期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 10, 页码 4890-4899出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00220
关键词
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资金
- National Institutes of Health (NIH) [UO1 CA89566, P30 CA023168]
- NIH, National Cancer Institute, Center for Cancer Research
- Developmental Therapeutics Program at the National Cancer Institute [NO1-CO-56000]
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 GI(50) values below 10 nM in a variety of human cancer cell lines.
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