title: N-Monosubstituted Methoxy-oligo(ethylene glycol) Carbamate Ester Prodrugs of Resveratrol.
abstract: Resveratrol is a natural polyphenol with many interesting biological activities. Its pharmacological exploitation in vivo is, however, hindered by its rapid elimination via phase II conjugative metabolism at the intestinal and, most importantly, hepatic levels. One approach to bypass this problem relies on prodrugs. We report here the synthesis, characterization, hydrolysis, and in vivo pharmacokinetic behavior of resveratrol prodrugs in which the OH groups are engaged in an N-monosubstituted carbamate ester linkage. As promoiety, methoxy-oligo(ethylene glycol) groups (m-OEG) (CH₃-[OCH₂CH₂]n-) of defined chain length (n = 3, 4, 6) were used. These are expected to modulate the chemico-physical properties of the resulting derivatives, much like longer poly(ethylene glycol) (PEG) chains, while retaining a relatively low MW and, thus, a favorable drug loading capacity. Intragastric administration to rats resulted in the appearance in the bloodstream of the prodrug and of the products of its partial hydrolysis, confirming protection from first-pass metabolism during absorption.
authors.affiliation: Department of Chemical Sciences, University of Padova, Via F. Marzolo, Padova 135131, Italy. andrea.mattarei@unipd.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattarei
authors.affiliation: Department of Biomedical Sciences, University of Padova, Viale G. Colombo, Padova 335121, Italy. michele.azzolini@gmail.com.|CNR Neuroscience Institute, Viale G. Colombo, Padova 335121, Italy. michele.azzolini@gmail.com.|OS srl, Via Campello sul Clitunno, Roma 3400181, Italy. michele.azzolini@gmail.com.
authors.forename: Michele
authors.initials: M
authors.lastname: Azzolini
authors.affiliation: Department of Biomedical Sciences, University of Padova, Viale G. Colombo, Padova 335121, Italy. zoratti@bio.unipd.it.|CNR Neuroscience Institute, Viale G. Colombo, Padova 335121, Italy. zoratti@bio.unipd.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Zoratti
authors.affiliation: Department of Biomedical Sciences, University of Padova, Viale G. Colombo, Padova 335121, Italy. lucia.biasutto@cnr.it.|CNR Neuroscience Institute, Viale G. Colombo, Padova 335121, Italy. lucia.biasutto@cnr.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Biasutto
authors.affiliation: Department of Chemical Sciences, University of Padova, Via F. Marzolo, Padova 135131, Italy. cristina.paradisi@unipd.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Paradisi
mesh_terms: D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry*
chemical_list: D002219:Carbamates; D011355:Prodrugs; D013267:Stilbenes; D011092:Polyethylene Glycols; D000077185:Resveratrol
keywords: bioavailability; carbamate ester; methoxy-oligo(ethylene glycol); poly(ethylene glycol); polyphenols; prodrugs; resveratrol