Liou Jing-Ping, Chang Chun-Wei, Song Jeng-Shin, Yang Yung-Ning, Yeh Ching-Fang, Tseng Huan-Yi, Lo Yu-Kang, Chang Yi-Ling, Chang Chung-Ming, Hsieh Hsing-Pang
Medicinal Synthetic Laboratory, Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 128 Yen-Chiu-Yuan Road, Sec II, Taipei 115, Taiwan, Republic of China.
J Med Chem. 2002 Jun 6;45(12):2556-62. doi: 10.1021/jm010365+.
A new type of inhibitor of tubulin polymerization was discovered on the basis of the combretastatin molecular skeleton. The lead compounds in this series, compounds 6 and 7, strongly inhibited tubulin polymerization in vitro and significantly arrested cells at the G(2)/M phase. Compounds 6 and 7 yielded 50- to 100-fold lower IC(50) values than did combretastatin A-4 against Colo 205, NUGC3, and HA22T human cancer cell lines as well as similar or greater growth inhibitory activities than did combretastain A-4 against DLD-1, HR, MCF-7, DU145, HONE-1, and MES-SA/DX5 human cancer cell lines. Structure-activity relationship information revealed that introduction of an amino group at the ortho position of the benzophenone ring plays an integral role for increased growth inhibition.
基于康普他汀分子骨架发现了一种新型微管蛋白聚合抑制剂。该系列中的先导化合物，即化合物6和7，在体外强烈抑制微管蛋白聚合，并在G(2)/M期显著阻滞细胞。与康普他汀A-4相比，化合物6和7对Colo 205、NUGC3和HA22T人癌细胞系的IC(50)值低50至100倍，对DLD-1、HR、MCF-7、DU145、HONE-1和MES-SA/DX5人癌细胞系的生长抑制活性与康普他汀A-4相似或更高。构效关系信息表明，在二苯甲酮环的邻位引入氨基对增强生长抑制起着不可或缺的作用。
