Walsby Research Group

Ruthenium Anticancer Compounds
Ru(III) complexes are the most promising candidates for the next-generation of metal-based anticancer drugs. Two of these compounds are currently undergoing phase II clinical trials. We are using spectroscopic methods to probe the interactions of these complexes with biomolecules and their ligand exchange properties. Our most rescent results demonstrate the importance of serum-protein interactions to the speciation of these compounds, which has inspired us to synthesize new complexes targeting these interactions for control of oxidation state, prevention of oligomerization and targeted delivery to cancer cells. Particrular areas of interest for the design of new complexes include tuning of protein interactions and the use of redox-active ligands

Protein-Metallodrug Conjugates
We have shown recently that the axial azole ligands typically found in Ru(III) anticancer complexes play a critical role in mediating interactions with serum proteins. These ligands can promote rapid non-coordinative binding to the hydrophobic domains of human serum albumin (hsA). They also influence the formation of coordinative protein interactions on longer time scales. This demonstrates that interactions with hsA can be tuned through ligand design. Compounds bound to hsA can be transported into cells and this protein has been targeted as a selective delivery system for chemotherapeutics. We are designing compounds for the development of hsA conjugates and characterising the transport of these species and their intracellular behaviour using spectroscopic methods.

Metalloproteins in ionic liquids
The reactivity and selectivity of enzymes can be modified by changes to their host solvent. Room-temperature Ionic liquids, salts that are molten at room temperature and thus consist only of ions, are unique solvent systems and the properties of these materials can be tuned through the choice of cations and anions. Our goals are to modify the properties of biocompatible ionic liquids to control metalloenzyme reactivity and selectivity and interpret these changes at a molecular level. Currently, we are focused on oxidation and hydroxylation reactions of heme proteins in phosphonium ionic liquids. Not only can these systems provide new reactivity for normally non-catalytic metalloproteins, but they also provide unique opportunities to study radical intermediates and reaction mechanisms.

Biomimetic inorganic catalysts
The tunable solvent environment provided by ionic liquids facilitates the control of metal-ion based homogeneous catalysis. We are particularly focused on the ability of these systems to mimic the chemistry of heme enzymes such as cytochrome P450. Through selection of anions and cations in phosphonium ionic liquids we are controlling the reactivity of iron porphyrins towards epoxidation and oxidation reactions. Particular areas of interest include assymetric catalysis in chiral ionic liquids and the mimicking of enzyme active sites through the control of hydrophobicity and hydrogen bonding. Mechanistic understanding is critical to the design of these systems and we are using EPR methods to study the catalytic metal centres and characterise unstable radical intermediates.