Development and Bioorthogonal Activation of Palladium-Labile Prodrugs of Gemcitabine

详细信息    查看全文

• 作者：Jason T. Weiss ; John C. Dawson ; Craig Fraser ; Witold Rybski ; Carmen Torres-S谩nchez ; Mark Bradley ; E. Elizabeth Patton ; Neil O. Carragher ; Asier Unciti-Broceta
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 26, 2014
• 年：2014
• 卷：57
• 期：12
• 页码：5395-5404
• 全文大小：582K
• ISSN：1520-4804

文摘

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 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鈥檚 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鈥?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.