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At least 397 records · Page 22Linked to original sources
PubMed1991

Hypochlorous acid induced activation of human neutrophil and gingival crevicular fluid collagenase can be inhibited by ascorbate.

Interstitial collagenase either obtained from human neutrophils by phorbol myristate acetate (PMA) induced degranulation or isolated from human gingival crevicular fluid was found to be activated by addition of an oxidative agent, hypochlorous acid (HOCl). Collagenase released by PMA stimulated neutrophils was completely in latent form but underwent partial autoactivation during 16 h incubation at 22 degrees C in the presence of soy bean trypsin inhibitor. The partial autoactivation was potentiated to complete activation of released collagenase after addition of exogenous HOCl. Ascorbate prevented this activation of neutrophil collagenase. Isolated human gingival crevicular fluid collagenase represented an apparent Mr of 70 kD in completely latent form, whereas 70/54 kD enzyme species were detected for partially autoactive form of the enzyme. Western blot analysis of gingival crevicular fluid using a polyclonal antibody raised against purified human neutrophil collagenase revealed the same 70/54 kD molecular forms of the enzyme. The latent gingival crevicular fluid collagenase was also activated by HOCl and this activation could be prevented by ascorbate. Activation of the 70 kD latent collagenase by HOCl as well as by other non-proteolytic activators such as an organomercurial compound (phenylmercuric chloride) and a gold(I) compound (gold thioglucose) was not associated with detectable changes in apparent Mr, whereas trypsin activation resulted in fragmentation of 70 kD enzyme to 54 kD species. Our results provide further evidence for the neutrophil origin of gingival crevicular fluid collagenase and suggest that, in addition to proteolytic activation, oxidative and antioxidative agents seem to be able to regulate neutrophil collagenase activity.

Ascorbic Acid↗
PubMed2005

Reactivity and stability of organocopper(I), silver(I), and gold(I) ate compounds and their trivalent derivatives.

Organocuprate (R(2)Cu(-)) reagents react with a carbon electrophile to form a new C-C bond, yet their silver and gold counterparts seldom serve for such purposes. The origin of this striking difference is discussed with the aid of the quantum mechanical calculations using hybrid density functional method. The copper reaction takes place through two steps, the nucleophilic reaction of the ate complex R(2)Cu(I)(-) with an electrophile E(+) and the decomposition of the resulting R(2)(E)Cu(III) intermediate. These two steps were examined for Cu, Ag, and Au to find the reasons for the superiority of organocopper compounds to the silver and the gold counterparts. The first reaction is favored because of the higher-lying d-orbitals that directly participate in the nucleophilic reaction. The second reaction is faster with copper because of the intrinsic instability of the high valent copper species.

Journal Article↗
PubMed2006

Anticancer cyclometalated [Au(III)m(C(wedge)N(wedge)C)mL]n+ compounds: Synthesis and cytotoxic properties.

A series of cyclometalated gold(III) compounds [Au(m)(C(wedge)N(wedge)C)mL]n+ (m = 1-3; n = 0-3; HC(wedge)N(wedge)CH = 2,6-diphenylpyridine) was prepared by ligand substitution reaction of L with N-donor or phosphine ligands. The [Au(m)(C(wedge)N(wedge)C)mL]n+ compounds are stable in solution in the presence of glutathione. Crystal structures of the gold(III) compounds containing bridging bi- and tridentate phosphino ligands reveal the presence of weak intramolecular pi pi stacking between the [Au(C(wedge)N(wedge)C)]+ units. Results of MTT assays demonstrated that the [Au(m)(C(wedge)N(wedge)C)mL]n+ compounds containing nontoxic N-donor auxiliary ligands (2) exert anticancer potency comparable to that of cisplatin, with IC50 values ranging from 1.5 to 84 microM. The use of [Au(C(wedge)N(wedge)C)(1-methylimidazole)]+ (2 a) as a model compound revealed that the gold(III)-induced cytotoxicity occurs through an apoptotic cell-death pathway. The cell-free interaction of 2 a with double-stranded DNA was also examined. Absorption titration showed that 2 a binds to calf-thymus DNA (ctDNA) with a binding constant of 4.5 x 10(5) dm3 mol(-1) at 298 K. Evidence from gel-mobility-shift assays and viscosity measurements supports an intercalating binding mode for the 2 a-DNA interaction. Cell-cycle analysis revealed that 2 a causes S-phase cell arrest after incubation for 24 and 48 hours. The cytotoxicity of 3 b-g toward cancer cells (IC50 = 0.04-4.3 microM) correlates to that of the metal-free phosphine ligands (IC50 = 0.1-38.0 microM), with [Au2(C(wedge)N(wedge)C)2(mu-dppp)]2+ (3 d) and dppp (dppp = 1,2-bis(diphenylphosphino)propane) being the most cytotoxic gold(III) and metal-free compounds, respectively. Compound 3 d shows a cytotoxicity at least ten-fold higher than the other gold(III) analogues; in vitro cellular-uptake experiments reveal similar absorptions for all the gold(III) compounds into nasopharyngeal carcinoma cells (SUNE1) (1.18-3.81 ng/cell; c.f., 3 d = 2.04 ng/cell), suggesting the presence of non-gold-mediated cytotoxicity. Unlike 2 a, both gold(III) compounds [Au(C(wedge)N(wedge)C)(PPh3)]+ (3 a) (PPh3 = triphenylphosphine) and [Au2(C(wedge)N(wedge)C)2(mu-dppp)]2+ (3 d) interact only weakly with ctDNA and do not arrest the cell cycle.

Antineoplastic Agents↗
PubMed2005

Formation of novel anionic gold-tin cluster compounds.

A straightforward procedure for the formation of mixed metal Au/Sn clusters is presented: reaction of the heteroborate [SnB11H11]2- with phosphine gold electrophiles gave the clusters [Bu3NH]3[{(Et3P)Au(SnB11H11)}3] and [Bu3MeN]4[{(dppm)Au2(SnB11H11)2}2], which were characterised by X-ray diffraction.

Journal Article↗
PubMed2004

Effects of chronic treatment with sodium tetrachloroaurate(III) in mice and membrane models.

Gold is a nonessential element with a variety of applications in medicine. A few gold(I) compounds are used in the clinics for treatment of rheumatoid arthritis and of discoid lupus. Some novel gold(III) compounds are under evaluation as anticancer agents. It is known that gold compounds generally produce toxic effects on the kidneys and characteristic lesions in the brain. However, information concerning the neurotoxicity of gold derivatives in humans as well as in experimental toxicology is rather scarce. For this reason we tried to shed some further light on this aspect of gold neurotoxicity by chronic treatment of mice with sodium tetrachloroaurate(III) in order to observe possible biophysical and morphological alterations that may occur in the brain. Chronic gold treatment resulted in a markedly decreased expression of metallothioneins and of glial fibrillary acidic protein in astrocytes of different brain areas. To examine its effects on cell membranes, interactions of sodium tetrachloroaurate(III) with molecular models were also evaluated. The models consisted in bilayers built-up of classes of phospholipids located in the outer and inner monolayers of biological membranes. Structural perturbation of cell membrane models was observed only at concentrations 10(5) times higher than those detected in the brains of animals after three months' treatment. These results show that toxic effects on animal brain upon treatment with sodium tetrachloroaurate develop with difficulty and may be observed only at high doses.

Animals↗
PubMed2004

Effect of metal complexes on thioredoxin reductase and the regulation of mitochondrial permeability conditions.

Gold(I) compounds such as auranofin, chloro(triethylphosphine) gold(I), and aurothiomalate act on mitochondrial functional parameters by determining an extensive permeability transition and a decrease of membrane potential. On the contrary, pyridine nucleotides and glutathione are not modified, whereas a slight but significant decrease of total thiols is apparent. The effect of gold(I) compounds is essentially referable to the inhibition, in the nanomolar range, of thioredoxin reductase activity and to an increase of hydrogen peroxide production. Metal ions and metal complexes (zinc and cadmium acetate, cisplatin, tributyltin) are also good inhibitors of thioredoxin reductase, although in the micromolar range, and in addition, they act as inducers of permeability transition and of membrane potential decrease. At variance with gold(I) compounds, which appear to work almost exclusively on thioredoxin reductase, metal ions and complexes are less specific, since they are active on different mitochondrial targets, including the respiratory chain.

Animals↗
PubMed1989

Mechanism of inhibition of human neutrophil collagenase by Gold(I) chrysotherapeutic compounds. Interaction at a heavy metal binding site.

The mechanism of inhibition of two forms of human neutrophil collagenase (HNC) by six Au(I) compounds, some of which are used as chrysotherapeutic agents, has been investigated. The two forms of enzyme studied are active and latent HNC, the latter of which is activated by p-chloromercuribenzoate (PCMB). The effects of PCMB and Zn(II), which are normally included in the assays, on the activity of both forms of HNC and on their inhibition by these Au(I) compounds have also been studied. Zn(II) stimulates the activity of both the active and PCMB-activated latent forms of HNC up to a concentration of 50-100 microM, after which it inhibits markedly. PCMB activates latent HNC up to a concentration of 100 microM followed by inhibition at higher concentrations. Active HNC is not stimulated at PCMB concentrations below 100 microM, but is inhibited at higher concentrations. The stimulatory effects of Zn(II) and PCMB on HNC and its inhibition by PCMB are all attributable to binding at distinct sites. The inhibition of both active and PCMB-activated latent HNC by the Au(I) compounds is noncompetitive and is reversed by Zn(II). The inhibition of both forms of HNC by SKF 80544 and SKF 36914, which do not contain thiol ligands, is weak to moderate and is not influenced by the PCMB concentration. In contrast, PCMB markedly enhances the inhibition by Myocrisin, Sanocrisin, and Solganol by complexing to their thiol ligands to facilitate release of the Au(I) atom for binding to HNC. Cd(II) and Cu(II) also inhibit HNC noncompetitively, and inhibition is also reversed by Zn(II). Collectively, these data indicate that latent HNC contains a heavy metal binding site distinct from the active site at which Au(I), Cd(II), and Cu(II) bind to cause noncompetitive inhibition. Occupancy of this site by Zn(II) is characterized by retention of activity.

Aurothioglucose↗
PubMed1999

Aurothioglucose inhibits murine thioredoxin reductase activity in vivo.

Gold (I)-containing compounds, including aurothioglucose (ATG), are potent in vitro inhibitors of several selenocysteine-containing enzymes. Gold compounds have also been shown to potentiate the virulence of several viruses in mice, including coxsackievirus, implicated as a possible infectious agent in Keshan disease. One possible mechanism by which gold compounds may be increasing the virulence of viral infections in mice is by acting as a selenium antagonist in vivo and inducing oxidative stress. To investigate the possible role of gold compounds in inducing oxidative stress in mice, we assessed the ability of ATG administered in vivo to inhibit the activity of the selenocysteine-containing enzymes thioredoxin reductase (TR) and glutathione peroxidase (GPX1). Doses as low as 0. 025 mg ATG/g body weight caused significant and prolonged inhibition of TR activity in all tissues examined. No such inhibition of GPX1 activity was seen, indicating differential in vivo sensitivity of the enzymes to inhibition by ATG. In liver and heart, some recovery of TR activity was observed after a 7-d period, but no recovery was observed in pancreas or kidney. Because TR is involved in several important cellular redox functions, its inhibition most likely will affect multiple cellular processes. These results indicate that in vivo administration of ATG results in significant and long-lasting inhibition of TR activity. Such inhibition of TR could lead to increased levels of oxidative stress in vivo, thereby increasing the virulence of several viruses including the coxsackievirus.

Animals↗
PubMed1988

Inhibition by anti-inflammatory agents of contraction induced by epidermal growth factor-urogastrone in isolated longitudinal smooth muscle strips from guinea-pig stomach.

1. Epidermal growth factor-urogastrone (EGF-URO) caused a concentration-dependent contractile response of longitudinal muscle strips from the gastric body of the guinea-pig stomach. The contractile response to EGF-URO was monophasic, with tension returning rapidly to baseline. Desensitization was evident in that further addition of EGF-URO to the organ bath did not cause a second contraction. 2. Preincubation with indomethacin, ibuprofen, naproxen and aspirin markedly inhibited the contractions induced by EGF-URO with an order of potency (indomethacin greater than naproxen greater than ibuprofen greater than aspirin) that reflected the ability of these agents to inhibit cyclo-oxygenase. 3. The data indicate that prostanoids mediate the action of EGF-URO in the longitudinal muscle preparation. 4. Auranofin (0.5 to 50 microM), a chrysotherapeutic agent with antiproliferative properties used for treating rheumatoid arthritis, also markedly inhibited the EGF-URO response; however, other gold-containing compounds (aurothioglucose or gold sodium thiomalate at 30 to 100 microM) failed to cause significant inhibition. 5. Preincubation of preparations for 2 h with 1 microM hydrocortisone, prednisolone or dexamethasone caused an inhibition of EGF-URO-induced contraction of approximately 50%. However, steroids lacking either a 17 alpha-hydroxyl (corticosterone) or an 11 beta-hydroxyl (cortisone, deoxycorticosterone, prednisone) substituent did not inhibit the contraction caused by EGF-URO. For hydrocortisone, the inhibitory effect was half-maximal at 0.2 microM and was maximal at 1 microM. Cycloheximide (10 microM) blocked the inhibitory action of hydrocortisone and potentiated the contractile action of EGF-URO. 6. The ability of a variety of steroidal and non-steroidal anti-inflammatory agents to interfere with the action of EGF-URO in a smooth muscle preparation suggests that these agents may also inhibit the action of EGF-URO mediated by prostanoids in other target tissues. 7. The data also point to a potential role for EGF-URO in regulating gastric motility.

Animals↗
PubMed2006

Chemoselective hydrogenation of nitro compounds with supported gold catalysts.

The selective reduction of a nitro group when other reducible functions are present is a difficult process that often requires stoichiometric amounts of reducing agents or, if H2 is used, the addition of soluble metals. Gold nanoparticles supported on TiO2 or Fe2O3 catalyzed the chemoselective hydrogenation of functionalized nitroarenes with H2 under mild reaction conditions that avoided the accumulation of hydroxylamines and their potential exothermic decomposition. These chemoselective hydrogenation gold catalysts also provide a previously unknown route for the synthesis of the industrially relevant cyclohexanone oxime from 1-nitro-1-cyclohexene.

Journal Article↗
PubMed1979

Acid dissociation and metal complex formation constants of penicillamine, cysteine, and antiarthritic gold complexes at simulated biological conditions.

Ionization constants for acid functions of D-penicillamine, L-cysteine, thiomalic acid, and thioglucose were measured by pH titration at 37 degrees and 0.15 M ionic strength. Chelate formation constants for these ligands with calcium(II), iron(III), and gold(I) were then determined under the same conditions chosen to approximate the in vivo situation. Only iron(III) formed both 1:1 and 1:2 chelates with D-penicillamine, L-cysteine, and thiomalate; calcium formed weak and gold strong 1:1 complexes with all ligands studied. Because of precipitate formation, the stability constants for the systems thioglucose-iron(III), D-penicillamine-gold(I), and L-cysteine-gold(I) had to be determined indirectly with thiomalic acid as the competing ligand. The in vivo fate of antiarthritic gold(I) compounds remained uncertain, but gold(I) chelates probably persist as such for extended periods.

Acids↗
PubMed1987

Gold lung: recent developments in pathogenesis, diagnosis, and therapy.

Gold lung is a hypersensitivity pneumonitis to gold-containing compounds. It can be distinguished from rheumatoid lung by its subacute or acute onset, diffuse interstitial and/or alveolar filling pattern on chest roentgenogram, presence of lymphocytes on BAL with an inverse helper/suppressor ratio, and response to withdrawal of gold and/or corticosteroid therapy. Other in vitro assays of gold hypersensitivity using peripheral blood lymphocytes are only sporadically positive and, therefore, of limited value in making the diagnosis. Physicians prescribing organic gold compounds should elicit pulmonary complaints throughout the duration of therapy. When patients receiving gold therapy present with signs and symptoms consistent with an acute or subacute hypersensitivity pneumonitis, the gold therapy should be withheld and a diagnostic workup initiated.

Aged↗
PubMed1995

Induction of stress proteins in mouse peritoneal macrophages by the anti-rheumatic agents gold sodium thiomalate and auranofin.

Gold sodium thiomalate and auranofin, anti-rheumatic gold-containing compounds, induced some stress proteins in cultured mouse peritoneal macrophages. The enhanced synthesis of two proteins, heme oxygenase (a 34-kDa protein) and a 23-kDa protein, was particularly prominent. The 23-kDa protein induced by the gold compounds was identical to that found in macrophages exposed to oxidative stress and was suggested to have antioxidant activity. Intraperitoneal injection of gold sodium thiomalate and oral administration of auranofin to mice induced enhanced synthesis of these proteins in peritoneal macrophages analyzed ex vivo. These data suggest that increased synthesis of these proteins may have a role in mediating the pharmacologic effect of these agents.

Animals↗
PubMed2006

Gold(I) and silver(I) mixed-metal trinuclear complexes: dimeric products from the reaction of gold(I) carbeniates or benzylimidazolates with silver(I) 3,5-diphenylpyrazolate.

Trinuclear mixed-metal gold-silver compounds are obtained by the reaction of gold(I) carbeniate [Au(mu-C(OEt)=NC6H4-p-CH3)]3, TR(carb), or gold(I) imidazolate [Au-mu-C,N-1-benzyl-2-imidazolate]3, TR(bzim), with silver(I) pyrazolate [Ag(mu-3,5-Ph2pz)]3. The crystalline products are mixed-ligand, mixed-metal dimeric products [Au(carb)Ag2(mu-3,5-Ph2pz)2], [Au2(carb)2Ag(mu-3,5-Ph2pz)].CH2Cl2, [Au(bzim)2Ag2(mu-3,5-Ph2pz)], and [Au2(bzim)2Ag(mu-3,5-Ph2pz)]. They have been characterized by elemental analysis and 1H NMR and mass spectrometry. The X-ray structure of [Au(carb)Ag2(mu-3,5-Ph2pz)2] shows it to be a dimer with two Ag...Au contacts between the trinuclear units of 3.083(2) and 3.310(2) A and with average intramolecular Ag...Ag and Au...Ag distances of approximately 3.3 and 3.2 A, respectively. The structure of [Au2(carb)2Ag(mu-3,5-Ph2pz)].CH2Cl2 is a dimer with one intermolecular Au...Au attraction of 3.3354(10) A and a short Ag...Au distance of approximately 3.42 A and intramolecular Ag...Au and Au...Au contacts of approximately 3.2 and approximately 3.3 A, respectively. Packing diagrams of both complexes show that the dimeric units are independent, similar to their parent molecules. The dimers of trinuclear [Au(carb)Ag2(mu-3,5-Ph2pz)2] and [Au2(carb)2Ag(mu-3,5-Ph2pz)].CH2Cl2 crystallize in the triclinic space group P (Z = 2), a = 9.688(3) A, b = 15.542(4) A, c = 23.689(6) A, alpha = 82.560(5) degrees , beta = 87.887(6) degrees , gamma = 78.060(5) degrees , and the orthorhombic space group Pca2(1) (Z = 4), a = 29.644(4) A, b = 7.4582(10) A, c = 30.473(4) A, respectively. The structure of [Au(bzim)Ag2(mu-3,5-Ph2pz)2] is a dimer with two metallophilic Ag...Au interactions of 3.14 A. The complex crystallizes in the monoclinic space group C2/c (Z = 4), a = 26.368(5) A, b = 15.672(3) A, c = 17.010(3) A, beta = 102.206(3) degrees .

Crystallography, X-Ray↗