N-Monosubstituted Methoxy-oligo(ethylene glycol) Carbamate Ester Prodrugs of Resveratrol

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 re...

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Published inMolecules (Basel, Switzerland) Vol. 20; no. 9; pp. 16085 - 16102
Main Authors Mattarei, Andrea, Azzolini, Michele, Zoratti, Mario, Biasutto, Lucia, Paradisi, Cristina
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 03.09.2015
MDPI
Subjects
Animals
Bioavailability
carbamate ester
Carbamates - chemical synthesis
Carbamates - chemistry
Carbamates - pharmacokinetics
Metabolism
Metabolites
methoxy-oligo(ethylene glycol)
Molecular Structure
Pharmacokinetics
poly(ethylene glycol)
Polyethylene Glycols - chemistry
Polyphenols
prodrugs
Prodrugs - chemical synthesis
Prodrugs - chemistry
Prodrugs - pharmacokinetics
Rats
Resveratrol
Stilbenes - chemistry
Italy
polyphenols
poly(ethylene glycol)
bioavailability
prodrugs
carbamate ester
methoxy-oligo(ethylene glycol)
resveratrol
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Summary: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.
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These authors contributed equally to this work.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules200916085