Synthesis and Biological Evaluation of Novel Millepachine Derivatives As a New Class of Tubulin Polymerization Inhibitors
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- 作者：Zhuang Yang ; Wenshuang Wu ; Jingjing Wang ; Li Liu ; Luyuan Li ; Jianhong Yang ; Guangcheng Wang ; Dong Cao ; Ronghong Zhang ; Minghai Tang ; Jiaolin Wen ; Jun Zhu ; Wei Xiang ; Fang Wang ; Liang Ma ; Mingli Xiang ; Jingsong You ; Lijuan Chen
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：October 9, 2014
- 年：2014
- 卷：57
- 期：19
- 页码：7977-7989
- 全文大小：622K
- ISSN：1520-4804
文摘
Twenty-one novel derivatives of millepachine were synthesized and evaluated for their in vitro antiproliferative activity. Among them, 8 exhibited the most potent activity, with IC50 values of 8鈥?7 nM against panel of cancer cell lines and retained full activity in multidrug resistant cancer cells. Treated cells were arrested in G2/M phase and resulted in cellular apoptosis. Microtubule dynamics confirmed 8 was a novel tubulin polymerization inhibitor by binding at the colchicine site. 8 also exhibited antivascular activity because it concentration dependently reduced the cell migration and disrupted capillary like tube formation in HUVEC cells. Furthermore, the hydrochloride salt of 8 (8路HCl) significantly improved the bioavailability up to 47% while retaining the antiproliferative activity. Importantly, 8路HCl significantly inhibited tumor growths in four xenograft models including resistance tumor-cell-bearing mice models without causing significant loss of body weight, suggesting that 8 is a promising new orally anticancer agent to be developed.