Massimo Carraro

Acetal derivatives as prodrugs of resveratrol.

The pharmacological exploitation of resveratrol is hindered by rapid phase-II conjugative metabolism in enterocytes and hepatocytes. One approach to the solution of this problem relies on prodrugs. We report the synthesis and characterization as well as the assessment of in vivo absorption and metabolism of a set of prodrugs of resveratrol in which the OH groups are engaged in the formal (-OCH2OR) or the more labile acetal (-OCH(CH3)OR) linkages. As carrier group (R) of the prodrug, we have used short ethyleneglycol oligomers (OEG) capped by a terminal methoxy group: -O-(CH2CH2O)n-CH3 (n = 0, 1, 2, 3, 4, 6). These moieties are expected to exhibit, to a degree, the favorable properties of longer polyethyleneglycol (PEG) chains, while their relatively small size makes for a more favorable drug loading capacity. After administration of formal-based prodrugs to rats by oral gavage, significant concentrations of derivatives were measured in blood samples over several hours, in all cases except for n = 0. Absorption was maximal for n = 4. Complete deprotection to give resveratrol and its metabolites was however too slow to be of practical use. Administration of the acetal prodrug carrying tetrameric OEG chains resulted instead in the protracted presence of resveratrol metabolites in blood, consistent with a progressive regeneration of the parent molecule from the prodrug after its absorption. The results suggest that prodrugs of polyphenols based on the acetal bond and short ethyleneglycol oligomers of homogeneous size may be a convenient tool for the systemic delivery of the unconjugated parent compound.

New Water-Soluble Carbamate Ester Derivatives of Resveratrol

Low bioavailability severely hinders exploitation of the biomedical potential of resveratrol. Extensive phase-II metabolism and poor water solubility contribute to lowering the concentrations of resveratrol in the bloodstream after oral administration. Prodrugs may provide a solution—protection of the phenolic functions hinders conjugative metabolism and can be exploited to modulate the physicochemical properties of the compound. We report here the synthesis and characterization of carbamate ester derivatives of resveratrol bearing on each nitrogen atom a methyl group and either a methoxy-poly(ethylene glycol)-350 (mPEG-350) or a butyl-glucosyl promoiety conferring high water solubility. Ex vivo absorption studies revealed that the butyl-glucosyl conjugate, unlike the mPEG-350 one, is able to permeate the intestinal wall. In vivo pharmacokinetics confirmed absorption after oral administration and showed that no hydrolysis of the carbamate groups takes place. Thus, sugar groups can be attached to resveratrol to obtain soluble derivatives maintaining to some degree the ability to permeate biomembranes, perhaps by facilitated or active transport.

Sol-Gel Entrapped TPAP: An Off-the-Shelf Catalyst Set for the Clean Oxidation of Alcohols

Whether in supercritical CO2 or in organic solvent and using O2 or aqueous H2O2 as primary oxidants, the series of sol-gel entrapped TPAP hybrid silica gels is a versatile class of oxidation catalysts suitable for the highly selective conversion of alcohols to carbonyls. These materials are generally more stable and active than traditional polymersupported analogues. This report summarizes recent findings showing the large potential of this technology for synthetic