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

被引:316
作者
Messori, L
Abbate, F
Marcon, G
Orioli, P
Fontani, M
Mini, E
Mazzei, T
Carotti, S
O'Connell, T
Zanello, P
机构
[1] Univ Florence, Dept Chem, I-50121 Florence, Italy
[2] Univ Florence, Dept Pharmacol, I-50121 Florence, Italy
[3] Univ Siena, Dept Chem, I-53100 Siena, Italy
关键词
D O I
10.1021/jm990492u
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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)](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 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 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 the free ligands were also determined under the same solution conditions. Ethylenediamine, 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 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.
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页码:3541 / 3548
页数:8
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