Soluble prodrugs for efficient instestinal delivery of resveratrol

Colitis is a widespread pathology; chronic inflammation is often involved in the process of tumorigenesis leading to colon cancer. Natural compounds such as flavonoids and stilbenes have been shown to have interesting anti-inflammatory and chemopreventive properties; their therapeutic potential is great, but low bioavailability and rapid metabolism hinder their full pharmacological exploitation. We are working on the development of prodrugs of natural polyphenols, with the aim of potentiating their effectiveness in specific pathophysiological contexts. The goal is to increase the levels of the intact natural compound at the site of action, improving its absorption and/or decreasing its metabolism, thanks to temporary protection of the phenolic hydroxyls in the molecule. We present here a series of resveratrol prodrugs functionalized with galactosyl moieties through N-monosubstituted carbamate linkages. These compounds turned out to be very soluble in water compared to resveratrol itself, greatly improving handling of the compound. Highly-soluble derivatives were not able to reach the systemic circulation after oral administration; however, poor intestinal absorption may be expected to allow their presence at high levels in the lumen of the lower intestinal tract, making them useful for the treatment of intestinal diseases. After chronic administration, a striking difference was observed in the intestinal fate of resveratrol compared to its tri-substituted galactosyl derivative: in colon and caecum the former was present mainly as its bacterial metabolite dihydroresveratrol, while the latter was mainly present as partially hydrolyzed derivatives. This points to protracted release of intact resveratrol, which is then inevitably reduced to dihydroresveratrol by bacterial enzymes. These findings suggest a possible use of glycosyl-resveratrol derivatives for the treatment of colitis and prevention of colon cancer.

Keywords: Resveratrol, prodrugs, intestine, colitis