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Design, synthesis, and evaluation of pharmacological properties of cinnamic derivatives as antiatherogenic agents
Caroline Lapeyre1, Mélanie Delomenède, Florence Bedos-Belval
1Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, Université Paul Sabatier, 118, Route de Narbonne, F-31062 Toulouse Cedex 4, France.
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.
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