title: Identification of N-Oxide and Sulfoxide Functionalities in Protonated Drug Metabolites by Using Ion-Molecule Reactions Followed by Collisionally Activated Dissociation in a Linear Quadrupole Ion Trap Mass Spectrometer.
abstract: The in vivo oxidation of sulfur and nitrogen atoms in many drugs into sulfoxide and N-oxide functionalities is a common biotransformation process. Unfortunately, the unambiguous identification of these metabolites can be challenging. In the present study, ion-molecule reactions of tris(dimethylamino)borane followed by collisionally activated dissociation (CAD) in an ion trap mass spectrometer are demonstrated to allow the identification of N-oxide and sulfoxide functionalities in protonated polyfunctional drug metabolites. Only ions with N-oxide or sulfoxide functionality formed diagnostic adducts that had lost dimethyl amine (DMA). This was demonstrated even for an analyte that contains a substantially more basic functionality than the functional group of interest. CAD of the diagnostic product ions (M) resulted mainly in type A (M - DMA) and B fragment ions (M - HO-B(N(CH3)2)2) for N-oxides, but sulfoxides also formed diagnostic C ions (M - O═BN(CH3)2), thus allowing differentiation of the functionalities. Some protonated analytes yielded abundant TDMAB adducts that had lost two DMA molecules instead of just one. This provides information on the environment of the N-oxide and sulfoxide functionalities. Quantum chemical calculations were performed to explore the mechanisms of the above-mentioned reactions. The method can be implemented on HPLC for real drug analysis.
authors.affiliation: Purdue University , Department of Chemistry, West Lafayette, Indiana 47907, United States.
authors.forename: Huaming
authors.initials: H
authors.lastname: Sheng
authors.affiliation: Purdue University , Department of Chemistry, West Lafayette, Indiana 47907, United States.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Tang
authors.affiliation: Purdue University , Department of Chemistry, West Lafayette, Indiana 47907, United States.
authors.forename: Ravikiran
authors.initials: R
authors.lastname: Yerabolu
authors.affiliation: Purdue University , Department of Chemistry, West Lafayette, Indiana 47907, United States.
authors.forename: Joann
authors.initials: J
authors.lastname: Max
authors.affiliation: Purdue University , Department of Chemistry, West Lafayette, Indiana 47907, United States.
authors.forename: Raghavendhar R
authors.initials: RR
authors.lastname: Kotha
authors.affiliation: Purdue University , Department of Chemistry, West Lafayette, Indiana 47907, United States.
authors.forename: James S
authors.initials: JS
authors.lastname: Riedeman
authors.affiliation: Purdue University , Department of Chemistry, West Lafayette, Indiana 47907, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Nash
authors.affiliation: AstraZeneca, Boston, Massachusetts 02130, United States.
authors.forename: Minli
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Purdue University , Department of Chemistry, West Lafayette, Indiana 47907, United States.
authors.forename: Hilkka I
authors.initials: HI
authors.lastname: Kenttämaa
mesh_terms: D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003497:Cyclic N-Oxides / Q000737:chemistry*; D004123:Dimethylamines / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D006865:Hydrogenation; D007477:Ions / Q000737:chemistry*; D011789:Quantum Theory; D013454:Sulfoxides / Q000737:chemistry*; D053719:Tandem Mass Spectrometry
chemical_list: D003497:Cyclic N-Oxides; D004123:Dimethylamines; D007477:Ions; D013454:Sulfoxides