STEREOSELECTIVE EFFECTS OF CHIRAL CLOFIBRIC ACID ANALOGS ON RAT PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA (RPPAR-ALPHA) ACTIVATION AND PEROXISOMAL FATTY-ACID BETA-OXIDATION

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 e ffects of these compounds were studied on the activation of the peroxi some proliferator-activated receptor a (PPAR alpha) in CV-1 cells usin g an in vitro co-transfection assay. Selected sets of isomers were tes ted for their ability to increase peroxisomal fatty acyl-CoA oxidase ( AGO) activity in H4IIEC3 (rat Reuber hepatoma) cells. Of the series of 2-substituted analogs studied, the isomers of the n-propyl and phenyl derivatives of CPAA showed a high degree of stereoselectivity [(S)-is omer much greater than (R)-isomer]. In general, the potency of the com pound to activate the receptor increased with the size of the 2-alkyl substituent. Among the 4-chlorobenzyloxy- and 4-(4'-chlorophenyl)benzy loxy- analogs studied, 2-[4-(4'-chlorophenyl)-benzyloxy]-propanoic aci d exhibited a high degree of stereoselectivity in both the biological systems studied [(R) much greater than (S)]. The congeners of 2-methyl substituted CPAA showed a reverse stereoselectivity [(R) > (S)] as co mpared to the other 2-substituted analogs [(S) > (R)]. Our results ind icate that (1) both structural and steric characteristics of CPAA anal ogs play an important role in the activation of rPPAR alpha and on sti mulation of peroxisomal ACO activities, and (2) clofibric acid and ana logs exert their peroxisome proliferative effects by interaction with a specific site on a protein. The enantiomers of the 2-n-propyl and th e 2-phenyl CPAA analogs may be useful as mechanistic probes in elucida ting the nature of this binding site. (C) 1997 Wiley-Liss, Inc.