Recent progress in topoisomerase inhibitors as anticancer agents: Research and design strategies for Topo I and II inhibitors via structural optimization.

Topoisomerase (Topo) is a crucial class of enzymes that play significant roles in DNA replication, transcription, and repair. Epidemiological research has highlighted the necessity of topoisomerase for the proliferation and genomic stability of tumor cells. Currently, the main topoisomerase inhibitors used in cancer therapy are toxins and catalytic inhibitors that target topoisomerase I (Topo I) and topoisomerase II (Topo II). These inhibitors hinder tumor cell proliferation by disrupting DNA topology regulation. However, prolonged use of these traditional drugs can lead to issues such as drug resistance, cardiotoxicity, and myelosuppression. Thus, there is a pressing need to develop innovative topoisomerase inhibitors with high efficacy and low toxicity. This review systematically summarizes and analyzes the structural and optimization advances of Topo I and II inhibitors over the past five years, with particular attention to catalytic inhibitors and multitarget agents, aiming to provide new perspectives for the development of safer and more effective small-molecule topoisomerase inhibitors for cancer therapy.