Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 9, Pages 4457-4478Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm300335n
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Funding
- National Institutes of Health (NIH) [UO1 CA89566]
- Purdue Research Foundation
- NIH, National Cancer Institute, Center for Cancer Research
- National Cancer Institute, National Institutes of Health [HHSN261200800001E]
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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 (IC50 = 1.52 +/- 0.05 mu M), and it was also equipotent to camptothecin as a Top 1 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.
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