Caffeic acid phenethyl ester is a potent inhibitor of HIF prolyl hydroxylase: structural analysis and pharmacological implication

Abstract 

Caffeic acid phenethyl ester (CAPE) is an active component of propolis from honeybee. We investigated a potential molecular mechanism underlying a CAPE-mediated protective effect against ischemia/reperfusion (I/R) injury and analyzed the structure contributing to the CAPE effect. CAPE induced hypoxia-inducible factor-1 (HIF-1) α protein, concomitantly transactivating the HIF-1 target genes vascular endothelial growth factor and heme oxygenase-1, which play a protective role in I/R injury. CAPE delayed the degradation of HIF-1α protein in cells, which occurred by inhibition of HIF prolyl hydroxylase (HPH), the key enzyme for von Hippel–Lindau-dependent HIF-1α degradation. CAPE inhibition of HPH and induction of HIF-1α protein were neutralized by an elevated dose of iron. The catechol moiety, a chelating group, is essential for HPH inhibition, while hydrogenation of the double bond (–CC–) in the Michael reaction acceptor markedly reduced potency. Removal of the phenethyl moiety of CAPE (substitution with the methyl moiety) severely deteriorated its inhibitory activity for HPH. Our data suggest that a beneficial effect of CAPE on I/R injury may be ascribed to the activation of HIF-1 pathway via inhibition of HPH and reveal that the chelating moiety of CAPE acted as a pharmacophore while the double bond and phenethyl moiety assisted in inhibiting HPH.

Abbreviations: CAPE, caffeic acid phenethyl ester, CNAPE, cinnamic acid phenethyl ester, DMC, dimethoxycinnamic acid phenethyl ester, DMDHC, dimethoxydihydrocinnamic acid phenethyl ester, DHC, dihydrocaffeic acid phenethyl ester, CAME, caffeic acid methyl ester, CAPEN, caffeic acid n-pentyl ester, CAHA, caffeic acid n-hexyl ester, HIF-1, hypoxia-inducible factor-1, HO-1, heme oxygenase-1, VEGF, vascular endothelial growth factor, HPH, HIF prolyl hydroxylase

Keywords: Hypoxia-inducible factor-1, HIF prolyl hydroxylase, Caffeic acid phenethylester, Ischemic/reperfusion injury, Structure–activity relationship