Design, Synthesis, and Biological Evaluation of Potential Prodrugs Related to the Experimental Anticancer Agent Indotecan (LMP400)

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（indenoisoquinoline）类拓扑异构酶I（Top1）抑制剂是一类新型抗癌剂，目前已有两款化合物处于临床试验阶段。针对英多替康（indotecan，LMP400）的近期代谢研究，成功发现了具有生物活性的2-羟基类似物与3-羟基代谢物，由此为这两种活性产物制备多种潜在酯类前药提供了位点明确的官能团。本研究详细阐述了两系列茚并异喹啉类前药的设计与合成工作，并揭示了在药物-DNA-Top1三元裂解复合物中，位于A环O-2与O-3位（紧邻断裂DNA链）的取代基如何影响Top1抑制活性与细胞毒性。诸多茚并异喹啉类前药展现出优异的抗增殖活性，在多种人类癌细胞系中的GI₅₀值低于10 nM。