title: Palladium-mediated dealkylation of N-propargyl-floxuridine as a bioorthogonal oxygen-independent prodrug strategy.
abstract: Herein we report the development and biological screening of a bioorthogonal palladium-labile prodrug of the nucleoside analogue floxuridine, a potent antineoplastic drug used in the clinic to treat advanced cancers. N-propargylation of the N3 position of its uracil ring resulted in a vast reduction of its biological activity (~6,250-fold). Cytotoxic properties were bioorthogonally rescued in cancer cell culture by heterogeneous palladium chemistry both in normoxia and hypoxia. Within the same environment, the reported chemo-reversible prodrug exhibited up to 1,450-fold difference of cytotoxicity whether it was in the absence or presence of the extracellular palladium source, underlining the precise modulation of bioactivity enabled by this bioorthogonally-activated prodrug strategy.
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: 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: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003640:Dealkylation; D004354:Drug Screening Assays, Antitumor; D005467:Floxuridine / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D000860:Hypoxia; D009019:Morphinans / Q000737:chemistry*; D010100:Oxygen / Q000378:metabolism*; D010165:Palladium / Q000737:chemistry*; D011355:Prodrugs
chemical_list: D000970:Antineoplastic Agents; D009019:Morphinans; C440369:N-propargyl; D011355:Prodrugs; D005467:Floxuridine; D010165:Palladium; D010100:Oxygen