A series of novel (C^N) cyclometallated Au(III) complexes of general formula Au(py(b)-H)L(1)L(2)(n+) (py(b)-H = C^N cyclometallated 2-benzylpyridine, L(1) and L(2) being chlorido, phosphane or ...glucosethiolato ligands, n = 0 or 1) have been synthesized and fully characterized using different techniques, including NMR, IR and far-IR, mass spectrometry, as well as elemental analysis. The crystal structure of one compound has been solved using X-ray diffraction methods. All compounds were tested in vitro in five human cancer cell lines including the lung, breast, colon and ovarian cancer cells. For comparison purposes, all compounds were also tested in a model of healthy human cells from the embryonic kidney. Notably, all new compounds were more toxic than their cyclometallated precursor bearing two chlorido ligands, and the derivative bearing one phosphane ligand presented the most promising toxicity profile in our in vitro screening, displaying a p53 dependent activity in colorectal cancer HCT116 cells. Finally, for the first time C^N cyclometallated gold(III) complexes were shown to be potent inhibitors of the zinc finger protein PARP-1, involved in the mechanism of cisplatin resistance.
The interactions of three representative gold(III) complexes with human telomeric DNA sequences were analysed using a variety of biophysical methods, including DNA melting, circular dichroism, SPR ...and ESI MS; remarkable interactions were highlighted for all tested complexes, although they were associated to significantly different binding profiles. The most interesting compound was Auoxo6, a dinuclear gold(III) complex, which beyond manifesting a conspicuous binding affinity for the G-quadruplex conformation, turned out to be very effective in inducing a non-canonical secondary structure. These findings may clear the way for novel biological and pharmacological applications of this class of metal compounds.
An auraoxetane, obtained from the reaction of norbornene with a gold(III) oxo complex, has been isolated and fully characterized (see structure). Action of the olefin leads to elimination of the ...epoxide from the auraoxetane.
The effects of gold(I) complexes (auranofin, triethylphosphine gold and aurothiomalate), gold(III) complexes (Au(2,2
′-diethylendiamine)ClCl
2, (Au(2-(1,1-dimethylbenzyl)-pyridine) (CH
3COO)
2, ...Au(6-(1,1-dimethylbenzyl)-2,2
′-bipyridine)(OH)(PF
6), Au(bipy
dmb-H)(2,6-xylidine)(PF
6)), metal ions (zinc and cadmium acetate) and metal complexes (cisplatin, zinc pyrithione and tributyltin) on mitochondrial thioredoxin reductase and mitochondrial functions have been examined. Both gold(I) and gold(III) complexes are extremely efficient inhibitors of thioredoxin reductase showing IC
50 ranging from 0.020 to 1.42 μM while metal ions and complexes not containing gold are less effective, exhibiting IC
50 going from 11.8 to 76.0 μM. At variance with thioredoxin reductase, auranofin is completely ineffective in inhibiting glutathione peroxidase and glutathione reductase, while gold(III) compounds show some effect on glutathione peroxidase. The mitochondrial respiratory chain is scarcely affected by gold compounds while the other metal complexes and metal ions, in particular zinc ion and zinc pyrithione, show a more marked inhibitory effect that is reflected on a rapid induction of membrane potential decrease that precedes swelling. Therefore, differently from gold compounds, the various metal ions and metal complexes exert their effect on different targets indicating a lower specificity. It is concluded that gold compounds are highly specific inhibitors of mitochondrial thioredoxin reductase and this action influences other functions such as membrane permeability properties. Metal ions and metal complexes markedly inhibit the activity of thioredoxin reductase although to an extent lower than that of gold compounds. They also inhibit mitochondrial respiration, decrease membrane potential and, finally, induce swelling.
The effects of a few cytotoxic organogold(III) compounds on ovarian A2780 human cancer cells were investigated in comparison to cisplatin and oxaliplatin. The tested compounds produced significant ...antiproliferative effects and promoted apoptosis to a greater extent than platinum drugs while causing only modest cell cycle modifications. The mechanistic implications of these findings are discussed: mitochondrial pathways are proposed to be directly involved in the apoptotic process in relation to selective inhibition of thioredoxin reductase.
Gold(III) compounds generally exhibit significant cytotoxic effects on cancer cell lines and are of potential interest as antitumor drugs. We report here on the solution chemistry, the cytotoxicity, ...and the DNA binding properties of two new bipyridyl gold(III) compounds: Au(bipy)(OH)2PF6 (1) and the organometallic compound Au(bipyc-H)(OH)PF6 (2) (bipyc = 6-(1,1-dimethylbenzyl)-2,2‘-bipyridine). Both compounds are sufficiently soluble, and stable for hours, within a physiological buffer at 37 °C; Au(bipy)(OH)2PF6, at variance with Au(bipyc-H)(OH)PF6, is quickly and quantitatively reduced by ascorbate. Both compounds showed relevant cytotoxic effects toward the A2780S, A2780R, and SKOV3 tumor cell lines; lower effects were detected on the CCRF-CEM/S and CCRF-CEM/R lines. In most cases the mechanisms of resistance to CDDP are only marginally effective against these gold(III) complexes. The interactions of Au(bipy)(OH)2PF6 and Au(bipyc-H)(OH)PF6 with calf thymus DNA were investigated in vitro by various techniques to establish whether DNA represents a primary target for these compounds. Addition of saturating amounts of DNA did not affect appreciably the visible spectra of these gold(III) complexes. Some slight modifications of the CD spectra of calf thymus DNA and of the DNA melting parameters were observed; in any case, ultrafiltration experiments showed that binding of these gold(III) complexes to DNA is weak and reversible. The mechanistic implications of these findings are discussed.
The seleno-enzyme thioredoxin reductase (TrxR) is a putative target for cytotoxic gold complexes. We investigated the mechanism of TrxR inhibition by a group of structurally diverse gold(iii) ...compounds; the antiarthritic gold(i) drugs auranofin and aurothiomalate were also studied for comparison purposes. The tested compounds - either gold(iii) or gold(i) - were found to produce potent enzyme inhibition only after pre-reduction of the enzyme with NADPH, indicating that TrxR inhibition is the result of protein structure modifications occurring upon cofactor binding. MALDI-ToF MS experiments on the intact enzyme provided evidence for extensive enzyme metallation, while experiments on trypsinized gold(iii)-protein adducts identified a specific protein fragment - namely 236IGEHMEEHGIK246 - bearing an attached gold(i) ion. Independent mechanistic information on the system was derived from BIAM assays capable of monitoring selective metal binding to cysteine and/or selenocysteine residues. While the effects produced by auranofin could be essentially ascribed to gold(i) coordination to the active site selenol, the effects caused by the various gold(iii) compounds were better interpreted in terms of oxidative protein damage.
With its impressive features, gold has led to completely new reaction types in recent years, which in turn have strongly influenced both organic catalysis and material science. Other fields where a ...significant amount of new results has been obtained include nanotechnology, self assembly/supramolecular systems and biochemical/medicinal chemistry. As a result, gold is one of the hottest topics in catalysis at the moment, with an increasing amount of research being carried out in this field. While focusing on homogeneous catalysis, this monograph also covers the main applications in heterogeneous catalysis. Following a look at the gold-catalyzed addition of heteroatom nucleophiles to alkynes, it goes on to discuss gold-catalyzed additions to allenes and alkenes, gold-catalyzed benzannulations, cycloisomerization and rearrangement reactions, as well as oxidation and reduction reactions. The whole is finished off with a section on gold-catalyzed aldol and related reactions and the application of gold-catalyzed reactions to natural product synthesis. Of interest to synthetic chemists and inorganic chemists, as well as organic chemists working in homogeneous catalysis, physical and technical chemists.
The reaction of the electron-rich derivatives cis-Pt(R)2(DMSO)2 (R = Me, Ph) with a series of 6-substituted-2,2‘-bipyridines, HL, occurs with loss of methane or benzene, respectively, to yield ...cyclometalated platinum(II) species Pt(R)(L)(DMSO) where L is an anionic ligand N‘,C(3) coordinated. The unusual C−H activation entails a consecutive reaction process through a detectable intermediate. The reaction is peculiar of 6-substituted ligands: for comparison no reaction occurs with 6,6‘-Me2-2,2‘-bipy and an adduct, Pt(R)2(HL), is obtained with 5-Me-2,2‘-bipy.
A number of gold( i ) complexes containing the proton pump inhibitor (PPI) lansoprazole and its reduced precursor 2-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylthio)-1 H -benzo d imidazole ...have been synthesized and their biological effects have been evaluated in human cancer and non-tumorigenic cells in vitro . The lansoprazole-based compounds appear to act through a V-H + -ATPase-mediated mechanism.
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