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Identifying the proton transfer reaction mechanism via a proton-bound dimeric intermediate for esomeprazoles by a kinetic method combined with density functional theory calculations.
Rapid Commun Mass Spectrom. 2014 May 15; 28(9):1045-50.RC

Abstract

RATIONALE

Esomeprazole analogs are a class of important proton pump inhibitors for the treatment of gastro-esophageal reflux diseases. Understanding the fragmentation reaction mechanism of the protonated esomeprazole analogs will facilitate the characterization of their complex metabolic fate in humans. In this paper, the kinetic method and theoretical calculations were applied to evaluate the fragmentation of protonated esomeprazole analogs.

METHODS

All collision-induced dissociation (CID) mass spectrometry experiments were carried out using electrospray ionization (ESI) ion trap mass spectrometry in positive ion mode. Also the accurate masses of fragments were measured on by ESI quadrupole time-of-flight (QTOF) MS in positive ion mode. Theoretical calculations were carried out by the density functional theory (DFT) method with the 6-31G(d) basis set in the Gaussian 03 program.

RESULTS

In the fragmentation of the protonated esomeprazole analogs, C-S bond breakage is observed, which gives rise to protonated 2-(sulfinylmethylene)pyridines and protonated benzimidazoles. DFT calculations demonstrate that the nitrogen atom of the pyridine part is the thermodynamically most favorable protonation site, and the C-S bond cleavage is triggered by the transfer of this ionizing proton from the nitrogen atom of the pyridine part to the carbon atom of the benzimidazole part to which the sulfinyl is attached. Moreover, with the kinetic plot, the intensity ratios of two protonated product ions yield a linear relationship with the differences in proton affinities of the corresponding neutral molecules, which provides strong experimental evidence that the reaction proceeds via proton-bound 2-(sulfinylmethylene)pyridine/benzimidazole complex intermediates.

CONCLUSIONS

The kinetic method combined with theoretical calculations was successfully applied to probe the proton transfer reaction by proton-bound 2-(sulfinylmethylene)pyridine/benzimidazole complexes in the fragmentation of protonated esomeprazole analogs by ESI CID MS, which is a strong evidence that the kinetic method can be applied in identifying a proton-bound dimeric intermediate in the fragmentation of protonated ions.

Authors+Show Affiliations

Research Center of Analysis and Measurement, Zhejiang University of Technology, 18 Chaowang Rd, Hangzhou, Zhejiang, 310014, P.R. China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24677526

Citation

Cao, Xiaoji, et al. "Identifying the Proton Transfer Reaction Mechanism Via a Proton-bound Dimeric Intermediate for Esomeprazoles By a Kinetic Method Combined With Density Functional Theory Calculations." Rapid Communications in Mass Spectrometry : RCM, vol. 28, no. 9, 2014, pp. 1045-50.
Cao X, Zhang F, Zhu K, et al. Identifying the proton transfer reaction mechanism via a proton-bound dimeric intermediate for esomeprazoles by a kinetic method combined with density functional theory calculations. Rapid Commun Mass Spectrom. 2014;28(9):1045-50.
Cao, X., Zhang, F., Zhu, K., Ye, X., Shen, L., Chen, J., & Mo, W. (2014). Identifying the proton transfer reaction mechanism via a proton-bound dimeric intermediate for esomeprazoles by a kinetic method combined with density functional theory calculations. Rapid Communications in Mass Spectrometry : RCM, 28(9), 1045-50. https://doi.org/10.1002/rcm.6877
Cao X, et al. Identifying the Proton Transfer Reaction Mechanism Via a Proton-bound Dimeric Intermediate for Esomeprazoles By a Kinetic Method Combined With Density Functional Theory Calculations. Rapid Commun Mass Spectrom. 2014 May 15;28(9):1045-50. PubMed PMID: 24677526.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identifying the proton transfer reaction mechanism via a proton-bound dimeric intermediate for esomeprazoles by a kinetic method combined with density functional theory calculations. AU - Cao,Xiaoji, AU - Zhang,Feifei, AU - Zhu,Kundan, AU - Ye,Xuemin, AU - Shen,Lingxiao, AU - Chen,Jiaoyu, AU - Mo,Weimin, PY - 2013/09/16/received PY - 2014/01/13/revised PY - 2014/02/19/accepted PY - 2014/3/29/entrez PY - 2014/3/29/pubmed PY - 2014/11/11/medline SP - 1045 EP - 50 JF - Rapid communications in mass spectrometry : RCM JO - Rapid Commun Mass Spectrom VL - 28 IS - 9 N2 - RATIONALE: Esomeprazole analogs are a class of important proton pump inhibitors for the treatment of gastro-esophageal reflux diseases. Understanding the fragmentation reaction mechanism of the protonated esomeprazole analogs will facilitate the characterization of their complex metabolic fate in humans. In this paper, the kinetic method and theoretical calculations were applied to evaluate the fragmentation of protonated esomeprazole analogs. METHODS: All collision-induced dissociation (CID) mass spectrometry experiments were carried out using electrospray ionization (ESI) ion trap mass spectrometry in positive ion mode. Also the accurate masses of fragments were measured on by ESI quadrupole time-of-flight (QTOF) MS in positive ion mode. Theoretical calculations were carried out by the density functional theory (DFT) method with the 6-31G(d) basis set in the Gaussian 03 program. RESULTS: In the fragmentation of the protonated esomeprazole analogs, C-S bond breakage is observed, which gives rise to protonated 2-(sulfinylmethylene)pyridines and protonated benzimidazoles. DFT calculations demonstrate that the nitrogen atom of the pyridine part is the thermodynamically most favorable protonation site, and the C-S bond cleavage is triggered by the transfer of this ionizing proton from the nitrogen atom of the pyridine part to the carbon atom of the benzimidazole part to which the sulfinyl is attached. Moreover, with the kinetic plot, the intensity ratios of two protonated product ions yield a linear relationship with the differences in proton affinities of the corresponding neutral molecules, which provides strong experimental evidence that the reaction proceeds via proton-bound 2-(sulfinylmethylene)pyridine/benzimidazole complex intermediates. CONCLUSIONS: The kinetic method combined with theoretical calculations was successfully applied to probe the proton transfer reaction by proton-bound 2-(sulfinylmethylene)pyridine/benzimidazole complexes in the fragmentation of protonated esomeprazole analogs by ESI CID MS, which is a strong evidence that the kinetic method can be applied in identifying a proton-bound dimeric intermediate in the fragmentation of protonated ions. SN - 1097-0231 UR - https://www.unboundmedicine.com/medline/citation/24677526/Identifying_the_proton_transfer_reaction_mechanism_via_a_proton_bound_dimeric_intermediate_for_esomeprazoles_by_a_kinetic_method_combined_with_density_functional_theory_calculations_ L2 - https://doi.org/10.1002/rcm.6877 DB - PRIME DP - Unbound Medicine ER -