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Extracellular Palladium-Catalysed Dealkylation of 5-fluoro-1-propargyl-uracil as a Bioorthogonally Activated Prodrug Approach

Extracellular Palladium-Catalysed Dealkylation of 5-fluoro-1-propargyl-uracil as a Bioorthogonally Activated Prodrug Approach

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

Nat Commun. 2014;5:3277.

PMID: 24522696

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP69849338	5-Fluoro-1-propargyl-uracil		69849-33-8	Price

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