Collision-induced dissociation of valdecoxib metabolites: a novel rearrangement involving an isoxazole ring

✍ Scribed by Ji Y. Zhang; Fran Xu; Alan P. Breau

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 149 KB
• Volume: 39
• Category: Article
• ISSN: 1076-5174
• DOI: 10.1002/jms.582

✦ Synopsis

Abstract

Valdecoxib is a potent COX‐2 inhibitor. During metabolism studies of valdecoxib by liquid chromatography/tandem mass spectrometry, we observed a novel mass spectral rearrangement involving an isoxazole ring for some of the metabolites in the negative ion mode. Accurate mass measurements were performed with quadrupole time‐of‐flight mass spectrometry to determine the elemental compositions of the fragments. Additionally, two types of stable‐isotope labeled analogues were prepared to assist with the assignments of these fragments and possible mechanistic rearrangements resulting from collision‐induced dissociation (CID). Detailed analyses of the CID mass spectra suggest that the fragmentation process involves a novel two‐step rearrangement. The first step consists of an intramolecular S~N~2 reaction with a five‐membered ring rearrangement to form an intermediate. The second step involves a four‐membered ring intramolecular rearrangement followed by a cleavage of the N—O bond on the isoxazole ring to form a unique fragment ion at m/z 196. The same phenomenon was observed for a group of structurally related metabolites that also contain a 5‐hydroxymethyl or 5‐carboxylic acid moieties. A mechanism for the novel rearrangement involving an isoxazole ring is proposed. Copyright © 2004 John Wiley & Sons, Ltd.