title: Design, synthesis, and evaluation of pharmacological properties of cinnamic derivatives as antiatherogenic agents.
abstract: A series of cinnamic and phosphonocinnamic derivatives have been synthesized and their ability to inhibit cell-mediated LDL oxidation and oxidized LDL-induced cytotoxicity was investigated. Electron-donating substituents surrounding the necessary 4-OH group of the aromatic ring showed the best results. Among the different series tested, amide 1, thioester 5c, phosphonoester 7c, and the fluorophosphonocinnamic analogue 12c exhibited a potent inhibitory effect against LDL oxidation (and subsequent toxicity) mediated by cultured human microvascular endothelial cells (HMEC-1), with an efficacy comparable to that observed with probucol. Beside this indirect protective effect, these compounds exhibited a direct protective effect against the toxicity of previously oxidized LDL in HMEC-1. These data suggest that the newly synthesized cinnamic compounds should protect against early events (cell-mediated LDL oxidation) occurring within the vascular wall in atherosclerosis.
authors.affiliation: Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, Université Paul Sabatier, 118, Route de Narbonne, F-31062 Toulouse Cedex 4, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lapeyre
authors.forename: Mélanie
authors.initials: M
authors.lastname: Delomenède
authors.forename: Florence
authors.initials: F
authors.lastname: Bedos-Belval
authors.forename: Hubert
authors.initials: H
authors.lastname: Duran
authors.forename: Anne
authors.initials: A
authors.lastname: Nègre-Salvayre
authors.forename: Michel
authors.initials: M
authors.lastname: Baltas
mesh_terms: D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology*; D050197:Atherosclerosis / Q000517:prevention & control*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000138:chemical synthesis / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects; D015195:Drug Design; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000633:toxicity; D008833:Microcirculation; D011341:Probucol / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D002934:Cinnamates; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D011341:Probucol