Design, synthesis and evaluation of thiohydantoin derivatives as potent topoisomerase I (Top1) inhibitors with anticancer activity.

Abstract

DNA topoisomerase I is a potential chemotherapeutic target. Here, we designed and synthesized a library comprising of hydantoin and thiohydantoin derivatives and tested them against human and Leishmania Top1. One of the thiohydantoin compounds with substituted thiophenyl as the central moiety (compound 15) exhibited potent inhibition of human Top1 (HTop1) through stabilization of Top1-DNA cleavage complexes and showed selective anticancer activity against human cervical carcinoma (HeLa) and breast carcinoma (MCF-7) cell lines. Molecular modeling studies with HTop1 rationalized the inhibitory mechanism of compound 15.

• Authors: Papiya Majumdar, Chandramohan Bathula, Suparna M Basu, Subhendu K Das, Rahul Agarwal, Santanu Hati, Ashutosh Singh, Subhabrata Sen, Benu Brata Das
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 102 Pg. 540-51 (Sep 18 2015) ISSN: 1768-3254 [Electronic] France
• PMID: 26312433 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Thiohydantoins
• Topoisomerase I Inhibitors
• DNA Topoisomerases, Type I

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• DNA Topoisomerases, Type I (metabolism)
• Dose-Response Relationship, Drug
• Drug Design
• Drug Screening Assays, Antitumor
• HEK293 Cells
• HeLa Cells
• Humans
• MCF-7 Cells
• Models, Molecular
• Molecular Structure
• Structure-Activity Relationship
• Thiohydantoins (chemical synthesis, chemistry, pharmacology)
• Topoisomerase I Inhibitors (chemical synthesis, chemistry, pharmacology)