Cargando…

Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach

A bioorthogonal organometallic reaction is a biocompatible transformation undergone by a synthetic material exclusively through the mediation of a non-biotic metal source; a selective process used to label biomolecules and activate probes in biological environs. Here we report the in vitro bioorthog...

Descripción completa

Detalles Bibliográficos
Autores principales: Weiss, Jason T., Dawson, John C., Macleod, Kenneth G., Rybski, Witold, Fraser, Craig, Torres-Sánchez, Carmen, Patton, E. Elizabeth, Bradley, Mark, Carragher, Neil O., Unciti-Broceta, Asier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Pub. Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929780/
https://www.ncbi.nlm.nih.gov/pubmed/24522696
http://dx.doi.org/10.1038/ncomms4277
_version_ 1782304445011329024
author Weiss, Jason T.
Dawson, John C.
Macleod, Kenneth G.
Rybski, Witold
Fraser, Craig
Torres-Sánchez, Carmen
Patton, E. Elizabeth
Bradley, Mark
Carragher, Neil O.
Unciti-Broceta, Asier
author_facet Weiss, Jason T.
Dawson, John C.
Macleod, Kenneth G.
Rybski, Witold
Fraser, Craig
Torres-Sánchez, Carmen
Patton, E. Elizabeth
Bradley, Mark
Carragher, Neil O.
Unciti-Broceta, Asier
author_sort Weiss, Jason T.
collection PubMed
description A bioorthogonal organometallic reaction is a biocompatible transformation undergone by a synthetic material exclusively through the mediation of a non-biotic metal source; a selective process used to label biomolecules and activate probes in biological environs. Here we report the in vitro bioorthogonal generation of 5-fluorouracil from a biologically inert precursor by heterogeneous Pd(0) catalysis. Although independently harmless, combined treatment of 5-fluoro-1-propargyl-uracil and Pd(0)-functionalized resins exhibits comparable antiproliferative properties to the unmodified drug in colorectal and pancreatic cancer cells. Live-cell imaging and immunoassay studies demonstrate that the cytotoxic activity of the prodrug/Pd(0)-resin combination is due to the in situ generation of 5-fluorouracil. Pd(0)-resins can be carefully implanted in the yolk sac of zebrafish embryos and display excellent biocompatibility and local catalytic activity. The in vitro efficacy shown by this masking/activation strategy underlines its potential to develop a bioorthogonally activated prodrug approach and supports further in vivo investigations.
format Online
Article
Text
id pubmed-3929780
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Nature Pub. Group
record_format MEDLINE/PubMed
spelling pubmed-39297802014-02-21 Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach Weiss, Jason T. Dawson, John C. Macleod, Kenneth G. Rybski, Witold Fraser, Craig Torres-Sánchez, Carmen Patton, E. Elizabeth Bradley, Mark Carragher, Neil O. Unciti-Broceta, Asier Nat Commun Article A bioorthogonal organometallic reaction is a biocompatible transformation undergone by a synthetic material exclusively through the mediation of a non-biotic metal source; a selective process used to label biomolecules and activate probes in biological environs. Here we report the in vitro bioorthogonal generation of 5-fluorouracil from a biologically inert precursor by heterogeneous Pd(0) catalysis. Although independently harmless, combined treatment of 5-fluoro-1-propargyl-uracil and Pd(0)-functionalized resins exhibits comparable antiproliferative properties to the unmodified drug in colorectal and pancreatic cancer cells. Live-cell imaging and immunoassay studies demonstrate that the cytotoxic activity of the prodrug/Pd(0)-resin combination is due to the in situ generation of 5-fluorouracil. Pd(0)-resins can be carefully implanted in the yolk sac of zebrafish embryos and display excellent biocompatibility and local catalytic activity. The in vitro efficacy shown by this masking/activation strategy underlines its potential to develop a bioorthogonally activated prodrug approach and supports further in vivo investigations. Nature Pub. Group 2014-02-13 /pmc/articles/PMC3929780/ /pubmed/24522696 http://dx.doi.org/10.1038/ncomms4277 Text en Copyright © 2014, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by-nc-sa/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Article
Weiss, Jason T.
Dawson, John C.
Macleod, Kenneth G.
Rybski, Witold
Fraser, Craig
Torres-Sánchez, Carmen
Patton, E. Elizabeth
Bradley, Mark
Carragher, Neil O.
Unciti-Broceta, Asier
Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach
title Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach
title_full Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach
title_fullStr Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach
title_full_unstemmed Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach
title_short Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach
title_sort extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929780/
https://www.ncbi.nlm.nih.gov/pubmed/24522696
http://dx.doi.org/10.1038/ncomms4277
work_keys_str_mv AT weissjasont extracellularpalladiumcatalyseddealkylationof5fluoro1propargyluracilasabioorthogonallyactivatedprodrugapproach
AT dawsonjohnc extracellularpalladiumcatalyseddealkylationof5fluoro1propargyluracilasabioorthogonallyactivatedprodrugapproach
AT macleodkennethg extracellularpalladiumcatalyseddealkylationof5fluoro1propargyluracilasabioorthogonallyactivatedprodrugapproach
AT rybskiwitold extracellularpalladiumcatalyseddealkylationof5fluoro1propargyluracilasabioorthogonallyactivatedprodrugapproach
AT frasercraig extracellularpalladiumcatalyseddealkylationof5fluoro1propargyluracilasabioorthogonallyactivatedprodrugapproach
AT torressanchezcarmen extracellularpalladiumcatalyseddealkylationof5fluoro1propargyluracilasabioorthogonallyactivatedprodrugapproach
AT pattoneelizabeth extracellularpalladiumcatalyseddealkylationof5fluoro1propargyluracilasabioorthogonallyactivatedprodrugapproach
AT bradleymark extracellularpalladiumcatalyseddealkylationof5fluoro1propargyluracilasabioorthogonallyactivatedprodrugapproach
AT carragherneilo extracellularpalladiumcatalyseddealkylationof5fluoro1propargyluracilasabioorthogonallyactivatedprodrugapproach
AT uncitibrocetaasier extracellularpalladiumcatalyseddealkylationof5fluoro1propargyluracilasabioorthogonallyactivatedprodrugapproach