title: Amino Acid Carbamates As Prodrugs Of Resveratrol.
abstract: Resveratrol (3, 5, 4'-trihydroxy-trans-stilbene), a plant polyphenol, has important drug-like properties, but its pharmacological exploitation in vivo is hindered by its rapid transformation via phase II conjugative metabolism. One approach to bypass this problem relies on prodrugs. We report here the synthesis, characterization, stability and in vivo pharmacokinetic behaviour of prodrugs of resveratrol in which the OH groups are engaged in an N-monosubstituted carbamate ester (-OC(O)NHR) linkage with a natural amino acid (Leu, Ile, Phe, Thr) to prevent conjugation and modulate the physicochemical properties of the molecule. We also report a convenient, high-yield protocol to obtain derivatives of this type. The new carbamate ester derivatives are stable at pH 1, while they undergo slow hydrolysis at physiological pH and hydrolyse with kinetics suitable for use in prodrugs in whole blood. After administration to rats by oral gavage the isoleucine-containing prodrug was significantly absorbed, and was present in the bloodstream as non-metabolized unaltered or partially deprotected species, demonstrating effective shielding from first-pass metabolism. We conclude that prodrugs based on the N-monosubstituted carbamate ester bond have the appropriate stability profile for the systemic delivery of phenolic compounds.
authors.affiliation: University of Padova, Department of Chemical Sciences, Via F. Marzolo 1, 35131 Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattarei
authors.affiliation: CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy.|University of Padova, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy.|NÓOS srl, via Campello sul Clitunno 34, 00181 Roma, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Azzolini
authors.affiliation: University of Padova, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: La Spina
authors.affiliation: CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy.|University of Padova, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Zoratti
authors.affiliation: University of Padova, Department of Chemical Sciences, Via F. Marzolo 1, 35131 Padova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Paradisi
authors.affiliation: CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy.|University of Padova, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Biasutto
mesh_terms: D000284:Administration, Oral; D000596:Amino Acids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D002219:Carbamates / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D015195:Drug Design; D008297:Male; D008657:Metabolic Clearance Rate; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D000596:Amino Acids; D002219:Carbamates; D011355:Prodrugs; D013267:Stilbenes; D000077185:Resveratrol