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

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• 作者：Dmitry V. Demchuk ; Alex ; er V. Samet ; Natalia B. Chernysheva ; Vladimir I. Ushkarov ; Galina A. Stashina ; Leonid D. Konyushkin ; Mikhail M. Raihstat ; Sergei I. Firgang ; Alex A. Philchenkov ; Michael P. Zavelevich ; Ludmila M. Kuiava ; Vasyl F. Chekhun ; Dmitry Yu. Blokhin ; Alex S. Kiselyov ; Marina N. Semenova ; Victor V. Semenov
• 关键词：VYIKEPOZDAQBBG-UHFFFAOYSA-N ; FXJWTEDHYUZWTB-UHFFFAOYSA-N ; KAADNOIRUAPIJA-UHFFFAOYSA-N ; FODBYKDYGDVMRL-UHFFFAOYSA-N ; HHGRWXNBXGCVQC-UHFFFAOYSA-N ; JHZMSGCUGQSNOA-UHFFFAOYSA-N ; DOZOVRQLBANESF-UHFFFAOYSA-N ; DGTARDXIKVVWRO-UHFFFAOYSA-N ; BLZMTDZGGLTDRK-UHFFFAOYSA-N ; ASLUYQCBIKMJEU-UHFFFAOYSA-N ; YZUDFBGHMYEADF-UHFFFAOYSA-N ; MNDDRAXBOYBUGK-UHFFFAOYSA-N ; LDAGHTYWGJDFRH-UHFFFAOYSA-N ; AODAGYGNZDUVNE-UHFFFAOYSA-N ; GMMZILPCMBXPAN-UHFFFAOYSA-N ; QZZHJHZNLFRILP-UHFFFAOYSA-N ; GZOVKXTXKMUHLY-UHFFFAOYSA-N ; PLIMGIL
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：15 January, 2014
• 年：2014
• 卷：22
• 期：2
• 页码：738-755
• 全文大小：2229 K

文摘

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鈥?/strong> 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.