N-[3-(tert-Butyl­dimethyl­siloxymeth­yl)-5-nitro­phen­yl]acetamide

The title compound, C15H24N2O4Si, was prepared by the reaction of (3-acetamido-5-nitro­benz­yl)methanol with tert-butyl­dimethyl­silyl chloride and is a key inter­mediate in the synthesis of novel nonsymmetrical DNA minor groove-binding agents. There are two independent mol­ecules in the structure, which differ primarily in the rotation about the C—O bond next to the Si atom. Two strong N—H⋯O hydrogen bonds align the mol­ecules into a wide ribbon extending approximately parallel to the b axis

Development and bioorthogonal activation of palladium-labile prodrugs of gemcitabine

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’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 <i>N</i>-propargyloxycarbonyl (<i>N</i>-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 <i>N</i>-Poc as the most suitable masking group for implementing <i>in vivo</i> bioorthogonal organometallic chemistry