Synthesis and Biological Evaluation of Indenoisoquinolines That Inhibit Both Tyrosyl-DNA Phosphodiesterase I (Tdp1) and Topoisomerase I (Top1)
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- 作者：Martin Conda-Sheridan ; P. V. Narasimha Reddy ; Andrew Morrell ; Brooklyn T. Cobb ; Christophe Marchand ; Keli Agama ; Adel Chergui ; Am茅lie Renaud ; Andrew G. Stephen ; Lakshman K. Bindu ; Yves Pommier ; Mark Cushman
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：January 10, 2013
- 年：2013
- 卷：56
- 期：1
- 页码：182-200
- 全文大小：686K
- 年卷期：v.56,no.1(January 10, 2013)
- ISSN：1520-4804
文摘
Tyrosyl-DNA phosphodiesterase I (Tdp1) plays a key role in the repair of damaged DNA resulting from the topoisomerase I (Top1) inhibitor camptothecin and a variety of other DNA-damaging anticancer agents. This report documents the design, synthesis, and evaluation of new indenoisoquinolines that are dual inhibitors of both Tdp1 and Top1. Enzyme inhibitory data and cytotoxicity data from human cancer cell cultures were used to establish structure鈥揳ctivity relationships. The potencies of the indenoisoquinolines against Tdp1 ranged from 5 渭M to 111 渭M, which places the more active compounds among the most potent known inhibitors of this target. The cytotoxicity mean graph midpoints ranged from 0.02 to 2.34 渭M. Dual Tdp1鈥揟op1 inhibitors are of interest because the Top1 and Tdp1 inhibitory activities could theoretically work synergistically to create more effective anticancer agents.