Synthesis and biological evaluation of indenoisoquinolines that inhibit both tyrosyl-DNA phosphodiesterase i (Tdp1) and topoisomerase i (Top1)

Martin Conda-Sheridan, P. V.Narasimha Reddy, Andrew Morrell, Brooklyn T. Cobb, Christophe Marchand, Keli Agama, Adel Chergui, Amélie Renaud, Andrew G. Stephen, Lakshman K. Bindu, Yves Pommier, Mark Cushman

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

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-activity relationships. The potencies of the indenoisoquinolines against Tdp1 ranged from 5 μM to 111 μM, 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 μM. Dual Tdp1-Top1 inhibitors are of interest because the Top1 and Tdp1 inhibitory activities could theoretically work synergistically to create more effective anticancer agents.

Original languageEnglish (US)
Pages (from-to)182-200
Number of pages19
JournalJournal of Medicinal Chemistry
Volume56
Issue number1
DOIs
StatePublished - Jan 10 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Conda-Sheridan, M., Reddy, P. V. N., Morrell, A., Cobb, B. T., Marchand, C., Agama, K., Chergui, A., Renaud, A., Stephen, A. G., Bindu, L. K., Pommier, Y., & Cushman, M. (2013). Synthesis and biological evaluation of indenoisoquinolines that inhibit both tyrosyl-DNA phosphodiesterase i (Tdp1) and topoisomerase i (Top1). Journal of Medicinal Chemistry, 56(1), 182-200. https://doi.org/10.1021/jm3014458