Design, Synthesis, and Biological Evaluation of O-2-Modified Indenoisoquinolines as Dual Topoisomerase I鈥揟yrosyl-DNA Phosphodiesterase I Inhibitors

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• 作者：Peng-Cheng Lv ; Keli Agama ; Christophe Marchand ; Yves Pommier ; Mark Cushman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 22, 2014
• 年：2014
• 卷：57
• 期：10
• 页码：4324-4336
• 全文大小：590K
• 年卷期：v.57,no.10(May 22, 2014)
• ISSN：1520-4804

文摘

Tyrosyl-DNA phosphodiesterase I (TDP1) repairs stalled topoisomerase I (Top1)鈥揇NA covalent complexes and has been proposed to be a promising and attractive target for cancer treatment. Inhibitors of TDP1 could conceivably act synergistically with Top1 inhibitors and thereby potentiate the effects of Top1 poisons. This study describes the successful design and synthesis of 2-position-modified indenoisoquinolines as dual Top1鈥揟DP1 inhibitors using a structure-based drug design approach. Enzyme inhibition studies indicate that indenoisoquinolines modified at the 2-position with three-carbon side chains ending with amino substituents show both promising Top1 and TDP1 inhibitory activity. Molecular modeling of selected target compounds bound to Top1 and TDP1 was used to rationalize the enzyme inhibition results and structure鈥揳ctivity relationship analysis.