Chapter 1 - Topoisomerase I Inhibitors Derived from Natural Products: Structure–Activity Relationships and Antitumor Potency

Abstract

Abstract Topoisomerase I (Top1) is an important target for developing novel anticancer agents. The discovery of natural product camptothecin (CPT) as a specific Top1 inhibitor and the development of synthetic CPT derivatives topotecan and irinotecan into clinical use represent a great achievement in antitumor drug discovery. However, clinically approved CPT derivatives have several major limitations such as chemical instability, drug resistance, and side effects. Thus, the discovery of novel Top1 inhibitors has recently emerged as a promising field to find better antitumor agents. Currently, identification of novel Top1 inhibitors is still largely dependent on the optimization of natural CPT and the screening of natural products. In recent years, a number of new CPT derivatives and natural products have been reported to be novel Top1 inhibitors. Several of them showed higher Top1 inhibitory activity, chemical stability, and antitumor activity, which had promising future for overcoming the limitations of CPT. This review will provide recent progress in novel Top1 inhibitors derived from natural products. In particular, we will focus on (1) new chemical scaffolds and structure–activity relationships; (2) their binding mode with Top1–DNA binary complex; (3) new natural product derivatives with improved pharmacological and pharmacodynamic profiles (eg, evodiamines, indolocarbazoles, lamellarins, wakayins, tsitsikammamines, berberines, and topopyrones).