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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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DNA Topoisomerases, Type I / metabolism*
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Drug Screening Assays, Antitumor
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Humans
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Indenes / chemical synthesis*
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Indenes / chemistry
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Indenes / pharmacology
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Isoquinolines / chemical synthesis*
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Isoquinolines / chemistry
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Isoquinolines / pharmacology
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Models, Molecular
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Phosphodiesterase Inhibitors / chemical synthesis*
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Phosphodiesterase Inhibitors / chemistry
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Phosphodiesterase Inhibitors / pharmacology
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Phosphoric Diester Hydrolases / metabolism*
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Structure-Activity Relationship
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Topoisomerase I Inhibitors / chemical synthesis*
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Topoisomerase I Inhibitors / chemistry
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Topoisomerase I Inhibitors / pharmacology
Substances
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Antineoplastic Agents
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Indenes
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Isoquinolines
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Phosphodiesterase Inhibitors
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Topoisomerase I Inhibitors
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Phosphoric Diester Hydrolases
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TDP1 protein, human
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DNA Topoisomerases, Type I
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TOP1 protein, human