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Optimization of the Natural Product Calothrixin A to Discover Novel Dual Topoisomerase I and II Inhibitors with Improved Anticancer Activity
Yang, Xiaohong1,2; Wang, Zhi-Peng1,2; Xiang, Sichuan1; Wang, Daoqiang3; Zhao, Yi4,5; Luo, Dong1; Qiu, Yanfei1; Huang, Chao1; Guo, Jian1; Dai, Yuanwei1
2022-06-09
摘要Calothrixin A (CAA) is a dual Topo I and II inhibitor but exhibits poor antiproliferative activities and water solubility. Herein, a library of novel CAA analogues was synthesized. Among them, compound F16 exhibited superior water solubility (5 mg/mL) as compared to CAA (<5 mu g/mL). The mechanism of action studies confirmed that F16 acted as a dual Topo I and II poison. Furthermore, F16 displayed potent antiproliferative activities against high Topo I and II expression cell lines A375 and HCT116, with IC50 values of 20 and 50 nM, respectively. In xenograft models, F16 reduced the tumor growth at a dose of 10 or 20 mg/kg without apparent effect on the mouse weight, while the clinically used Topo II inhibitor VP-16 dramatically reduced the mouse weight. Collectively, our data demonstrated that F16 could be a promising lead for the development of novel dual Topo I and II antitumor agents.
DOI10.1021/acs.jmedchem.2c00615
发表期刊JOURNAL OF MEDICINAL CHEMISTRY
ISSN0022-2623
卷号65期号:11页码:8040-8061
通讯作者Zhang, Shao-Lin(zhangsl@cqu.edu.cn) ; He, Yun(yun.he@cqu.edu.cn)
收录类别SCI
WOS记录号WOS:000810300800001
语种英语