title: Synthesis and biological evaluation of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines as potential dual topoisomerase I (Top1)-tyrosyl-DNA phosphodiesterase I (TDP1) inhibitors.
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.
authors: †Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors: Trung Xuan
authors: TX
authors: Nguyen
authors: ‡Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4255, United States.
authors: Monica
authors: M
authors: Abdelmalak
authors: ‡Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4255, United States.
authors: Christophe
authors: C
authors: Marchand
authors: ‡Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4255, United States.
authors: Keli
authors: K
authors: Agama
authors: ‡Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4255, United States.
authors: Yves
authors: Y
authors: Pommier
authors: †Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors: Mark
authors: M
authors: Cushman
mesh_terms: D002166:Camptothecin / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D007192:Indenes / Q000737:chemistry; D007546:Isoquinolines / Q000737:chemistry; D009566:Nitrates; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D007192:Indenes; D007546:Isoquinolines; D009566:Nitrates; D010726:Phosphodiesterase Inhibitors; D059004:Topoisomerase I Inhibitors; C510007:norindenoisoquinoline; D010727:Phosphoric Diester Hydrolases; C122147:tyrosyl-DNA phosphodiesterase; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D002166:Camptothecin