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.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
ABBREVIATIONS:
- AO
- aldehyde oxidase
- XO
- xanthine oxidase
- P450
- cytochrome P450
- 5BPO
- 5-(3-bromophenyl)oxazole
- HPLC
- high-performance liquid chromatography
- DMSO
- dimethyl sulfoxide
- LC
- liquid chromatography
- LC-UV/MS/MS
- liquid chromatography-product ion mass spectrum with UV detection
- CID
- collision-induced dissociation
- NMR
- nuclear magnetic resonance
- MS
- mass spectrometry
- MS/MS
- product ion spectrum
- L-696229
- 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one.
- Received January 8, 2012.
- Accepted May 23, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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