Structure activity relationships of caffeic acid phenethyl ester (CAPE) and its amide derivative caffeic acid phenethyl amide (CAPA) against oxidant stress in human endothelial cells

Abstract

Numerous reports have described the amelioration of ischemia/reperfusion injury by CAPE post‐injury, and we have recently shown that induction of heme oxygenase‐1 (HO‐1) in vitro is highly correlated with this cytoprotection. In vivo, the presence of esterases which are abundant in blood and tissues, would severely limit the effectiveness of CAPE by degrading it to caffeic acid and phenethyl alcohol, neither of which is cytoprotective in vitro. Therefore an amide derivative of CAPE, CAPA was synthesized and screened for cytoprotection by examining its ability to induce HO‐1 mRNA in human endothelial cells. CAPA was produced by a Wittig reaction between 3,4 dihydroxy‐benzaldehyde and the corresponding amide phosphonium salt and was 95% pure by nuclear magnetic resonance spectroscopy. CAPA was as effective as CAPE in inducing HO‐1 mRNA (9‐fold over vehicle control) as determined by RT‐PCR. It remains to be determined if it exhibits greater stability than CAPE in vivo.