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.
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.