PUBLICATION
Development and Bioorthogonal Activation of Palladium-Labile Prodrugs of Gemcitabine
- Authors
- Weiss, J.T., Dawson, J.C., Fraser, C., Rybski, W., Torres-Sanchez, C., Bradley, M., Patton, E.E., Carragher, N.O., Unciti-Broceta, A.
- ID
- ZDB-PUB-140529-4
- Date
- 2014
- Source
- Journal of medicinal chemistry 57(12): 5395-404 (Journal)
- Registered Authors
- Patton, E. Elizabeth
- Keywords
- none
- MeSH Terms
-
- Animals
- Antimetabolites, Antineoplastic/chemistry*
- Antimetabolites, Antineoplastic/metabolism
- Antimetabolites, Antineoplastic/pharmacology
- Carbamates/chemistry
- Carbamates/metabolism
- Carbamates/pharmacology
- Cell Line, Tumor
- Cell Survival/drug effects
- DNA Damage
- Deoxycytidine/analogs & derivatives*
- Deoxycytidine/chemistry
- Deoxycytidine/pharmacology
- Drug Carriers
- Drug Screening Assays, Antitumor
- Embryo, Nonmammalian/metabolism
- Humans
- Nanoparticles
- Palladium/chemistry*
- Polystyrenes
- Prodrugs/chemistry*
- Prodrugs/metabolism
- Prodrugs/pharmacology
- Rhodamines/chemistry
- Rhodamines/metabolism
- Rhodamines/pharmacology
- Structure-Activity Relationship
- Zebrafish
- PubMed
- 24867590 Full text @ J. Med. Chem.
Citation
Weiss, J.T., Dawson, J.C., Fraser, C., Rybski, W., Torres-Sanchez, C., Bradley, M., Patton, E.E., Carragher, N.O., Unciti-Broceta, A. (2014) Development and Bioorthogonal Activation of Palladium-Labile Prodrugs of Gemcitabine. Journal of medicinal chemistry. 57(12):5395-404.
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 last decade. Alongside the well-established labelling strategies that originated the bioorthogonal paradigm, we have recently proposed the use of heterogeneous palladium chemistry and bioorthogonal Pd0-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) 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.
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