Synthesis and biological evaluation of the first dual tyrosyl-DNA phosphodiesterase i (Tdp1)-topoisomerase i (Top1) inhibitors

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'Keefe, Yves Pommier, Mark Cushman

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Abstract

Substances with dual tyrosyl-DNA phosphodiesterase I-topoisomerase 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-Tdp1 inhibitors, which are based on the indenoisoquinoline chemotype. One bis(indenoisoquinoline) had significant activity against human Tdp1 (IC 50 = 1.52 ± 0.05 μM), and it was also equipotent to camptothecin as a Top1 inhibitor. Significant insights into enzyme-drug interactions were gained via structure-activity 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-Tdp1 inhibitors.

Original languageEnglish (US)
Pages (from-to)4457-4478
Number of pages22
JournalJournal of Medicinal Chemistry
Volume55
Issue number9
DOIs
StatePublished - May 10 2012

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Nguyen, T. X., Morrell, A., Conda-Sheridan, M., Marchand, C., Agama, K., Bermingam, A., Stephen, A. G., Chergui, A., Naumova, A., Fisher, R., O'Keefe, B. R., Pommier, Y., & Cushman, M. (2012). Synthesis and biological evaluation of the first dual tyrosyl-DNA phosphodiesterase i (Tdp1)-topoisomerase i (Top1) inhibitors. Journal of Medicinal Chemistry, 55(9), 4457-4478. https://doi.org/10.1021/jm300335n