Au2phen and Auoxo6, Two Dinuclear Oxo-Bridged Gold({III}) Compounds, Induce Apoptotic Signaling in Human Ovarian A2780 Cancer Cells

Au(2)phen ((2,9-dimethyl-1,10-phenanthroline)(2)Au(2)(µ-O)(2))(PF(6))(2) and Auoxo6 ((6,6′-dimethyl-2,2′-bipyridine)(2)Au(2)(µ-O)(2))(PF(6))(2) are two structurally related gold(III) complexes that were previously reported to display relevant and promising anticancer properties in vitro toward a large number of human cancer cell lines. To expand the knowledge on the molecular mechanisms through which these gold(III) complexes trigger apoptosis in cancer cells, further studies have been performed using A2780 ovarian cancer cells as reference models. For comparative purposes, parallel studies were carried out on the gold(III) complex AuL12 (dibromo(ethylsarcosinedithiocarbamate)gold(III)), whose proapoptotic profile had been earlier characterized in several cancer cell lines. Our results pointed out that all these gold(III) compounds manifest a significant degree of similarity in their cellular and proapoptotic effects; the main observed perturbations consist of potent thioredoxin reductase inhibition, disruption of the cell redox balance, impairment of the mitochondrial membrane potential, and induction of associated metabolic changes. In addition, evidence was gained of the remarkable contribution of ASK1 (apoptosis-signal-regulating kinase-1) and AKT pathways to gold(III)-induced apoptotic signaling. Overall, the observed effects may be traced back to gold(III) reduction and subsequent formation and release of gold(I) species that are able to bind and inhibit several enzymes responsible for the intracellular redox homeostasis, in particular the selenoenzyme thioredoxin reductase

Synthesis, chemical characterization, and biological evaluation of a novel auranofin derivative as an anticancer agent

A novel gold(I) complex inspired by the known medicinal inorganic compounds auranofin and thimerosal, namely ethylthiosalicylate(triethylphosphine)gold(I) (AFETT hereafter), was synthesized and characterised and its structure was resolved through X-ray diffraction. The solution behavior of AFETT and its interactions with two biologically relevant proteins (i.e. human serum albumin and haemoglobin) and with a synthetic dodecapeptide reproducing the C-terminal portion of thioredoxin reductase were comparatively analyzed through 31P NMR and ESI-MS. Remarkable binding properties toward these biomolecules were disclosed. Moreover, the cytotoxic effects produced by AFETT on two ovarian cancer cell lines (A2780 and A2780 R) and one colorectal cancer cell line (HCT116) were analyzed and found to be strong and nearly superimposable to those of auranofin. Interestingly, for both compounds, the ability to induce downregulation of vimentin expression in A2780 R cells was evidenced. Despite its close similarity to auranofin, AFETT is reported to exhibit some peculiar and distinctive features such as a lower lipophilicity, an increased water solubility and a faster reactivity towards the selected target biomolecules. These differences might confer to AFETT significant pharmaceutical and therapeutic advantages over auranofin itself

Urban consumer trust and food certifications in China

China has experienced frequent food safety incidents that have undermined consumer trust in the food supply chain. To overcome this problem, China requalified the legislative framework and adopted a comprehensive food certification system over the years. Here, we investigated the influences of food traceability and Chinese certifications (QS/SC—food quality safety market access/production system, hazard-free, green, and organic) on Chinese consumer trust of food safety for different types of products: fish, meat, milk, eggs, and rice. Data were collected through face-to-face surveys conducted in rural and urban Chinese areas. With a sample of 757 questionnaires, we ran a logit model. The results show consumers’ uncertainty and skepticism of certifications guaranteeing food safety attributes, especially for animal-based products. We found that price is used as a cue of safety by Chinese consumers. Individuals with higher education seem less influenced by certifications and other cues included in the analysis. The findings demonstrate that Chinese policy makers should implement new strategies to enhance consumer food safety trust, and design policies by considering different categories (e.g., vegetables, meat, fish, etc.) of food

Editorial: The Golden Future in Medicinal Chemistry: Perspectives and Resources From Old and New Gold-Based Drug Candidates

Editorial: The Golden Future in Medicinal Chemistry: Perspectives and Resources From Old and New Gold-Based Drug Candidate

Chemical Modification of Auranofin Yields a New Family of Anticancer Drug Candidates: The Gold(I) Phosphite Analogues

A panel of four novel gold(I) complexes, inspired by the clinically established gold drug auranofin (1-Thio-β-D-glucopyranosatotriethylphosphine gold-2,3,4,6-tetraacetate), was prepared and characterized. All these compounds feature the replacement of the triethylphosphine ligand of the parent compound auranofin with a trimethylphosphite ligand. The linear coordination around the gold(I) center is completed by Cl−, Br−, I− or by the thioglucose tetraacetate ligand (SAtg). The in-solution behavior of these gold compounds as well as their interactions with some representative model proteins were comparatively analyzed through 31PNMR and ESI-MS measurements. Notably, all panel compounds turned out to be stable in aqueous media, but significant differences with respect to auranofin were disclosed in their interactions with a few leading proteins. In addition, the cytotoxic effects produced by the panel compounds toward A2780, A2780R and SKOV-3 ovarian cancer cells were quantitated and found to be in the low micromolar range, since the IC50 of all compounds was found to be between 1 μM and 10 μM. Notably, these novel gold complexes showed large and similar inhibition capabilities towards the key enzyme thioredoxin reductase, again comparable to those of auranofin. The implications of these results for the discovery of new and effective gold-based anticancer agents are discussed

Conjugates of Gold Nanoparticles and Antitumor Gold(III) Complexes as a Tool for Their AFM and SERS Detection in Biological Tissue

Citrate-capped gold nanoparticles (AuNPs) were functionalized with three distinct antitumor gold(III) complexes, e.g., [Au(N,N)(OH)2][PF6], where (N,N)=2,2′-bipyridine; [Au(C,N)(AcO)2], where (C,N)=deprotonated 6-(1,1-dimethylbenzyl)-pyridine; [Au(C,N,N)(OH)][PF6], where (C,N,N)=deprotonated 6-(1,1-dimethylbenzyl)-2,2′-bipyridine, to assess the chance of tracking their subcellular distribution by atomic force microscopy (AFM), and surface enhanced Raman spectroscopy (SERS) techniques. An extensive physicochemical characterization of the formed conjugates was, thus, carried out by applying a variety of methods (density functional theory—DFT, UV/Vis spectrophotometry, AFM, Raman spectroscopy, and SERS). The resulting gold(III) complexes/AuNPs conjugates turned out to be pretty stable. Interestingly, they exhibited a dramatically increased resonance intensity in the Raman spectra induced by AuNPs. For testing the use of the functionalized AuNPs for biosensing, their distribution in the nuclear, cytosolic, and membrane cell fractions obtained from human lymphocytes was investigated by AFM and SERS. The conjugates were detected in the membrane and nuclear cell fractions but not in the cytosol. The AFM method confirmed that conjugates induced changes in the morphology and nanostructure of the membrane and nuclear fractions. The obtained results point out that the conjugates formed between AuNPs and gold(III) complexes may be used as a tool for tracking metallodrug distribution in the different cell fractions

Auranofin and its analogs as prospective agents for the treatment of colorectal cancer

Today colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. This disease is poorly chemo-sensitive toward the existing medical treatments so that new and more effective therapeutic agents are urgently needed and intensely sought. Platinum drugs, oxaliplatin in particular, were reported to produce some significant benefit in CRC treatment, triggering the general interest of medicinal chemists and oncologists for metal-based compounds as candidate anti-CRC drugs. Within this frame, gold compounds and, specifically, the established antiarthritic drug auranofin with its analogs, form a novel group of promising anticancer agents. Owing to its innovative mechanism of action and its favorable pharmacological profile, auranofin together with its derivatives are proposed here as novel experimental agents for CRC treatment, capable of overcoming resistance to platinum drugs. Some encouraging results in this direction have already been obtained. A few recent studies demonstrate that the action of auranofin may be further potentiated through the preparation of suitable pharmaceutical formulations capable of protecting the gold pharmacophore from unselective reactivity or through the design of highly synergic drug combinations. The perspectives of the research in this field are outlined

The cisplatin/serum albumin system: A reappraisal

Since the first approval of cisplatin for cancer treatment in 1978, a lot of attempts have been carried out to characterize in detail its interactions with serum albumin, by far the most important and most abundant plasma protein. The state of the art of those studies was recapitulated by Keppler and coworkers in a comprehensive review article which appeared in Chem. Rev. in 2006. Yet, the general picture was still rather incomplete at that time due to the lack of conclusive structural data. We report here on the main achievements obtained on this system in the period 2006–2018 and try to describe what is now clearly ascertained and what are the still open issues. Remarkably, a detailed structural characterization of this metallodrug/protein system was recently gained thanks to the resolution of the crystal structure of a cisplatin/serum albumin adduct; crystallographic results are nicely complemented by independent MS data. Accordingly, detailed information is obtained on the number and the location of the platinum binding sites. In turn, metallomics investigations permitted to monitor platination of this serum protein in real blood samples. Thus, a rather complete molecular description of the system could be achieved. Conversely, the biological and pharmacological profiles of platinum drugs/serum albumin adducts were drafted in a couple of specific studies; however the results on theses issue are in our opinion still preliminary and controversial and more studies are needed, aimed in particular at establishing clear correlations between the nature of the various platinum/serum albumin derivatives and their biological actions. In any case, the relevance and the impact of cisplatin/serum albumin adducts are herein highlighted and future perspectives briefly depicted.Canadian Institutes of Health Research (CIHR)Alberta Innovates - Research Gran

Mechanistic studies on cytotoxic gold compounds

Gold compounds form an attractive class of antiproliferative agents of potential use as anticancer agents. The molecular mechanisms through which gold compounds produce their biological effects are still largely unknown and the subject of intense investigations. Recent studies point out that the mechanism of action of cytotoxic gold compounds are essentially DNA-independent and cisplatin-unrelated, most likely relying on gold interactions with a few crucial proteins. Notably, various cellular proteins playing relevant functional roles were proposed to represent effective targets for cytotoxic gold compounds but these hypotheses still need validation [1]. Our research group has focused attention on the likely protein targets for cytotoxic gold compounds and on the elucidation of their molecular mechanisms. At present this goal is being pursued through two distinct approaches that will be described in detail. On one hand, studies are being carried out on isolated proteins; their interactions with representative gold compounds are studied through independent biophysical methods. Particularly informative is the joint use of X-ray diffraction and ESI MS on small model proteins that allowed us to define the actual molecular mechanisms of protein metalation [2]. On the other hand, studies are directed to monitor the alterations in the cell proteome caused by cancer cell exposure to cytotoxic gold compounds. This goal may be achieved through classical proteomic strategies. In a recent study we considered the effects of the gold(III) complex Aubipyc on A2780 ovarian cancer cells. From comparative analysis of 2D gels of treated versus control cancer cells it was possible to highlight a few protein spots that showed appreciable changes in their expression rates following drug exposure [3]. Subsequent bioinformatic analysis of these proteomic alterations provided valuable insight on the underlying biochemical processes ultimately leading to cell death