Stereoselective effects of chiral clofibric acid analogs on rat peroxisome proliferator-activated receptor alpha (rPPAR alpha) activation and peroxisomal fatty acid beta-oxidation.

Abstract

Enantiomers of a series of substituted analogs of 2-(4-chlorophenoxy) -acetic acid (CPAA) were synthesized and used to examine the influence of steric and structural parameters on peroxisome proliferation. The effects of these compounds were studied on the activation of the peroxisome proliferator-activated receptor alpha (PPAR alpha) in CV-1 cells using an in vitro co-transfection assay. Selected sets of isomers were tested for their ability to increase peroxisomal fatty acyl-CoA oxidase (ACO) activity in H4IIEC3 (rat Reuber hepatoma) cells. Of the series of 2-substituted analogs studied, the isomers of the nu-propyl and phenyl derivatives of CPAA showed a high degree of stereoselectivity [(S)-isomer >> (R)-isomer]. In general, the potency of the compound to activate the receptor increased with the size of the 2-alkyl substituent. Among the 4-chlorobenzyloxy- and 4-(4'-chlorophenyl)benzyloxy- analogs studied, 2-[4-(4'-chlorophenyl)-benzyloxy]-propanoic acid exhibited a high degree of stereoselectivity in both the biological systems studied [(R) >> (S)]. The congeners of 2-methyl substituted CPAA showed a reverse stereoselectivity (R) > (S)] as compared to the other 2-substituted analogs [(S) > (R)]. Our results indicate that (1) both structural and steric characteristics of CPAA analogs play an important role in the activation of rPPAR alpha and on stimulation of peroxisomal ACO activities, and (2) clofibric acid and analogs exert their peroxisome proliferative effects by interaction with a specific site on a protein. The enantiomers of the 2-nu-propyl and the 2-phenyl CPAA analogs may be useful as mechanistic probes in elucidating the nature of this binding site.