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.

Gold(III) compounds are emerging as a new class of metal complexes with outstanding cytotoxic properties and are presently being evaluated as potential antitumor agents. We report here on the solution and electrochemical properties, and the biological behavior of some gold(III) dithiocarbamate derivatives which have been recently proved to be one to 4 orders of magnitude more cytotoxic in vitro than the reference drug (cisplatin) and to be able to overcome to a large extent both intrinsic and acquired resistance to cisplatin itself. Their solution properties have been monitored in order to study their stability under physiological conditions; remarkably, they have shown to undergo complete hydrolysis within 1 h, the metal center remaining in the +3 oxidation state. Their DNA binding properties and ability in hemolyzing red blood cells have been also evaluated. These gold(III) complexes show high reactivity toward some biologically important isolated macromolecules, resulting in a dramatic inhibition of both DNA and RNA synthesis and inducing DNA lesions with a faster kinetics than cisplatin. Nevertheless, they also induce a strong and fast hemolytic effect (compared to cisplatin), suggesting that intracellular DNA might not represent their primary or exclusive biological target.

In continuation of our work on Wanzlick/Arduengo carbenes containing redox-active ferrocenyl substituents we report on the synthesis of N,N‘-diferrocenyl imidazol(in)ium salts as precursors of imidazol(in)-2-ylidenes. The necessary starting material for this chemistry is aminoferrocene, which was prepared by an improved and large-scale synthesis by the sequence solid lithioferrocene, iodoferrocene, N-ferrocenylphthalimide, aminoferrocene. The preparation of N,N‘-diferrocenyl heterocycles involves condensation of aminoferrocene with glyoxal to afford N,N‘-diferrocenyldiazabutadiene [Fc-DAB], reduction, condensation with formaldehyde, and oxidation with trityl salts to yield N,N‘-diferrocenylimidazol(in)ium salts. In situ deprotonation and trapping with electrophiles yielded the expected metal complexes and derivatives in some cases [Ag+ or S8], but attempted reaction with other transition metals [e.g., Pd(II)] failed to give the corresponding complexes, due to (i) steric hindrance by the two N-ferrocenyl substituents, (ii) reduced acidity of the imidazol(in)ium precursors, and (iii) inaccessibility of the free carbenes. Spectroscopic [IR, Raman, UV−vis, MS, NMR (1H, 13C, 109Ag)], structural [X-ray], and electrochemical [CV] properties are reported and compared to those of other N-heterocyclic carbene derivatives.

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Dinuclear copper(II) complexes with the new ligand 1,6-bis[[bis(1-methyl-2-benzimidazolyl)methyl]amino]-n-hexane (EBA) have been synthesized, and their reactivity as models for tyrosinase has been investigated in comparison with that of previously reported dinuclear complexes containing similar aminobis(benzimidazole) donor groups. The complex [Cu2(EBA)(H2O)4]4+, five-coordinated SPY, with three nitrogen donors from the ligand and two water molecules per copper, can be reversibly converted into the bis(hydroxo) complex [Cu2(EBA)(OH)2]2+ by addition of base (pK a1 = 7.77, pK a2 = 9.01). The latter complex can also be obtained by air oxidation of [Cu2(EBA)]2+ in methanol. The X-ray structural characterization of [Cu2(EBA)(OH)2]2+ shows that a double μ-hydroxo bridge is established between the two Cu(II) centers in this complex. The coordination geometry of the coppers is distorted square planar, with two benzimidazole donors and two hydroxo groups in the equatorial plane, and an additional, lengthened and severely distorted axial interaction (∼2.5 Å) with the tertiary amine donor. The small size and the quality of the single crystal as well as the fair loss of crystallinity during data collection required the use of synchrotron radiation at 100 K. [Cu2(EBA)(OH)2][PF6]2:  orthorhombic Pca21 space group, a = 22.458(2) Å, b = 10.728(1) Å, c = 19.843(2) Å, R = 0.089. Besides OH-, the [Cu2(EBA)(H2O)4]4+ complex binds azide as a bridging ligand, with the μ-1,3 mode. Azide can also displace μ-OH in [Cu2(EBA)(OH)2]2+ as a bridging ligand. In general, the binding constants indicate that the long alkyl chain of EBA is less easily folded in the structures containing bridging ligands than the m-xylyl residue present in the previously reported dicopper(II) complexes. Electrochemical experiments show that [Cu2(EBA)(H2O)4]4+ undergoes a single, partially chemically reversible, two-electron reduction to the corresponding dicopper(I) congener at positive potential values (E 0‘ = 0.22 V, vs SCE). Interestingly, however, coordination to azide ion makes the reduction process proceed through two separated one-electron steps. The catalytic activity of [Cu2(EBA)(H2O)4]4+ in the oxidation of 3,5-di-tert-butylcatechol has been examined in methanol/aqueous buffer, pH 5.1. The mechanism of the catalytic cycle parallels that of tyrosinase, where no hydrogen peroxide is released and dioxygen is reduced to water. Low-temperature (−80 °C) spectroscopic experiments show that oxygenation of the reduced complex [Cu2(EBA)]2+ does not produce a stable dioxygen adduct and leads to a μ-oxodicopper(II) species in a fast reaction.

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The new compounds 1,3-dibromo-5-(ferrocenylethynyl)benzene (1), 1-bromo-3,5-bis(ferrocenylethynyl)benzene (2), and 1,3,5-tris(ferrocenylethynyl)benzene (3) have been synthesized by palladium-catalyzed cross-coupling reactions and characterized, and the crystal structures of 1 and 3 have been determined; electrochemical studies show chemically reversible oxidations with single-step one-electron, two-electron, and three-electron processes per molecule, respectively, indicating that in 2 and 3 the iron(II) centers do not electronically communicate with each other.