The oxidation of alkyl and aromatic tertiary nitrogen-containing substrates by flavin-containing monooxygenase (FMO) and, to a lesser extent, by cytochrome P450, generates N-oxide metabolites. Since FMO is the primary driver of N-oxidation, specific examples will be presented in the section on FMO-catalyzed reactions that follows.
5.05.2.1.5.3 Mechanism for oxidation at a sulfur atom
Where N-hydroxylation and N-oxide formation are minor pathways relative to N-dealkylation, the exact opposite is true of sulfur oxidation. S-Dealkylation is a minor pathway of metabolism, while direct oxidation of sulfur to a sulfoxide and/ or a sulfone is a major pathway. Both FMO and cytochrome P450 can catalyze sulfur oxidation, but cytochrome P450 is often the major contributor. If the reaction is initiated by electron abstraction to generate a sulfur radical cation (the SET mechanism), it could serve as a common intermediate for both sulfoxidation and S-dealkylation. Product formation would reflect competition between the two pathways. However, independent mechanisms, a SET mechanism for sulfoxidation versus a HAT mechanism for S-dealkylation, could account for the data, since the energy required for ionization is much lower for sulfur than it is for nitrogen.
Several examples of drugs that are subject to S-oxidation follow. Tazofelone (92) is a new drug that has been shown to be highly effective in the treatment of inflammatory bowel disease in animal models but has poor bioavailability because of rapid turnover. Determination of the metabolic profile of 92 revealed that a mixture of tazofelone sulfoxide diastereoisomers (93) was a major metabolite of the drug, and that CYP3A4 was primarily responsible for its formation (eqn ).134
The major human metabolites135 of SNI-2011 (94), a new agent being developed to treat a chronic autoimmune disorder known as Sjogren's syndrome, are a mixture of sulfoxide diastereoisomers (95) and, to a lesser extent, the N-oxide (96) (Scheme 8). Interestingly, while 95 arises from the action of cytochrome P450, 96 is formed by FMO in the kidney.
A major human metabolite of sulfinpyrazone (97), a sulfoxide-containing uricosuric agent, is the sulfone136 98 (eqn ). Similarly, a sulfone is a significant human metabolite of the proton pump inhibitor omeprazole137 (99) (eqn ).
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