New lipophenols prevent carbonyl and oxidative stresses involved in macular degeneration

Dry age-related macular degeneration and Stargardt disease undergo a known toxic mechanism caused by carbonyl and oxidative stresses (COS). This is responsible for accumulation in the retinal pigment epithelium (RPE) of A2E, a main toxic pyridinium bis-retinoid lipofuscin component. Previous studies have shown that carbonyl stress in retinal cells could be reduced by an alkyl-phloroglucinol-DHA conjugate (lipophenol). Here, we performed a rational design of different families of lipophenols to conserve anti-carbonyl stress activities and improve antioxidant properties. Five synthetic pathways leading to alkyl-(poly)phenol derivatives, with phloroglucinol, resveratrol, catechin and quercetin as the main backbone, linked to poly-unsaturated fatty acid, are presented. These lipophenols were evaluated in ARPE-19 cell line for their anti-COS properties and a structure-activity relationship study is proposed. Protection of ARPE-19 cells against A2E toxicity was assessed for the four best candidates. Finally, interesting anti-COS properties of the most promising quercetin lipophenol were confirmed in primary RPE cells.