Gold(III) Complexes as Potential Antitumor Agents: Solution Chemistry and Cytotoxic Properties of Some Selected Gold(III) Compounds

Abstract

Gold(III) complexes generally exhibit interesting cytotoxic and antitumor properties, but until now, their development has been heavily hampered by their poor stability under physiological conditions. To enhance the stability of the gold(III) center, we prepared a number of gold(III) complexes with multidentate ligands - namely [Au(en)(2)]Cl(3), [Au(dien)Cl]Cl(2), [Au(cyclam)](ClO(4))(2)Cl, [Au(terpy)Cl]Cl(2), and [Au(phen)Cl(2)]Cl - and analyzed their behavior in solution. The solution properties of these complexes were monitored by visible absorption spectroscopy, mass spectrometry, and chloride-selective potentiometric measurements; the electrochemical properties were also studied by cyclic voltammetry and coulometry. Since all the investigated compounds exhibited sufficient stability under physiological conditions, their cytotoxic properties were tested in vitro, via the sulforhodamine B assay, on the representative human ovarian tumor cell line A2780, either sensitive or resistant to cisplatin. In most cases the investigated compounds showed relevant cell-killing properties with IC(50) values falling in the 0.2-10 microM range; noticeably most investigated gold(III) complexes were able to overcome, to a large extent, resistance to cisplatin when tested on the corresponding cisplatin-resistant cell line. The cytotoxic properties of the free ligands were also determined under the same solution conditions. Ethylenediamine, diethylenetriamine, and cyclam were virtually nontoxic (IC(50) values > 100 microM) so that the relevant cytotoxic effects observed for [Au(en)(2)]Cl(3) and [Au(dien)Cl]Cl(2) could be quite unambiguously ascribed to the presence of the gold(III) center. In contrast the phenanthroline and terpyridine ligands turned out to be even more cytotoxic than the corresponding gold(III) complexes rendering the interpretation of the cytotoxicity profiles of the latter complexes less straightforward. The implications of the present findings for the development of novel gold(III) complexes as possible cytotoxic and antitumor drugs are discussed.

Synthesis, Structures, and Electrochemistry of Gold(III) Ethylenediamine Complexes and Interactions with Guanosine 5‘-Monophosphate

“…This indicated that a bidentate ethylenediamine ligand stabilized the Au(III) oxidation state against reduction, as previously reported for chelating N donor ligands. 31 The position of the peaks B, B1, and C, which developed on consecutive voltammetric scans, was essentially not influenced by the composition of the gold complex. The gold complexes displayed good electrochemical stability as indicated by their peak currents and peak potentials, which were stable (± 10%) at least for 4 h.…”

Sublethal concentrations of diverse gold compounds inhibit mammalian cytosolic thioredoxin reductase (TrxR1)

“…Gold compounds (Table 1) were selected based on known ability of AF and GSTM to inhibit TrxR (Fricker et al, 1996;Simon et al, 2000;Gromer et al, 2004) or proposed use as therapeutic agents for arthritis or cancer (Messori et al, 2000;Che et al, 2003;Messori et al, 2004). Stock solutions of the gold compounds were added to the enzyme mixture to provide an appropriate final concentration range before the enzyme mixture was added to the substrate-buffer mixture.…”

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].…”