Ruthenium(III) complexes have been described as the next generation of metal-based anticancer compounds. Two of the most promising clinical candidates are imidazolium [trans-RuCl4(1H-imidazole)(DMSO-S)] (NAMI-A) and indazolium [trans-RuCl4(1H-indazole)2] (KP1019). The proposed mode of action of these compounds involves ligand substitution, protein-mediated delivery, and reduction from Ru(III) to Ru(II), either within the hypoxic environment of tumour cells or by biological reducing agents. Electron paramagnetic resonance spectroscopy (EPR) was used to demonstrate the importance of protein binding for these complexes, specifically to human serum albumin (hsA), and the effect this has on their speciation and redox stability. Electron nuclear double resonance spectroscopy (ENDOR) has helped identify the nature of coordinate hsA interactions. Inspired by these results, several derivatives of both complexes were synthesized, targeting hydrophobic interactions with hsA. By increasing the hydrophobicity of the axial ligands, these complexes bind non-covalently to hsA with greater affinity and stability. This stabilization can allow for the delivery of the unsubstituted complexes to tumour cells, potentially enhancing their anticancer activity. Additional in vitro EPR studies on both NAMI-A and KP1019 have helped probe the potential biological targets of both complexes, since NAMI-A interacts predominantly with cell walls, while KP1019 readily enters eukaryotic cells and binds with the mitochondria and cystoplasmic protein components.
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Thesis advisor: Walsby, Charles
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