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A series of novel (C∧N∧N) cyclometalated AuIII complexes of general formula [Au(bipydmb-H)X][PF6] (bipydmb-H = C∧N∧N cyclometalated 6-(1,1-dimethylbenzyl)-2,2′-bipyridine) were prepared with a range of anionic ligands X in the fourth coordination position, featuring C (alkynyl)-, N-, O-, or S-donor atoms. The X ligands are varied in nature and include three coumarins, 4-ethynylaniline, saccharine, and thio-β-d-glucose tetraacetate, the tripeptide glutathione (GSH), and a coumarin-substituted amide derived from 4-ethynylaniline. The gold(I) complex [Au(C2ArNHCOQ)(PPh3)] (HC2ArNHCOQ = N-(4-ethynylphenyl)-2-oxo-2H-chromene-3-carboxamide) was also prepared for comparison. The new compounds were fully characterized by means of analytical techniques, including NMR, absorption, and emission spectroscopy. The crystal structures of three cyclometalated AuIII complexes and of the AuI derivative were solved by single-crystal X-ray diffraction. The antiproliferative activity of the new AuIII cyclometalated derivative...

Sulphur and nitrogen oxide pollutants cause acid rain that can eventually lead to the dissolution of calcite in marble and limestones. Calcium oxalate is an inorganic protective agent, which is obtained by treatment with ammonium oxalate. The functionalization of oxalic acid to give monoesters and monoamides (oxamates) allows tailoring the solubility of the relevant ammonium and calcium salts. In this context, theoretical calculations carried out at the Density Functional Theory (DFT) level were exploited to investigate the capability of oxalate, methyloxalate, phenyloxalate, oxamate, methyloxamate, and phenyloxamate to interact with the calcium carbonate lattice. An in-depth validation based on the structural data showed that DFT calculations with the PBE0 functional along with a single or triple-zeta def2 basis set allow understanding the different reactivity of the oxalate and oxamate derivatives and their efficiency in interacting with stones containing calcium carbonate, such as Carrara marble and biomicritic limestones.

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.

A series of novel (C

The encapsulation of Pt and Au-based anticancer agents within a protein cage is a promising way to enhance the selectivity of these potential drugs. Here a cytotoxic organometallic compound containing platinum(II) and gold(I) has been encapsulated within a ferritin nanocage (AFt). Inductively plasma coupled mass spectrometry data, collected to evaluate the amount of Pt and Au within the cage, indicate disruption of the starting heterobimetallic complex upon encapsulation within the nanocage. The drug-loaded protein (Pt(II)/Au(I)-AFt) has been characterized by UV–Vis spectroscopy, circular dichroism and X-ray diffraction analysis. Data indicate that the protein maintains its fold upon encapsulation of the metallodrug and that Au(I) and Pt(II)-containing fragments are encapsulated within the AFt cage, with Au(I) ion that binds the side chain of Cys126 and Pt(II) in the bulk, respectively. The in vitro cytotoxicity of Pt(II)Au(I)-AFt, as well as that of the free heterobimetallic complex, has been comparatively evaluated on human cervix and breast cancer cells and against cardiomyoblasts and keratinocytes non-tumorigenic cells. Our data demonstrate that it is possible to obtain a protein nanocarrier containing both Pt and Au atoms starting from a bimetallic compound, opening the way for the design and development of new potential drugs based on protein nanocarriers. Previous article in issue

Two anticancer gold(iii) compounds, Au2phen and Auoxo4, were encapsulated within a ferritin nanocage. The gold-compound loaded proteins were characterized by UV-Vis spectroscopy, inductively coupled plasma mass spectrometry and circular dichroism. X-ray crystallography shows that the compounds degrade upon encapsulation and gold(i) ions bind Ft within the cage, close to the side chains of Cys126. The gold-encapsulated nanocarriers are cytotoxic to human cancer cells. Au(i)-loaded Ft, obtained upon the encapsulation of Au2phen within the cage, induces oxidative stress activation, which finally leads to apoptosis in MCF-7 cells.

Gold(I) and gold(III) complexes derived from 2-(2'-pyridyl)benzimidazole (pbiH) were proven to be a promising class of in vitro antitumor agents against A2780 human ovarian cancer cells. In this paper, a comparative electrochemical, UV-vis absorption, and emission spectroscopic investigation is reported on pbiH, the two mononuclear Au(III) complexes [(pbi)AuX2] (X = Cl (1), AcO (2)), the four mononuclear Au(I) derivatives [(pbiH)AuCl] (3), [(pbiH)Au(PPh3)]PF6 ((4(+))(PF6(-))), [(pbi)Au(PPh3)] (5), and [(pbi)Au(TPA)] (6), the three mixed-valence Au(III)/Au(I) complexes [(μ-pbi)Au2Cl3] (7), [(Ph3P)Au(μ-pbi)AuX2]PF6 (X = Cl ((8(+))(PF6(-))), AcO ((9(+))(PF6(-)))), and the binuclear Au(I)-Au(I) compound [(μ-pbi)Au2(PPh3)2]PF6 ((10(+))(PF6(-))). All complexes feature irreversible reduction processes related to the Au(III)/Au(I) or Au(I)/Au(0) processes and peculiar luminescent emission at about 360-370 nm in CH2Cl2, with quantum yields that are remarkably lower ((0.7-14.5) × 10(-2)) in comparison to that determined for the free pbiH ligand (31.5 × 10(-2)) in the same solvent. The spectroscopic and electrochemical properties of all complexes were interpreted on the grounds of time-dependent PBE0/DFT calculations carried out both in the gas phase and in CH2Cl2 implicitly considered within the IEF-PCM SCRF approach. The electronic structure of the complexes, and in particular the energy and composition of the Kohn-Sham LUMOs, can be related to the antiproliferative properties against the A2780 ovarian carcinoma cell line, providing sound quantitative structure-activity relationships and shedding a light on the role played by the global charge and nature of ancillary ligands in the effectiveness of Au-based antitumor drugs.

The novel heteroleptic cyclometalated complex [Au

Gold(III) compounds form a family of promising cytotoxic and potentially anticancer agents that are currently undergoing intense preclinical investigations. Four recently synthesized and characterized gold(III) derivatives of 2-substituted pyridines are evaluated here for their biological and pharmacological behavior. These include two cationic adducts with 2-pyridinyl-oxazolines, [Au(pyox(R))Cl(2)][PF(6)], [pyox(R)=(S)-4-benzyl-2-(pyridin-2-yl)-4,5-dihydrooxazole, I; (S)-4-iso-propyl-2-(pyridin-2-yl)-4,5-dihydrooxazole, II] and two neutral complexes [Au(N,N'OH)Cl(2)], III, and [Au(N,N',O)Cl], IV, containing the deprotonated ligand N-(1-hydroxy-3-iso-propyl-2-yl)pyridine-2-carboxamide, N,N'H,OH, resulting from ring opening of bound pyox(R) ligand of complex II by hydroxide ions. The solution behavior of these compounds was analyzed. These behave as classical prodrugs: activation of the metal center typically takes place through release of the labile chloride ligands while the rest of the molecule is not altered; alternatively, activation may occur through gold(III) reduction. All compounds react eagerly with the model protein cyt c leading to extensive protein metalation. ESI MS experiments revealed details of gold-cyt c interactions and allowed us to establish the nature of protein bound metal containing fragments. The different behavior displayed by I and II compared to III and IV is highlighted. Remarkable cytotoxic properties, against the reference human ovarian carcinoma cell lines A2780/S and A2780/R were disclosed for all tested compounds with IC(50) values ranging from 1.43 to 6.18 μM in the sensitive cell line and from 1.59 to 10.86 μM in the resistant one. The common ability of these compounds to overcome cisplatin resistance is highlighted. The obtained results are thoroughly discussed in the frame of current knowledge on cytotoxic gold compounds.

A series of new gold(I) and gold(III) complexes based on the saccharinate (sac) ligand, namely M[Au( sac ) 2 ] (with M being Na + , K + or NH 4 + ), [(PTA)Au( sac )], K[Au( sac ) 3 Cl] and Na[Au( sac ) 4 ], were synthesized and characterized, and some aspects of their biological profile investigated. Spectrophotometric analysis revealed that these gold compounds, upon dissolution in aqueous media, at physiological pH, manifest a rather favourable balance between stability and reactivity. Their reactions with the model proteins cytochrome c and lysozyme were monitored by mass spectrometry to predict their likely interactions with protein targets. In the case of disaccharinato gold(I) complexes, cytochrome c adducts bearing four coordinated gold(I) ions were preferentially formed in high yield. In contrast, [(PTA)Au(sac)] (PTA = 1,3,5-triaza-7-phosphaadamantane) turned out to be poorly effective, only producing a mono-metalated adduct in very low amount. In turn, the gold(III) saccharinate derivatives were less reactive than their gold(I) analogues: K[Au(sac) 3 Cl] and Na[Au(sac) 4 ] caused moderate protein metalation, again with evidence of formation of tetragold adducts. Finally, the above mentioned gold compounds were challenged against the reference human tumor cell line A2780S and its cisplatin resistant subline A2780R and their respective cytotoxic profiles determined. [(PTA)Au( sac )] turned out to be highly cytotoxic whereas moderate cytotoxicities were observed for the gold(III) complexes and only modest activities for disaccharinato gold(I) complexes. The implications of these results are thoroughly discussed in the light of current knowledge on gold based drugs.

Novel gold(III) pyridinyl-oxazoline cationic complexes [Au(pyoxR)Cl2][X] [pyoxR = (S)-4-R-2-(pyridin-2-yl)-4,5-dihydrooxazole, with R = iPr, Bn, and (R)-4-phenyl-2-(pyridin-2-yl)-4,5-dihydrooxazole; X = PF6, AuCl4, or mixtures of the two anions] were synthesized and structurally characterized. Reaction of the adducts with NaOAc in aqueous solution afforded the neutral complexes [Au(N,N′,O)Cl] of the deprotonated ligands N-(1-hydroxy-3-R-2-yl)pyridine-2-carboxamide (R = iPr, Ph), N,N′H,OH, resulting from ring-opening of the bound pyox ligand by hydroxide ions and incorporation of hydroxide into the ring-opened products. Reaction of [Au(N,N′,O)Cl] (R = iPr) with HX (X = Cl, BF4, OTf) in aqueous solution resulted in protonation of the coordinated alkoxo group and its displacement from the coordination sphere to give the adducts [Au(N,N′,OH)ClX] (X = OTf, Cl) or the aquo complex [Au(N,N′,OH)(OH2)Cl]+ (X = BF4). Crystal structure characterizations were carried out on both [Au(N,N′,O)Cl] and [Au(N,N′,OH)Cl2] (R...

Three gold(I) saccharinate complexes of the type M[Au(Sac)2] (M = Na, K and NH4) have been prepared by treatment of Au(tht)Cl (tht = tetrahydrothiophene) with saccharine and MOH in MeOHacetone. The compounds are very stable in the solid state but moderately soluble and of limited stability in water. Single crystal X-ray diffraction analysis of the three compounds revealed a linear coordination of the gold atom by the two N-bonded saccharinato ligands. For M = Na, the two heterobicyclic ligands are roughly coplanar with a cis orientation of the two carbonyl groups which allows for a chelation of the sodium cation. For M = K, NH4, the ligands form large dihedral angles with a trans orientation of the donor sites out of which the potassium cations are coordinated in bridging positions between neighboring anions, and the ammonium ions are hydrogen-bonded, respectively.

The ammonium salt of N-phenyloxamic acid (AmPhOxam) was synthesised, characterised by FT-IR, FT-Raman, UV-Vis, 1H-NMR spectroscopic methods and single crystal X-ray diffraction, and evaluated as a protective and consolidating agent for calcareous stone substrates under mild conditions. Hydro-alcoholic solutions of AmPhOxam were tested for the treatment of naturally weathered white marble and biomicritic limestone. Mercury intrusion porosimetry, FT-NIR spectroscopy measurements and SEM microscopy showed the formation of a superficial protective layer of crystals of the corresponding monohydrated calcium salt, CaPhOxam, on both treated stones. Publisher PDF

Air pollution, and in particular the presence of sulphur and nitrogen oxides, results in acidic rain determining the dissolution of calcite in marble and limestones. This degradation process induces evident roughness of the stone surfaces and the partial loss of carved details in artefacts. The formation of an artificial coating of calcium oxalate, obtained by treatment with ammonium oxalate, was proved to be a very promising technique for the protection of stone items. The functionalization of oxalic acid to give monoesters and monoamides (oxamates) allows tailoring the solubility of the relevant ammonium and calcium salts. In this context, theoretical calculations carried out at Density Functional Theory (DFT) level can help predicting the capability of the investigated compounds in interacting with the calcium carbonate lattice. We summarize here the experimental (X-ray diffraction, Mercury Intrusion Porosimetry, FT- MIR and FT-Raman spectroscopy, SEM) and theoretical (DFT PES and NBO analysis) investigations on the effects induced by the variation of the functionalized anions in oxalate and oxamate salts on the efficiency of the treatment of marble from the Cimitero Monumentale di Bonaria in Cagliari (Italy) and limestone samples from Cava Flore (Santa Caterina di Pittinuri, Oristano, Italy).

A novel platinum(ii) organometallic complex, [Pt(pbi)(Me)(DMSO)], bearing the 2-(2'-pyridyl)-benzimidazole (pbiH) ligand, was synthesized and fully characterized. Interestingly, the reaction of this organometallic platinum(ii) complex with two distinct gold(i) phosphane compounds afforded the corresponding heterobimetallic derivatives with the pbi ligand bridging the two metal centers. The antiproliferative properties in vitro of [Pt(pbi)(Me)(DMSO)] and its gold(i) derivatives as well as those of the known coordination platinum(ii) and palladium(ii) complexes with the same ligand, of the general formula [MCl2(pbiH)], were comparatively evaluated against A2780 cancer cells, either sensitive or resistant to cisplatin. A superior biological activity of the organometallic compound clearly emerged compared to the corresponding platinum(ii) complex; the antiproliferative effects are further enhanced upon attaching the gold(i) triphenylphosphine moiety to the organometallic Pt compound. Remarkably, these novel metal species are able to overcome nearly complete resistance to cisplatin. Significant mechanistic insight into the study compounds was gained after investigating their reactions with a few representative biomolecules by electrospray mass spectrometry and X-ray crystallography. The obtained results are comprehensively discussed.

The ammonium salts of oxamate (AmOxam) and monomethyloxalate (AmMeox), structurally related to ammonium oxalate (AmOx), were synthesized and characterized as protecting agents/filler for calcareous stone substrates. Both compounds featured an improved solubility in water and alcoholic-water mixtures with respect to AmOx. While AmOxam is stable in aqueous solution and reacts with calcite to afford the corresponding insoluble calcium oxamate (CaOxam), AmMeox spontaneously undergoes hydrolysis to give ammonium monohydrogen oxalate hemihydrate (AmBiox) and calcium oxalate (CaOx). Both compounds have been tested for the restoration of naturally weathered marble and biomicritic limestone. The formation of a superficial layer of CaOxam and CaOx was observed on stone samples treated with AmOxam and AmMeox, respectively, depending on the solvent mixture. A quantum–mechanical study was carried out at DFT level in order to investigate the nature of the interactions occurring between the lithic substrate (calcite) and the passivating agents, showing how the structural modifications on oxalic acid derivatives can be exploited to fine-tune their interaction with the calcite surface.

Treatment of 6,6′-dimethoxy-2,2′-bipyridine (bipy2OMe) with gold(III) acetate results in the exclusive formation of a cyclometalated gold(III) derivative arising from activation of the C(3)−H bond of a pyridine ring.

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 ( PPh 3 )] PF 6 , turns out to be the most potent inhibitor of all three enzyme activities with sub-micromolar IC 50 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.

International audience; : Picking a fight with parasites! Trypanothione reductase (TR) is a validated drug target for the development of antileishmanial agents. A group of structurally diverse gold-containing compounds was evaluated in vitro for TR inhibition. A number of compounds exhibited potent activity and deserve further pharmacological evaluation.

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.

Protein metalation processes are crucial for the mechanism of action of several anticancer metallodrugs and warrant deeper characterisation. We have explored the reactions of three cytotoxic gold(III) compounds-namely [(bipy(2Me))(2)Au(2)(μ-O)(2)][PF(6)](2) (where bipy(2Me) is 6,6'-dimethyl-2,2'-bipyridine) (Auoxo6), [(phen(2Me))(2)Au(2)(μ-O)(2)][PF(6)](2) (where phen(2Me) is 2,9-dimethyl-1,10-phenanthroline) (Au(2)phen) and [(bipy(dmb)-H)Au(OH)][PF(6)] [where bipy(dmb)-H is deprotonated 6-(1,1-dimethylbenzyl)-2,2'-bipyridine] (Aubipyc)-with two representative model proteins, i.e. horse heart cytochrome c and hen egg white lysozyme, through UV-visible absorption spectroscopy and electrospray ionisation mass spectrometry (ESI MS) to characterise the inherent protein metalation processes. Notably, Auoxo6 and Au(2)phen produced stable protein adducts where one or more "naked" gold(I) ions are protein-coordinated; very characteristic is the case of cytochrome c, which upon reaction with Auoxo6 or Au(2)phen preferentially forms "tetragold" adducts with four protein-bound gold(I) ions. In turn, Aubipyc afforded monometalated protein adducts where the structural core of the gold(III) centre and its +3 oxidation state are conserved. Auranofin yielded protein derivatives containing the intact auranofin molecule. Additional studies were performed to assess the role played by a reducing environment in protein metalation. Overall, the approach adopted provides detailed insight into the formation of metallodrug-protein derivatives and permits trends, peculiarities and mechanistic details of the underlying processes to be highlighted. In this respect, electrospray ionisation mass spectrometry is a very straightforward and informative research tool. The protein metalation processes investigated critically depend on the nature of both the metal compound and the interacting protein and also on the solution conditions used; thus, predicting with accuracy the nature and the amounts of the adducts formed for a given metallodrug-protein pair is currently extremely difficult.

Aubipyc , i.e.[(bipy dmb -H)Au(OH)][PF 6 ] (where bipy dmb -H = deprotonated 6-(1,1-dimethylbenzyl)-2,2′-bipyridine), Auoxo6 , i.e. [(bipy 2Me ) 2 Au 2 (μ-O) 2 ][PF 6 ] 2 (where bipy 2Me = 6,6′-dimethyl-2,2′-bipyridine) and Au 2 phen i.e. [(phen 2Me ) 2 Au 2 (μ-O) 2 ][PF 6 ] 2 (where phen 2Me = 2,9-dimethyl-1,10-phenanthroline), are three representative gold(III) compounds prepared and characterised in our laboratories during the last few years that manifested remarkable anticancer properties in vitro . Herein, the main chemical features of these compounds are summarised. Aubipyc is a mononuclear organogold(III) compound while Auoxo6 and Au 2 phen are binuclear gold(III) complexes. These compounds manifest a reasonable stability of their gold(III) chromophore in aqueous solutions at physiological pH; yet, a rather different redox behaviour was highlighted as Aubipyc displays high stability toward reduction while both Auoxo6 and Au 2 phen are rapidly reduced by ascorbic acid and glutathione. The antiproliferative properties of these gold(III) compounds were analysed in detail against a wide panel of human tumour cell lines. Remarkably, Auoxo6 and Au 2 phen revealed potent and rather similar patterns of antiproliferative actions while Aubipyc turned out to be less effective. For Auoxo6 and Au 2 phen more detailed biochemical studies are available documenting their effects on the proteome of treated cancer cells. Recent studies described the reactions of these gold compounds with various proteins at the molecular level; adduct formation was clearly documented in a few cases and their nature determined. Preliminary results suggest that these gold compounds may act as strong inhibitors of the selenoenzyme thioredoxin reductase and cause mitochondrial dysfunction. Based on the available in vitro data, these gold compounds look quite promising as prospective anticancer agents. Studies will soon be extended to assess their safety and efficacy in relevant animal models of cancer.

A number of structurally diverse gold compounds were evaluated as possible inhibitors of Falcipain 2 (Fp2), a cysteine protease from P. falciparum that is a validated target for the development of novel antimalarial drugs. Remarkably, most tested compounds caused pronounced but reversible inhibition of Fp2 with K(i) values falling in the micromolar range. Enzyme inhibition is basically ascribed to gold binding to catalytic active site cysteine. The same gold compounds were then tested for their ability to inhibit P. falciparum growth in vitro; important parasite growth inhibition was indeed observed. However, careful analysis of the two sets of data failed to establish any direct correlation between enzyme inhibition and reduction of P. falciparum growth suggesting that Fp2 inhibition represents just one of the various mechanisms through which gold compounds effectively antagonize P. falciparum replication.

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.