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

Abstract

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.

Keywords: 1,2,3-Triazole; AODAGYGNZDUVNE-UHFFFAOYSA-N; ASLUYQCBIKMJEU-UHFFFAOYSA-N; Apoptosis; B-cell lymphoma 2; BKSKBNPDOWPAIO-UHFFFAOYSA-N; BLZMTDZGGLTDRK-UHFFFAOYSA-N; Bcl-2; CA2; CA4; CA4 disodium phosphate; CA4P; Caspases; DGTARDXIKVVWRO-UHFFFAOYSA-N; DOZOVRQLBANESF-UHFFFAOYSA-N; FODBYKDYGDVMRL-UHFFFAOYSA-N; FXJWTEDHYUZWTB-UHFFFAOYSA-N; GMMZILPCMBXPAN-UHFFFAOYSA-N; GZOVKXTXKMUHLY-UHFFFAOYSA-N; HDKAKWQYWMYIBD-UHFFFAOYSA-N; HHGRWXNBXGCVQC-UHFFFAOYSA-N; IMOWNIZUMDTJSQ-UHFFFAOYSA-N; JHZMSGCUGQSNOA-UHFFFAOYSA-N; JNDJXILHVKVNJP-UHFFFAOYSA-N; KAADNOIRUAPIJA-UHFFFAOYSA-N; KSXSFROOOPRMBN-UHFFFAOYSA-N; LDAGHTYWGJDFRH-UHFFFAOYSA-N; MNDDRAXBOYBUGK-UHFFFAOYSA-N; Microtubule destabilizing agents; MoAb; OXFHSVYQNFVGTK-UHFFFAOYSA-N; PARP-1; PI; PLIMGILENGQOOC-UHFFFAOYSA-N; Plant polyalkoxybenzenes; QZZHJHZNLFRILP-UHFFFAOYSA-N; SAR; Sea urchin embryo; VFOXVLIPSYMQEK-UHFFFAOYSA-N; VYIKEPOZDAQBBG-UHFFFAOYSA-N; X-linked inhibitor of apoptosis; XAYFGZPYFSZKTA-UHFFFAOYSA-N; XIAP; YZUDFBGHMYEADF-UHFFFAOYSA-N; combretastatin A-2; combretastatin A-4; monoclonal antibody; poly(ADP-ribose) polymerase-1; propidium iodide; structure–activity relationship.