Title |
Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach
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Published in |
Nature Communications, February 2014
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DOI | 10.1038/ncomms4277 |
Pubmed ID | |
Authors |
Jason T. Weiss, John C. Dawson, Kenneth G. Macleod, Witold Rybski, Craig Fraser, Carmen Torres-Sánchez, E. Elizabeth Patton, Mark Bradley, Neil O. Carragher, Asier Unciti-Broceta, Weiss JT, Dawson JC, Macleod KG, Rybski W, Fraser C, Torres-Sánchez C, Patton EE, Bradley M, Carragher NO, Unciti-Broceta A |
Abstract |
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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