Synthesis, Evaluation, and Mechanism Study of Novel Indole-Chalcone Derivatives Exerting Effective Antitumor Activity Through Microtubule Destabilization in Vitro and in Vivo

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• 作者：Jun Yan ; Jie Chen ; Shun Zhang ; Jinhui Hu ; Ling Huang ; Xingshu Li
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：June 9, 2016
• 年：2016
• 卷：59
• 期：11
• 页码：5264-5283
• 全文大小：1147K
• 年卷期：0
• ISSN：1520-4804

文摘

Twenty-nine novel indole-chalcone derivatives were synthesized and evaluated for antiproliferative activity. Among them, 14k exhibited most potent activity, with IC₅₀ values of 3–9 nM against six cancer cells, which displayed a 3.8–8.7-fold increase in activity when compare with compound 2. Further investigation revealed 14k was a novel tubulin polymerization inhibitor binding to the colchicine site. Its low cytotoxicity toward normal human cells and nearly equally potent activity against drug-resistant cells revealed the possibility for cancer therapy. Cellular mechanism studies elucidated 14k arrests cell cycle at G₂/M phase and induces apoptosis along with the decrease of mitochondrial membrane potential. Furthermore, good metabolic stability of 14k was observed in mouse liver microsomes. Importantly, 14k and its phosphate salt 14k-P inhibited tumor growth in xenograft models in vivo without apparent toxicity, which was better than the reference compound CA-4P and 2. In summary, 14k deserves consideration for cancer therapy.