Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach.pdf (2.04 MB)
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Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach

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posted on 30.09.2016, 09:36 authored by Jason T. Weiss, John C. Dawson, Kenneth G. Macleod, Witold Rybski, Craig Fraser, Carmen TorresCarmen Torres, E. Elizabeth Patton, Mark Bradley, Neil O. Carragher, Asier Unciti-Broceta
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 Pd0 catalysis. Although independently harmless, combined treatment of 5-fluoro-1-propargyl-uracil and Pd0-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/Pd0-resin combination is due to the in situ generation of 5-fluorouracil. Pd0-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.

Funding

J.T.W. thanks the College of Medicine and Veterinary Medicine and the University of Edinburgh for a Darwin International Scholarship and an Edinburgh Global Research Scholarship. N.O.C. and A.U.-B. thank RCUK and IGMM, respectively, for an Academic Fellowship. We are grateful to the Edinburgh Cancer Research UK Centre for funding this research through the CRUK Development Fund. E.E.P., C.F. and W.R. are funded by the MRC.

History

School

  • Mechanical, Electrical and Manufacturing Engineering

Published in

Nature Communications

Volume

5

Citation

WEISS, J. ... et al., 2014. Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach. Nature Communications, 5, doi: 10.1038/ncomms4277.

Publisher

© Macmillan

Version

VoR (Version of Record)

Publisher statement

This work is made available according to the conditions of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) licence. Full details of this licence are available at: http://creativecommons.org/licenses/by-nc-sa/4.0/

Publication date

2014

eISSN

2041-1723

Language

en