title: 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) alpha 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-1alpha protein in cells, which occurred by inhibition of HIF prolyl hydroxylase (HPH), the key enzyme for von Hippel-Lindau-dependent HIF-1alpha degradation. CAPE inhibition of HPH and induction of HIF-1alpha 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 (-C=C-) 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.
authors.affiliation: Laboratory of Biomedicinal/Medicinal Chemistry, College of Pharmacy, Pusan National University, Pusan, Republic of Korea.
authors.forename: Daekyu
authors.initials: D
authors.lastname: Choi
authors.forename: Jeongoh
authors.initials: J
authors.lastname: Han
authors.forename: Youna
authors.initials: Y
authors.lastname: Lee
authors.forename: Jungyun
authors.initials: J
authors.lastname: Choi
authors.forename: Songyi
authors.initials: S
authors.lastname: Han
authors.forename: Sungchae
authors.initials: S
authors.lastname: Hong
authors.forename: Hyunchu
authors.initials: H
authors.lastname: Jeon
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Jung
mesh_terms: D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000517:prevention & control; D013329:Structure-Activity Relationship; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D002109:Caffeic Acids; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D011393:Procollagen-Proline Dioxygenase; D051547:Heme Oxygenase-1; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol