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Synthesis and Biological Evaluation of Coumarin-Based Inhibitors of NAD(P)H: Quinone Oxidoreductase-1 (NQO1)

DOI: 10.1021/jm9011609 DOI Help
PMID: 19877692 PMID Help

Authors: Karen Nolan (University of Manchester) , Jeremy R. Doncaster (University of Manchester) , Mark Dunstan (University of Manchester) , Katherine A. Scott (University of Manchester) , A. David Frenkel (University of Manchester) , David Siegel (University of Colorado) , David Ross (University of Colorado) , John Barnes (University of Manchester) , Colin Levy (School of Chemistry & Manchester Interdisciplinary Biocentre, The University of Manchester) , Roger C. Whitehead (University of Manchester) , Ian J. Stratford (University of Manchester) , Richard A. Bryce (University of Manchester) , David Leys (School of Chemistry & Manchester Interdisciplinary Biocentre, The University of Manchester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 52 (22) , PAGES 7142-7156

State: Published (Approved)
Published: November 2009

Abstract: The synthesis is reported here of two novel series of inhibitors of human NAD(P)H quinone oxidoreductase-1 (NQO1), an enzyme overexpressed in several types of tumor cell. The first series comprises substituted symmetric dicoumarol analogues; the second series contains hybrid compounds where one 4-hydroxycoumarin system is replaced by a different aromatic moiety. Several compounds show equivalent or improved NQO1 inhibition over dicoumarol, both in the presence and in the absence of added protein. Further, correlation is demonstrated between the ability of these agents to inhibit NQO1 and computed binding affinity. We have solved the crystal structure of NQO1 complexed to a hybrid compound and find good agreement with the in silico model. For both MIA PaCa-2 pancreatic tumor cells and HCT116 colon cancer cells, dicoumarol shows the greatest toxicity of all compounds. Thus, we provide a computational, synthetic, and biological platform to generate competitive NQO1 inhibitors with superior pharmacological properties to dicoumarol. This will allow a more definitive study of NQO1 activity in cells, in particular, its drug activating/detoxifying properties and ability to modulate oncoprotein stability.

Journal Keywords: Animals; Cattle; Cell; Tumor; Crystallography; X-Ray; Enzyme; Humans; Inhibitory; Models; Molecular; NAD(P)H; Quantitative Structure-Activity Relationship

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography