Development and bioorthogonal activation of palladium-labile prodrugs of gemcitabine

Jason T Weiss, John C Dawson, Craig Fraser, Witold Rybski, Carmen Torres-Sánchez, Mark Bradley, E Elizabeth Patton, Neil O Carragher, Asier Unciti-Broceta

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)5395-404
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number12
Early online date27 May 2014
Publication statusPublished - 26 Jun 2014


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