File(s) under permanent embargo

Reason: This item is currently closed access.

Development and bioorthogonal activation of palladium-labile prodrugs of gemcitabine

journal contribution
posted on 29.09.2016 by Jason T. Weiss, John C. Dawson, Craig Fraser, Witold Rybski, Carmen 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.

Funding

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.

History

School

  • Mechanical, Electrical and Manufacturing Engineering

Published in

Journal of Medicinal Chemistry

Volume

57

Issue

12

Pages

5395 - 5404

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.

Publisher

© American Chemical Society

Version

VoR (Version of Record)

Publisher statement

This work is made available according to the conditions of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) licence. Full details of this licence are available at: https://creativecommons.org/licenses/by-nc-nd/4.0/

Publication date

2014

Notes

Closed access.

ISSN

0022-2623

eISSN

1520-4804

Language

en

Exports

Logo branding

Exports