title: Synthesis and biological evaluation of the first dual tyrosyl-DNA phosphodiesterase I (Tdp1)-topoisomerase I (Top1) inhibitors.
abstract: Substances with dual tyrosyl-DNA phosphodiesterase I-topoisomerase I inhibitory activity in one low molecular weight compound would constitute a unique class of anticancer agents that could potentially have significant advantages over drugs that work against the individual enzymes. The present study demonstrates the successful synthesis and evaluation of the first dual Top1-Tdp1 inhibitors, which are based on the indenoisoquinoline chemotype. One bis(indenoisoquinoline) had significant activity against human Tdp1 (IC(50) = 1.52 ± 0.05 μM), and it was also equipotent to camptothecin as a Top1 inhibitor. Significant insights into enzyme-drug interactions were gained via structure-activity relationship studies of the series. The present results also document the failure of the previously reported sulfonyl ester pharmacophore to confer Tdp1 inhibition in this indenoisoquinoline class of inhibitors even though it was demonstrated to work well for the steroid NSC 88915 (7). The current study will facilitate future efforts to optimize dual Top1-Tdp1 inhibitors.
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: Trung Xuan
authors.initials: TX
authors.lastname: Nguyen
authors.forename: Andrew
authors.initials: A
authors.lastname: Morrell
authors.forename: Martin
authors.initials: M
authors.lastname: Conda-Sheridan
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.forename: Keli
authors.initials: K
authors.lastname: Agama
authors.forename: Alun
authors.initials: A
authors.lastname: Bermingham
authors.forename: Alun
authors.initials: A
authors.lastname: Bermingam
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Stephen
authors.forename: Adel
authors.initials: A
authors.lastname: Chergui
authors.forename: Alena
authors.initials: A
authors.lastname: Naumova
authors.forename: Robert
authors.initials: R
authors.lastname: Fisher
authors.forename: Barry R
authors.initials: BR
authors.lastname: O'Keefe
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007192:Indenes; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D059004:Topoisomerase I Inhibitors; D010727:Phosphoric Diester Hydrolases; C122147:tyrosyl-DNA phosphodiesterase; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human