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Synthesis and biological evaluation of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines as potential dual topoisomerase I (Top1)-tyrosyl-DNA phosphodiesterase I (TDP1) inhibitors.
Nguyen, Trung Xuan; Abdelmalak, Monica; Marchand, Christophe; Agama, Keli; Pommier, Yves; Cushman, Mark.
Affiliation
  • Nguyen TX; †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.
  • Abdelmalak M; ‡Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4255, United States.
  • Marchand C; ‡Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4255, United States.
  • Agama K; ‡Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4255, United States.
  • Pommier Y; ‡Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4255, United States.
  • Cushman M; †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.
J Med Chem ; 58(7): 3188-208, 2015 Apr 09.
Article in En | MEDLINE | ID: mdl-25811317
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phosphodiesterase Inhibitors / Topoisomerase I Inhibitors Limits: Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2015 Type: Article Affiliation country: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phosphodiesterase Inhibitors / Topoisomerase I Inhibitors Limits: Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2015 Type: Article Affiliation country: United States