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2016 Vol 14 # 1


Synthesis and biological evaluation of new derivatives of tricyclic heteroaromatic carboxamides as potential topoisomerase I inhibitors

V.G. Kostina, I.V. Alexeeva, N.A. Lysenko, V.V. Negrutska, I.Ya. Dubey

Institute of Molecular Biology and Genetics, NAS of Ukraine
150, Akademika Zabolotnoho Str., 03680, Kyiv, Ukraine

Summary. A series of new N-functionalized amide derivatives of phenazine-1- and acridone-4-carboxylic acids were synthesized and tested in vitro as potential topoisomerase I inhibitors. Their tricyclic heteroaromatic cores with intercalative properties contained carboxamide functions modified with pyridyl and N,N-dimethylamino groups attached via short linkers. These basic substituents are able to be protonated in water and thus could provide additional binding interactions of ligands with DNA and/or topoisomerase complex enhancing the inhibitory activity of compounds. Pyridyl-modified derivatives of both heterocycles were found to inhibit topoisomerase in vitro at 100 mM concentration, in contrast to non-modified carboxamides which are inactive against the enzyme.

Keywords: topoisomerase I, inhibitors, acridone, phenazine, carboxamides.

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The development of algorithm for pharmacophore model optimization and rescoring of pharmacophore screening results

S.A. Starosyla, G.P. Volynets, M.V. Protopopov, V.G. Bdzhola, S.M. Yarmoluk

Institute of Molecular Biology and Genetics, NAS of Ukraine
150, Zabolotnoho Str., Kyiv, 03680, Ukraine

Summary. Pharmacophore modeling is modern efficient approach which is widely used in drug discovery. This method has several drawbacks. First of all, pharmacophore models are not selective to structurally similar compounds that belong to one chemical class but possess different activity. Another drawback is that during pharmacophore screening a number of non_active compounds can be selected in the top of results. We have developed novel algorithm for pharmacophore model optimization and for rescoring of pharmacophore screening results. The advantages of our algorithm are optimization of pharmacophore feature radii, application of the concept of pharmacophore feature weights and molecular descriptors. The algorithm was validated based on pharmacophore models of FGFR1 and CK2 inhibitors. In the case of FGFR1 pharmacophore model, the application of algorithm allowed to increase the number of active compounds identified during screening of validation set from 21 to 43 and percent of correctly found active compounds in the top was increased from 38 to 60 %. In the case of CK2 pharmacophore model, the number of active compounds identified during screening of validation set increased from 12 to 39 and percent of correctly found active compounds in the top increased from 58 to 74 %.

Keywords: pharmacophore model, pharmacophore screening, inhibitor, protein kinase FGFR1, protein kinase 2, optimization algorithm.

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Chemical optimization of 3-carboxyquinoline amides as inhibitors of protein kinase CK2

O.V. Ostrynska, A.R. Syniugin, M.O. Chekanov, M.V. Protopopov, O.P. Kukharenko, S.M.Yarmoluk

Institute of Molecular Biology and Genetics, NAS of Ukraine
150, Zabolotnoho Str., Kyiv, 03680, Ukraine

Summary. This work is devoted to the chemical optimization of 2-quinolinone derivatives as promising inhibitors of protein kinase CK2. The structures of new compounds were proposed and 15 compounds were synthesized. The complex of the most active compounds (inhibitors 7a, IC50=2.3 mM) with the ATP-acceptor site of CK2 was obtained and investigated by molecular modeling.

Keywords: K2 inhibitors, 2-quinolinone, 3-carboxyquinoline amides.

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Acetylcholine: What happens when it interacts with reducing agents?

B.A. Kurchii

IEC, 9, Gagarina Str., Irpin, 08200, Ukraine

Summary. Animal organisms produce acetylcholine that is the main neurotransmitter in the parasympathetic nervous system, as well as neurotransmitter performing neuromuscular transmission. This paper presents possible mechanism for acetylcholine in vivo transformation into free radical state in the reaction with reducing agents and its action by a free radical chain reaction mechanism.

Keywords: acetylcholine, free radicals, reductases, NADH, NADPH.

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