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N-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell culture

Palladium-activated prodrug therapy is an experimental therapeutic approach that relies on the unique chemical properties and biocompatibility of heterogeneous palladium catalysis to enable the spatially-controlled in vivo conversion of a biochemically-stable prodrug into its active form. This strat...

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Autores principales: Weiss, Jason T., Fraser, Craig, Rubio-Ruiz, Belén, Myers, Samuel H., Crispin, Richard, Dawson, John C., Brunton, Valerie G., Patton, E. Elizabeth, Carragher, Neil O., Unciti-Broceta, Asier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114543/
https://www.ncbi.nlm.nih.gov/pubmed/25121087
http://dx.doi.org/10.3389/fchem.2014.00056
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author Weiss, Jason T.
Fraser, Craig
Rubio-Ruiz, Belén
Myers, Samuel H.
Crispin, Richard
Dawson, John C.
Brunton, Valerie G.
Patton, E. Elizabeth
Carragher, Neil O.
Unciti-Broceta, Asier
author_facet Weiss, Jason T.
Fraser, Craig
Rubio-Ruiz, Belén
Myers, Samuel H.
Crispin, Richard
Dawson, John C.
Brunton, Valerie G.
Patton, E. Elizabeth
Carragher, Neil O.
Unciti-Broceta, Asier
author_sort Weiss, Jason T.
collection PubMed
description Palladium-activated prodrug therapy is an experimental therapeutic approach that relies on the unique chemical properties and biocompatibility of heterogeneous palladium catalysis to enable the spatially-controlled in vivo conversion of a biochemically-stable prodrug into its active form. This strategy, which would allow inducing local activation of systemically administered drug precursors by mediation of an implantable activating device made of Pd(0), has been proposed by our group as a way to reach therapeutic levels of the active drug in the affected tissue/organ while reducing its systemic toxicity. In the seminal study of such an approach, we reported that propargylation of the N1 position of 5-fluorouracil suppressed the drug's cytotoxic properties, showed high stability in cell culture and facilitated the bioorthogonal restoration of the drug's pharmacological activity in the presence of extracellular Pd(0)-functionalized resins. To provide additional insight on the properties of this system, we have investigated different N1-alkynyl derivatives of 5-fluorouracil and shown that the presence of substituents near the triple bond influence negatively on its sensitivity to palladium catalysis under biocompatible conditions. Comparative studies of the N1- vs. the N3-propargyl derivatives of 5-fluorouracil revealed that masking each or both positions equally led to inactive derivatives (>200-fold reduction of cytotoxicity relative to the unmodified drug), whereas the depropargylation process occurred faster at the N1 position than at the N3, thus resulting in greater toxigenic properties in cancer cell culture.
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spelling pubmed-41145432014-08-12 N-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell culture Weiss, Jason T. Fraser, Craig Rubio-Ruiz, Belén Myers, Samuel H. Crispin, Richard Dawson, John C. Brunton, Valerie G. Patton, E. Elizabeth Carragher, Neil O. Unciti-Broceta, Asier Front Chem Chemistry Palladium-activated prodrug therapy is an experimental therapeutic approach that relies on the unique chemical properties and biocompatibility of heterogeneous palladium catalysis to enable the spatially-controlled in vivo conversion of a biochemically-stable prodrug into its active form. This strategy, which would allow inducing local activation of systemically administered drug precursors by mediation of an implantable activating device made of Pd(0), has been proposed by our group as a way to reach therapeutic levels of the active drug in the affected tissue/organ while reducing its systemic toxicity. In the seminal study of such an approach, we reported that propargylation of the N1 position of 5-fluorouracil suppressed the drug's cytotoxic properties, showed high stability in cell culture and facilitated the bioorthogonal restoration of the drug's pharmacological activity in the presence of extracellular Pd(0)-functionalized resins. To provide additional insight on the properties of this system, we have investigated different N1-alkynyl derivatives of 5-fluorouracil and shown that the presence of substituents near the triple bond influence negatively on its sensitivity to palladium catalysis under biocompatible conditions. Comparative studies of the N1- vs. the N3-propargyl derivatives of 5-fluorouracil revealed that masking each or both positions equally led to inactive derivatives (>200-fold reduction of cytotoxicity relative to the unmodified drug), whereas the depropargylation process occurred faster at the N1 position than at the N3, thus resulting in greater toxigenic properties in cancer cell culture. Frontiers Media S.A. 2014-07-29 /pmc/articles/PMC4114543/ /pubmed/25121087 http://dx.doi.org/10.3389/fchem.2014.00056 Text en Copyright © 2014 Weiss, Fraser, Rubio-Ruiz, Myers, Crispin, Dawson, Brunton, Patton, Carragher and Unciti-Broceta. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Chemistry
Weiss, Jason T.
Fraser, Craig
Rubio-Ruiz, Belén
Myers, Samuel H.
Crispin, Richard
Dawson, John C.
Brunton, Valerie G.
Patton, E. Elizabeth
Carragher, Neil O.
Unciti-Broceta, Asier
N-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell culture
title N-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell culture
title_full N-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell culture
title_fullStr N-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell culture
title_full_unstemmed N-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell culture
title_short N-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell culture
title_sort n-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell culture
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114543/
https://www.ncbi.nlm.nih.gov/pubmed/25121087
http://dx.doi.org/10.3389/fchem.2014.00056
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