Abstract
The structure-activity relationships and hit-to-lead optimization of dual Top1-TDP1 inhibitors in the indenoisoquinoline drug class were investigated. A series of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines were synthesized and evaluated. Several compounds displayed potent dual Top1-TDP1 inhibition. The 9-hydroxy series exhibited potencies and cytotoxicities vs Top1 that surpassed those of camptothecin (CPT), the natural alkaloid that is being used as a standard in the Top1-mediated DNA cleavage assay. One member of this series was a more potent Top1 inhibitor at a concentration of 5 nM and produced a more stable ternary drug-DNA-Top1 cleavage complex than CPT.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, N.I.H., Intramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Camptothecin / pharmacology
-
Chemistry Techniques, Synthetic
-
DNA Topoisomerases, Type I / chemistry
-
DNA Topoisomerases, Type I / metabolism
-
Dose-Response Relationship, Drug
-
Drug Design
-
Drug Evaluation, Preclinical / methods
-
Humans
-
Indenes / chemistry
-
Isoquinolines / chemistry
-
Nitrates
-
Phosphodiesterase Inhibitors / chemical synthesis
-
Phosphodiesterase Inhibitors / chemistry*
-
Phosphodiesterase Inhibitors / pharmacology*
-
Phosphoric Diester Hydrolases / chemistry
-
Phosphoric Diester Hydrolases / genetics
-
Phosphoric Diester Hydrolases / metabolism
-
Structure-Activity Relationship
-
Topoisomerase I Inhibitors / chemical synthesis
-
Topoisomerase I Inhibitors / chemistry*
-
Topoisomerase I Inhibitors / pharmacology*
Substances
-
Indenes
-
Isoquinolines
-
Nitrates
-
Phosphodiesterase Inhibitors
-
Topoisomerase I Inhibitors
-
norindenoisoquinoline
-
Phosphoric Diester Hydrolases
-
tyrosyl-DNA phosphodiesterase
-
DNA Topoisomerases, Type I
-
TOP1 protein, human
-
Camptothecin