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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

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
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
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. An MS3 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 drug metabolite identification is discussed.
0951-4198
2017-2025
Holman, Stephen W.
32d02653-e41d-4615-a660-356fb38b1988
Wright, Patricia
553f5be8-e0fc-41be-ac24-8ffb21cfca82
Langley, G. John
7ac80d61-b91d-4261-ad17-255f94ea21ea
Holman, Stephen W.
32d02653-e41d-4615-a660-356fb38b1988
Wright, Patricia
553f5be8-e0fc-41be-ac24-8ffb21cfca82
Langley, G. John
7ac80d61-b91d-4261-ad17-255f94ea21ea

Holman, Stephen W., Wright, Patricia and Langley, G. John (2009) 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. Rapid Communications in Mass Spectrometry, 23 (13), 2017-2025. (doi:10.1002/rcm.4103).

Record type: Article

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. An MS3 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 drug metabolite identification is discussed.

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Published date: July 2009
Organisations: Chemistry, Faculty of Natural and Environmental Sciences

Identifiers

Local EPrints ID: 147639
URI: http://eprints.soton.ac.uk/id/eprint/147639
ISSN: 0951-4198
PURE UUID: e2a9119d-9cce-4e4c-925d-1c64b4b8e43e
ORCID for G. John Langley: ORCID iD orcid.org/0000-0002-8323-7235

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Date deposited: 26 Apr 2010 10:17
Last modified: 20 Jul 2019 01:23

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