茚并异喹啉酮类拓扑异构酶1抑制剂的研究进展

拓扑异构酶1（Top1）在调控DNA的拓扑形态中起关键作用,是抗肿瘤药物研发的重要靶点。喜树碱是强效的Top1抑制剂,但具有较多缺陷,在众多寻找成药性更好的非喜树碱类Top1抑制剂的研究中,Cushman小组发展的茚并异喹啉酮类新型化合物是其中的典型代表。目前该领域的研究,已经发现了数十个活性优良的先导化合物,并先后有3个进入临床研究阶段。本文综述了茚并异喹啉酮类新药发展历程及其研究策略。

Development of Indenoisoquinoline Derivatives as Novel Topoisomerase 1 Inhibitors

Topoisomerase 1 plays a key role in regulating the topological form of DNA, therefore it is the important target of anticancer drugs. Camptothecin demonstrates effective Top1 inhibitory activities, unfortunately, it has a lot of defects. Many efforts have been taken to overcome the disadvantages of camptothecin, including development of new noncamptothecin Top1inhibitors. Indenoisoquinolines developed by Cushman group are the representative class of noncamptothecin Top1 inhibitors.After systematic structural optimization, a number of promising compounds were developed and three of them had been selected as new drug candidates for clinical development. This review focuses on the development process of indenoisoquinoline and the research strategy.