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

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

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z