Talukdar Arindam, Kundu Biswajit, Sarkar Dipayan, Goon Sunny, Mondal Mohabul Alam
Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700032, WB, India; Academy of Scientific and Innovative Research, Ghaziabad, 201002, India.
Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700032, WB, India.
Eur J Med Chem. 2022 Jun 5;236:114304. doi: 10.1016/j.ejmech.2022.114304. Epub 2022 Apr 2.
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.
拓扑异构酶IB（Top1）是DNA拓扑异构酶的一个亚类，在几种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一个重要药物靶点。美国食品药品监督管理局（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裂解复合物发挥抗癌活性，该复合物在DNA-Top1-药物之间形成三元复合物。然而，CPT衍生物存在一些局限性，这促使人们对开发“非喜树碱”类Top1抑制剂作为抗癌药物产生了兴趣。本综述旨在通过策略性的构效关系（SAR）分析，按时间顺序介绍来自天然和合成来源的不同类别的Top1抑制剂的发展，深入了解不同化学类型中赋予Top1抑制作用的重要结构特征，以及对抑制作用的结构基础的理解。本综述还简要介绍了近年来Top1抑制剂在各种联合疗法中的应用。我们相信，这样一篇全面的综述将有助于药物化学界利用现有知识设计高效的药物开发策略。
