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Title: Development and bioorthogonal activation of palladium-labile prodrugs of gemcitabine
Authors: Weiss, Jason T.
Dawson, John C.
Fraser, Craig
Rybski, Witold
Torres-Sanchez, Carmen
Bradley, Mark
Patton, E. Elizabeth
Carragher, Neil O.
Unciti-Broceta, Asier
Keywords: Bioorthogonal chemistry
Pharmaceuticals
Medicine
Issue Date: 2014
Publisher: © American Chemical Society
Citation: WEISS, J. ... et al., 2014. Development and bioorthogonal activation of palladium-labile prodrugs of gemcitabine. Journal of Medicinal Chemistry, 57 (12), pp.5395-5404.
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 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.
Description: Closed access.
Sponsor: 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.
Version: Published
DOI: 10.1021/jm500531z
URI: https://dspace.lboro.ac.uk/2134/22600
Publisher Link: http://dx.doi.org/10.1021/jm500531z
ISSN: 0022-2623
Appears in Collections:Closed Access (Mechanical, Electrical and Manufacturing Engineering)

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