Comparison between electrochemistry/mass spectrometry and cytochrome P450 catalyzed oxidation reactions

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Abstract

The extent to which electrochemistry on-line with electrospray mass spectrometry can be used to mimic cytochrome P450 catalyzed oxidations has been investigated. Comparisons on the mechanistic level have been made for most reactions in an effort to explain why certain reactions can, and some cannot, be mimicked by electrochemical oxidations. The EC/MS/MS system used successfully mimics in cases where the P450 catalyzed reactions are supposed to proceed via a mechanism initiated by a one-electron oxidation, such as N-dealkylation, S-oxidation, P-oxidation, alcohol oxidation and dehydrogenation. The P450 catalyzed reactions initiated via direct hydrogen atom abstraction, such as O-dealkylation and hydroxylation of unsubstituted aromatic rings, generally had a too high oxidation potential to be electrochemically oxidized below the oxidation potential limit of water, and were not mimicked by the EC/MS/MS system. Even though the EC/MS/MS system is not able to mimic all oxidations performed by cytochrome P450, valuable information can be obtained concerning the sensitivity of the substrate towards oxidation and in which position of the molecule oxidations are likely to take place. For small-scale electrochemical synthesis of metabolites, starting from the drug, the EC/MS/MS system should be very useful for quick optimization of the electrochemical conditions. The simplicity of the system, and the ease and speed with which it can be applied to a large number of compounds, make it a useful tool in drug metabolism research.

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