Gold(III) complexes as potential antitumor agents: Solution chemistry and cytotoxic properties of some selected gold(III) compounds

Gold(III) complexes generally exhibit interesting cytotoxic and antitumor p roperties, but until now, their development has been heavily hampered by th eir 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 )](ClO4)(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 moni tored by visible absorption spectroscopy, mass spectrometry, and chloride-s elective potentiometric measurements; the electrochemical properties were a lso studied by cyclic voltammetry and coulometry. Since all the investigate d compounds exhibited sufficient stability under physiological conditions, their cytotoxic properties were tested in vitro, via the sulforhodamine B a ssay, on the representative human ovarian tumor cell line A2780, either sen sitive or resistant to cisplatin. In most cases the investigated compounds showed relevant cell-killing properties with IC50 values falling in the 0.2 -10 mu M 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 th e free ligands were also determined under the same solution conditions. Eth ylenediamine, diethylenetriamine, and cyclam were virtually nontoxic (IC50 values > 100 mu M) 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 t he presence of the gold(III) center. In contrast the phenanthroline and ter pyridine ligands turned out to be even more cytotoxic than the correspondin g gold(III) complexes rendering the interpretation of the cytotoxicity prof iles of the latter complexes less straightforward. The implications of the present findings for the development of novel gold(III) complexes as possib le cytotoxic and antitumor drugs are discussed.