Cytotoxic Gold(I) N-heterocyclic Carbene Complexes with Phosphane Ligands as Potent Enzyme Inhibitors (original) (raw)
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Cancer cell death induced by phosphine gold(I) compounds targeting thioredoxin reductase
2010
The thioredoxin system, composed of thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH (Nicotinamide adenine dinucleotide phosphate), plays a central role in regulating cellular redox homeostasis and signaling pathways. TrxR, overexpressed in many tumor cells and contributing to drug resistance, has emerged as a new target for anticancer drugs. Gold complexes have been validated as potent TrxR inhibitors in vitro in the nanomolar range. In order to obtain potent and selective TrxR inhibitors, we have synthesized a series of linear, 'auranofin-like' gold(I) complexes all containing the [Au(PEt 3 )] + synthon and the ligands: Cl -, Br -, cyanate, thiocyanate, ethylxanthate, diethyldithiocarbamate and thiourea. Phosphine gold(I) complexes efficiently inhibited cytosolic and mitochondrial TrxR at concentrations that did not affect the two related oxidoreductases glutathione reductase (GR) and glutathione peroxidase (GPx). The inhibitory effect of the redox proteins was also observed intracellularly in cancer cells pretreated with gold(I) complexes. Gold(I) compounds were found to induce antiproliferative effects towards several human cancer cells some of which endowed with cisplatin or multidrug resistance. In addition, they were able to activate caspase-3 and induce apoptosis observed as nucleosome formation and sub-G1 cell accumulation. The complexes with thiocyanate and xanthate ligands were particularly effective in inhibiting thioredoxin reductase and inducing apoptosis.
The Open Crystallography Journal, 2010
Six homologous gold(III) dinuclear oxo-bridged complexes, of the type [(bipy nR )Au(µ-O) 2 Au(bipy nR )][PF 6 ] 2 , bearing variously substituted 2,2'-bipyridine ligands (bipy nR = 2,2'-bipyridine, 4,4'-di-tert-butyl-, 6-methyl-, 6-neopentyl-, 6-o-xylyl-and 6,6'-dimethyl-2,2'-bipyridine), here called Auoxos, were prepared, characterised and recently tested as potential anticancer agents. Crystal structures were obtained for five members of the series that allowed us to perform detailed comparative analyses. Interestingly, the various Auoxos showed an acceptable stability profile in buffer solution and turned out to manifest outstanding antitumor properties in vitro. In particular, one member of this family, Auoxo6 (bipy nR = 6,6'-dimethyl-2,2'-bipyridine), produced more selective and far greater antiproliferative effects than all other tested Auoxos, qualifying itself as the best "drug candidate". In turn, COMPARE analysis of the cytotoxicity profiles of five Auoxos, toward an established panel of thirty-six human tumor cell lines, revealed important mechanistic differences; a number of likely biomolecular targets could thus be proposed such as HDAC and PKC. Biophysical studies revealed markedly different modes of interaction with calf thymus DNA for two representative Auoxo compounds. In addition, a peculiar reactivity with model proteins was documented on the ground of spectrophotometric and ESI MS data, most likely as the result of redox processes. In view of the several experimental evidences gathered so far, it can be stated that Auoxos constitute a novel family of promising cytotoxic gold compounds with an innovative mechanism of action that merit a more extensive pharmacological evaluation.
MedChemComm, 2013
Gold compounds with N-heterocyclic carbene (NHC) ligands have been widely described as potent thioredoxin reductase (TrxR) inhibitors and effective anticancer agents. However, despite these promising aspects structure-activity-relationship (SAR) studies still remain limited. In this study a structurally diverse library of gold(I) and gold(III) NHC complexes was investigated for inhibitory capacity against TrxR and for antiproliferative activity in HT-29 human colon adenocarcinoma cells with the aim of identifying a valid SAR. Overall results indicated that the bioactivity, carried by the gold center, is intimately linked to the chemical properties of the residues at the NHC scaffold as well as other ligands coordinated to the gold atom. Although a direct correlation between IC 50 values for cytotoxicity and enzyme inhibition could not be established, the inhibition of TrxR represents an important parameter to achieve a good cytotoxic activity.
2010
Six homologous gold(III) dinuclear oxo-bridged complexes, of the type [(bipy nR )Au(µ-O) 2 Au(bipy nR )][PF 6 ] 2 , bearing variously substituted 2,2'-bipyridine ligands (bipy nR = 2,2'-bipyridine, 4,4'-di-tert-butyl-, 6-methyl-, 6-neopentyl-, 6-o-xylyl-and 6,6'-dimethyl-2,2'-bipyridine), here called Auoxos, were prepared, characterised and recently tested as potential anticancer agents. Crystal structures were obtained for five members of the series that allowed us to perform detailed comparative analyses. Interestingly, the various Auoxos showed an acceptable stability profile in buffer solution and turned out to manifest outstanding antitumor properties in vitro. In particular, one member of this family, Auoxo6 (bipy nR = 6,6'-dimethyl-2,2'-bipyridine), produced more selective and far greater antiproliferative effects than all other tested Auoxos, qualifying itself as the best "drug candidate". In turn, COMPARE analysis of the cytotoxicity profiles of five Auoxos, toward an established panel of thirty-six human tumor cell lines, revealed important mechanistic differences; a number of likely biomolecular targets could thus be proposed such as HDAC and PKC. Biophysical studies revealed markedly different modes of interaction with calf thymus DNA for two representative Auoxo compounds. In addition, a peculiar reactivity with model proteins was documented on the ground of spectrophotometric and ESI MS data, most likely as the result of redox processes. In view of the several experimental evidences gathered so far, it can be stated that Auoxos constitute a novel family of promising cytotoxic gold compounds with an innovative mechanism of action that merit a more extensive pharmacological evaluation.
Anticancer properties of gold complexes with biologically relevant ligands
Pure and Applied Chemistry, 2018
The present review highlights our findings in the field of antitumor gold complexes bearing biologically relevant molecules, such as DNA-bases, amino acids or peptide derivatives. The results show that very active complexes are achieved with this sort of ligands in several cancer cells. In these compounds the gold center is bonded to these biological molecules mainly through a sulfur atom belonging to a cysteine moiety or to a thionicotinic moiety as result of the functionalization of the biological compounds, and additionally phosphines or N-heterocyclic carbenes are present as ancillary ligands. These robust compounds are stable in the biological media and can be transported to their targets without previous deactivation. The presence of these scaffolds represents a good approach to obtain complexes with improved biologically activity, better transport and biodistribution to cancer cells. Thioredoxin reductase (TrxR) has been shown as the main target for these complexes and in some cases, DNA interactions has been also observed.
Inorganica Chimica Acta, 2014
Heterocyclic compounds and their metal complexes display a broad spectrum of pharmacological properties. This work reports the preparation and characterization of four novel gold(I) complexes containing tertiary phosphine and 3-benzyl-1,3-thiazolidine-2-thione, 5-phenyl-1,3,4-oxadiazole-2-thione as ligands. The reaction of chloro(triphenylphosphine)gold(I) and chloro(triethylphosphine)gold(I) with thioamides, 3-benzyl-1,3-thiazolidine-2-thione and 5-phenyl-1,3,4-oxadiazole-2-thione in dichloromethane or dichloromethane/acetone resulted in the formation of the gold(I) complexes of general formula: [SAuPR 3 ]Cl, S = 3-benzyl-1,3-thiazolidine-2-thione, R = Ph or Et and [SAuPR 3 ] , S = 5-phenyl-1,3,4-oxadiazole-2-thione, R = Ph or Et. Spectroscopic evidence suggested that gold is coordinated to the exocyclic sulfur atom in all cases and this was confirmed by X-ray crystallographic data obtained for complex (4). The cytotoxicity of the compounds has been evaluated in comparison to cisplatin in two different tumor cell lines, colon cancer (CT26WT) and metastatic skin melanoma (B16F10), and also in a kidney normal cell (BHK-21). The gold complexes showed a better activity than cisplatin and presented a high selectivity index.
Chemical Science, 2013
Materials and Methods Materials Analytical grade organic solvents were used in all experiments unless otherwise stated. Gold(III) complexes 2, Au1−Au6 and platinum(II) complex 5 have been reported previously [Chem. Eur. J., 2006, 12, 5253]. (C^N^C)AuCl (where C^N^C = 2,6diphenylpyridine), 1,3-dibutyl-1H-imidazol-3-ium bromide and 1,1'-(propane-1,3diyl)bis(3-butyl-1H-imidazol-3-ium) bromide were synthesized according to the literature procedure [Chem. Sci., 2011, 2, 728]. Fast Atom Bombardment (FAB) mass spectra were obtained on a Finnigan Mat 95 mass spectrometer. 1 H NMR and 13 C NMR spectra were obtained on DPX 300, 400 M Bruker FT-NMR spectrometers relative to the signal of tetramethylsilane. Elemental analysis was performed by the Institute of Chemistry at the Chinese Academy of Science, Beijing. Soluble human recombinant TRAIL/APO2L was obtained from PeproTech. Other chemicals unless otherwise stated were purchased from Sigma-Aldrich Co. Synthesis and characterization of the gold(III)-carbene complexes Complex 3. A mixture of 1,1'-(propane-1,3-diyl)bis(3-butyl-1H-imidazol-3-ium) bromide (30 mg, 0.071 mmol) and KOBu (23.9 mg, 0.213 mmol) in 30 mL methanol was heated to reflux for 0.5 h; then (C^N^C)AuCl (72.0 mg, 0.156 mmol) was added to the reaction mixture and were refluxed for 12 h. Excess lithium trifluoromethanesulfonate was added and the reaction mixture was further refluxed for 0.5 h. After cooling to room temperature, methanol was removed by rotavapor and the residue was washed with water and hence diethyl ether. Light yellow product was obtained after silica-gel chromatography separation. Yield: 45 %.