Structures and Mechanisms of Reactive Metal Centres: Metal-based Drugs and Bioinorganic Catalysts

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Our research is developing metal-based anticancer compounds and novel bioinorganic catalysts. To probe structure-activity relationships in these systems, we use a combination of spectroscopic methods to characterize paramagnetic metal centres, intermediates, and radical species. These mechanistic studies are leading our design and synthesis of reactive metal complexes and new reaction systems. (i) Ruthenium-based chemotherapeutics have shown great promise in clinical studies. We are developing new Ru(III) anticancer compounds that target interactions with albumin for selective delivery to cancer cells. Using magnetic resonance spectroscopic methods, we are studying protein mediated intercellular transport and the fate of these compounds in cellular environments. (ii) Reduction of Ru(III) complexes in vivo can activate them towards ligand exchange with biomolecules. We are preparing complexes with redox-active ligands, whose reduction potentials can be tuned by aqueous and biomolecule ligand exchange in vivo. These compounds target the hypoxic, reducing environment of tumours for selective activation, both by production of activated Ru(II) species and reactive oxygen species. (iii) Solvent systems that are comprised only of cations and anions provide unique environments for biocatalysis. We are using biocompatible "ionic liquids" with heme proteins such as cytochrome c to develop new systems for selective oxidations and hydroxylations. Mechanistic studies guide our design of new catalysts and provide insight into the influence of solvent effects on the chemistry of metalloproteins. (iv) We are developing biomimetic porphyrin and non-heme iron catalysts, using ionic liquids to act as non-biological substitutes for the protein environment at the active sites of metalloenzymes. Studies of reactivity and reaction intermediates allow us to determine how the ionic liquids influence catalytic mechanisms. This work seeks to develop new catalytic systems whose utility is tailored by the tunable solvent environment of ionic liquids.