Design, Synthesis, and Biological Evaluation of Resveratrol Derivatives as PPARα Agonists

The peroxisome proliferator-activated receptor subtype alpha (PPAR alpha) was established as a molecular target in drug discovery research for new lipid-lowering drugs. Pterostilbene is a naturally occurring PPAR alpha agonist that has been shown to lower plasma lipid concentrations via the activation of PPAR alpha. In this study, various pterostilbene conjugates with methyl, amino acid, and pivaloxymethyl (POM) groups at the 4-OH position were synthesized, and the activating effect on PPAR alpha were investigated. Of the conjugates investigated, 4-OMe-pterostilbene had lower activating effect than pterostilbene, but the pterostilbenes with either amino acid (4a and 4b) or POM moiety (5) showed a small but significant increase in PPAR alpha activation of PPAR alpha activity compared to pterostilbene. Therefore, the structure-activity relationship of the pterostilbene conjugates studied indicates that substitution of the free 4-OH moiety of pterostilbene with a nonmethyl group can increase PPAR alpha agonistic activity. This finding warrants further investigation of the structure-activity relationship of the pterostilbene conjugates as potent PPAR alpha agonists.