Synthesis of Hydrophobic Derivatives of Stilbenes with Improved Permeability and Limited Phase II Reactions

Stilbenes can promote human health due to their several bioactivities. However, their low bioavailability is a limiting factor for the in vivo bioactivity of these plant bioactive compounds. This low bioavailability has been previously associated with their rapid absorption and phase II metabolism. In this work, the synthesis of hydrophobic stilbene derivatives is explored as a promising alternative. Chemical and enzymatic syntheses were compared, achieving higher efficiency with the former. The synthesized derivatives were characterized to ease future research. Hydrophobic resveratrol derivatives improved the apparent permeability of resveratrol across the Caco-2 intestinal cells. Moreover, hydrophobic derivatives of resveratrol and oxyresveratrol showed a lower degree of sulfation and glucuronidation compared to original stilbenes, which could be an advantage in avoiding phase II reactions that decrease the bioavailability of stilbenes. These results support hydrophobic stilbene derivatives as precursors of natural stilbenes, highlighting their strong potential for oral administration through functional foods in humans.