title: Development and bioorthogonal activation of palladium-labile prodrugs of gemcitabine.
abstract: Bioorthogonal chemistry has become one of the main driving forces in current chemical biology, inspiring the search for novel biocompatible chemospecific reactions for the past decade. Alongside the well-established labeling strategies that originated the bioorthogonal paradigm, we have recently proposed the use of heterogeneous palladium chemistry and bioorthogonal Pd(0)-labile prodrugs to develop spatially targeted therapies. Herein, we report the generation of biologically inert precursors of cytotoxic gemcitabine by introducing Pd(0)-cleavable groups in positions that are mechanistically relevant for gemcitabine's pharmacological activity. Cell viability studies in pancreatic cancer cells showed that carbamate functionalization of the 4-amino group of gemcitabine significantly reduced (>23-fold) the prodrugs' cytotoxicity. The N-propargyloxycarbonyl (N-Poc) promoiety displayed the highest sensitivity to heterogeneous palladium catalysis under biocompatible conditions, with a reaction half-life of less than 6 h. Zebrafish studies with allyl, propargyl, and benzyl carbamate-protected rhodamines confirmed N-Poc as the most suitable masking group for implementing in vivo bioorthogonal organometallic chemistry.
authors.affiliation: Edinburgh Cancer Research UK Centre, and ‡MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh , Crewe Road South, Edinburgh EH4 2XR, U.K.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Weiss
authors.forename: John C
authors.initials: JC
authors.lastname: Dawson
authors.forename: Craig
authors.initials: C
authors.lastname: Fraser
authors.forename: Witold
authors.initials: W
authors.lastname: Rybski
authors.forename: Carmen
authors.initials: C
authors.lastname: Torres-Sánchez
authors.forename: Mark
authors.initials: M
authors.lastname: Bradley
authors.forename: E Elizabeth
authors.initials: EE
authors.lastname: Patton
authors.forename: Neil O
authors.initials: NO
authors.lastname: Carragher
authors.forename: Asier
authors.initials: A
authors.lastname: Unciti-Broceta
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002219:Carbamates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor; D004625:Embryo, Nonmammalian / Q000378:metabolism; D006801:Humans; D053758:Nanoparticles; D010165:Palladium / Q000737:chemistry*; D011137:Polystyrenes; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D012235:Rhodamines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015027:Zebrafish; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D002219:Carbamates; D004337:Drug Carriers; D011137:Polystyrenes; D011355:Prodrugs; D012235:Rhodamines; D003841:Deoxycytidine; D010165:Palladium; D000093542:Gemcitabine