Identification of novel 1-indolyl acetate-5-nitroimidazole derivatives of combretastatin A-4 as potential tubulin polymerization inhibitors
Identification of novel 1-indolyl acetate-5-nitroimidazole derivatives of combretastatin A-4 as potential tubulin polymerization inhibitors
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DOI：
10.1016/j.bcp.2017.04.026
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Hai-Liang Zhu
中科院分区：
文献类型：
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作者：
Yong-Fang Yao;Zhong-Chang Wang;Song-Yu Wu;Qing-fang Li;Chen Yu;Xin-Yi Liang;Peng-Cheng Lv;Yong-Tao Duan;Hai-Liang Zhu
Microtubules are essential for the mitotic division of cells and have become an attractive target for antitumour.drugs due to the increased incidence of cancer and significant mitosis rate of tumour cells. In this.study, a total of six indole 1-position modified 1-indolyl acetate-5-nitroimidazole derivatives were.designed, synthesized, and evaluated for their ability to inhibit tubulin polymerization caused by binding.to the colchicine-binding site of tubulin. Among them, compound 3 displayed the best ability to inhibit.tubulin polymerization; it also exhibited better anti-proliferative activities than colchicine against a.panel of human cancer cells (with IC50 values ranging from 15 to 40 nM), especially HeLa cells (with.IC50 values of 15 nM), based on the cellular cytotoxicity assay results. Moreover, cellular mechanism.studies indicated that compound 3 could induce G2/M phase arrest and apoptosis of HeLa and MCF-7.cells, which were associated with alterations in the expression of cell cycle-checkpoint related proteins.(Cyclin B1, Cdc2, and P21) and a reduction in the mitochondrial membrane potential as well as alterations.in the levels of apoptosis-related proteins (PARP, Caspase 9, Bcl-2, and Bax) of these cells, respectively..Importantly, in vivo studies further revealed that compound 3 could dramatically suppress HeLa cell.xenograft tumour growth compared with vehicle and CA-4 phosphate (CA-4P), and no signs of toxicity.were observed in these mice. Collectively, these in vitro and in vivo results indicated that compound 3.might be a promising lead compound for further development as a potential anti-cancer drug.
