Dinuclear Gold(III) Complexes as Potential Anticancer Agents. Structure, Reactivity and Biological Profile of a Series of Gold(III) Oxo-Bridged Derivatives

Six homologous gold(III) dinuclear oxo-bridged complexes, of the type [(bipynR)Au(μ-O)2Au(bipynR)][PF6]2,
bearing variously substituted 2,2’-bipyridine ligands (bipynR
= 2,2’-bipyridine, 4,4’-di-tert-butyl-, 6-methyl-, 6-neopentyl-,
6-o-xylyl- and 6,6’-dimethyl-2,2’-bipyridine), here called Auoxos, were prepared, characterised and recently tested as
potential anticancer agents. Crystal structures were obtained for five members of the series that allowed us to perform
detailed comparative analyses. Interestingly, the various Auoxos showed an acceptable stability profile in buffer solution
and turned out to manifest outstanding antitumor properties in vitro. In particular, one member of this family, Auoxo6
(bipynR = 6,6’-dimethyl-2,2’-bipyridine), produced more selective and far greater antiproliferative effects than all other
tested Auoxos, qualifying itself as the best “drug candidate”. In turn, COMPARE analysis of the cytotoxicity profiles of
five Auoxos, toward an established panel of thirty-six human tumor cell lines, revealed important mechanistic differences;
a number of likely biomolecular targets could thus be proposed such as HDAC and PKC. Biophysical studies revealed
markedly different modes of interaction with calf thymus DNA for two representative Auoxo compounds. In addition, a
peculiar reactivity with model proteins was documented on the ground of spectrophotometric and ESI MS data, most
likely as the result of redox processes. In view of the several experimental evidences gathered so far, it can be stated that
Auoxos constitute a novel family of promising cytotoxic gold compounds with an innovative mechanism of action that
merit a more extensive pharmacological evaluation.