title: New water-soluble carbamate ester derivatives of resveratrol.
abstract: 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.
authors.affiliation: Department of Chemical Sciences, University of Padova, Via F. Marzolo 1, 35131 Padova, Italy. andrea.mattarei@unipd.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattarei
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, Viale Vienna 2, 07100 Sassari, Italy. mcarraro@uniss.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Carraro
authors.affiliation: Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy. michele.azzolini@gmail.com.
authors.forename: Michele
authors.initials: M
authors.lastname: Azzolini
authors.affiliation: Department of Chemical Sciences, University of Padova, Via F. Marzolo 1, 35131 Padova, Italy. cristina.paradisi@unipd.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Paradisi
authors.affiliation: Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy. zoratti@mail.bio.unipd.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Zoratti
authors.affiliation: Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy. lucia.biasutto@cnr.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Biasutto
mesh_terms: D000818:Animals; D002219:Carbamates / Q000737:chemistry*; D004952:Esters; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D010539:Permeability; D011355:Prodrugs; D051381:Rats; D000077185:Resveratrol; D012995:Solubility; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D014867:Water
chemical_list: D002219:Carbamates; D004952:Esters; D011355:Prodrugs; D013267:Stilbenes; D014867:Water; D000077185:Resveratrol