Organogold(III) compounds as experimental anticancer agents: chemical and biological profiles.

In the last few years gold(III) complexes have attracted growing attention in the medicinal chemistry community as candidate anticancer agents. In particular some organogold(III) compounds manifested quite attractive pharmacological behaviors in preclinical studies. Here we compare the chemical and biological properties of the novel organogold(III) complex [Au(bipy(dmb)-H)(NH(CO)CH3)][PF6] (Aubipy(aa)) with those of its parent compounds [Au(bipy(dmb)-H)(OH)][PF6] (Aubipy(c)) and [Au2(bipy(dmb)-H)2)(µ-O)][PF6]2 (Au2bipy(c)), previously synthesized and characterized. The three study compounds were comparatively assessed for their antiproliferative actions against HCT-116 cancer cells, revealing moderate cytotoxic effects. Proapoptotic and cell cycle effects were also monitored. Afterward, to gain additional mechanistic insight, the three gold compounds were challenged against the model proteins HEWL, RNase A and cytochrome c and reactions investigated through UV-Vis and ESI-MS analysis. A peculiar and roughly invariant protein metalation profile emerges in the three cases consisting of protein binding of {Au(bipy(dmb)-H)} moieties. The implications of these results are discussed in the frame of current knowledge on anticancer gold compounds.

Synthesis, structural characterization, solution behavior, and in vitro antiproliferative properties of a series of gold complexes with 2-(2'-pyridyl)benzimidazole as ligand: comparisons of gold(III) versus gold(I) and mononuclear versus binuclear derivatives.

A variety of gold(III) and gold(I) derivatives of 2-(2'-pyridyl)benzimidazole (pbiH) were synthesized and fully characterized and their antiproliferative properties evaluated in a representative ovarian cancer cell line. The complexes include the mononuclear species [(pbi)AuX(2)] (X = Cl, 1; OAc, 2), [(pbiH)AuCl] (3), [(pbiH)Au(PPh(3))][PF(6)] (4-PF(6)), and [(pbi)Au(L)] (L = PPh(3), 5; TPA, 6), and the binuclear gold(I)/gold(I) and gold(I)/gold(III) derivatives [(PPh(3))(2)Au(2)(µ(2)-pbi)][PF(6)] (10-PF(6)), [ClAu(µ(3)-pbi)AuCl(2)] (7),and [(PPh(3))Au(µ(3)-pbi)AuX(2)][PF(6)] (X = Cl, 8-PF(6); OAc, 9-PF(6)). The molecular structures of 6, 7, and 10-PF(6) were determined by X-ray diffraction analysis. The chemical behavior of these compounds in solution was analyzed both by cyclic voltammetry in DMF and absorption UV-vis spectroscopy in an aqueous buffer. Overall, the stability of these gold compounds was found to be acceptable for the cellular studies. For all complexes, relevant antiproliferative activities in vitro were documented against A2780 human ovarian carcinoma cells, either resistant or sensitive to cisplatin, with IC(50) values falling in the low micromolar or even in the nanomolar range. The investigated gold compounds were found to overcome resistance to cisplatin to a large degree. Results are interpreted and discussed in the frame of current knowledge on cytotoxic and antitumor gold compounds.

[Au(pyb-H)(mnt)]: A novel gold(III) 1,2-dithiolene cyclometalated complex with antimicrobial activity (pyb-H=C-deprotonated 2-benzylpyridine; mnt=1,2-dicyanoethene-1,2-dithiolate).

The novel heteroleptic cyclometalated complex [AuIII(pyb-H)(mnt)] (1; pyb-H=C-deprotonated 2-benzylpyridine; mnt =1,2-dicyanoethene-1,2-dithiolate) was tested against a panel of ten Gram positive (belonging to the Staphylococcus, Streptococcus spp. and Bacillus clausii), Gram negative (E. coli, K. pneumoniae, P. aeruginosa) bacteria and three yeasts belonging to the Candida spp. Complex 1 showed a remarkable bacteriostatic antimicrobial activity against staphylococci, with Minimum Inhibitory Concentration (MIC) values of 1.56 and 3.13µg/mL for S. haemoliticus and S. aureus, respectively. Spectroscopic and electrochemical measurements, supported by Density Functional Theory (DFT) calculations, were exploited to fully investigate the electronic structure of complex 1 and its relationship with the antimicrobial activity.

Reaction of gold(III) oxo complexes with alkenes. Synthesis of unprecedented gold alkene complexes, [Au(N,N)(alkene)][PF6]. Crystal structure of [Au(bipy(ip))(eta2-CH2=CHPh)][PF6] (bipy(ip) = 6-isopropyl-2,2'-bipyridine).

Gold alkene complexes [Au(bipyR)(eta2-alkene)][PF6] (bipyR = 6-alkyl-2,2'-bipyridine) have been obtained by reaction of gold(III) oxo complexes [Au2(bipyR)2(mu-O)2][PF6]2 with alkenes. The crystal structure of the styrene adduct [Au(bipy(ip))(eta2-CH2=CHPh)][PF6] (bipy(ip) = 6-isopropyl-2,2'-bipyridine) has been solved by X-ray analysis.

Selected cytotoxic gold compounds cause significant inhibition of 20S proteasome catalytic activities.

Six structurally diverse cytotoxic gold compounds are reported to cause profound and differential inhibition of the three main catalytic activities of purified 20S proteasome whilst auranofin, an established gold(I) drug in clinical use, is nearly ineffective. In particular, the gold(I) complex [(pbiH)Au(PPh3)]PF6, turns out to be the most potent inhibitor of all three enzyme activities with sub-micromolar IC50 values. The present results further support the view that proteasome inhibition may play a major--yet not exclusive--role in the cytotoxic actions of gold based anticancer agents.

The mode of action of anticancer gold-based drugs: a structural perspective.

The interactions between a few representative gold-based drugs and hen egg white lysozyme were studied by X-ray crystallography. High resolution crystal structures solved for three metallodrug-protein adducts provide valuable insight into the molecular mechanism of these promising metal compounds and the inherent protein metalation processes.

Medicinal gold compounds form tight adducts with the copper chaperone Atox-1: biological and pharmacological implications.

Based on ESI-MS measurements, we show here that some representative cytotoxic gold(III) compounds produce stable adducts upon reaction with the copper chaperone Atox-1; notably, such adducts contain gold in the oxidation state +1. These findings are of interest to understand the intracellular metabolism of medicinal gold species and to develop new potent inhibitors of the copper trafficking system.

[Au2(phen(2Me))2(µ-O)2](PF6)2, a Novel Dinuclear Gold(III) Complex Showing Excellent Antiproliferative Properties.

A novel dioxo-bridged dinuclear gold(III) complex with two 2,9-dimethylphenanthroline ligands was synthesized and thoroughly characterized. Its crystal structure was solved, and its solution behavior assessed. Remarkably, this compound revealed excellent antiproliferative properties in vitro against a wide panel of 36 cancer cell lines, combining a high cytotoxic potency to pronounced tumor selectivity. Very likely, these properties arise from an innovative mode of action (possibly involving histone deacetylase inhibition), as suggested by COMPARE analysis. In turn, electrospray ionization-mass spectrometry studies provided valuable insight into its molecular mechanisms of activation and of interaction with protein targets. Gold(III) reduction, dioxo bridge disruption, coordinative gold(I) binding to the protein, and concomitant release of the phenanthroline ligand were proposed to occur upon interaction with superoxide dismutase, used here as a model protein. Because of the reported results, this new gold(III) compound qualifies itself as an optimal candidate for further pharmacological testing.

Outstanding plasmodicidal properties within a small panel of metallic compounds: Hints for the development of new metal-based antimalarials.

A variegate group of metallodrugs was evaluated in vitro for antimalarial activity through the pLDH test. The panel comprised one mononuclear gold(III) complex, (Aubipy), three dinuclear gold(III) compounds (Auoxo4, Auoxo5 and Auoxo6), three ruthenium(III) complexes (NAMI A, PMRU20, PMRU27), one ruthenium(II) complex (PMRU52), one bismuth(III) compound (Bismuth citrate), antimony trichloride (SbCl(3)) and arsenic trioxide (As(2)O(3)). This panel, although relatively small, was built up in such a way to include a variety of metal centers, structural motifs and metal coordination environments. In general, the tested compounds turned out to contrast effectively Plasmodium falciparum growth in vitro. In two cases, i.e. NAMI A and antimony trichloride, IC(50) values in the high nanomolar range were measured. Notably, the antiplasmodial effects appear not to be correlated to in vitro anticancer properties. The mechanistic and pharmacological implications of the obtained results are discussed.

Synthesis and properties of gold alkene complexes. Crystal structure of [Au(bipy(oXyl))(eta(2)-CH(2)=CHPh)](PF(6)) and DFT calculations on the model cation [Au(bipy)(eta(2)-CH(2)=CH(2))](+).

Unprecedented 16-electron gold(i) olefin complexes of general formula [Au(bipy(R,R'))(eta(2)-olefin)](PF(6)) and [Au(2)(bipy(R,R'))(2)(mu-eta(2):eta(2)-diolefin)](PF(6))(2) (bipy(R,R') = 6-substituted-2,2'-bipyridine) have been prepared by reaction of dinuclear gold(III) oxo complexes [Au(2)(bipy(R,R'))(2)(mu-O)(2)](PF(6))(2) with the appropriate olefin. The X-ray crystal structures of two mononuclear complexes (olefin = styrene) show in-plane coordination of the olefin and a C[double bond, length as m-dash]C bond distance considerably lengthened with respect to the free olefin. The spectroscopic properties of the complexes are discussed and compared with those of analogous d(10) metal derivatives. Both structural and spectroscopic information indicate a substantial contribution of pi-back-donation to the Au-olefin bond in the three-coordinate species. Theoretical calculations carried out at the hybrid-DFT level on the model compound [Au(bipy)(eta(2)-CH(2)[double bond, length as m-dash]CH(2))](+) show excellent agreement with the experimental findings giving in addition an estimate of a pi-back-bonding contribution higher than that of the sigma-bonding.