High-throughput approaches towards the definitive identification of pharmaceutical drug metabolites. 2. An example of how unexpected dissociation behaviour could preclude correct assignment of sites of metabolism

Stephen W. Holman, Patricia Wright, G. John Langley

    Research output: Contribution to journalArticlepeer-review

    Abstract

    S-oxidation is a common metabolic route for sulfur-containing compounds. Whilst investigating the dissociation of a series of chemically synthesised model S-oxide metabolites, two unexpected losses of 62 m/z units were observed in the collision-induced dissociation (CID) product ion spectrum of protonated 3-dimethylaminomethyl-4-(4-methanesulfinyl-3-methylphenoxy)benzenesulfonamide. A single loss was initially assigned using the low-resolution product ion spectrum, acquired by electrospray ionisation quadrupole ion trap mass spectrometry (ESI-QIT-MS), as methanethial, S-oxide via a charge-remote, four-centred rearrangement. This assignment was consistent with well-documented hydrogen rearrangements in the literature. Further, the loss was not observed for the parent compound. Thus, it was inferred that the site of metabolism was involved in the dissociation and the attractive nature of the four-centred rearrangement meant that the loss of methanethial, S-oxide was a logical assignment. However, deuterium-labelling experiments and accurate mass measurements, performed using electrospray ionisation Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-ICR-MS), showed that the nominal loss of 62 m/z units occurs via two distinct dissociation pathways. Neither of these losses was of methanethial, S-oxide as initially hypothesised from the low-resolution product ion spectrum of the protonated molecule. Mechanisms consistent with the experimental findings are postulated. AnMS3 spectrum of the fully exchanged, deuterated species supported the proposed mechanisms by suggesting that 3-dimethylaminomethyl-4-(4-methanesulfinyl-3- methylphenoxy)benzenesulfonamide has multiple sites of protonation in the gas phase. The planar structures of the posited product ions are likely to provide the driving force for the rearrangements. The relevance of the observations with regards to pharmaceutical drugmetabolite identification is discussed. © 2009 by John Wiley & Sons, Ltd.
    Original languageEnglish
    Pages (from-to)2017-2025
    Number of pages8
    JournalRapid communications in mass spectrometry : RCM
    Volume23
    Issue number13
    DOIs
    Publication statusPublished - 15 Jul 2009

    Keywords

    • CHROMATOGRAPHY/TANDEM MASS-SPECTROMETRY; PHASE INTRAMOLECULAR REARRANGEMENT; FRAGMENTATION; DISCOVERY; PEPTIDE; RULE

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