拓扑异构酶 I 抑制剂：挑战、进展和未来之路,European Journal of Medicinal Chemistry

拓扑异构酶 IB (Top1) 是 DNA 拓扑异构酶的一个亚类，在几个肿瘤细胞中的表达要高得多。因此，调节肿瘤细胞中Top1的活性以阻止DNA复制和随后的细胞分裂使其成为抗癌治疗的重要药物靶点。FDA 批准的喜树碱 (CPT) 衍生物拓扑替康和伊立替康通过稳定酶介导的 DNA 切割复合物在 DNA-Top1-药物之间形成三元复合物发挥抗癌活性。然而，CPT 衍生物受到一些限制，这促使人们对开发“非喜树碱”Top1 毒物作为抗癌剂产生了兴趣。

本综述旨在通过战略构效关系 (SAR) 分析提供来自天然和合成来源的不同类型 Top1 毒物的时间发展，并深入了解赋予 Top1 抑制的不同化学型的重要结构特征以及对结构的理解。抑制的基础。这篇综述还提供了近期 Top1 毒物在各种联合疗法中的应用的快照。我们相信，如此全面的审查将有利于药物化学界利用现有知识设计有效的药物开发策略。

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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.