Identification of novel 1-indolyl acetate-5-nitroimidazole derivatives of combretastatin A-4 as potential tubulin polymerization inhibitors

• Published in: Biochemical pharmacology Vol. 137; pp. 10 - 28
• Main Authors: Yao, Yong-Fang, Wang, Zhong-Chang, Wu, Song-Yu, Li, Qing-fang, Yu, Chen, Liang, Xin-Yi, Lv, Peng-Cheng, Duan, Yong-Tao, Zhu, Hai-Liang
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.08.2017
• Subjects: A549 Cells; Animals; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Cell cycle; Cell Proliferation - drug effects; Cell Proliferation - physiology; Colchicine; Combretastatin A-4 (CA-4); Dose-Response Relationship, Drug; Female; HEK293 Cells; HeLa Cells; Hep G2 Cells; HT29 Cells; Humans; MCF-7 Cells; Mice; Mice, Nude; Microtubule; Nitroimidazoles - chemistry; Nitroimidazoles - pharmacology; Protein Structure, Secondary; Random Allocation; Stilbenes - chemistry; Stilbenes - pharmacology; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Xenograft Model Antitumor Assays - methods; PBS; DMSO; SAR; Combretastatin A-4 (PubChem CID: 5351344); DAPI; TLC; MTT; BSA; NMR; Cell cycle; PI; CA-4; TMS; Microtubule; Colchicine; Colchicine (PubChem CID: 6167); Paclitaxel (PubChem CID: 36314); Combretastatin A-4 (CA-4); Apoptosis
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2017.04.026

[Display omitted] Microtubules are essential for the mitotic division of cells and have become an attractive target for anti-tumour 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 40nM), especially HeLa cells (with IC50 values of 15nM), 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.