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Development and bioorthogonal activation of palladium-labile prodrugs of gemcitabine
journal contributionposted on 29.09.2016, 08:59 by Jason T. Weiss, John C. Dawson, Craig Fraser, Witold Rybski, Carmen TorresCarmen Torres, Mark Bradley, E. Elizabeth Patton, Neil O. Carragher, Asier Unciti-Broceta
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 Pd0-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.
J.T.W. is grateful to the College of Medicine and Veterinary Medicine and the University of Edinburgh for a Darwin International Scholarship and an Edinburgh Global Research Scholarship. N.O.C. and A.U.B. thank RCUK and IGMM, respectively, for an Academic Fellowship. W.R., C.F., and E.E.P. are funded by the MRC. We are grateful to the Edinburgh Cancer Research UK Centre for funding this research through the CRUK Development Fund. This work has been partly funded by a Heriot Watt University − IGMM pilot project and the MSD Scottish Life Sciences Fund.
- Mechanical, Electrical and Manufacturing Engineering