1374209-80-9Relevant academic research and scientific papers
SYNTHESIS AND USE OF DUAL TYROSYL-DNA PHOSPHODIESTERASE I (TDP1)- TOPOISOMERASE I (TOP1) INHIBITORS
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Paragraph 0164, (2014/02/15)
The invention described herein pertains to the synthesis and use of certain N-substituted indenoisoquinoline compounds which inhibit the activity Tyrosyl-DNA Phosphodiesterase I (Tdp1) or Topoisomerase I (Top1) or both, or otherwise demonstrate anticancer activity. Also disclosed are novel N-substituted indenoisoquinoline compounds and pharmaceutical compositions comprising the novel N-substituted indenoisoquinoline compounds.
Synthesis and biological evaluation of the first dual tyrosyl-DNA phosphodiesterase i (Tdp1)-topoisomerase i (Top1) inhibitors
Nguyen, Trung Xuan,Morrell, Andrew,Conda-Sheridan, Martin,Marchand, Christophe,Agama, Keli,Bermingam, Alun,Stephen, Andrew G.,Chergui, Adel,Naumova, Alena,Fisher, Robert,O'Keefe, Barry R.,Pommier, Yves,Cushman, Mark
, p. 4457 - 4478 (2012/08/07)
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.
