title: Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach.
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.
authors: Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.
authors: Jason T
authors: JT
authors: Weiss
authors: Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.
authors: John C
authors: JC
authors: Dawson
authors: Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.
authors: Kenneth G
authors: KG
authors: Macleod
authors: 1] Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK [2] MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.
authors: Witold
authors: W
authors: Rybski
authors: Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.
authors: Craig
authors: C
authors: Fraser
authors: Wolfson School of Mechanical and Manufacturing Engineering, Loughborough University, Loughborough LE11 3TU, UK.
authors: Carmen
authors: C
authors: Torres-Sánchez
authors: 1] Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK [2] MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.
authors: E Elizabeth
authors: EE
authors: Patton
authors: School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK.
authors: Mark
authors: M
authors: Bradley
authors: Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.
authors: Neil O
authors: NO
authors: Carragher
authors: Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.
authors: Asier
authors: A
authors: Unciti-Broceta
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry* / Q000627:therapeutic use; D003640:Dealkylation; D004353:Drug Evaluation, Preclinical; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D045325:HCT116 Cells; D006801:Humans; D010165:Palladium / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D015027:Zebrafish
chemical_list: C000602557:5-fluoro-1-propargyluracil; D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D010165:Palladium; D005472:Fluorouracil