title: Coumarin-based inhibitors of human NAD(P)H:quinone oxidoreductase-1. Identification, structure-activity, off-target effects and in vitro human pancreatic cancer toxicity.
abstract: The enzyme human NAD(P)H quinone oxidoreductase-1 (NQO1), which is overexpressed in several types of tumor cell, is considered a design target for cancer therapeutics. We identify new coumarin-based competitive inhibitors of NQO1, one of which is nanomolar. Using computational docking and molecular dynamics, we obtain insights into the structural basis of inhibition. Selected inhibitors were then assessed for off-target effects associated with dicoumarol and were found to have differing effects on superoxide formation and mitochondrial respiration. A comparison of NQO1 inhibition and off-target effects for dicoumarol and its derivatives suggests that the ability of dicoumarol to kill cancer cells is independent of NQO1 inhibition, that cellular superoxide production by dicoumarol does not seem linked to NQO1 inhibition but may be related to mitochondrial decoupling, and that superoxide does not appear to be a major determinant of cytotoxicity. Implications are discussed for NQO1 inhibition as an anticancer drug design target and superoxide generation as the dicoumarol-mediated mechanism of cytotoxicity.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Nolan
authors.forename: He
authors.initials: H
authors.lastname: Zhao
authors.forename: Paul F
authors.initials: PF
authors.lastname: Faulder
authors.forename: A David
authors.initials: AD
authors.lastname: Frenkel
authors.forename: David J
authors.initials: DJ
authors.lastname: Timson
authors.forename: David
authors.initials: D
authors.lastname: Siegel
authors.forename: David
authors.initials: D
authors.lastname: Ross
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Stratford
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bryce
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001665:Binding Sites; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D001728:Dicumarol / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D010101:Oxygen Consumption / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D013481:Superoxides; D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human