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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Pub. Group
2014
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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 |
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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 |
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