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A novel dioxo-bridged dinuclear gold(III) complex with two 2,9-dimethylphenanthroline ligands was synthesized and thoroughly characterized. Its crystal structure was solved, and its solution behavior assessed. Remarkably, this compound revealed excellent antiproliferative properties in vitro against a wide panel of 36 cancer cell lines, combining a high cytotoxic potency to pronounced tumor selectivity. Very likely, these properties arise from an innovative mode of action (possibly involving histone deacetylase inhibition), as suggested by COMPARE analysis. In turn, electrospray ionization-mass spectrometry studies provided valuable insight into its molecular mechanisms of activation and of interaction with protein targets. Gold (III) reduction, dioxo bridge-disruption, coordinative gold(I) binding to the protein, and concomitant release of the phenanthroline ligand were proposed to occur upon interaction with superoxide dismutase, used here as a model protein. Because of the reported results, this new gold(III) compund qualifies itself as an optimal candidate for further pharmocological testing.

The structure and stability of the adduct formed in the reaction between Auoxo3, a dinuclear gold(III) compound, and the model protein hen egg white lysozyme (HEWL) are investigated by X-ray crystallography, UV-Vis absorption spectroscopy and circular dichroism (CD). It is found that Auoxo3 breaks down completely, undergoes reduction and produces reactive gold(I) species able to bind the protein and form stable derivatives. The behaviour of Auoxo3 is compared with that of two analogous gold(III) complexes previously studied: a few significant differences are highlighted. The general implications of these new results for the mode of action of cytotoxic gold complexes are discussed.