Regioselective synthesis of diacylglycerol rosmarinates and evaluation of their antioxidant activity in fibroblasts
Authors: Durand Erwann , Bayrasy Christelle , Laguerre Mickaël , Barouh Nathalie , Lecomte Jérôme , Durand Thierry , Balas Laurence , Wrutniak‐Cabello Chantal , Cabello Gérard , Villeneuve Pierre 
Published: February 2015

A series of new model of lipophilized phenolic compound derived from the rosmarinic acid was synthesized: 1,2‐diacylglycerol rosmarinate (RDAG) with different alkyl chain lengths from five to eighteen carbons. These RDAG were obtained through a chemo‐enzymatic synthesis: A chemical esterification based on the Mitsunobu reaction, followed by a lipase‐catalyzed transesterification to link the different lipophilic moieties. The antioxidant abilities of these molecules were assessed on reactive oxygen species (ROS) overexpressing fibroblasts. The RDAG12 displayed the best antioxidant activity of the series. Lengthening of the lipid chain beyond twelve carbon atoms leads to a decrease in the antioxidant activity, thus confirming the occurrence of a cut‐off effect. Antioxidant RDAG12 activity was then compared with that of vitamins C and E, rosmarinic acid and decyl rosmarinate (R10). The order of activity was R10 > RDAG12 > RDAG5 > rosmarinic acid ∼ vitamin C ∼ vitamin E. At 5 μM, R10 exhibited an even better antioxidant activity than the combination of vitamins C and E at 5 μM each. These results confirm, firstly, that catechol structure is very effective in terms of antioxidant activity and secondly, that linking an appropriate hydrophobic domain is a powerful strategy to synthesize effective antioxidants.

Practical applications: Phenolic compounds (especially phenolic acids and flavonoids) are potent antioxidants that may play an important role as well in biological system (to prevent some risk factors associated with cancers, cardiovascular, and neurodegenerative diseases) as in formulated‐lipid dispersions. However, their activity is often limited by low solubility and stability in such systems. Lipophilization of phenolic compounds may increase their solubility in lipophilic matrices, conferring better antioxidant protection for food or non‐food application. In biological system, lipophilization may contribute to easier penetration of antioxidants through lipid bilayer of cell membranes, which can significantly increase their bioavailability. Thus, lipophilic phenolic derivatives provide a perspective of substances with maintained or improved biological properties for food, cosmetic, and pharmaceutical applications, playing an important role in the development of new drugs or food additives.

A series of new model of lipophilized phenolic compound (1,2‐diacylglycerol rosmarinate, RDAG) were synthesized through a chemo‐enzymatic synthesis. In terms of antioxidant activity assessed in fibroblasts, all synthesized RDAG exhibited higher ROS inhibition level than free rosmarinic acid. RDAG with two lauryl chains (RDAG12) displayed the best antioxidant ability of the series, with higher activity than vitamins E and C. These results confirm that linking an appropriate hydrophobic domain is a powerful strategy to synthesize effective antioxidants.