title: Synthesis and biological evaluation of indenoisoquinolines that inhibit both tyrosyl-DNA phosphodiesterase I (Tdp1) and topoisomerase I (Top1).
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.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Conda-Sheridan
authors.forename: P V Narasimha
authors.initials: PV
authors.lastname: Reddy
authors.forename: Andrew
authors.initials: A
authors.lastname: Morrell
authors.forename: Brooklyn T
authors.initials: BT
authors.lastname: Cobb
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.forename: Keli
authors.initials: K
authors.lastname: Agama
authors.forename: Adel
authors.initials: A
authors.lastname: Chergui
authors.forename: Amélie
authors.initials: A
authors.lastname: Renaud
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Stephen
authors.forename: Lakshman K
authors.initials: LK
authors.lastname: Bindu
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007192:Indenes; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D059004:Topoisomerase I Inhibitors; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human