Cargando…

Amino Acid Carbamates As Prodrugs Of Resveratrol

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 t...

Descripción completa

Detalles Bibliográficos
Autores principales: Mattarei, Andrea, Azzolini, Michele, La Spina, Martina, Zoratti, Mario, Paradisi, Cristina, Biasutto, Lucia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604475/
https://www.ncbi.nlm.nih.gov/pubmed/26463125
http://dx.doi.org/10.1038/srep15216
_version_ 1782395060092928000
author Mattarei, Andrea
Azzolini, Michele
La Spina, Martina
Zoratti, Mario
Paradisi, Cristina
Biasutto, Lucia
author_facet Mattarei, Andrea
Azzolini, Michele
La Spina, Martina
Zoratti, Mario
Paradisi, Cristina
Biasutto, Lucia
author_sort Mattarei, Andrea
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4604475
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-46044752015-12-07 Amino Acid Carbamates As Prodrugs Of Resveratrol Mattarei, Andrea Azzolini, Michele La Spina, Martina Zoratti, Mario Paradisi, Cristina Biasutto, Lucia Sci Rep Article 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. Nature Publishing Group 2015-10-14 /pmc/articles/PMC4604475/ /pubmed/26463125 http://dx.doi.org/10.1038/srep15216 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Mattarei, Andrea
Azzolini, Michele
La Spina, Martina
Zoratti, Mario
Paradisi, Cristina
Biasutto, Lucia
Amino Acid Carbamates As Prodrugs Of Resveratrol
title Amino Acid Carbamates As Prodrugs Of Resveratrol
title_full Amino Acid Carbamates As Prodrugs Of Resveratrol
title_fullStr Amino Acid Carbamates As Prodrugs Of Resveratrol
title_full_unstemmed Amino Acid Carbamates As Prodrugs Of Resveratrol
title_short Amino Acid Carbamates As Prodrugs Of Resveratrol
title_sort amino acid carbamates as prodrugs of resveratrol
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604475/
https://www.ncbi.nlm.nih.gov/pubmed/26463125
http://dx.doi.org/10.1038/srep15216
work_keys_str_mv AT mattareiandrea aminoacidcarbamatesasprodrugsofresveratrol
AT azzolinimichele aminoacidcarbamatesasprodrugsofresveratrol
AT laspinamartina aminoacidcarbamatesasprodrugsofresveratrol
AT zorattimario aminoacidcarbamatesasprodrugsofresveratrol
AT paradisicristina aminoacidcarbamatesasprodrugsofresveratrol
AT biasuttolucia aminoacidcarbamatesasprodrugsofresveratrol