Catalytic and Biological Activity of Silver and Gold Complexes Stabilized by NHC with Hydroxy Derivatives on Nitrogen Atoms

In this paper is reported the synthesis of N,N′ hydroxy derivative of NHC silver (3a–4a) and gold(I) (3b–4b) complexes of general formula [M(NHC)2]+ [MX2]−. All compounds were characterized by spectroscopic and analytic techniques. The complexes turned out to be effective in both catalytic and biological applications. They catalyzed the coupling of aldehyde, piperidine, and phenylacetylene in A3-reaction to produce propargylamines and showed antimicrobial activity. In fact, minimal inhibition concentration (MIC) tests with Gram-positive and Gram-negative bacteria demonstrated that the silver compounds are selective toward E. coli, whereas the gold analogues are active against S. aureus. Moreover, the N,N′ hydroxy derivative of NHC silver complexes 3a and 4a exhibited good anticancer activity on the HeLA cancer cells (3a-IC50 = 12.2 ± 0.1 µM, 4a-IC50 = 11.9 ± 1.2 µM), whereas gold complex 4b displayed good anticancer activity towards the MCF-7 cells (IC50 = 12.2 ± 1.2 µM).

Auranofin and ICG-001 Emerge Synergistic Anti-tumor Effect on Canine Breast Cancer by Inducing Apoptosis via Mitochondrial Pathway

Canine breast cancer (CBC) is the most common spontaneous tumor in intact female dogs, especially in developing countries. The effective anti-tumor agents or therapies for the clinical treatment of CBC are still in need. Auranofin (AF) is a gold complex that has been attested by FDA for treating human rheumatism, which has been found as a great anti-tumor agent in recent years. ICG-001 is a small molecule inhibitor of Wnt/β-catenin pathway. In the present study, we demonstrated that a combination of AF and ICG-001 could synergistically suppress the proliferation of CBC in vitro and in vivo. Moreover, the synergistical effect was related with apoptosis caused by mitochondrial damage and ROS production. In conclusion, combination of AF and ICG-001 could synergistically suppress the growth of CBC in vitro and in vivo by leading apoptosis via mitochondrial signaling pathway and might provide a novel potential choice for the clinical treatment of CBC.

Combination of Auranofin and ICG-001 Suppress the Proliferation and Metastasis of Colon Cancer

Colon cancer is one of the deadliest tumors in the world, and with high metastasis rate and mortality, effective drugs for its treatment are still in need. Auranofin (AF) is a gold complex that has been attested by FDA for treating human rheumatism, and researchers have found that AF acts as a great antitumor drug in recent years. ICG-001 is a small molecule inhibitor of Wnt/β-catenin pathway. In the present study, we aimed to explore the synergistic antitumor effects and the underlying mechanisms of AF and ICG-001 combination therapy on human colon cancer. The results showed that AF and ICG-001 synergistically depressed the growth and invasion of human colon cancer cells by inhibiting the phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) and its downstream mediator B-cell lymphoma-2-like 1 (Bcl-xL) and inducing caspase-3-dependent apoptosis. Moreover, AF combined with ICG-001 synergistically inhibited the growth of colon cancer in subcutaneous xenograft mice models and restrained metastasis in lung metastasis mice models. In conclusion, our results demonstrated that combination of AF and ICG-001 suppressed the proliferation and metastasis of colon cancer by inhibiting STAT3 phosphorylation. Therefore, this combination therapy may possess potential therapeutic properties for human colon cancer.

Cytotoxic activity of a unique monomeric heterogeneous two-coordinate ligand monovalent gold complex with tiopronin and a heterocyclic mercapto-tetrazole compound

Background: Importance of the role of NF-κB is recognized in situations such as malignant transformation and metastasis of cancer, and it has been suggested that inhibiting this role can be one of the cancer treatment strategies. Gold preparations such as auranofin are known to have an indirect NF-κB inhibitory effect. Objective: We synthesized a novel gold complex [tiopronin monovalent gold-5-mercapto-1-methyltetrazole, abbreviated as TPN-Au(Ⅰ)-MM4], with different physical properties and chemical structure from auranofin, and evaluated its cytotoxic activity and radiation sensitizing effect on human THP1 cells. Methods: The number of viable cells was counted by the trypan blue dye exclusion method. The cell death evaluation was performed by FITC-Annexin V+ and PI staining. In investigating the radiation sensitizing effect of TPN-Au(Ⅰ)-MM4, this compound [10 or 25 μM] was added into the culture medium 1 h before X-ray irradiation. Results: In the cells treated with 25 μM TPN-Au(Ⅰ)-MM4 for 72 h, where a decrease in the proliferation of THP1 cells were observed [The relative values of viable cells in the control group and the 25 μM treatment group were approximately 6.8 and 4.2, respectively]. In the combination of 25 μM of the compound treatment and X-ray irradiation, an increase of approximately 3.0-fold was observed in 2 Gy irradiation, and approximately 1.4-fold in 4 Gy irradiation as in comparison to the case of irradiation alone. Conclusion: These results suggest that TPN-Au(Ⅰ)-MM4 reduces the proliferation of THP1 cells through the induction of cell death, and the combined use of TPN-Au(Ⅰ)-MM4 and X-ray irradiation shows effective cytotoxicity against THP1 cells.

Simultaneous construction of axial and planar chirality by gold/TY-Phos-catalyzed asymmetric hydroarylation

The simultaneous construction of two different chiralities via a simple operation poses considerable challenge. Herein a cationic gold-catalyzed asymmetric hydroarylation of ortho-alkynylaryl ferrocenes derivatives is developed, which enable the simultaneous construction of axial and planar chirality. The here identified TY-Phos derived gold complex is responsible for the high yield, good diastereoselectivity (>20:1 dr), high enantioselectivities (up to 99% ee) and mild conditions. The catalyst system also shows potential application in the synthesis of chiral biaryl compounds. The cause of high enantioselectivity of this hydroarylation is investigated with density functional theory caculation.

FLOTATION REAGENTS FOR FINELY DISSEMINATED GOLD EXTRACTION FROM UNENRICHED ORES AND TECHNOGENIC PRODUCTS

At the present stage of development of the mineral resource base of precious metals, the wider involvement of refractory ores and technogenic products in the mineral processing is playing a very important role. It is due to these types of mineral resources the main Russian and foreign companies plan to get the increase in the production of gold and other precious metals. Refractory ores are characterized by low content and uneven distribution of valuable components, emulsion dissemination of gold, complex material composition, flotation active silicate and carbonaceous rock components. The main technologies for their processing include combined schemes that provide intensive preliminary preparation of ore, fine and ultrafine grinding. Creation of effective reagents for flotation of fine classes of noble metals, selective depression of gold-free sulfides, like pyrite, pyrrhotite, arsenopyrite, and rock minerals is one of the recognized innovative solutions for intensifying the enrichment process of this type of raw material. The studies performed at IPKON RAS in the framework of the scientific school of Academician V.A. Chanturiya helped to develop and substantiate the novel selective reagents-collectors of dithiocarbamate type (DEDTCm, OPDTC, DBDTC, MDTC) and herbal modifiers that possess complexing properties in relation to noble metals and provide an increase in the recovery of valuable components of gold by 5-7%. A set of analytical methods - scanning electron (LEO 1420VP, Carl Zeiss) and laser microscopy (KEYNCE VK-9700, Shimadzu), X-ray fluorescence spectroscopy (ARL ADVANT’X), ICP –MS (Agilent 725 ICP-OES, Agilent Technologies), X-ray diffractometry (DRON-2.0, XRD 7000, Shimadzu), potentiometry, titrimetric analysis, methods of mathematical statistics helped to study the adsorption layer of the reagents on natural minerals and model sulfides with micro- and nanosized gold. Using an original technique for quantitative assessment of the reagent coating by image analysis (SLM), the surface area of the mineral occupied by the reagent was calculated. A method for selective flotation of gold-containing sulfides using OPDTC and oak bark extract has been developed and tested in the separation of the collective gold-arsenic concentrate of the Olympiada deposit. It showed the possibility of obtaining a gold-pyrite concentrate with an arsenic content of less than 2%. The prospect of using plant modifiers for gold recovery during flotation of complex ores has been substantiated.

Temperature-Dependent X-Ray Studies of Discotic Hexagonal Columnar Mesophases in Trinuclear Gold(I) Pyrazolate Complex

Gold(I) pyrazolate complex ([Au3Pz3]C10TEG) has been widely studied due to its interesting liquid crystalline properties by exhibiting the discotic hexagonal columnar arrangement. Generally, the liquid crystalline properties of the gold complex were confirmed based on their differential scanning calorimetry thermogram and polarized optical microscopy (POM) images. However, there is still no in-depth study on the phase transition in liquid crystals of [Au3Pz3]C10TEG especially on its structural change at variable temperature. In this study, the resulting liquid crystalline properties of [Au3Pz3]C10TEG upon being heated and cooled was extensively demonstrated via variable-temperature POM (VT-POM) and small angle X-ray scattering (VT-SAXS). Based on the VT-POM images, it was indicated that [Au3Pz3]C10TEG displayed a fan-shaped texture for typical arrangements of discotic hexagonal columnar of liquid crystals. Moreover, VT-SAXS results was in good agreement with the VT-POM images as it showed that [Au3Pz3]C10TEG might consist of two types of stacking system, which are ordered and disordered hexagonal discotic arrangements. Likewise, VT-SAXS analysis also demonstrated that hexagonal columnar mesophase of [Au3Pz3]C10TEG could be recovered even after the heating and cooling for two cycles.

Anticancer effects against colorectal cancer models of chloro(triethylphosphine)gold(I) encapsulated in PLGA–PEG nanoparticles

Chloro(triethylphosphine)gold(I), (Et3PAuCl hereafter), is an Auranofin (AF)-related compound showing very similar biological and pharmacological properties. Like AF, Et3PAuCl exhibits potent antiproliferative properties in vitro toward a variety of cancer cell lines and is a promising anticancer drug candidate. We wondered whether Et3PAuCl encapsulation might lead to an improved pharmacological profile also considering the likely reduction of unwanted side-reactions that are responsible for adverse effects and for drug inactivation. Et3PAuCl was encapsulated in biocompatible PLGA–PEG nanoparticles (NPs) and the new formulation evaluated in colorectal HCT-116 cancer cells in comparison to the free gold complex. Notably, encapsulated Et3PAuCl (nano-Et3PAuCl hereafter) mostly retains the cellular properties of the free gold complex and elicits even greater cytotoxic effects in colorectal cancer (CRC) cells, mediated by apoptosis and autophagy. Moreover, a remarkable inhibition of two crucial signaling pathways, i.e. ERK and AKT, by nano-Et3PAuCl, was clearly documented. The implications of these findings are discussed.