Lv Peng-Cheng, Elsayed Mohamed S A, Agama Keli, Marchand Christophe, Pommier Yves, Cushman Mark
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University , West Lafayette, Indiana 47907, United States .
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute , Bethesda, Maryland 20892-4255, United States.
J Med Chem. 2016 May 26;59(10):4890-9. doi: 10.1021/acs.jmedchem.6b00220. Epub 2016 Apr 20.
Indenoisoquinoline topoisomerase I (Top1) inhibitors are a novel class of anticancer agents with two compounds in clinical trials. Recent metabolism studies of indotecan (LMP400) led to the discovery of the biologically active 2-hydroxylated analogue and 3-hydroxylated metabolite, thus providing strategically placed functional groups for the preparation of a variety of potential ester prodrugs of these two compounds. The current study details the design and synthesis of two series of indenoisoquinoline prodrugs, and it also reveals how substituents on the O-2 and O-3 positions of the A ring, which are next to the cleaved DNA strand in the drug-DNA-Top1 ternary cleavage complex, affect Top1 inhibitory activity and cytotoxicity. Many of the indenoisoquinoline prodrugs were very potent antiproliferative agents with GI50 values below 10 nM in a variety of human cancer cell lines.
茚并异喹啉拓扑异构酶I（Top1）抑制剂是一类新型抗癌药物，有两种化合物正在进行临床试验。最近对茚托替康（LMP400）的代谢研究发现了具有生物活性的2-羟基化类似物和3-羟基化代谢物，从而为制备这两种化合物的多种潜在酯前药提供了具有战略意义的官能团。当前的研究详细介绍了两个系列茚并异喹啉前药的设计与合成，还揭示了在药物-DNA-Top1三元切割复合物中紧邻切割DNA链的A环O-2和O-3位上的取代基如何影响Top1抑制活性和细胞毒性。许多茚并异喹啉前药都是非常有效的抗增殖剂，在多种人类癌细胞系中的GI50值低于10 nM。
