[Au₂(phen^2Me)₂(μ-O)₂](PF₆)₂, a Novel Dinuclear Gold(III) Complex Showing Excellent Antiproliferative Properties

Abstract

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) compound qualifies itself as an optimal candidate for further pharmacological testing.

Gold peroxide complexes and the conversion of hydroperoxides into gold hydrides by successive oxygen-transfer reactions

“…A number of computational studies modelling oxidation reactions envisage the formation and interconversion of species with Au-O-O-Au, Au-OOH and Au-O-Au linkages [16][17][18] . To-date, there is, however, very little precise information available on the structures and bonding of such species; and although a number of gold oxo and hydroxo complexes have been reported 5 0 -bipyridyl and bipy a substituted 2,2 0 -bipyridyl [23][24][25][26][27][28][29][30][31], to the best of our knowledge isolable peroxo, hydroperoxo and alkylperoxo complexes of gold (in any oxidation state) were unknown.…”

Polypyridyl Metal Complexes with Biological Activity

“…The complex is as cytotoxic as cisplatin for these cell lines, having IC 50 values of 6.4 μm for HT-29 and 3.3 μm for MCF-7 cells. Higher IC 50 values are found for the other derivatives investigated. The cytotoxic activity correlates well with the size of the aromatic surface in the N-N ligand.…”

“…Complexes 9a-c were individually synthesized on a larger scale and purified. Complex 9a (Scheme 3) was found to display the lowest IC 50 values, and it was therefore selected for further structureactivity relationship studies aimed at understanding which ligand played a key role in the cytotoxicity effect of the compound. By varying single and multiple ligands and monitoring the effect of such changes on cytotoxicity, it was observed that substitution of the bpy ligand by a tBu 2 -bpy ligand in 9a to prepare complex 10 resulted in an outstanding IC 50 value (1.3 μm for 24 h drug exposure or 0.3 μm for 72 h).…”

“…[33] The flexible 23 and 24 (Scheme 10) were designed to induce DNA binding modes analogous to other metallosupramolecular cylinders developed by the same group. [34] Although it was not possible to obtain the absolute IC 50 value for these complexes for solubility reasons, it was observed that 23 and 24 would have an IC 50 of approximately 80-100 μm for HBL100 cells. No significant difference in cytotoxicity is present between the mixture and the enantiopure complexes.…”

2D-DIGE analysis of ovarian cancer cell responses to cytotoxic gold compounds

“…Au 2 Phen was synthesized as described by Cinellu et al 11 The gold(III) complex AuL12 was synthesized and purified as previously described. 32 All other chemicals were of analytical grade.…”