Optimization of the Natural Product Calothrixin A to Discover Novel Dual Topoisomerase I and II Inhibitors with Improved Anticancer Activity.
J Med Chem
; 65(11): 8040-8061, 2022 06 09.
Article
em En
| MEDLINE
| ID: mdl-35612499
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Produtos Biológicos
/
Antineoplásicos
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article