Cytotoxic gold compounds showing selectivity between cancerous and normal cells: synthesis and biological characterization.

The new gold(III) complexes: [Au{2-(2′-pyridyl)imidazolate}Cl2] and [Au{2,6-bis(2′-benzimidazolate)
pyridine}(OCOCH3)] and the mono- and binuclear gold(I) complexes: [Au{2-(2′-pyridyl)imidazole}
(PPh3)](PF6), [Au(2-phenylimidazolate)(DAPTA)] (DAPTA = 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo
[3.3.1]nonane), [(PPh3Au)2(2-R-imidazolate)](PF6) (R = 2-C5H4N, Ph) have been synthesized and
characterized. The structure of the [(PPh3Au)2{2-(2′-pyridyl)imidazolate)](PF6) complex was also
characterized by X-ray crystallography. The antiproliferative properties of the complexes were assayed
against human ovarian carcinoma cell lines, either sensitive (A2780) or resistant to cisplatin (A2780cisR),
human mammary carcinoma cells (MCF7) and non-tumorigenic human kidney (HEK293) cells. Most of
the studied compounds showed important cytotoxic effects. Interestingly, the compounds containing the
2-(2′-pyridyl)imidazolate ligand showed selectivity towards cancer cells with respect to the nontumorigenic
ones, with the dinuclear compound [(PPh3Au)2{2-(2′-pyridyl)imidazolate)](PF6) being the
most active. Some compounds were also screened for their inhibitory effect of the zinc-finger protein
PARP-1, essential for DNA repair and relevant to the mechanisms of cancer cell resistance to cisplatin.
Interaction studies of the compounds with the model protein ubiquitin were undertaken by electrospray
ionization mass spectrometry (ESI MS). The results are discussed in relation to the putative mechanisms
of action of the cytotoxic gold compounds.