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

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• 作者：Peng-Cheng Lv ; Mohamed S. A. Elsayed ; Keli Agama ; Christophe Marchand ; Yves Pommier ; Mark Cushman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 26, 2016
• 年：2016
• 卷：59
• 期：10
• 页码：4890-4899
• 全文大小：404K
• 年卷期：0
• ISSN：1520-4804

文摘

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.