Optimization of the Natural Product Calothrixin A to Discover Novel Dual Topoisomerase I and II Inhibitors with Improved Anticancer Activity
Xiaohong Yang, Zhi‐Peng Wang, Sichuan Xiang, Daoqiang Wang, Yi Zhao, Dong Luo, Yanfei Qiu, Chao Huang, Jian Guo, Yuanwei Dai, Shaolin Zhang, Yun He
Abstract
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 μg/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.