Chiral inversion and poxidation

Ibuprofen (62, Figure 20) and other arylpropionic acids (i.e., profens) are chiral drugs existing as the (+ )-(S)-eutomer and the ( — )-(R)-distomer. Some of these compounds undergo an intriguing metabolic reaction such that the inactive (R)-enantiomer is converted to the active (S)-enantiomer, while the reverse reaction is negligible. This unidirectional chiral inversion is thus a reaction of bioactivation, and its mechanism is now reasonably well understood.100 The initial step is the formation of an acyl-CoA conjugate, a reaction that is highly substrate stereoselective since only the (R)-form but not the (S)-form produces the acyl-CoA conjugate, indicating a high enantiospecificity of the ligase. The (R)-acyl-CoA conjugate then undergoes a reaction of epimerization believed to be catalyzed by 2-methylacyl-CoA 2-epimerase (EC, resulting in a mixture of the (R)-profenoyl-CoA and (S)-profenoyl-CoA conjugates. Both epimers can then be hydrolyzed or undergo other reactions such as hybrid triglyceride formation (see Section This reaction of chiral inversion is not limited to profens, and a few other structurally related xenobiotics are known to undergo this metabolic route.

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