A rapid methodology for the characterization of dialkyl tertiary amine-n-oxide metabolites using structurally dependent dissociation pathways and reconstructed ion current chromatograms

Holman, Stephen W., Wright, Patricia and Langley, G. John (2010) A rapid methodology for the characterization of dialkyl tertiary amine-n-oxide metabolites using structurally dependent dissociation pathways and reconstructed ion current chromatograms. Analytical Chemistry, 82 (6), 2347-2354. (doi:10.1021/ac902540b).

Abstract

A high-performance liquid chromatography-electrospray
ionization-tandem mass spectrometry (HPLC-ESI-MS/MS)approach to the characterization of dialkyl tertiary amine-
N-oxides is presented. The methodology is based upon forming reconstructed ion current chromatograms (RICCs)
of m/z values of product ions known to form through diagnostic losses from dialkyl tertiary amine-N-oxides. The
diagnostic losses of N,N-dimethylhydroxylamine and N,Ndiethylhydroxylamine were identified through the analysis of a structurally diverse library of compounds by ESI-lowenergy collision-induced dissociation (CID)-MS/MS using quadrupole ion trap-mass spectrometry (QIT-MS) and quadrupole time-of-flight-mass spectrometry (QqTOF-MS). The
library consisted of dialkyl tertiary amine-containing ommercially available pharmaceuticals, along with a number
of model, synthetic N-oxides. The loss of the nitrogen containing group was observed in 89% of the low-energy CID
product ion spectra acquired using various collision energies.
Further, the resultant product ions, formed through the loss of the nitrogen-containing group, were shown to be
unstable because of the observation of second-generation
dissociation. These observations regarding gas-phase ion
chemistry could be useful to developers of in silico programs for fragmentation prediction by allowing the creation of improved algorithms and models for predicting dissociation.
Using the information derived from the library analysis, the characterization methodology was developed and demonstrated using tetracaine. The approach is rapid, MS/MS
platform independent, utilizes existing technology, and could be automated. Further, it is definitive and overcomes the limitations of other tools for N-oxide identification by localizing the site of oxidation. Thus, it provides a useful addition to the existing approaches for metabolite identification.

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Contributors

Author: G. John Langley

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