Structure-activity relationships in the cytoprotective effect of caffeic acid phenethyl ester (CAPE) and fluorinated derivatives: effects on heme oxygenase-1 induction and antioxidant activities.
To determine the relationship between catechol ring modifications and the activity of caffeic acid phenethyl ester (CAPE) as a cytoprotective agent, six catechol ring-fluorinated CAPE derivatives were evaluated for their cytoprotective abilities, as well as for their antioxidant and heme oxygenase-1 (HO-1) inducing capacity in a human umbilical vein endothelial cell (HUVEC) model of oxidant stress. To ascertain the involvement of HO-1 induction in the cytoprotective effects of CAPE analogues, their ability to induce HO-1 at 20microM was determined by reverse transcriptase polymerase chain reaction, western blotting and the use of HO-1 inhibitor tin protoporphyrin IX. There was significant induction of HO-1 by CAPE derivatives. Inhibition of HO-1 enzymatic activity resulted in reduced cytoprotection. Modification of the catechol ring of CAPE by introduction of fluorine at various positions resulted in dramatic changes in cytoprotective activity. The maintenance of at least one hydroxyl group on the CAPE catechol ring and the phenethyl ester portion was required for HO-1 induction. CAPE and its derivatives were screened for their ability to scavenge intracellular reactive oxygen species generated in HUVECs by measuring 5-(and-6)-chlormethyl-2', 7'-dichlorodihydrofluorescein diacetate oxidation. The maintenance of 3, 4-dihydroxyl groups on the catechol ring was required for antioxidant activity, but antioxidant activity did not guarantee cytoprotection. Methylation or replacement of one hydroxyl group on the catechol ring of CAPE, however, provided both pro-oxidant and cytoprotective activities. These results indicate that the induction of HO-1 plays a more important role in the cytoprotective activity of CAPE derivatives than their direct antioxidant activity.
Pharmaceutics Division, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA.
Xinyu
X
Wang
Salomon
S
Stavchansky
Sean M
SM
Kerwin
Phillip D
PD
Bowman
D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology*; D002109:Caffeic Acids / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D019610:Cytoprotection / Q000187:drug effects*; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D054879:Halogenation; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D024483:Vitamin K 3 / Q000494:pharmacology
D000975:Antioxidants; D002109:Caffeic Acids; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D024483:Vitamin K 3; D051547:Heme Oxygenase-1; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol