Synthesis and Biological Evaluation of the First Dual Tyrosyl-DNA Phosphodiesterase I (Tdp1)鈥揟opoisomerase I (Top1) Inhibitors

详细信息    查看全文

• 作者：Trung Xuan Nguyen ; Andrew Morrell ; Martin Conda-Sheridan ; Christophe Marchand ; Keli Agama ; Alun Bermingam ; Andrew G. Stephen ; Adel Chergui ; Alena Naumova ; Robert Fisher ; Barry R. O鈥橩eefe ; Yves Pommier ; Mark Cushman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：55
• 期：9
• 页码：4457-4478
• 全文大小：1001K
• 年卷期：v.55,no.9(May 10, 2012)
• ISSN：1520-4804

文摘

Substances with dual tyrosyl-DNA phosphodiesterase I鈥搕opoisomerase I inhibitory activity in one low molecular weight compound would constitute a unique class of anticancer agents that could potentially have significant advantages over drugs that work against the individual enzymes. The present study demonstrates the successful synthesis and evaluation of the first dual Top1鈥揟dp1 inhibitors, which are based on the indenoisoquinoline chemotype. One bis(indenoisoquinoline) had significant activity against human Tdp1 (IC₅₀ = 1.52 卤 0.05 渭M), and it was also equipotent to camptothecin as a Top1 inhibitor. Significant insights into enzyme鈥揹rug interactions were gained via structure鈥揳ctivity relationship studies of the series. The present results also document the failure of the previously reported sulfonyl ester pharmacophore to confer Tdp1 inhibition in this indenoisoquinoline class of inhibitors even though it was demonstrated to work well for the steroid NSC 88915 (7). The current study will facilitate future efforts to optimize dual Top1鈥揟dp1 inhibitors.