Bioorthogonal intermingling of prodrugs and metal catalysts

Performing abiotic reactions in biological settings, so-called bioorthogonal chemistry, has challenged us to search for novel biocompatible transformations for over two decades. The use of nonbiological transition metals such as Pd and Au enables us to produce supra-stoichiometric amounts of xenobiotics in living systems in a non-enzymatic fashion, which has opened new avenues in chemical biology and biomedicine. Capitalising on the biocompatibility of some metals and their catalytic properties, our lab has led the exploration of heterogeneous catalysis for the site-specific “manufacture” of chemotherapeutic agents in specific anatomical locations (e.g. inside tumours). In contrast to classical biolabile prodrugs, whose activation process relies on metabolic pathways, an efficient bioorthogonally-activated prodrug therapy would be entirely dependent on the distinct catalytic properties of the metal and, ideally, the prodrug should remain intact in the absence of the metal source. In this talk, I will present our last advances on the design and application of bioorthogonal prodrugs and catalysts to elicit spatially controlled pharmacological effects.