Journal
NATURE COMMUNICATIONS
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms4277
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Funding
- College of Medicine and Veterinary Medicine and the University of Edinburgh for a Darwin International Scholarship
- Edinburgh Global Research Scholarship
- RCUK
- IGMM
- Edinburgh Cancer Research UK Centre through the CRUK Development Fund
- MRC
- MRC [MC_PC_U127585840, MC_U127585840] Funding Source: UKRI
- Medical Research Council [MC_U127585840, MC_PC_U127585840] Funding Source: researchfish
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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.
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