Synthesis and biological evaluation of coumarin-based inhibitors of NAD(P)H: quinone oxidoreductase-1 (NQO1).
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.
Nolan
Karen A
KA
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester Cancer Research Center, Manchester, M13 9PT, United Kingdom.
Doncaster
Jeremy R
JR
Dunstan
Mark S
MS
Scott
Katherine A
KA
Frenkel
A David
AD
Siegel
David
D
Ross
David
D
Barnes
John
J
Levy
Colin
C
Leys
David
D
Whitehead
Roger C
RC
Stratford
Ian J
IJ
Bryce
Richard A
RA
D015110:4-Hydroxycoumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship
D015110:4-Hydroxycoumarins; D004791:Enzyme Inhibitors; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C068805:4-hydroxycoumarin