Structural and Solution Chemistry, Antiproliferative Effects, and DNA and Protein Binding Properties of a Series of Dinuclear Gold(III) Compounds with Bipyridyl Ligands

Abstract

A series of six dinuclear gold(III) oxo complexes with bipyridyl ligands, of general formula [Au2(N,N)2(mu-O)2][PF6]2 (Auoxo1-Auoxo6) [where N,N = 2,2'-bipyridine (1), 4,4'-di-tert-butyl- (2), 6-methyl- (3), 6-neopentyl- (4), 6-(2,6-dimethylphenyl)- (5), 6,6'-dimethyl-2,2'-bipyridine (6)], were investigated as potential cytotoxic and anticancer agents, and their antiproliferative properties were evaluated in vitro toward the reference A2780 human ovarian carcinoma cell line. While five compounds manifested moderate cytotoxic properties (with IC50 approximately 10-30 microM), the sixth one (Auoxo6), turned out to be approximately 5-15 times more active against both cell lines and will merit further pharmacological studies. The interactions of Auoxo1 and Auoxo6 with a few model proteins (serum albumin, cytochrome c, ubiquitin) and with calf thymus DNA were analyzed in detail by various spectroscopic methods. Both tested compounds manifested a high and peculiar reactivity toward the mentioned model proteins; specific differences were detected in their reactivity with DNA. The mechanistic implications of these results are discussed.

Exploring the biochemical mechanisms of cytotoxic gold compounds: a proteomic study

“…On the ground of the SRB assay results, IC 50 values of 0.5 and 0.3 lM were determined for auranofin on the sensitive and resistant cell lines, respectively, after 72-h drug exposure. In turn, the measured IC 50 values for Auoxo6 were found to be perfectly consistent with those previously reported by Casini et al [5] (1.8 and 4.9 lM for A2780/S and A2780/R, respectively). We also observed that very limited cell death was evident, for both compounds, at 24 h, this rendering a classic proteomic approach well feasible.…”

“…Previous studies had highlighted that Auoxo6, a binuclear gold(III) compound developed in our laboratories, manifests remarkable cytotoxic properties, with IC 50 values falling in the low micromolar range [5]. Moreover, Auoxo6 is characterized by a rather pronounced selectivity in its cytotoxic properties toward a large panel of 36 cell lines as reported earlier [37].…”

“…Owing to the still appreciable oxidizing properties of the gold(III) center, it can be assumed that Auoxo6 may undergo facile reduction and cleavage, thus being a source of gold(I) species. Indeed, ESI-MS interaction studies with model proteins strongly supported this view [57].…”

“…Accordingly, our laboratories have developed a variety of structurally diverse gold(III) compounds as potential chemotherapeutic leads [4]. We previously reported that one of these complexes, namely, the binuclear gold(III) complex Auoxo6, manifests very encouraging cytotoxic properties in vitro and constitutes a new promising chemotherapeutic lead [5,6].…”

Oxidation of methionine residue in Gly-Met dipeptide induced by [Au(en)Cl2]+ and influence of the chelated ligand on the rate of this redox process

“…Some gold(I) complexes, such as auranofin and aurothiomalate, have been used very successfully in the treatment of rheumatoid arthritis [2], while gold(III) complexes have gained considerable attention as potential antitumor agents [3]. During the recent years, a large number of gold(III) complexes, in which the reduction potential of the Au(III) was lowered by the use of polydentate ligands, have been reported to be appreciably stable under physiologically relevant conditions and to manifest relevant cytotoxic activity against different human tumor cell lines [4][5][6][7][8][9][10][11][12][13][14][15][16]. The possible involvement of gold(III) complexes in cancer treatment initiated an interest in the area of gold(III) interactions with different biologically important ligands, such as amino acids and peptides [17].…”