Optimization of the Natural Product Calothrixin A to Discover Novel Dual Topoisomerase I and II Inhibitors with Improved Anticancer Activity

  • J Med Chem. 2022 Jun 9;65(11):8040-8061. doi: 10.1021/acs.jmedchem.2c00615.
Xiaohong Yang  1  2 ,  Zhi-Peng Wang  1  2 ,  Sichuan Xiang  1 ,  Daoqiang Wang  3 ,  Yi Zhao  2  4 ,  Dong Luo  1 ,  Yanfei Qiu  1 ,  Chao Huang  1 ,  Jian Guo  1 ,  Yuanwei Dai  1 ,  Shao-Lin Zhang  1 ,  Yun He  1
Affiliations
  • 1. School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing 401331, P. R. China.
  • 2. Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing 400714, P. R. China.
  • 3. School of Environment and Resources, Chongqing Technology and Business University, Chongqing 400067, China.
  • 4. School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
PMID: 35612499 DOI: 10.1021/acs.jmedchem.2c00615
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.

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