Synthesis and antiproliferative activity of conformationally restricted 1,2,3-triazole analogues of combretastatins in the sea urchin embryo model and against human cancer cell lines

被引：76

作者：

Demchuk, Dmitry V. ^{[1
]}

Samet, Alexander V. ^{[1
]}

Chernysheva, Natalia B. ^{[1
]}

Ushkarov, Vladimir I. ^{[1
]}

Stashina, Galina A. ^{[1
]}

Konyushkin, Leonid D. ^{[1
]}

Raihstat, Mikhail M. ^{[1
,2
]}

Firgang, Sergei I. ^{[1
]}

Philchenkov, Alex A. ^{[3
]}

Zavelevich, Michael P. ^{[3
]}

Kuiava, Ludmila M. ^{[3
]}

Chekhun, Vasyl F. ^{[3
]}

Blokhin, Dmitry Yu. ^{[4
]}

Kiselyov, Alex S. ^{[5
]}

Semenova, Marina N. ^{[2
,6
]}

Semenov, Victor V. ^{[1
,2
]}

机构：

[1] ND Zelinsky Inst Organ Chem RAS, Moscow 119991, Russia

[2] Chem Block Ltd, CY-3723 Limassol, Cyprus

[3] Natl Acad Sci Ukraine, RE Kavetsky Inst Expt Oncol Pathol & Radiobiol, UA-03022 Kiev, Ukraine

[4] Moscow Inst Phys & Technol, Dept Biol & Med Chem, Dolgoprudnyi 141700, Moscow Region, Russia

[5] ChemDiv, San Diego, CA 92121 USA

[6] NK Koltsov Inst Dev Biol RAS, Moscow 119334, Russia

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2014年 / 22卷 / 02期

基金：

俄罗斯基础研究基金会;

关键词：

1,2,3-Triazole; Apoptosis; Caspases; Plant polyalkoxybenzenes; Microtubule destabilizing agents; Sea urchin embryo; BIOLOGICAL EVALUATION; ANTINEOPLASTIC AGENTS; MITOTIC CATASTROPHE; NATURAL-PRODUCTS; A-4; TUBULIN; DERIVATIVES; APOPTOSIS; POTENT; POLYALKOXYBENZENES;

D O I：

10.1016/j.bmc.2013.12.015

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 G(2)/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. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：738 / 755

页数：18

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