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Optimization of the Natural Product Calothrixin A to Discover Novel Dual Topoisomerase I and II Inhibitors with Improved Anticancer Activity.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2022 Jun 09; Vol. 65 (11), pp. 8040-8061. Date of Electronic Publication: 2022 May 25. - Publication Year :
- 2022
-
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 IC <subscript>50</subscript> 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.
- Subjects :
- Animals
Cell Line, Tumor
Cell Proliferation
DNA Topoisomerases, Type I metabolism
DNA Topoisomerases, Type II metabolism
Drug Screening Assays, Antitumor
Humans
Indole Alkaloids
Mice
Structure-Activity Relationship
Topoisomerase I Inhibitors pharmacology
Topoisomerase I Inhibitors therapeutic use
Topoisomerase II Inhibitors pharmacology
Water metabolism
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Biological Products pharmacology
Biological Products therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 65
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 35612499
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.2c00615