was also able to significantly interact
with STAT3-SH2 domain, with a dose-dependent profile and an IC50 of 17.7 μM
(AlphaScreen-based assay). Moreover, it displayed a significant growth inhibitory
activity evaluated on a panel of tumor cell lines with a GI50 around 2 μM for most
of them. Modeling, docking and crystallographic studies were also performed and
they gave a key support in understanding the binding mode of MD77 to the STAT3SH2 domain. In light of these results, MD77 became our starting point for the
development of new direct STAT3 inhibitors. Initially, the optimized derivatives
were designed following the classical methodologies of medicinal chemistry, in
which the molecule undergoes a gradual modification on the basis of SAR studies
and with the support of molecular modeling studies. In particular, the substitution
of the amidic functionality with a bioisosteric thioamidic group and the nature of
the substituent at position 5 were considered. In detail, alkyl groups or halogens
were introduced in the aromatic ring. In addition, since docking studies on MD77
suggested that in the binding mode of its favoured conformation to the SH2 domain,
which is comparable to that of phosphorylated Tyr-705, the trifluoromethyl group
could play an important role by establishing three hydrogen bond interactions with
the guanidine moiety of Arg-595 residue, we synthesized the analogue lacking the
substituent to verify this hypothesis. The main results from the biological screening
will be displayed in the poster.
CF3
Cl
MD77
HN
O
N
O
N
Acknowledgements: The financial support by PUR 2008 and PRIN 2010-2011 is
acknowledged
References: 1. Masciocchi, D.; Villa S.; Meneghetti, F. et al. MedChemComm.
2012, 3, 592.
173
PO 125 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
novel FPEP nucleotide analogues as
inhibitors of the plasmodial HG(X)PRTs
Ondřej Baszczyňskia, Dana Hockováa, Zlatko Janebaa*, Antonín Holýa, Petr
Jansaa, Martin Dračínskýa, Dianne T. Keoughb and Luke W. Guddatb
Institute of Organic Chemistry and Biochemistry, ASCR, v.v.i., Flemingovo nám. 2, CZ-166 10
Prague 6, Czech Republic; b The School of Chemistry and Molecular Biosciences, The University of
Queensland, Brisbane, 4072 QLD, Australia
[email protected]
a
The causative agents of malaria are protozoan parasites from the Plasmodiidae
family. Hypoxanthine-guanine-(xanthine) phosphoribosyltransferase, HG(X)
PRT, has been suggested as a target for the development of new anti-malarial
therapeutics. Acyclic nucleoside phosphonates (ANPs) are potent and selective
inhibitors of plasmodial HG(X)PRTs.1 A new series of ANPs, bearing the [3‑fluoro(2-phosphonoethoxy)propyl] (FPEP) and [3-fluoro-(2-phosphono­methoxy)­propyl]
(FPMP) moiety has been prepared and tested towards human and plasmodial HG(X)
PRTs (Fig. 1). Some of the FPEPG analogues were found to be potent inhibitors of
human HGPRT, PfHGXPRT, and PvHGPRT with Kis ranging from 0.1 to 29 µM.
Target ANPs
Acknowledgements: This work was supported by the GACR (grant no.
P207/11/0108); NHMRC, AU (grant nos. 569703 and 1030353), MI of the CR
(project VG20102015046); Gilead Sciences (Foster City, CA, USA).
References:
1. de Jersey, J.; Holý, A.; Hocková, D.; Naesens, L.; Keough, D. T.; Guddat,
L. W. Current Topics in Medicinal Chemistry 2011, 11, 2085.
174
Poster presentations / PO 126
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
preperation and characterization of
benperidol solvates and polymorphs
Agris Bērziņš, Edgars Skarbulis, Andris Actiņš
Faculty of Chemistry, University of Latvia, Riga, LV-1013, Latvia
[email protected]
Benperidol
(1-{1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl}-1,3-dihydro2H-benzimidazol-2-one) is butyrophenone derivative, an antipsychotic, which
can be used for the treatment of schizophrenia [1]. In the literature it is described
that benperidol exists in three polymorphic forms, hydrate and ethanol solvate [2].
However, only crystal structure of polymorphic form I is reported [3]. In this study
we examined the possibility of formation and the stability of various crystal forms
of benperidol.
Benperidol was crystallized from various organic solvents. Crystallization
from ethanol, methanol and acetonitrile resulted in formation of solvates with
corresponding solvents, while from other solvents polymorph I was obtained. The
only exception was isopropanol from which polymorph II was obtained in case
of slow crystallization. Crystallization form water resulted in formation of the
dihydrate. Crystal structure of polymorph II, dihydrate and all three solvates was
determined.
Desolvation process of all solvates was studied and obtained results were associated
with crystal structures of solvates and polymorphous forms.
Dehydration kinetics of benperidol dihydrate was studied in isothermal mode and
dehydration activation energy and kinetic model was determined.
References:
1. Bobon, J.; Collard, J.; Lecoq, R. Acta Neurol. Belg. 1963, 63, 839.
2. Azibi, M.; Draguet-Brughmans, M.; Bouche, R. Pharm. Acta Helv. 1982, 57,
182.
3. Declercq, J.P., Germain, G., Koch, M. H. J. Acta Cryst. 1973, B29, 2311
175
PO 127 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
CLICK IMMOBILIZATION OF CALIX[4]ARENE
IONOPHOREs oN Azide-modified PVC
MATRIces
János B. Cziroka, Márton Bojtára, Gyula Jágerszkib, Zsuzsanna Őric,
Géza Nagyc and István Bittera
Budapest University of Technology and Economics, Budapest, H-1111, Hungary: aDepartment of
Organic Chemistry and Technology, bInstitute of Inorganic and Analytical Chemistry; cUniversity of
Pécs, Department of Analytical and Physical Chemisty, Pécs, H-7600, Hungary
[email protected]
The Cu+ catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) yielding
1,2,3-triazoles is the premier example of ‘click’ reactions that has been frequently
applied in bioconjugation, drug discovery and materials science. This method was
lately utilized in the development of a new, PVC-based ion-selective electrode
(ISE) in which the sensing molecule was anchored to the polymer matrix, thereby
eliminating the disadvantage of the traditional ISEs (leakage of the membrane
components), a longer electrode lifetime was achieved.
O
O
O
O
O
O
( )n
OR
I
O
O
PVC-N3
O
O
O
Cu(I)
O
OR
( )n
N
II
N N
PVC
Now our current results concerning the synthesis of K -selective alkyne- modified
calix[4]crown-5 ionophores (I) and coupling thereof to PVC-azide via CuAAC
(Fig.), along with the potentiometric ion-selectivity of ISEs fabricated from the
covalently immobilized ionophores (II) are presented.
+
Acknowledgements: Financial supports by the Hungarian Scientific Research
Fund (OTKA No. K 67585) are gratefully acknowledged. The project is cofinanced by the European Union and Hungary and implemented in the framework
of the Hungarian ‘Social Renewal Operational Programme’ fellow sponsorship
(TÁMOP 4.2.4.A/1-11-1-2012-0001).
176
Poster presentations / PO 128
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
zn AND Pd PYRAZOLE COMPLEXES AS
PHOTOLUMINESCENT MATERIALS
MP. Cornagoa, RM. Claramunta, L. Soriab, M. Canob, P. Ovejerob, R. Torres
Dpto, Química Orgánica, UNED and b Dpto, Química Inorgánica, UCM. E-28040 Madrid, Spain
[email protected]
a
Self-assembly of transition metal complexes is a domain of increasing interest for
the design of supramolecular structures 1, 2. New pyridine-functionalized pyrazole
N,N,N-tridentate ligands [pypzR(n)py] (R(n) = C6H4OCnH2n+1; n = 1, 12, 14, 16, 18 (I)
and their corresponding zinc and palladium complexes [MCl2(pypz R(n)py)] (M = Zn;
Pd) (II, III), have been synthesized and studied. Multinuclear NMR spectroscopy
(1H, 13C and 15N) in solution as well as in the solid state is used to quantify the
coordination effects induced by Zn and Pd on the chemical shifts of the substituted
pyrazole ligand and allows establishing the coordination modes in each case.
N
N
H2n+1CnO
N
N
N
N
(I)
H2n+1CnO
Cl Cl
Zn
N
N
(II)
Cl
N
N
H2n+1CnO
N
Pd
Cl
N
(III)
The 13C and 15N CPMAS NMR results are in agreement with the X-ray structures.
Furthermore, the analysis of the optical data of these complexes pointed out the
luminescent behavior of complexes (II) n = 12 and 18.
Acknowledgements:
This work has been financed by the Ministerio de Ciencia e Innovación, Spain
(Project number CTQ2010-16122) and Universidad Complutense de Madrid,
Spain (Project number GR35/10-A-910300).
References:
1. Mayoral, M. J., Cornago, P., Claramunt, R. M., Cano, M. New. Journal. Chem.
2011, 35, 1020.
2. Ovejero, P., Asensio, E., Heras, J. V., Campo, J. A., Cano, M., Torres, M. R.,
Núñez, C., Lodeiro, C. Dalton Trans. 2013, 42, 2107.
177
PO 129 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
3-Alkenyl indoles as tryptophan
2,3-dioxygenase inhibitors for
the enhancement of cancer
immunotherapy
E. Dolušić,a L. Pilotte,b L. Moineaux,a P. Larrieu,b V. Stroobant,b D. Colau,b
L. Pochet,a E. De Plaen,b C. Uyttenhove,b B. Van den Eynde,b J. Wouters,a
B. Masereel,a S. Lannersa and R. Frédéricka
a
Namur Medicine & Drug Innovation Center (NAMEDIC), Namur Research Institute for Life
Sciences (NARILIS), University of Namur, B-5000 Namur, Belgium;
b
Ludwig Institute for Cancer Research, Brussels Branch, and de Duve Institute, Université
Catholique de Louvain, B-1200 Brussels, Belgium
[email protected] Recently, our group has shown that tryptophan 2,3 dioxygenase (TDO), a hepatic
enzyme catalyzing the first step of tryptophan degradation, is expressed in many
tumors, thereby contributing to tumoral immune resistance.1 The complementary
role of tryptophan catabolites has been demonstrated by others.2
We set out to develop new, improved TDO inhibitors using as the starting point
the only (unoptimized) series previously known in the literature.3
N N
F
N
H
N
N
H
Herein, we describe the syntheses and structure-activity studies around a series of
3-alkenyl indoles and their derivatives.4 The TDO inhibitory potency was evaluated
and rationalized by molecular modeling studies, while solubility, stability and oral
bioavailability were determined for selected compounds. The most promising
candidate was evaluated in a preclinical model in mice where, upon systemic
treatment, it indeed reversed TDO-mediated tumoral immune resistance.5
References:
1. Van den Eynde, B., et al, WO2010008427, 2010.
2. Opitz, C. A., et al, Nature 2011, 478, 197-203.
3. Madge, D. G., et al, Bioorg. Med. Chem. Lett. 1996, 6, 857-860.
4. Dolušić, E., et al, J. Med. Chem. 2011, 54, 5320-5334; Moineaux, L., et al, Eur.
J. Med. Chem. 2012, 54, 95-102.
5. Pilotte, L., et al, Proc. Natl. Acad. Sci. USA 2012, 109, 2497 – 2502.
178
Poster presentations / PO 130
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
EFFECTS OF ALKYLSULFANYLPYRIDINES
AND PYRIDOTHIAZINES ON P-gp mediated
multidrug resistance
Signe Grinberga, Aivars Krauze, Laura Krasnova, Elina Jaschenko,
Ilona Domracheva, Irina Shestakova, Gunars Duburs
Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia
[email protected]
P-glycoprotein (P-gp) mediated multidrug resistance (MDR) is recognized as
major type of MDR in various kinds of cancer cells. The dihydropyridine (DHP)
derivatives were one of the first class of drugs which was identified as MDR
inhibitors, but their advancement to clinical applications has been restricted
due to their cardiovascular side effects. As part of our ongoing project to design
new MDR modulators, we represent the synthesis and biological activity of
alkylsulfanylpyridines 2-3 and pyridothiazines 4.
Compounds 2-3 having arylpiperazine moiety variously linked to DHP or pyridine
nucleus were synthesized and selective P-gp modulating activity was revealed. When
chloroalkylsulfanyl-1,4-DHP 1 were treated with NaOH or NaOEt, intramolecular
alkylation at N-1 atom occurred. Various substituents were introduced by acylation
or alkylation of hydroxyl group at the position 3.
O
Ar
1
O
CN
1
R
N
H
O
Ar
S
1
S
N
4
O
CN
1
2
Hal
N
H
R
O
CN
R
1
R
( )n
1
1
Ar
Ar
S
2
( )n
N
2
R
N
Ar
2
1
CN
1
R
N
S
3
( )n
2
R
N
N
Ar
2
3
R
179
PO 131 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
novel CLASS of acyclic nucleOside
phosphonates:
(S)-3-hydroxy-2-(phosphonO­ETHOXY)
propyl ANALOGUES
Martin M. Kaiser, Martin Dračínský, Lenka Poštová Slavětínská,
Dana Hocková, Dianne T. Keough, Luke W. Guddat, Zlatko Janeba*
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i.
CZ-16610, Prague 6, Czech Republic;
The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
[email protected]; [email protected]
Acyclic nucleoside phophonates1 (ANPs) are nucleotide analogues well-known
for the wide range of biological activities, especially antiviral,2 antiparasitic,3 and
cytostatic.4 In the present study, an efficient synthesis of the (S)-3-hydroxy-2-(phos­
phonoethoxy)propyl (HPEP) analogues has been developed. Biological properties
of the prepared HPEP derivatives and of their bis-amidate prodrugs have been
eva­luated. None of the prepared compounds 1-4, bearing the 6-oxopurine nucleo­
bases, was active at subtoxic concentration against the viruses tested (HIV-1, HIV-2,
MSV, HSV-1, HSV-2, CMV, VZV) but all of them revealed interesting inhibitory
effects on human and/or Plasmodium hypoxanthine-guanine-(xanthine) phosphor­
ribosyltransferases (HG(X)PRTases). HG(X)PRTase is the key enzyme of the purine
metabolism of Plasmodium species, protozoan parasites causing malaria, and thus
represents a potential drug target to combat this serious infectious disease.
O
O
N
HN
N
N
1
O
HO
N
OEt
P OEt
O
N
HO
O
O
O
O
NH
P NH
O
O
O
2
O
N
HN
H2N
N
HN
N
N
3
HO
N
HN
O
OEt
P OEt
O
H2N
N
N
HO
O
O
4
O
NH
P NH
O
O
O
This work was supported by the Grant Agency of the Czech Republic (grant No. P207/11/0108), National
Health and Medical Research Council, Australia (grant No. 1030353), and by Gilead Sciences, Inc.
(Foster City, U.S.A.).
References:
1. De Clercq E., Holý A., Rosenberg I., Sakuma T., Balzarini J., Maudgal P.: Nature 1986,
323, 464.
2. a) Holý A.: Antiviral Res. 2006, 71, 248; b) De Clercq E.: Antiviral Res. 2007, 75, 1.
3. a) de Jersey J.; Holý A.; Hocková D.; Naesens L.; Keough D. T.; Guddat L. W. Curr. Top.
Med. Chem. 2011, 11, 2085. b) Hocková D., et al.: J. Med. Chem. 2012, 55, 6209.
4. Zídek Z., Potměšil P., Holý A.: Toxicol. Appl. Pharm. 2003, 192, 246.
180
Poster presentations / PO 132
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
use of Sesquiterpene lactones in
medicinal chemistry
Sergey Klochkov, Sergey Pukhov
Laboratory of natural products, Institute of Physiologically Active Compounds RAS, Chernogolovka,
142432, Russian Federation
[email protected]
Natural products are the inexhaustible source of chemical diversity that can be
compared only with the powerful combinatorial chemistry techniques [1]. Plant
secondary metabolites cause active interest in connection with their authentic
influence on development of new drugs with outstanding properties. The object of
our work - sesquiterpene lactones are widespread among higher plants. Biological
activities of sesquiterpene lactones are well known and documented, since their use
in national medicine and numerous scientific researches in recent years [2].
In the present report data on biological activity of sesquiterpene lactones of plant
family Asteraceae for last 20 years are summarized, the basic biochemical targets
are considered. The structure-activity relationship, the molecular mechanisms and
the potential application are considered. Special interest is represented with complex
researches in which interaction of sesquiterpene lactones with enzymes and receptor
structures and role of these interactions in development of disease are considered
with the most in detail emphasis on the use of sesquiterpene lactones as potential
antineoplasts. Examples of their influences on development of a tumor growth
are shown and discussed, as well as specific biochemical targets. The potential of
sesquiterpene lactones in anticancer drug development lays down in their complex
action on different biochemical targets and that is why sesquiterpene lactones are
emerging as promising multitarget anticancer agents with potential applications in
both cancer chemotherapy and chemoprevention.
References:
1. A.L. Harvey. Trends Pharmacol Sci., 1999, 20, 196
2. B.M.Fraga. Nat. Prod. Rep., 2006, 23, 943
181
PO 133 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
In Situ Powder X-ray Diffraction
Investigation of xylazine
hydrochloride phase transition from
X to A form
Kristīne Krūkle-Bērziņa, Andris Actiņš
Department of Chemistry, University of Latvia, Riga, LV-1045, Latvia
[email protected]
Xylazine hydrochloride (2-(2,6-xylidino)-5,6-dihydro-4H-1,3-thiazine hydro­
chloride) is an adrenergic α-agonist used as a sedative, analgesic, and muscle
relaxant in veterinary medicine [1]. It known to exist in four polymorphs (A, M, Z
and X) and several pseudopolymorphs. It has been reported that the polymorph X
is thermodynamically the least stable of these polymorphs, while the form A is the
most stable at temperatures above 50 oC [2, 3].
Most commonly during the examination of solid phase transformation each time it
is necessary to analyse the sample it should be removed from the conditions where
transformation is studied. This perturbation can introduce error into experimental
data and alert the transformation process; therefore to collect the accurate data it is
better to analyse the sample in situ and in real time.
In this study the phase transition from xylazine hydrochloride polymorph X to A
was investigated with powder x-ray diffractometer in in situ mode. Phase transition
was studied in temperature interval 80-120 oC. Obtained results were compared
with data obtained in traditional manner.
References:
1. European pharmacopoeia, 4th edition. Council of Europe, Strasbourg, 2001,
2152.
2. Bērziņš, A., Actiņš, A., Veldre, K. Lat. J. Chem. 2008, 3, 263.
3. Bērziņš A., Krūkle K., Actiņš A, Kreišmanis J. P. Pharm. Dev. Technol. 2010,
15, 217.
182
Poster presentations / PO 134
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
COMPLEXES BASED ON THE
OCTATHIOTETRAPHOSPHETANE
AMMONIUM SALTS.
STRUCTURE AND PROPERTIES
Lidiya Kursheva, Elvira Batyeva, Elena Zvereva,
Elena Badeeva, Elena Platova, Oleg Sinyashin
A.E. Arbuzov Institute of Organic and Physical Chemistry of Kazan Scientific Centre of Russian
Academy of Sciences, Arbuzov Str. 8, 420 088, Kazan, Russia
e-mail: [email protected]
Modern stage of development of organometallic and co-ordinated chemistry
is characterized by the wide use of polyfunctional ligands. Cyclic octathiophos­
phe­tanes, namely their ammonium salts pertain to the novel heterocyclic ligands
of such type. To study their complexation with transition metals, the reaction of
piperidinium and triethylammonium salts of octathiotetraphosphetane with Cu(I),
Ag(I), Co(II), Fe(II) halides was performed. Complexes obtained were character­
rized by the X-ray diffraction and IR/Raman spectroscopy combined with DFT
calculations.
As heterocyclic compounds bearing a various functional groups in molecules
these compounds are expected to possess wide set of useful properties, including
biological activity. They were systematically assessed for their anti-fungal
properties. Some of the tetraphosphetane derivatives have been identified as potent
and promising anti-fungal (Candida albicans) agents whose activity are
comparable to that of Amphotericin B, the fungicidal activity of metal derivatives
exceeding twice that of initial ammonium salts of octathiotetraphosphetane.
Acknowledgements: The grants of RFBR (№ 12-03-00479-а, and DCSM RAS
Program 6) are gratefully acknowledged
183
PO 135 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
The bezo[c][1,2]oxaboroles heterocycles as active
fragments for transformation of clarithromycin
Lapa G.B.1, Malyutina N.M.1, Korolev A.M.1, Luzikov Y.N.1, Mirchnk E.P.1, Xia
A.2, Plattner J.J.2, Preobrazhenskaya M.N.1
Gause research institute of new antibiotics, Moscow, Russia.
Anacor Pharmaceutical Inc., Palo Alto, CA, USA
[email protected]
1
2
OH
B
O
O
N
H
HO
OH
O
O
HO
OH
O
H2N
O
O
HO
O
O
O
O
O
MIC in μg/
ml
CLA
BB
1
2
OH
B
O CLA
O
N 9
1
O
BB
O
O
O
N
N
H
B
HO
OH
Streptococcus
pneumoniae
4.0
>64
4.0
0.5
N
HO
O
O
O
O
O
4''
O
2
Klebsiella
pneumoniae
>64
1.0
>64
>64
It is known that 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaboroles (BB) interact
with bacterial Leu-tRNA of Gram-negative strains. Clarithromycin (CLA) is the
ligand of bacterial rRNA of Gram-positive microbes. We made computer models
and elaborated two synthetic approaches for conjugates CLA and BB. The first
pathway explored the substitution of the C-9 carbonyl group of CLA, the second
direction used the addition to the 4’’-OH group of cladinose via formation of
carbamates of BB. Antibiotic 1 was as a mixture of syn- and anti-isomers. All
final products (1, 2) had just one peak in ESI-MS. The main side reaction of
second direction was deboration of 2. Antibiotics 1 and 2 showed no broad
efficacy simultaneously on Gr- and Gr+ strains. Antibiotic 2 was more active
than CLA.
184
Poster presentations / PO 136
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
1,2-benzoxathiine 2,2-dioxides as
inhibitors of CA
Alons Lends, Aiga Grandane, Raivis Zalubovskis, Edvards Liepinsh
Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia
[email protected]
Carbonic anhydrases (CA) are proteins which catalyze the hydration of CO2 and
dehydration of bicarbonate in vivo [1]. There are 15 different isoforms of CA,
which are expressed in different cell types. Recently in Latvian Institute of Organic
Synthesis coumarin bioisosters - 1,2-benzoxathiine 2,2-dioxides (sulfocoumarines)
were synthesized [2]. Sulfocoumarines (1) act as CA IX inhibitors.
We used 1D (1H, STD, WaterLOGSY and T1ρ) and 2D (15N-1H HSQC) NMR
experiments to study the hydrolysis, Z/E isomerisation and possible interactions of
these compounds with CA.
CA
1
O
SO2
OH
SO3
Fig.1.CA catalyzed hydrolysis of sulfocoumarines.
Based on protein backbone amide chemical shift perturbation data, we modeled
the 3D structures of the protein-inhibitor complex using molecular docking
(OPLS 2005 force field). Chemical shift changes of the inhibitor suggested that
sulfocoumarines bind in an opened form and the SO3 group interacts with the zinc
ion of CA.
References
1. V. M. Krishnamurthy, G. K. Kaufman, A. R. Urbach, I. Gitlin, K. L. Gudiksen,
D. B. Weibel, G. M. Whitesides. Chem. Rev. 2008, 108, 946.
2. A. Grandane, S. Belyakov, P. Trapencieris, R. Zalubovskis, Tetradron 2012, 68,
554.
185
PO 137 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
BIOACTIVE MACROCYCLIC CARBENOIDS OF
AZOLE SERIES
Kostiantyn Marichev, Nikolai Korotkikh, Artem Kiselyov, Oles Shvaika
L.M. Litvinenko Institute of Physical Organic & Coal Chemistry NASU, 83114, Donetsk, Ukraine
[email protected]
A series of carbene complexes of transition metals as well as some azolium
salts and carbenoid derivatives of azoles have been studied for antimicrobial
activity recently [1, 2]. However the structural influence of anions and bridges in
carbenoid compounds has been less studied up to now. The goal of our research
was studying antimicrobial activity of crown-azolium salts: 1,1’,3,3’-bis(3-oxa1,5-pentylene)bisimidazolium and 1,1’,3,3’-bis(3-oxa-1,5-pentylene)bisbenz­imid­
azolium chlorides, isothiocyanates, thiosulfates 1; cyclophane-azolium derivatives
‑ 1,1’,3,3’-bis(1,12-dodecamethylene)bisimidazolium salts 2; polymeric copper(I)
and nickel biscarbene complexes 3. The antimicrobial and antifungal activities
were studied on test-cultures of the bacteriums E. coli, S. aureus, M. luteum and
the mushrooms C. tenuis, A. niger using the diffusion into agar and serial dilution
methods. The highest antimicrobial activity of 1,1’,3,3’-bis(1,12-dodeca­methylene)
bisimidazolium salts 2 was found in vitro: chloride – for S. aureus (МBSC 31.2 and
МBCC 62.5 mg/l), M. luteum (МBSC and МBCC 3.9 mg/l); thiocyanate – for
S. aureus (МBSC 3.9 and МBCC 7.8 mg/l), M. luteum (МBSC 1.9 and МBCC
3.9 mg/l).
R
+
N
R'
N
O
O
1
N
+
N
nX
R
R'
z-
+
N
N
(
)
10 N
)
10
(
2
(
+
N
nX
z-
)m
O
N
RR
N
N
R' R'
O
N
(
M
Xz
n
)m
3
Acknowledgement: Financial support ‑ grant № 83/09.02.12, NAS of Ukraine.
References:
1. Ray, L., Katiyar, V., Raihan, M. J., Nanavati H., Shaikh, M. M., Ghosh, P. Eur. J.
Inorg. Chem., 2006, 18, 3724;
2. Hindi, K. M., Siciliano, T. J., Durmus, S. et al. J. Med. Chem., 2008, 51, 1577.
186
Poster presentations / PO 138
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
The biological activity of HETARENO[e]
PyrROLe-2,3-diones
Irina Mashevskaia, Nadia Suchkova, Andrei Maslivetc
Department of Chemistry, Perm State University, Perm, 614990, Russia
[email protected]
Reactions of polycarbonyl derivatives of pyrrole-2,3-diones provide a wide
opportunities of molecular design of compounds, containing groups of pharmaco­
phores. Substances exhibiting antimicrobial, analgesic, anti-inflammatory and
antihypoxic activity were detected among hetareno[e]pyrrole-2,3-diones and their
derivatives [1-3].
H
N
O
H
N
O
N
O
Ar
H
N
O
N
O
N
O
NNHCOR
HO
Ar
V
O
O
N
O
N N CO
H
O
BH
OH
H
N
O
Ar
N
O
II
O
O
Ar
IV
N NHCOR
HO
O
I
H
N
O
HO Ar
III O
O
Ar
N
HO
VI
CONH N
N
N
Compounds I-IV showed analgesic activity and substances with pronounced
analgesic activity comparable with effect of Voltaren were found. Compound V
(B=OH) showed high activity against St.aureous. Compounds VI have a good
percentage of inhibition (~ 75%) on carrageenan-induced rat paw edema model.
Expressed antihypoxic activity was found for compounds V (B=SCH2COOH).
References:
1.I. Mashevskaia, R. Mahmudov, G. Aleksandrova, o. Golovnina, A. Duvalov, A.
Maslivets. Pharmaceutical Chemistry Journal 2001, 35(4), 20.
2.I. Mashevskaia, L. Anikina, Y. Viharev, S. Koltcova, А. Maslivets. Patent
2199537. Russian Federation. 2003.
3.I. Mashevskaia, R. Mahmudov, L. Kuslina and А. Maslivets. Pharmaceutical
Chemistry Journal 2011, 45(11), 106.
187
PO 139 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Utilizing EPRI as a In-vivo detection
method for amyloidogenic proteins
Jeffrey J. Masona, Håkan Gustafssona, Mikael Lindgrena,b,
Per Hammarströma, K. Peter, R. Nilssona
a
Linköping University Department of Physics,Chemistry and Biology (IFM), SE-58183 Linköping,
Sweden. bNTNU, Department of Physics, 7491 Trøndheim, Norway.
[email protected]
Herein we report the synthesis of a novel set of biomarkers which utilize
luminescent conjugated oligothiophenes (LCOs), containing stabilized radicals, to
provide insight into the detection of amyloidogenic protein aggregates through the
used of electro-paramagnetic resonance imaging (EPRI) for in-vivo detection of
amyloid diseases.
Luminescent conjugated polythiophenes (LCPs) have recently been introduced as
a class of amyloid-binding fluorescent probes. In 2009, Åslund et al. improved
on the concept, presenting defined structures (LCOs) which could be utilized for
postmortem imaging of protein aggregates.[1] LCPs and LCOs are comprised of
a conjugated thiophene backbone, giving a combination of flexibility and rigidity,
which results in conformation-sensitive spectral signatures when coordinated with
amyloid proteins. This concept was further expanded upon where a library of
oligothiophenes of defined lengths (4-7 thiophene units) displayed variations in
their spectra. Some LCOs were also shown to be spectrally discriminative between
two different types of amyloid proteins (Aβ and Tau) present in the tissue samples
[2].
The introduction of stabilized radical moieties, as spin labels, to the LCOs for imaging
in-vivo samples of amyloid proteins is the next evolution in our investigations.
This study explores optimization between selected LCOs and suitably stabilized
EPRI spin labels including the establishing the relationship between spacers to
observe any changes in response between the binding of spin-LCOs.
References:
1. Åslund,A.; Sigrudson, C. J.; Kilngstedt, T.; Grathwohl, S.;Bolmont, T.;
Dickstein, D. L.; Glimsdal, E.; Prokop, S.; Lindgren, M.; Konradsson, P.;
Holtzman, D. M.; Hof, P. R.; Heppner, F. L.; Grandy, S.; Jucker, M.; Aguzzi, A.;
Hammarström, P.; Nilsson, K. P. R.: ACS Chem. Biol. 2009, 4, 673.
2. Klingstedt, T.; Åslund, A.; Simon, R. A.; Johansson, L. B. G.; Mason, J. J.;
Nyström, S.; Hammarström, P. and Nilsson, K. P. R. Org. Biomol. Chem., 2011,
9, 8356.
188
Poster presentations / PO 140
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
FURODIHYDROQUINOLINES –SENSITIZERS
FOR PUVA THERAPY
Tatiana N. Nekipelova, V.A. Kuzmin, E.N. Khodot, V.V. Shakhmatov
Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, 119334 Russia
[email protected]
PUVA therapy, the method based on combined action of psoralen preparations and
long-wavelength UV irradiation (UVA), is widely used for medical treatment of skin
diseases. The formation of the cycloaddition adducts of psoralens to thymine bases
of DNA upon UVA irradiation is the main factor causing the therapeutic efficacy of
these compounds. The disadvantage of psoralens is the possibility of cross-linking
of two DNA molecules with a psoralen molecule that causes the genotoxicity
and may provoke cancer. That is why novel photo­sen­sitizers for PUVA therapy
deprived of this disadvantage are examined. Several angular furodihydroquinolines
(FDQ) with different positions of the furan ring and different substituents in the
aromatics were synthesized.
R
CH3
O
O
N
H
CH 3
CH3
R
CH 3
N
H
CH 3
CH3
R = H, NO2, NHCO(CH3)
The FDQ displayed very low total toxicity on cell cultures without irradiation,
toxicity under UVA irradiation by the mechanism of apoptosis and the
antioxidation activity. FDQ have a yield of the triplet state. The monoadducts of
photocycloaddition reaction between FDQ and thymidine monophosphate (TMP)
were identified in the photolysate of the FDQ + TMP mixture. Our results show that
FDQ can be considered as potential photosensitizers for PUVA therapy.
Acknowledgements: The study is supported by the Program no. 9 “Medicinal and
Biomolecular Chemistry”of the Division of Chemistry and Material Sciences RAS
189
PO 141 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
NEW ORGANOPHOSPHORUS ACIDS
WITH HETEROCYCLIC FRAGMENTS
AS PERSPECTIVE ANTIOXIDANTS AND
CYTOPROTECTORS
A.A. Prishchenko, M.V. Livantsov, O.P. Novikova, L.I. Livantsova,
E.R. Milaeva, V.S. Petrosyan
Department of Chemistry, M.V. Lomonosov Moscow University,Moscow, 119991, Russia.
[email protected]
Functionalized organophosphorus acids and their derivatives with heterocyclic
and aromatic fragments are of great interest as effective chelating ligands and
perspective bioactive substances with various properties. These acids are wellknown analogs of hydroxyl(amino)carbonic acids and natural pyrophosphates.
We have developed the convenient methods of synthesis of new functionalized
organophosphorus acids and their derivatives including heterocyclic, aromatic and
unsaturated fragments as well as hydroxyl, amino, and carboxyl groups using as
starting compounds the trimethylsilyl esters of several trivalent phosphorus acids
and functionalized alkenes, aldehydes, and carbonic acids1,2. The new water soluble
organophosphorus acids or their salts which are presented here.
HO
PCH(OH)Ar
x O
[(HO)2P]2CHNHAr
HO
P C(OH)R
x
O 2
Ar Alk
[(HO)2P]2CHAr
O
O
CH(OH)Ar
(HO)2PCHNC(O)R ArNHCH P
O
O
OH
HOP[CH(Y)R]2
O
2
R = MeCH=CH, Me(CH=CH)2, PhCH=CH, Me(CH2)7CH=CH(CH2)7, Py (2-, 3-, 4-), Ar;
t-Bu
Ar = Ph , HO
t-Bu
,
O
,
S
,
, Py;
NH
O
x = OH, (CH2)2Ph, (CH2)2Py, (CH2)2COOH, (CH2)nN
, n = 1,2;
Y = OH, NHR, N(R)Ac, N(R)C(O)(CH2)7CH=CH(CH2)7Me.
Multifactor antioxidative activity of these acids was investigated on homogenates
of rat liver, fish sperm (Asipenser gueldenstaedti B.), and rat liver mitohondria.
Also the influence of these compounds was studied on functional characteristics
of rat liver mitohondria and on tert-BHP- and Fem+- induced toxicity in cerebellar
granule cells of rats. This work was supported by RFBR, grants 11-03-00402 and
12-03-00003.
1. Prishchenko, A.A., Livantsov, M.V., Novikova, O.P., Livantsova, L.I., Petrosyan,
V.S. Heteroatom Chemistry, 2010, 21, 361; 2012, 23, 27 and 32.
2. Patent RU 2405032 C 1, Rus. Patent Bull., 2010, 33; Patent RU 2457240 C 2,
Rus. Patent Bull., 2012, 21.
190
Poster presentations / PO 142
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Discovery and hit-to-lead optimization
of Tetrahydro­Quinolines and
Tetrahydro­[1,6]naphtiridines as novel
mGlur5 positive allosteric modulators
Victoria Ryabova, Alvina Haritonova, Guna Sakaine and Ronalds Zemrībo
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia
[email protected]
The therapeutic potential of metabotropic glutamate receptor 5 (mGluR5) as a drug
target, has recently been explored and expanded. It is considered that mGluR5
receptor agonists have treatment potential for both positive and negative, as well
as cognitive symptoms of schisophrenia.1 Positive allosteric modulators (PAMs)
of mGluR5 receptor have several important advantages over orthosteric agonists,
including increased subtype selectivity and much better brain penet­ration.
R1
R2
N
N
Lead Series 1
R1
O
N
O
O
N
"Hit"
R2
N
Lead Series 2
Herein, we report the discovery of novel, selective mGluR5 positive allosteric
modulators based on an earlier identified hit2. The synthesis, in vitro studies and
structure-activity relationships of the newly identified lead series will be presented.
References:
1. Spooren, W. et.al. Expert Opin. Ther. Patents (2008) 18(2); 123-142
2. WO2012/52451A1
191
PO 143 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
biological activity of pyrrolo-[1,2-a]
thieno[3,2-e]pyrimidineS
Sergey Shipilovskikh, Aleksandr Rubtsov
Department of Natural and Biological Active Compounds, Perm State University, Perm, Russia
[email protected]
Earlier we proposed a simple method for the production of a series of N‑substituted
5-aryl-3-imino-3H-furan-2-ones by the intramolecular cyclization of N-substituted
2-amino-4-aryl-4-oxobuten-2-oic acids in the presence of acetic anhydride [1]. At
the same time, the rare type of 2-furanone derivatives seemed extremely promising
from the standpoint of high reactivity and the possible presence of biologically
active compounds in series of furan derivatives. Moreover, the introduction of a
thiophene substituent into the structure at the imine nitrogen atom increases the
prospects of these compounds even further. The Gewald reaction products are
widely employed in drug discovery as an important biological entity, which were
actively employed in synthesis of a variety of target family classes [2].
We synthesized ethyl 2-(2-oxofuran-3(2H)-ylideneamino)thiophene-3-carboxy­
lates 1 and investigated their recyclization reactions.
R3
R2
S
ON
N
R1
O
1
R4
Et3N
O
O
R4
OEt
H2N
O
R1
N
S
EtO
R3
2
O
R4
O
R2
HN
H+
-EtOH O
R3
O
R1
N
S
3
R2
R1=Ar, Het; R2,R3=Alk, Ar; R4=COOAlk, CONH2
It was found that 2, in the presence of derivatives of cyanoacetic acid, undergo
smooth cyclization into tricyclic compounds 3.
The mechanism of reactions and biological activity of compounds 2,3 will be
discussed.
Acknowledgements: The work was carried out with support from the Russian
Fundamental Research Fund (11-03-00882 and 12-03-31739) and Ministry of
Education Perm Region.
References:
1. Rubtsov, A.E., Zalesov, V.V., Russ. J. Org. Chem., 2003, 39, 918.
2. Puterová, Z., Krutošíková, A., Véghc D., ARKIVOC, 2010, (i), 209-246.
192
Poster presentations / PO 144
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
imidazole and its derivatives in protein
refolding process
Jolanta Sereikaite1, Andrejus Cirkovas1, Albinas Zilinskas1,2
Department of Chemistry and Bioengineering, Vilnius Gediminas Technical University, Vilnius,
LT-10223, Lithuania
2
Department of Organic Chemistry, Vilnius University, Vilnius, LT-03225, Lithuania
[email protected]
1
Recombinant DNA technology allows the production of proteins in large quantities
and supplies them as needed for genomics and proteomics research. However,
heterologous proteins can form aggregates, which are called inclusion bodies.
To recover biologically active protein, inclusion bodies have to be isolated and
solubilized, and the target protein has to be refolded to its native structure. However,
the renaturation process of proteins deals with their aggregation [1]. Imidazole 1
and its derivatives, i.e., 2-(1H-imidazol-4-yl)­ethan­amine (histamine) 2 and N-(1Himidazol-5-yl)guanidine 3 were tested as anti-aggregatory additives in the protein
refolding process from Escherichia coli inclusion bodies.
N
N
N
H
N
H
1
N
NH2
2
N
H
NH
3
N
H
NH 2
Veterinary growth hormones were used as model proteins. It was found that
imidazole and its derivatives inhibit protein aggregation, and the effect is dependent
on the concentration of additive.
Acknowledgements: This research was funded by a grant (No PRO-12/2012)
from the Research Council of Lithuania.
References:
1. Zilinskas, A; Sereikaite, J. Biotechnol. Appl. Biochem. 2011, 58, 277.
193
PO 145 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
NEW 5-ARYLIMINO-2,5-DIHYDROISOTHIAZOLE DERIVATIVES
Ingrida Skrastiņa, Dzintra Muceniece, Andrei Baran
Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia
[email protected]
Isothiazoles (1,2-thiazoles) are known since 1950-s as biocides, antiviral and
anti-inflammatory agents [1]. However partially hydrogenated, especially 2,5-di­
hydroisothiazole derivatives were studied to a much lesser extent [2]. Conven­
tional synthetic approach for these compounds includes oxidative cyclization of the
available amides of 3-amino-2-propenthioic acid.
R
R
1
R
N
2
H
H
N
S
1
[oxidant]
R
3
-2H
R
1
R N S
R
2
N
R
3
2
R = Alk; R1 = Alk, Ar; R2 = H, acyl, aroyl, ester, amide; R3 = Alk, OAlk, Hal
The best results were obtained by using Br2, I2, DEAD and H2O2 in acidic
media, giving products 2 in good to excellent yields. The obtained derivatives have
shown high cytotoxic activity towards cancer HT-1080 and MG-22A cell lines
and induced NO generation (up to 400–700 %) in these cells while causing no
mutagenic effect and/or morphological changes.
Compounds 2 could be studied either themselves, or as useful starting
materials to obtain fully hydrogenated 1,2-thiazolidines (tetrahydroisothiazoles),
sulfonamides (sultams, sulfa drugs, used as antibacterial agents and diuretics),
1,2,4-thiadiazoles (sphingosine receptor agonists, neuroprotectors, anti-inflammatory agents), and other biologically active heterocyclic derivatives.
References:
1. Volpp, G.P., US Patent Appl. 3375161, 1968; and Cutrì, C. C. C., Garozzo, A., et
al. Antiviral Chem. Chemother., 15, 201 (2004).
2. Goerdeler, J., Gnad, J. Chem. Ber., 98, 1531 (1965).
194
Poster presentations / PO 146
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
3,4-Dihydro-2(1H)-pyridone linked
cationic amphiphiles
Rufus Smits, Iveta Luntēna, Gunārs Duburs
Latvian Institute of Organic Synthesis, Aizkraukles str. 21, Riga, LV-1006, Latvia
[email protected]
Dihydropyridones are important intermediates for the synthesis of natural products,
particularly alkaloids and they have been extensively investigated as valuable
building blocks for the construction of piperidines, perhydroquinolines, indolizines,
quinolizidines and other alkaloid systems, with a wide range of biological and
pharmacological activities.
There is only one published work [1] of 3,4-dihydro-2(1H)-pyridone being used as
a linker in cationic amphiphile synthesis. The dihydropyridone scaffold (Figure),
provides an opportunity for a single cation to be placed on the methyl group at
carbon 6 and also long chain alkyl or perflouro alkyl ester groups at carbon 5.
The cationic amphiphiles self-assemble in aqueous solutions forming aggregates
in the 50-200 nm range as observed by atomic force microscopy and dynamic light
scattering. These amphiphiles may find use in gene transfection and drug delivery
applications in addition to their own inherent pharmacological activity.
R1 O
O
R2
O
Br-
N+
H R3
R1 : Ar, H
R2 : alkyl or perfluoroalkyl
R3 : Py, PPh3 , or alkylammonium
Acknowledgements:
The study was partially supported by the State Research Programme “Biomedicine”
References:
1. R. Smits, Y. Goncharenko, I. Vesere, B. Skrivele, O. Petrichenko, B. Vigante, M.
Petrova, A. Plotniece, G. Duburs, J. Fluorine Chem. 132, 2011, 414-419.
195
PO 147 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
pyrido[1,2-a]benzimidazoles with
potential antitumor activity
Alexander Sokolov1, Roman Begunov1 Svetlana Kalina1,
Mikhail Syroeshkin2,Vadim Gul’tyai2
Department of Chemistry, Yaroslavl State University, Yaroslavl, Sovetskaya St.14, Russia
N.D. Zelinsky Institute of Organic Chemistry, Moscow, Russia
[email protected]
1
2
One of the most promising chemical compounds for cancer chemotherapy are
pyrido[1,2-a]benzimidazoles. Their anti-tumor activity is based on the ability to
intercalation into the double helix of DNA of cancer cells and suppress them in the
replication process.
Known methods of the synthesis of these heterocyclic compounds are ineffective.
Disadvantages include the use of inaccessible reagents, formation of the desired
compounds in low yield and the presence of by-products.
Previously, we have proposed the method for the synthesis of pyrido[1,2-a]­
benzimidazole is based on reductive cyclization of N-(2-nitrophenyl) pyridinium
salts in acidic aqueous-alcoholic medium using SnCl2. This method has shown
good results (yield> 90%), but the widespread use of the new approach for the
synthesis of polycyclic condensed imidazole derivatives requires to simplify the
isolation of products and solve the problem of Sn4+ compounds disposal. Both of
these problems can be eliminated by using electric current as an electron source in
reduction.
Cl
N
+
O2N
R
N
i-PrOH,HCl
R
N
R = CF3,CN,COOCH3,COOC2H5
There have been studied features of electrochemical synthesis of pyrido[1,2-a]­
benzimidazoles. The influence of the structure of the substrate, temperature,
the reaction media and the cathode material were investigated in the process of
reductive cyclization. The best results were observed when the reaction was carried
out in acidic-aqueous medium in galvanostatic mode with diaphragm, on lead
cathode, with a current 0.2 A. Anolyte was 15% sulfuric acid, the anode - platinum.
The yields were 77-94%.
During cytological experiments on chromosomes was found that the new
pyrido[1,2-a]benzimidazoles have high intercalating activity, is superior analogs.
Acknowledgements:
The study was supported by The Ministry of education and science of Russian
Federation, project 14.B37.21.0823
196
Poster presentations / PO 148
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
INTERACTION OF BODIPY WITH ALBUMIN AND
ITS BILIRUBIN COMLEX
Boris A. Kochergin, Alexey V. Solomonov, Evgeniy V. Rumyantsev
Ivanovo State University of Chemical Technology, Ivanovo, Russia
[email protected]
Boron-dipirrolylmethene complexes (BODIPY), which are used as limiters of
intensive laser radiation, already known to be effective fluorophores. There was
described a large number of BODIPY-labeled compounds, many of them are
widely used in biological research, especially in photodynamic therapy. Being
injected into the body BODIPY can bind with blood plasma proteins like albumin
(BSA). Universal transport function of BSA can be used as a convenient model for
the study of even weak intermolecular interactions. Emerging interactions causing
corresponding changes in protein molecules can be traced through its own or
induced fluorescence. The high sensitivity of the spectra fluorescence changes the
polarity of molecule environment allows making important conclusions about the
interaction mechanisms of small molecules to the protein molecule. The intrinsic
fluorescence quenching of BSA under the influence of substances with different
nature is the basis for the development test systems to specify the type and ability
of small molecules to interact with proteins. There is an interesting fact about
albumin to have the ability to form macromolecular complexes with bilirubin (BR),
bile pigment formed from the decay of heme. BODIPY accession to the protein in
the nature of things will lead to the changes in the properties of both molecules. In
connection with this, the present study aimed to determine the characteristics of the
interaction of BODIPY with BSA and BR•BSA using fluorescence and absorption
spectroscopy.
Acknowledgements: This study was financially supported by the Russian
Foundation for Basic Research (Project No. 12-03-31309).
197
PO 149 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
DIVERSITY OF furagin POLyMORPHs AND
SOLVATE crystal FORMS
Dmitrijs Stepanovs, Anatoly Mishnev
Latvian Institute of Organic Synthesis, 21 Aizkraukles Street, Riga, LV-1001, Latvia
[email protected]
Furagin, 1-[(3-(5-nitro-2-furyl)allylidene)amino]hydantoin, or Furazidin, an
anti-infective agent for treating urinary tract infections was developed in Latvian
Institute of Organic Synthesis. Despite of its long-term use the crystal structure of
Furagin, its polymorphism and solvatomorphism have not been studied.
Search for polymorphs was performed in 12 solvents. Three stable polymorphs and
four solvates were found and characterized by powder X-ray diffraction, Raman
spectroscopy and DTA/TG. For two polymorphs and all solvate forms the crystal
structure was determined by a single crystal X-ray structure analysis. Polymorphic
forms differ in molecular packing. There are molecular chains formed by hydrogen
bonds in 1 and dimers in 2. Furagin molecule is planar in all crystals, except 4.
Solvate molecules in 3 and 6 are connected to Furagin molecules via water
molecules by hydrogen bonds making planar systems.
198
Poster presentations / PO 150
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
THE FLAVONOIDS OF LOPHANTHUS ANISATUS
Alexey Tyrkov, Marina Samotrueva, Ekaterina Yurtaeva
Department of Chemistry, Astrakhan State University, Astrakhan, 414000, Russia
[email protected]
With the help of HPLC method in aqua-ethanol extraction of leaves Lophanthus
anisatus Benth. identified flavonoids, coumarin, phenolic compounds and found
immunotropic activity.
Flavonoids
%
oumarin
%
OH
OH
O
HO
HO
3.05
HO
O
Phenolic compounds
OH
O
OH
1.31
CO2 H
HO
OH
2.15
Galic acid
HO
OH
O
1.22
HO
0.86
O
O
O
HO
Apigenin
quinic acid
Chlorogenic acid
CO2 H
OH
HO
OH
O
HO
O
HO
0.95
0.52
HO
trans-Caffeic acid
rutinosa
O
Rutin
%
HO
Quercetin
HO
0.85
HO
O
HO
O
Umbelliferone
Luteolin
HO
O
CO2 H
HO
0.33
p-Coumaric acid
As a result activation of cell-mediated immunity was recorded, which was
expressed by the increased index of the HRT local reaction by more than 35% аnd
the increased number of the leucocytes by more than 20%.
199
PO 151 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Selenolocoumarins: synthetic design
and activity
Jelena Vasiljeva, Pavel Arsenyan
Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia
[email protected]
Since the coumarin system is found in the composition of many natural compounds,
derivatives of coumarin have excited considerable attention. On this basis medicinal
preparations have been obtained and developed with a wide range of biological
activities (Psoralen, Angelicin, Xanthotoxin, Bergapten, Nodakenetin, etc). On the
other hand, the synthesis and studies of a series of organic and inorganic selenium
compounds in many cases revealed a wide spectrum of biological activity. We
developed a straightforward method for the preparation of a new heterocyclic
systems, namely selenolocoumarins, via reaction of in situ prepared selenium(IV)
bromide with ethynylcoumarins.
R'
R
Se
Se
R
O
O
R'
O
O
R'
O
Se
R
R''
O
O
R=Br, NHHetAr; R′=Me2COH, CH2N(Alkyl)2, R′=OMe, OH
In most cases, the cyclization proceeds smoothly and desired selenolo[2,3-c],
[3,2-c] and [2,3-f]coumarins were obtained in good yields. Molecular structures
of selenolocoumarins have been unambiguously confirmed by X-ray analysis.
Structure and cytotoxic activity relationship on various cancer cell lines will be
discussed. It was found that selected coumarines exhibit high inhibiting activity
selectively on matrix metalloproteinase MMP-2.
200
Poster presentations / PO 152
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
NEW ORIGINAL ADAPTOGEN AND IMMUNOMODULATOR
- 2- (METHYLPHENOXYACETOXY) PROTATRAN, ITS
APPLICATION IN MEDICINE AND IN AGRICULTURE
Michail G. Voronkov, Maksud M. Rasulov
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
664033 Irkutsk, Russian Federation. FAX: +7 3952 419 346; e-mail:[email protected]
Long-term preclinical and clinical trials of the biological activity of 2-(methylphenoxyacetoxy)
protatran (trecrezan, crezacyn) [(2-MeC6H4O)CH2COO]- N+H(CH2CH2OH)3, developed under the
leadership of Academician M.G. Voronkov, found to have strong adaptogenic and immunostimulating
effects. Trecrezan both as an adaptogen and prophylactic agent exhibits a positive effect on the human
body at overstressed physical and mental loads, especially under extremal conditions of climate
(high and low atmospheric pressure and temperature, stresses in emergency situations, etc.), but it
also is affective as prophylactic and medicinal remedy for many diseases. Particularly, it is already
being used for the rehabilitation of the patients with acute myocardial infarction and chronic heart
failure, for the correction of pulmonary tuberculosis patients states, against hyperlipidemia and
atherosclerosis, coronary disease and diabetes, at treatment of septic wounds and pneumonia, as
anti-alcohol drug in the periods of abstinence and remission, and as the strengthening agent of the
adaptive human responses in extremal situations. The medicine administration to herpes patients
resulted in depressing of the objective disease signs for 5-6 days earlier than that for the control
patient group. It is also used as an immunopoiesis and cytostatic modulator, as well as during the
process of tissue formation in embryonic stem cells. The study of possible mechanisms of trecrezan
action shows that trecrezan activates protein synthesis in the organism of patients with cardiovascular
pathology. It activates all tryptophanyl synthetases i.e. transport, matrix and information ones.
Trecrezan inhibits A1 and A2 phospholipases.
In agriculture trecrezan is often used under crezacyn name. In animal experiments trecrezan is
found to have heparin-like and antihypoxic action, significantly improve the state animals in the sexual
deprivation, the memory and trace processes that positively affect the manifestation of the maternal
instinct. Its administration results in increasing the amount of globulins, especially gamma globulins
that are responsible for the immune status of the animal body. The special theoretical and practical
interests are the crezacyn’s stimulations of fertilities (productivity, number of litters and its viability)
of mammals. This medicine stimulates the ovo- and spermatogenesis, accelerating the maturation of
primordial ovarian follicles and the sperm motion intensity within 72-100 hours. Meanwhile, crezacyn
has a positive effect on the natal development of the embryo. The productivity of hydrocoles, the
viability of hutchlings is increased even in the presence of trecrezan traces in water. It accelerates the
increases of live fish weight: fry peled at 10-27%, crucian carp at 15%, carp at 35-40%. Crezacyn
adds the average weight of silkworm and oak bombyx cocoons by 5-10%, mainly due to the silk shell
production that is the target sericulture product. The productivity increasing leads to the improvement
of quality of the silk cocoon shells as well as the multiplication of high grade cocoons, the average
weight increment for silkworm is 16.5%.
Trecrezan and its analogues are also the effective stimulators of microbiological synthesis. When
Trecrezan used as a stimulant of microbiological protein synthesis of yeast of the genus Candida (C.
sake, C. tropicalis, C. guilliermondii, C. parapsilosis, C. caemonicola, S. utieis, C. boidinii), Hansenula,
Torulopsis, and others, as well as bacteria of the genus Pseudomonas, Methylomonas, Acetobacter, etc.,
it exhibits the increase of the biomass yield at 15-20%, the average productivity at 50-65%, and the
protein content at 5-20%. Being added to milk at the production of Bifidobacterium and other cultured
milk foods it multiplies the number of beneficial bifidus bacteria at 2-4 orders and reaches 1010 cells per
ml of the product (Control is 106). At the same time the contents of B1 (thiamine) and C vitamins are
increased by 3 times and 1.5-2.8 times, respectively.
201
PO 153 / Poster presentations
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
BENZO-1,3-DIOXOLANES POSSESSING
BIOLOGICAL ACTIVITY
Simon Zlotsky, Anna Kazakova, Natalia Mikhailova
Department of General Chemistry, Ufa State Petroleum Technological University, Russia, Ufa
[email protected] As a result of accomplishing of biological activity of different cyclic acetals and
ketals according to program PASS [1] we have found out that benzo-1,3-di­oxo­lanes
(on the base of catechol and substituted cyclopropanes) shows the high potential
antibacterial and antivirus properties.
Synthesis of compounds representative the most interest was accomplished by
condensation of the substituted catechols with gem-dichlorocyclopropanes.
O
OH
R1
OH
O
R1=Ph, CH2CH
R2=H
R1
Cl
R2
Cl
OH
O
O
OH
O
R1= ClCH2
R2=H
OH
R1= ClCH2
R2=Cl
Cl
O
+
Cl
OH
Cl
O
Phenil- and vinyl-gem-dichlorocyclopropanes, possessing the high selectivity,
generate ketals whereas chloromethyl-gem-dichloropropanes react as exo- as endocyclic atoms of chlorine in DMSO and the main products are vinyl ketals. The last
are more biologically active than saturated benzo-1,3-dioxocyclanes.
The same result was achieved in an interaction tetrachloroderivative with phenol.
However linear ketals have lower antivirus and antibacterial activity than cyclic.
It should be noted that monosubstituted catechols have exactly signified antioxi­
dant properties and their using for inhibition of free-radical processing in polar
bioorganic objects is very prospective.
References:
Poroikov V., Filimonov D. PASS Online. – URL: http://www. pharmaexpert.ru/
PASSOnline/index.php.
202
Poster presentations / PO 154
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
STRUCTURE DETERMINATION OF
PIMOBENDANE FORM b AND DIOXANE
SOLVATE
Alvis Zvirgzdiņša, Māra Dēliņaa, Anatolijs Mišņevsb, Andris Actiņša
Department of Chemistry, University of Latvia, Riga, LV-1013, Latvia;
Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia
[email protected]
a
b
Pimobendan, 2-(4-hydroxy-phenyl)-5-(5-methyl-3-oxo-4,5-dihydo-2H-6-pyri­da­
zinyl)benzimidazole, is a drug with both inotropic and vasodilatory properties and
is widely used for the treatment of heart failure in dogs. It is a benzimidazolepyridazinone derivative that exerts its inotropic and vasodilatory effects through a
combination of calcium sensitization and phosphodiesterase inhibition.
Data for structure determination were collected on a Bruker D8 Advance using
Sol-X detector. The pattern indexing was performed with DICVOL06. Structures
were determined with EXPO2009 and FOX 1.9.5.0. Determinations were
performed from different initial conditions by changing cost function, cooling rate
and other conditions of simulated annealing or parallel tempering. Final structures
were refined using Rietveld method.
Pimobendane form B crystalizes in P21/c and dioxane solvate in P21/a space goup.
For both structures Z’=1 and Z=4. In a both structures there is observed π stacking
between pimobendane molecules.
Acknowledgements: This work was supported by the European Regional
Development Fund (No. 2011/0014/2DP/2.1.1.1.0/10/APIA/VIAA/092).
203
AUTHOR INDEX
Author index
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
A
Abaev V. PO-001, PO026
Abass M. PO-021
Abel A. PO-007
Actiņš A. PO-105, PO126, PO-133, PO-154
Adlere I. PO-002
Afanasyeva S. PO-003
Akué-Gédu R. PO-076
Albericio F. PO-093
Alfini R. PO-027
Almqvist F. PL-06
Alonso C. PO-075
Alshammari M. B. PO004
Altundas R. PO-030
Álvarez M. PO-093
Amat M. PL-08
Ananikov V. IN-03
Andzans Z. PO-002
Anfimov A. PO-005
Anizon F. PO-076, PO096
Antipin R. PO-073
Arja K. PO-082
Arsenyan P. PO-099,
PO-102, PO-151
Astakhina V. PO-006
Averin A. PO-007
B
Baashen M. A. PO-077
Babkin V. PO-119
Badeeva E. PO-134
Bagi P. PO-031
Bagley M. C. PO-077
Balázs B. PO-081
Bálint E. PO-008
Balintová J. PO-123
Balova I. OR-01, PO-018
Baran A. PO-145
Baranin S. V. PO-059,
PO-067
Barlocco D. PO-124
Baszczyňski O. PO-125
Batyeva E. PO-134
Begunov R. PO-147
206
Beletskaya I. PL-02, PO007, PO-012, PO-038
Belikov N. PO-019
Beloglazkina E. PO-073,
PO-074
Belyakov S. PO-047,
PO-068, PO-108, PO-115
Benohoud M. PO-009
Bērziņš A. PO-105
Bērziņš A. PO-126
Bhosale D. PO-109
Bindini E. PO-027
Bisenieks E. PO-078
Bisenieks I. PO-078
Bitter I. PO-127
Bizdēna Ē. PO-010, PO047
Black D. StC. PO-060
Blaskó G. PO-081
Blums E. PO-111
Bojtár M. PO-127
Bölcskei H. PO-011
Bondarenko G. PO-012
Bondarenko O. PO-052
Bonnefoy N. PO-096
Borovika D. PO-013
Boumber A. PO-026
Brahmkshatriya P. PO103
Brandi A. PO-027, PO079
Bräse S. PO-018
Bratkovskaja I. PO-089
Bredikhin A. PO-014
Bredikhina Z. PO-014
Bregadze V. PO-085
Bruvere I. PO-078
Bubnov Y. PO-005
Butin A. PO-001, PO015, PO-065
C
Calamai E. PO-027
Cano M. PO-128
Carell T. PL-07
Cauņa I. PO-016
Cekavicus B. PO-107
Chigorina E. A. PO-020
Chkanikov N. PO-091
Cirkovas A. PO-144
Claramunt R. M. PO128
Colau D. PO-129
Cordero F. M. PO-079
Cornago M. P. PO-128
Costas M. PO-113
Czirok J. B. PO-127
Černova N. PO-114
Čerňová M. PO-017
D
Dambrova M. PO-070
Danilkina N. PO-018
Daugulis O. IN-05
De Plaen E. PO-129
Debaud A. L. PO-096
Dékány M. PO-011
Demchenko D. A. PO080
Demidov M. PO-049
Demina O. PO-019
Denislamova E. PO-094
Dēliņa M. PO-154
Dmitriev M. PO-094
Dolušić E. PO-129
Domracheva I. PO-100,
PO-130
Dorogov M. PO-088
Dorokhov V. A. PO-059,
PO-067
Dotsenko V. V. PO-020
Dračínský M. PO-125,
PO-131
Dubrovay Z. PO-011
Duburs G. PO-002, PO078, PO-130, PO-146
Dudnik R. V. PO-101
Dudnik V. N. PO-101
Dzyubenko S. PO-121
E
Elgland M. PO-082
El-Hiti G. A. PO-004
Erdyakov S. PO-005
Eremkina T. PO-110
Ermatova A. PO-003
Author index
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
F
Farat O. PO-022
Fayzullin R. PO-014
Fazekas E. PO-008
Fedorov V. PO-098
Fedyushkina I. V. PO116
Feliu L. PO-023, PO-113
Fernández de Trocóniz
G. PO-050
Fogassy E. PO-031
Fokin V. IN-01
Frédérick R. PO-129
Fuertes F. PO-075
Fülöp F. PO-024
Gul’tyai V. PO-147
Gustafsson H. PO-139
Karabuga S. PO-030
Karakaya I. PO-030
Karalius A. PO-056
Kazachenok G. PO-111
H
Kazakova A. PO-153
Hammarström P. POKeglevich G. OR-02, PO139
008, PO-031, PO-034,
Haritonova A. PO-142
PO-035
Hobza P. PO-103
Hocek M. PO-017, PO- Keough D. T. PO-125,
PO-131
036, PO-117, PO-123
Keresztély L. PO-081
Hocková D. PO-125
Khairnar B. B. PO-079
Hocková D. PO-131
Khairulin A. R. PO-032
Holý A. PO-125
Kharchenko O. PO-006
Holzer W. PO-051
Kher S. PO-087
Khlebnikov A. PO-018
I
Khodonov A. PO-019
G
Ichetovkina E. V. POKhodot E. N. PO-140
Gábor I. PO-011
101
Kinens A. PO-033
Galeta J. PO-025, POIgnatovich L. PO-084,
Kirilova E. M. PO-029
064
PO-106, PO-115
Kirsch G. OR-09
Ganina O. PO-012, PO- Ilin V. PO-098
Kiselyov A. PO-137
026
Ilinova A. PO-085
Gelain A. PO-124
Imramovský A. PO-109 Kiss L. PO-024
Kiss N. Z. PO-034, POGerasimov V. PO-074
Ioffe S. PO-063
035
Gere A. PO-011
Ivanova I. D. PO-029
Klečka M. PO-036
Gevorgyan V. PL-03
Ivanova J. PO-086
Klimaviciusa L. PO-107
Gholipour H. PO-066
Klimochkin Y. PO-048,
Giniyatullin R. Kh. PO- J
PO-049, PO-052
112
Jabłońska A. PO-085
Klimovica K. PO-057
Giomi D. PO-027
Jágerszki G. PO-127
Klochkov S. PO-003,
Giraud F. PO-076
Janeba Z. IN-10, POPO-132
Goba I. PO-092
125, PO-131
Klusa V. PO-107
Golik N. PO-120
Jansa P. PO-125
Knolker H. J. PL-04
Gomtsyan A. IN-07
Jansone B. PO-107
Kocevar M. PO-008
Gonzalez J. IN-11
Jansone I. PO-078
Kochergin B. A. PO-148
González M. PO-075
Jaschenko E. PO-130
Kocsis P. PO-011
Gorbacheva E. PO-063 Jaudzems K. PO-087
Kónya K. PO-053
Gosteva M. PO-100, PO- Jirgensons A. PO-028,
Konradsson P. PO-082
107
PO-057, PO-061, POKorolev A. M. PO-135
Grandane A. PO-136,
062, PO-087, PO-097
Korotkikh N. PO-137
PO-016, PO-071, PO-083 Jorda R. PO-103
Korsakov M. PO-088
Grigorjeva L. PO-028,
Jure M. PO-045
Korshin E. E. PO-037
PO-062
Just-Baringo X. OR-06 Körtvélyesi T. PO-034
Grinberga S. PO-130
Kosychova L. PO-056,
Grushin V. IN-06
PO-089
Grynevych A. I. PO-080 K
Kotovshchikov Y. POGubaidullin A. PO-014 Kaiser M. M. PO-131
Kalina S. PO-147
038
Guddat L. W. PO-125,
Kanepe-Lapsa I. PO-107 Koutentis P. A. PO-039
PO-131
207
Author index
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Kovács T. PO-031
Koval D. PO-006
Koval’chuk T. A. PO040
Krasnova L. PO-130
Krasnovskaya O. PO074
Krauze A. PO-002, PO130
Krivenko K. PO-013
Kriviča T. PO-090
Krylova E. S. PO-112
Kryštof V. PO-103
Krūkle-Bērziņa K. PO133
Kumar N. PO-060
Kursheva L. PO-134
Kuz’menok N. M. PO040, PO-095
Kuzmin V. A. PO-140
Kuznecovs J. PO-068,
PO-070
Kwon B. M. PO-124
Luzikov Y. N. PO-135
Lvov S. V. PO-101
M
Maiorov M. PO-111
Majouga A. PO-073,
PO-074
Malik I. PO-053
Malinina J. PO-044
Malyutina N. M. PO-135
Manoli M. PO-039
Marichev K. PO-137
Markov V. PO-022
Masciocchi D. PO-124
Masereel B. PO-129
Mashevskaia I. PO-138
Maslivetc A. PO-094,
PO-138
Mason J. J. PO-139
Masson G. PO-009
Mayas A. S. PO-021
Meanwell N. PL-05
Meneghetti F. PO-124
Merkushev A. PO-042
Micoli A. PO-027
L
Mierina I. PO-045
Labodneva N. PO-091
Mikhailov A. S. PO-112
Langer P. PO-053
Mikhailova N. PO-153
Lanners S. PO-129
Mikhalyonok S. G. POLapa G. B. PO-135
040, PO-095
Larrieu P. PO-129
Milaeva E. R. PO-141
Latyshev G. PO-038
Lebedyeva I. O. PO-041 Mirallai S. I. PO-039
Mirchnk E. P. PO-135
Lends A. PO-136
Misharin A. Yu. PO-116
Lesnikowski Z. J. POMishnev A. PO-068, PO085
111, PO-149
Levin Y. A. PO-037
Mišņevs A. PO-154
Lielpētere A. PO-092
Mohamed El-H. A. POLiepinsh E. PO-068,
021
PO-136
Moineaux L. PO-129
Lindgren M. PO-139
Moiseeva A. PO-073
Lisovenko N. PO-042
Livantsov M. V. PO-141 Molchanov A. PO-044
Livantsova L. I. PO-141 Molodtsova N. PO-065
Moreau P. PO-076
Lobanova I. PO-085
Moreau P. PO-096
Lorente A. PO-093
Lugiņina J. PO-043, PO- Muceniece D. PO-145
Muceniece R. PO-107
058
Mucsi Z. PO-034, POLukashev N. PO-038
081
Luntēna I. PO-146
208
Muravenko V. PO-084,
PO-115
Musilová L. PO-103
Myannik K. PO-073
N
Nagy G. PO-127
Nakamura H. IN-08
Nauton L. PO-076
Nekipelova T. N. PO-140
Nelyubina Y. PO-063
Nenajdenko V. IN-04
Nevolina T. PO-015
Ng-Choi I. PO-023
Nikitjuka A. PO-097
Nikolaev A. PO-046
Nikolaev A. E. PO-112
Nikolajeva V. PO-110,
PO-111
Nilsson P. PO-082
Nilsson R. PO-139
Nonn M. PO-024
Novák T. PO-081
Novakov I. PO-007
Novikov R. PO-063
Novikov R. A. PO-116
Novikova O. P. PO-141
Novosjolova I. PO-010,
PO-047
Nyerges M. PO-081
O
Ochoa de Retana A. M.
PO-050
Omelkov A. PO-098
Őri Z. PO-127
Örkényi R. PO-035
Orlinson B. PO-007
Orlova N. PO-068, PO070
Orlova N. V. PO-029
Orola L. PO-108
Osipov D. PO-048, PO049
Osyanin V. PO-048, PO049
Ovejero P. PO-128
Author index
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
P
Paegle E. PO-099
Pajuste K. PO-100, PO107
Pajuste K. PO-100, PO107
Palacios F. PO-050, PO075
Paliulis O. PO-051
Panfilova A. PO-052
Paponov B. V. PO-101
Paradowska E. PO-085
Parkova A. PO-122
Paruch K. PO-103
Pascual S. PO-050
Pashagin A. PO-014
Patonay T. PO-053
Pelšs J. PO-054
Peter K. PO-139
Peters D. PO-051
Petrenko A. PO-102
Petrosyan V. S. PO-141
Petrůjová M. PO-103
Pihko P. IN-09
Pilotte L. PO-129
Pilsl L. OR-07
Planas M. PO-023, PO113
Platova E. PO-134
Plattner J. J. PO-135
Plieva A. PO-001
Plotniece A. PO-100,
PO-107
Pochet L. PO-129
Podeniene D. PO-056,
PO-089
Poikans J. PO-078
Popelis J. PO-110
Postnov V. PO-088
Poštová Slavětínská L.
PO-131
Potacek M. OR-10, PO025, PO-064
Potapova T. PO-005
Potorochina I. OR-12
Povstyanoy M. V. PO041
Pozņaks V. PO-055
Preobrazhenskaya M.
N. PO-135
Prishchenko A. A. PO141
Procter D. PL-09
Puchkin A. I. PO-029
Puhkov S. OR-08, PO003, PO-132
PO-112
Semioshkin A. PO-085
Sengul I. F. PO-060
Sereikaite J. PO-144
Sestakova I. PO-107
Shakhmatov V. V. PO140
Sharkh A. A. PO-121
Shchekotikhin A. POR
118
Rádai Z. PO-035
Shestakova I. OR-12,
Ragaleviciene V. POPO-084, PO-100, PO056, PO-089
106, PO-110, PO-115,
Rasina D. PO-057
Rasulov M. M. PO-152 PO-130
Shipilovskikh S. PO-143
Ravina I. PO-072, POShumilova L. PO-088
104
Shvaika O. PO-137
Reznik V. PO-046
Shyshov A. V. PO-101
Reznik V. S. PO-112
Sigan A. PO-091
Rēķis T. PO-105
Silaichev P. PO-094
Ribas X. PO-113
Sillanpää R. PO-024
Rijkure I. PO-104
Sinyashin O. PO-134
Rjabovs V. PO-043
Sirotkina J. PO-061
Rodins V. PO-058
Skarbulis E. PO-126
Rolava E. PO-058
Skrastiņa I. PO-145
Romanovs V. PO-106
Skvorcova M. PO-062
Rosés C. PO-023
Sleiksha I. PO-084
Roze M. PO-090
Smith K. PO-004
Ruban S. V. PO-059
Smits G. OR-04
Rubiales G. PO-075
Rubtzov A. PO-042, PO- Smits R. PO-146
Sobolev A. PO-100, PO143
Rucins M. PO-100, PO- 107, PO-147
Soler M. PO-113
107
Solomonov A. V. PO-148
Rumyantsev E. V. POSoria L. PO-128
148
Sorotskaya L. PO-015
Ryabova V. PO-142
Sprūdža A. PO-071, PO114
S
Spura J. PO-106, PO-115
Sabirova L. A. PO-037
Stankeviciute J. PO-089
Saifina L. PO-046
Stepanovs D. PO-149
Sakaine G. PO-142
Samodelkina N. PO-015 Stepkina N. PO-069
Samotrueva M. PO-150 Stikute A. PO-045
Stolpovskaya E. PO-119
Sarcevica I. PO-108
Stonans I. PO-078
Saugues E. PO-096
Streifinger B. OR-11
Sedlák M. PO-109
Segal I. PO-110, PO-111 Stroobant V. PO-129
Studzińska M. PO-085
Semenov V. PO-046,
Stulov S. V. PO-116
209
Author index
XVth Conference on Heterocycles in Bio-organic Chemistry - 2013
Suchkova N. PO-138
Suffert J. IN-12
Suna E. IN-02, PO-033
Syroeshkin M. PO-147
Šačkus A. PO-051
T
Tabolin A. PO-063
Tenora L. PO-064
Tetere Z. PO-072
Théry V. PO-076
Tichý M. PO-117
Tikhomirov A. PO-118
Titova O. PO-069
Torres R. PO-128
Trapencieris P. PO-013,
PO-086, PO-122
Trofimova N. PO-119
Trushkov I. OR-05, PO001, PO-065
Tskhovrebova M. PO026
Tsupova S. OR-03
Turks M. PO-010, PO043, PO-047, PO-055,
PO-058, PO-072, PO-104
Turovska B. PO-092
Tyrkov A. PO-150
U
Vélez del Burgo A. PO050
Velikaya E. PO-022
Velikorodov A. PO-069
Vendiņa I. PO-122
Vidziunaite R. PO-089
Vigante B. PO-078
Vilà S. PO-023
Villa S. PO-124
Voievudskyi M. PO-006
Volkonskii A. PO-091
Vorona M. OR-12, PO068, PO-070
Voronkov M. G. PO-152
Vozny I. PO-071
Vurchio C. PO-079
W
Wender P. PL-01
Wouters J. PO-129
X
Xia A. PO-135
Y
Yamamoto Y. PL-10
Yanchenko V. A. PO-080
Yurtaeva E. PO-150
Z
Zablotskaya A. PO-110,
PO-111
Zakharychev D. PO-014
Zemrībo R. PO-142
Zhitov R. PO-119
V
Zicane D. PO-072, POValizadeh H. PO-066
104
Van den Eynde B. POZilinskas A. PO-144
129
Zlotsky S. PO-153
Varenichenko S. PO-022 Zvejniece L. PO-070
Varfolomeev S. PO-019 Zvereva E. PO-134
Vasil`ev L. S. PO-067
Zvirgzdiņš A. PO-154
Vasiljeva J. PO-151
Zvonok A. M. PO-095
Vastagh M. PO-011
Zyk N. PO-052, PO-073,
Vavers E. PO-070
PO-074
Vedejs E. PO-033
Žalubovskis R. PO-016,
Veidis M. V. PO-108
PO-054, PO-071, POVeinberg G. OR-12, PO- 083, PO-086, PO-114,
068, PO-070
PO-136
Uchuskin M. PO-015,
PO-065
Ulukanli S. PO-030
Uyttenhove C. PO-129
210
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