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Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach

Author

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  • Jason T. Weiss

    (Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh)

  • John C. Dawson

    (Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh)

  • Kenneth G. Macleod

    (Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh)

  • Witold Rybski

    (Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh
    MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh)

  • Craig Fraser

    (Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh)

  • Carmen Torres-Sánchez

    (Wolfson School of Mechanical and Manufacturing Engineering, Loughborough University)

  • E. Elizabeth Patton

    (Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh
    MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh)

  • Mark Bradley

    (School of Chemistry, University of Edinburgh, West Mains Road)

  • Neil O. Carragher

    (Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh)

  • Asier Unciti-Broceta

    (Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh)

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 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.

Suggested Citation

  • 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, 2014. "Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach," Nature Communications, Nature, vol. 5(1), pages 1-9, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4277
    DOI: 10.1038/ncomms4277
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    Cited by:

    1. Qing Wang & Yikang Song & Shuowei Yuan & Yaoji Zhu & Wenjing Wang & Ling Chu, 2024. "Prodrug activation by 4,4’-bipyridine-mediated aromatic nitro reduction," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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