title: Synthesis and Evaluation as Prodrugs of Hydrophilic Carbamate Ester Analogues of Resveratrol.
abstract: Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is an unfulfilled promise for health care: its exploitation is hindered by rapid conjugative metabolism in enterocytes and hepatocytes; low water solubility is a serious practical problem. To advantageously modify the physicochemical properties of the compound we have developed prodrugs in which all or part of the hydroxyl groups are linked via an N-monosubstituted carbamate ester bond to promoieties derived from glycerol or galactose, conferring higher water solubility. Kinetic studies of hydrolysis in aqueous solutions and in blood indicated that regeneration of resveratrol takes place in an appropriate time frame for delivery via oral administration. Despite their hydrophilicity some of the synthesized compounds were absorbed in the gastrointestinal tract of rats. In these cases the species found in blood after administration of a bolus consisted mainly of partially deprotected resveratrol derivatives and of the products of their glucuronidation, thus providing proof-of-principle evidence of behavior as prodrugs. The soluble compounds largely reached the lower intestinal tract. Upon administration of resveratrol, the major species found in this region was dihydroresveratrol, produced by enzymes of the intestinal flora. In experiments with a fully protected (trisubstituted) deoxygalactose containing prodrug, the major species were the prodrug itself and partially deprotected derivatives, along with small amounts of dihydroresveratrol. We conclude that the N-monosubstituted carbamate moiety is suitable for use in prodrugs of polyphenols.
authors.affiliation: Department of Biomedical Sciences, University of Padova , viale G. Colombo 3, 35131 Padova, Italy.|NÓOS Srl , via Campello sul Clitunno 34, 00181 Roma, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Azzolini
authors.affiliation: Department of Chemical Sciences, University of Padova , via Marzolo 1, 35121 Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattarei
authors.affiliation: Department of Biomedical Sciences, University of Padova , viale G. Colombo 3, 35131 Padova, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: La Spina
authors.affiliation: Department of Chemical Sciences, University of Padova , via Marzolo 1, 35121 Padova, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Marotta
authors.affiliation: Department of Biomedical Sciences, University of Padova , viale G. Colombo 3, 35131 Padova, Italy.|CNR Neuroscience Institute , viale G. Colombo 3, 35131 Padova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Zoratti
authors.affiliation: Department of Chemical Sciences, University of Padova , via Marzolo 1, 35121 Padova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Paradisi
authors.affiliation: Department of Biomedical Sciences, University of Padova , viale G. Colombo 3, 35131 Padova, Italy.|CNR Neuroscience Institute , viale G. Colombo 3, 35131 Padova, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Biasutto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002219:Carbamates / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004952:Esters / Q000737:chemistry*; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D007413:Intestinal Mucosa / Q000378:metabolism; D007700:Kinetics; D008297:Male; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000077185:Resveratrol; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002219:Carbamates; D004952:Esters; D011355:Prodrugs; D013267:Stilbenes; D000077185:Resveratrol
keywords: bioavailability; carbamate ester; galactose; glycerol; pharmacokinetics; prodrugs; resveratrol