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ID: ALA5113389
Journal: Eur J Med Chem
Title: Topoisomerase I inhibitors: Challenges, progress and the road ahead.
Authors: Talukdar A, Kundu B, Sarkar D, Goon S, Mondal MA.
Abstract: Topoisomerase IB (Top1), a subcategory of DNA topoisomerase enzymes is expressed much higher in several tumor cells. Therefore, modulating the activity of Top1 in tumor cells to prevent DNA replication and subsequent cell division made it an important drug target for anticancer therapy. FDA-approved camptothecin (CPT) derivatives topotecan and irinotecan exert anticancer activity through stabilization of enzyme-mediated DNA cleavage complex forming a ternary complex between DNA-Top1-drug. However, CPT derivatives suffer from several limitations which prompted interest in the development of 'non-camptothecin' Top1 poisons as anticancer agents. This review aims to provide chronological development of different classes of Top1 poisons from both natural and synthetic sources through strategic structure-activity relationship (SAR) analysis with insight into the important structural features in different chemotypes that imparted Top1 inhibition along with the understanding of the structural basis of inhibition. This review also provides a snapshot of the application of Top1 poisons in various combination therapies in recent times. We believe such a comprehensive review is going to be beneficial for the medicinal chemistry community to design efficient drug development strategies using existing knowledge.
CiteXplore: 35413618