title: A novel ring oxidation of 4- or 5-substituted 2H-oxazole to corresponding 2-oxazolone catalyzed by cytosolic aldehyde oxidase.
abstract: The ring oxidation of 2H-oxazole, or C2-unsubstituted oxazole, to 2-oxazolone, a cyclic carbamate, was observed on various 4- or 5-substituted oxazoles. Using 5-(3-bromophenyl)oxazole as a model compound, its 2-oxazolone metabolite M1 was fully characterized by liquid chromatography/tandem mass spectrometry and nuclear magnetic resonance. The reaction mainly occurred in the liver cytosolic fraction without the requirement of cytochrome P450 enzymes and cofactor NADPH. Investigations into the mechanism of formation of 2-oxazolone using various chemical inhibitors indicated that the reaction was primarily catalyzed by aldehyde oxidase and not by xanthine oxidase. In addition, cytosol incubation of 5-(3-bromophenyl)oxazole in the medium containing H₂¹⁸O led to the ¹⁸O incorporation into M1, substantiating the reaction mechanism of a typical molybdenum hydroxylase. The rank order of liver cytosols for the 2-oxazolone formation was mouse > monkey ≫ rat and human liver cytosol, whereas M1 was not formed in dog liver cytosol. Because the reaction was observed with a number of 4- or 5-substituted 2H-oxazoles in mouse liver cytosols, 2H-oxazoles represent a new substrate chemotype for ring oxidation catalyzed by aldehyde oxidase.
authors.affiliation: Department of Biotransformation, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. vinod.arora@bms.com
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Arora
authors.forename: Thomas
authors.initials: T
authors.lastname: Philip
authors.forename: Stella
authors.initials: S
authors.lastname: Huang
authors.forename: Yue-Zhong
authors.initials: YZ
authors.lastname: Shu
mesh_terms: D042931:Aldehyde Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000201:enzymology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000882:Haplorhini; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism*; D010081:Oxazolone / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D010103:Oxygen Isotopes; D051381:Rats; D013045:Species Specificity; D013379:Substrate Specificity; D053719:Tandem Mass Spectrometry; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D010080:Oxazoles; D010103:Oxygen Isotopes; D010081:Oxazolone; D014969:Xanthine Oxidase; D042931:Aldehyde Oxidase