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 5.1.99.4), 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 5.06.3.6.3). 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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