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Limassol, Cyprus

Kiselyov A.S.,deCODE Chemistry Inc. | Semenova M.N.,Russian Academy of Sciences | Chernyshova N.B.,RAS N. D. Zelinsky Institute of Organic Chemistry | Leitao A.,University of New Mexico | And 10 more authors.
European Journal of Medicinal Chemistry | Year: 2010

A series of novel 1,3,4-oxadiazole derivatives based on structural and electronic overlap with combretastatins have been designed and synthesized. Initially, we tested all new compounds in vivo using the phenotypic sea urchin embryo assay to yield a number of agents with anti-proliferative, anti-mitotic, and microtubule destabilizing activities. The experimental data led to identification of 1,3,4-oxadiazole derivatives with isothiazole (5-8) and phenyl (9-12) pharmacophores featuring activity profiles comparable to that of combretastatins, podophyllotoxin and nocodazole. Cytotoxic effects of the two lead molecules, namely 6 and 12, were further confirmed and evaluated by conventional assays with the A549 human cancer cell line including cell proliferation, cell cycle arrest at the G2/M phase, cellular microtubule distribution, and finally in vitro microtubule assembly with purified tubulin. The modeling results using 3D similarity (ROCS) and docking (FRED) correlated well with the observed activity of the molecules. Docking data suggested that the most potent molecules are likely to target the colchicine binding site. © 2010 Elsevier Masson SAS. All rights reserved. Source


Sheremetev A.B.,RAS N. D. Zelinsky Institute of Organic Chemistry | Dmitriev D.E.,RAS N. D. Zelinsky Institute of Organic Chemistry | Lagutina N.K.,RAS N. D. Zelinsky Institute of Organic Chemistry | Raihstat M.M.,RAS N. D. Zelinsky Institute of Organic Chemistry | And 4 more authors.
Mendeleev Communications | Year: 2010

A series of new furazan (1,2,5-oxadiazole) derivatives based on structural overlap with combretastatin have been synthesized. Targeted molecules were evaluated using the sea urchin embryo assay; several agents demonstrated 1-4 μmol dm-3 antiproliferative activity in this in vivo model. © 2010 Mendeleev Communications. All rights reserved. Source


Titov I.Y.,RAS N. D. Zelinsky Institute of Organic Chemistry | Sagamanova I.K.,RAS N. D. Zelinsky Institute of Organic Chemistry | Gritsenko R.T.,RAS N. D. Zelinsky Institute of Organic Chemistry | Karmanova I.B.,RAS N. D. Zelinsky Institute of Organic Chemistry | And 4 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

Phenstatin and its derivatives with the modified ring A have been synthesized, using plant allylpolyalkoxybenzenes as a starting material. The targeted molecules were evaluated in a phenotypic sea urchin embryo assay for antiproliferative activity. It was found that phenstatin ring A modifications yielded antimitotic compounds. The most effective myristicin derivative 7d (combretastatin A-2 analogue) was determined to be ca. 10 times more potent than phenstatin, displaying antimitotic tubulin-destabilizing activity at the same concentration range as combretastatins. In contrast to combretastatins, 7d featured the steric stability with potential for further design as anticancer agent. © 2010 Elsevier Ltd. All rights reserved. Source


Semenova M.N.,Russian Academy of Sciences | Kiselyov A.S.,080 Center Drive | Tsyganov D.V.,RAS N. D. Zelinsky Institute of Organic Chemistry | Konyushkin L.D.,RAS N. D. Zelinsky Institute of Organic Chemistry | And 14 more authors.
Journal of Medicinal Chemistry | Year: 2011

A series of 4-azapodophyllotoxin derivatives with modified rings B and E have been synthesized using allylpolyalkoxybenzenes from parsley seed oil. The targeted molecules were evaluated in vivo in a phenotypic sea urchin embryo assay for antimitotic and tubulin destabilizing activity. The most active compounds identified by the in vivo sea urchin embryo assay featured myristicin-derived ring E (4e, 6e, and 8e). These molecules were determined to be more potent than podophyllotoxin. Cytotoxic effects of selected molecules were further confirmed and evaluated by conventional assays with A549 and Jurkat human leukemic T-cell lines including cell growth inhibition, cell cycle arrest, cellular microtubule disruption, and induction of apoptosis. The ring B modification yielded 6-OMe substituted molecule 8e as the most active compound. Finally, in Jurkat cells, compound 8e induced caspase-dependent apoptosis mediated by the apical caspases-2 and -9 and not caspase-8, implying the involvement of the intrinsic caspase-9-dependent apoptotic pathway. © 2011 American Chemical Society. Source


Demchuk D.V.,RAS N. D. Zelinsky Institute of Organic Chemistry | Samet A.V.,RAS N. D. Zelinsky Institute of Organic Chemistry | Chernysheva N.B.,RAS N. D. Zelinsky Institute of Organic Chemistry | Ushkarov V.I.,RAS N. D. Zelinsky Institute of Organic Chemistry | And 13 more authors.
Bioorganic and Medicinal Chemistry | Year: 2014

A series of 1,5-diaryl- and 4,5-diaryl-1,2,3-triazole derivatives of combretastatin A4 were synthesized and evaluated as antimitotic microtubule destabilizing agents using the sea urchin embryo model. Structure-activity relationship studies identified compounds substituted with 3,4,5- trimethoxyphenyl and 3,4-methylenedioxy-5-methoxyphenyl ring A and 4-methoxyphenyl ring B as potent antiproliferative agents with high cytotoxicity against a panel of human cancer cell lines including multi-drug resistant cells. 4,5-Diaryl-1,2,3-triazoles (C-C geometry) were found to be considerably more active than the respective 1,5-diaryl-1,2,3-triazoles (N-C geometry). Compound 10ad′ induced G2/M cell cycle arrest and apoptosis in human T-leukemia Jurkat cells via caspase 2/3/9 activation and downregulation of the antiapoptotic protein XIAP. A mitotic catastrophe has been evaluated as another possible cell death mode. © 2013 Elsevier Ltd. All rights reserved. Source

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