Collision-induced dissociation of valdecoxib metabolites: a novel rearrangement involving an isoxazole ring.
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 SN2 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.
Zhang
Ji Y
JY
Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Skokie, Illinois 60077, USA. ji.y.zhang@GSK.com
Xu
Fran
F
Breau
Alan P
AP
D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods*; D016861:Cyclooxygenase Inhibitors / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007555:Isoxazoles / Q000032:analysis* / Q000737:chemistry* / Q000493:pharmacokinetics*; D013058:Mass Spectrometry / Q000379:methods*; D013449:Sulfonamides / Q000032:analysis* / Q000737:chemistry / Q000493:pharmacokinetics*; D000096926:Benzenesulfonamides
D016861:Cyclooxygenase Inhibitors; D007555:Isoxazoles; D013449:Sulfonamides; C406224:valdecoxib; D000096926:Benzenesulfonamides