Metabolic chiral inversion of anti-inflammatory 2-arylpropionates: Lack of reaction in liver homogenates, and study of methine proton acidity

Abstract

1. Enrichment in the (S)-enantiomers for (R)-flurbiprofen, (R)-naproxen, (R)-suprofen and (R; S)-ibuprofen was investigated in various subcellular hepatic preparations containing coenzyme A. While such preparations were able to form hippuric acid from benzoic acid, the chiral inversion was never seen.

2. Using 2-dimethylaminoethanethiol 2-phenylpropionate (DEPP) as a model acyl thioester, the acidity of the methine proton was investigated by monitoring the proton deuterium exchange occurring in deuterated solvents using high-resolution n.m.r. The compound was inert up to 22 h in D₂O at 37°C and pD 7˙ 4. In pure methanol or a methanol-water mixture, only solvolysis was seen. In contrast, competitive hydrolysis (k = 0˙ 005 h⁻¹) and proton/deuterium exchange (k = 0˙ 09h⁻¹) were seen in a CD₃CN/D₂O (50:50) mixture at 37˙ C.

3. It is speculated that the failure to characterize chiral inversion of 2-arylpropionates in subcellular preparations may be due to the absence of a microenvironment of adequately moderate polarity.