PUBLICATION

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

Authors
Weiss, J.T., Dawson, J.C., Macleod, K.G., Rybski, W., Fraser, C., Torres-Sánchez, C., Patton, E.E., Bradley, M., Carragher, N.O., and Unciti-Broceta, A.
ID
ZDB-PUB-140502-11
Date
2014
Source
Nature communications   5: 3277 (Journal)
Registered Authors
Patton, E. Elizabeth
Keywords
none
MeSH Terms
  • Animals
  • Antimetabolites, Antineoplastic/chemistry*
  • Antimetabolites, Antineoplastic/therapeutic use
  • Dealkylation
  • Drug Evaluation, Preclinical
  • Fluorouracil/analogs & derivatives*
  • Fluorouracil/chemistry
  • Fluorouracil/therapeutic use
  • HCT116 Cells
  • Humans
  • Palladium/chemistry*
  • Prodrugs/chemistry*
  • Zebrafish
PubMed
24522696 Full text @ Nat. Commun.
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.

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