Ching-Shih Chen

Metabolic stereoisomeric inversion of 2-arylpropionic acids. on the mechanism of ibuprofen epimerization in rats

Kinetic and mechanistic studies are described for the metabolic stereoisomeric inversion of R-ibuprofen in rats. After oral administration of R-ibuprofen to rats, the plasma levels and enantiomeric compositions of ibuprofen and its major metabolite were monitored. Although individual animals exhibited great variations in metabolic rates, the concentration ratios of the S- and R-enantiomers of ibuprofen and also its metabolite remained roughly unchanged within 90 min. Even though it is generally believed that this bioconversion is strictly stereospecific in nature, chromatographic analysis revealed that S-ibuprofen also underwent metabolic inversion, however, at a much slower rate, than its R counterpart. The inversion mechanism was assessed by monitoring the loss of labeled deuterium from specifically deuterated ibuprofen. No significant isotope effect was observed for the metabolism of these deuterated derivatives. One deuterium atom was lost in the S-ibuprofen resulted from R-[2-2H]ibuprofen metabolism, whereas all the three deuterium atoms were retained when R-[3,3,3-2H3]ibuprofen was used as the substrate. These results reinforce the proposed mechanism that the inversion proceeds via a thioester carbanion intermediate. The pKa of the alpha-methine proton of ibuprofen N-acetylcysteamine thioester was shown to be 10.34 +/- 0.06, which excludes the possibility that ibuprofen may undergo inversion through the nonenzymatic isomerization of its acyl thioester.

Biocatalytic resolution of DL-propranolol. A successful example of computer-aided substrate design☆

Abstract An approach entailing computer-aided substrate design was taken to develop biocatalytic resolution of racemic propranolol. This strategy provided useful insight into potential steric factors within the substrate, which might be crucial to the catalytic turnover and enantiomeric selection.

D-myo-inositol 1,4,5-trisphosphate analogues as useful tools in biochemical studies of intracellular calcium mobilization.

Two types of structural variants of D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] were prepared by a chemoenzymatic route. These 6-O-substituted analogues retained the biological activity of Ins(1,4,5)P3, and were able to elicit Ca2+ release from porcine brain microsomes. Moreover, these derivatives allowed the preparation of Ins(1,4,5)P3-based immunogens and affinity matrix which were successfully applied to the preparation and purification of antibodies against Ins(1,4,5)P3. These antibodies displayed discriminative affinity towards Ins(1,4,5)P3, and provide a useful tool to study intracellular Ca2+ mobilization.

Clinical Implications of Using Racemic Drugs

Many of the therapeutic agents for the treatment of chronic adult diseases are marketed as a racemic mixture. It is of concern from a clinical perspective because most of the patients in whom the drugs are used have compromised metabolic functions and/or are receiving co-medications. The less active component of the racemate may contribute to adverse consequences through stereoselective metabolism or drug-drug interactions. Therefore, this article discusses the potential problems associated with using racemic drugs, especially, the 2-arylpropionic acid NSAIDs.

A convenient chemoenzymatic synthesis of (R)- and (S)-(chloromethyl)oxirane

(R)- and (S)-1-Chloro-3-tosyloxypropan-2-ol have been prepared by biocatalysed enantioselective esterification in hexane, and in turn could be readily converted into optically active (chloromethyl)oxirane in high yield.

Computer-aided substrate design for biocatalysis : an enzymatic access to optically active propranolol

Computer-aided molecular modelling was used to examine the conformations of various propranolol derivatives, which has led to a facile enzymatic preparation of optically active propranolol.