Design, Synthesis, and Evaluation of Pharmacological Properties of Cinnamic Derivatives as Antiatherogenic Agents

Caroline Lapeyre (1) , Mélanie Delomenède (1) , Florence Bedos-Belval (1) , Hubert Duran (1) , Anne Nègre-Salvayre (2) , Michel Baltas (1)

1 SPCMIB - Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique
2 IFR 31 - IFR 31 Louis Bugnard

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.

Mots clés: Aromatic compounds; Oxidation; Reaction products; Toxicity; Antioxidants

Domaines: Chimie thérapeutique

Caroline Lapeyre, Mélanie Delomenède, Florence Bedos-Belval, Hubert Duran, Anne Nègre-Salvayre, et al.. Design, Synthesis, and Evaluation of Pharmacological Properties of Cinnamic Derivatives as Antiatherogenic Agents. Journal of Medicinal Chemistry, 2005, 48 (26), pp.8115-8124. ⟨10.1021/jm050454c⟩. ⟨hal-02444200⟩