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PubMed2006

Gold(III) compounds of 1,4,7-triazacyclononane showing high cytotoxicity against A-549 and HCT-116 tumor cell lines.

Two gold(III) compounds [Au(TACN)Cl(2)]Cl (1) and [Au(TACN)Cl(2)][AuCl(4)] (2) (where TACN=1,4,7-triazacyclononane), have been synthesized and characterized by electrospray ionization mass spectrometry (ESI-MS), (1)H NMR spectroscopy and elemental analyses. The structure of compound 2 was determined by X-ray crystallography, in which TACN coordinates to the gold(III) center in a bidentate mode and the unbound amine group forms a very short intramolecular Au-H(-N) contact (1.91A). Biological activity data showed that compound 1 is more cytotoxic than cisplatin against A-549 and HCT-116 tumor cell lines. The interactions of compound 1 with CT-DNA were studied by UV-Vis, fluorescence and CD spectroscopy, which suggests that compound 1 can induce the distortion of DNA double helix.

Antineoplastic Agents↗
PubMed2001

Self-Assembled Monolayers of Organoselenium Compounds on Gold: Surface-Enhanced Raman Scattering Study.

To understand the binding nature of organoselenium compounds on gold, we have examined the adsorption behavior of several representative organoselenium compounds, i.e., benzeneselenol (BSe), diphenyl diselenide, dibenzyl diselenide, dioctyl diselenide, and benzyl phenyl selenide (BPSe) on the Au surface by virtue of surface-enhanced Raman spectroscopy (SERS). BSe chemisorbs on gold as selenolate with a tilted orientation. Upon adsorption, the Se-Se bonds of diselenides are cleaved to form selenolates, analogous to the formation of thiolate monolayers from disulfides. BPSe adsorbs on gold without any C-Se bond scission. The benzyl moiety of BPSe assumes a rather vertical stance while the phenyl moiety is more tilted to the gold surface. Copyright 2001 Academic Press.

Journal Article↗
PubMed1980

Impaired suppression of sympathetic activity during fasting in the gold thioglucose-treated mouse.

Sympathetic activity in rats and mice is diminished by fasting and increased by sucrose feeding. The central neural mechanisms coordinating changes in the functional state of sympathetic nerves with changes in dietary intake are unknown, but a role for neurons in the ventromedial hypothalamus (VMH) is suggested by the existence of sympathetic connections within the VMH and the importance of this region in the regulation of feeding behavior. To investigate the potential role of the VMH in dietary regulation of sympathetic activity [(3)H]norepinephrine turnover was measured in the hearts of fasted and sucrose-fed mice after treatment with gold thioglucose (AuTG). In control mice, norepinephrine (NE) turnover was 1.60+/-0.92 ng NE/heart per h (95% confidence limits) after 1 d of fasting and 4.58+/-0.98 after 3 d of sucrose feeding, although, in AuTG-treated mice, cardiac NE turnover in fasting was 5.45+/-1.56 and with sucrose feeding, 5.44+/-0.76. Experiments with ganglionic blockade indicate that the absence of dietary effect on NE turnover in AuTG-treated mice reflects a corresponding lack of change in central sympathetic outflow. AuTG administration, therefore, disrupts dietary regulation of sympathetic activity by abolishing the suppression of sympathetic activity that occurs with fasting. This effect of AuTG is unrelated to duration of fasting (up to 3 d) and is specific for AuTG because neither treatment with another gold thio compound (gold thiomalate) nor the presence of genetic obesity (ob/ob) prevented fasting suppression of sympathetic activity. Moreover, AuTG treatment did not impair sympathetic activation by cold exposure (4 degrees C) nor adrenal medullary stimulation by 2-deoxy-d-glucose. Thus, AuTG treatment selectively impairs dietary regulation of sympathetic activity, possibly by destruction of neurons in the VMH.

Adrenal Glands↗
PubMed1983

Loose stools during auranofin treatment: clinical study and some pathogenetic possibilities.

Loose stools, one of the most frequent adverse reactions ascribed to the orally absorbed gold compound auranofin (AF), was studied during a longterm trial. At some time during the study 44% of 25 patients reported the occurrence of loose stools. No infection or signs of malabsorption were found; nor were loose stools caused by the presence of osmotically active substances in the gut lumen. Arguments for a direct effect of AF on the ion and water absorption in the intestine are given. Although no morphological studies on biopsy material are available, the known side effects of the drug do not seem to warrant its discontinuation in suitable patients.

Arthritis, Rheumatoid↗
PubMed2003

Organometallic gold(III) compounds as catalysts for the addition of water and methanol to terminal alkynes.

Different inorganic and organometallic gold(III) and gold(I) complexes have been tested in the addition of water and methanol to terminal alkynes. Anionic and neutral organometallic gold(III) compounds can efficiently mediate these reactions in neutral media in refluxing methanol. The compounds are added in catalytic amounts (1.6-4.5 mol % with respect to the alkyne). Thus, compounds of the general formula Q[AuRCl(3)], Q[AuR(2)Cl(2)], [AuRCl(2)](2), and [AuR(2)Cl](2) (Q = BzPPh(3)(+), PPN: N(PPh(3))(2)(+) or N(Bu)(4)(+); R = C(6)F(5) or 2,4,6-(CH(3))(3)C(6)H(2)) seem to behave as Lewis acids in nucleophilic additions to triple bonds. Some intermediates could be detected in the stoichiometric reaction between [Au(C(6)F(5))(2)Cl](2) and phenylacetylene that was followed by variable temperature (1)H, (19)F[(1)H], COSY (19)F[(1)H]-(19)F[(1)H], and (2)H[(1)H] NMR experiments. Compound [Au(C(6)F(5))(2)Cl](2) is also able to catalyze the hydration of phenylacetylene at room temperature. A plausible mechanism for the hydration reaction has been proposed.

Journal Article↗
PubMed1990

Responses of the colonic epithelium to auranofin: evidence for involvement of enteric nerves.

Auranofin, the orally effective gold compound, stimulated the canine colonic epithelium in vitro. It increased short circuit currents across both the innervated mucosal and functionally "nerve-free" epithelial preparation, when added to either the luminal or serosal solutions. Serosal responses were inhibited by tetrodotoxin (TTX). A hydrophilic gold compound, sodium aurothiosulphate produced similar effects but only on serosal addition. Gold compounds can thus alter colonic transport activating enteric nerves and releasing a neurotransmitter. Thus gold induced diarrhea could have a significant neural component.

Animals↗
PubMed2006

Structural and solution chemistry, antiproliferative effects, and DNA and protein binding properties of a series of dinuclear gold(III) compounds with bipyridyl ligands.

A series of six dinuclear gold(III) oxo complexes with bipyridyl ligands, of general formula [Au2(N,N)2(mu-O)2][PF6]2 (Auoxo1-Auoxo6) [where N,N = 2,2'-bipyridine (1), 4,4'-di-tert-butyl- (2), 6-methyl- (3), 6-neopentyl- (4), 6-(2,6-dimethylphenyl)- (5), 6,6'-dimethyl-2,2'-bipyridine (6)], were investigated as potential cytotoxic and anticancer agents, and their antiproliferative properties were evaluated in vitro toward the reference A2780 human ovarian carcinoma cell line. While five compounds manifested moderate cytotoxic properties (with IC50 approximately 10-30 microM), the sixth one (Auoxo6), turned out to be approximately 5-15 times more active against both cell lines and will merit further pharmacological studies. The interactions of Auoxo1 and Auoxo6 with a few model proteins (serum albumin, cytochrome c, ubiquitin) and with calf thymus DNA were analyzed in detail by various spectroscopic methods. Both tested compounds manifested a high and peculiar reactivity toward the mentioned model proteins; specific differences were detected in their reactivity with DNA. The mechanistic implications of these results are discussed.

2,2'-Dipyridyl↗
PubMed1998

Alveolar-interstitial pneumopathy after gold-salts compounds administration, requiring mechanical ventilation.

The pulmonary toxicity of gold salts is an uncommon cause of life-threatening respiratory failure. Currently, patients who suffer from this do not need mechanical ventilation, and the toxicity can be difficult to diagnose when it occurs in patient with an illness producing pulmonary manifestations. We report a case of severe respiratory failure due to gold salt toxicity in a patient suffering from rheumatoid arthritis requiring mechanical ventilation. At such a time, the poor respiratory function makes some diagnostic procedures harmful. The diagnosis can be made after the exclusion of other causes of rheumatoid lung when the patient's poor respiratory status precludes invasive exploration. The clinical findings, radiological features, and results of pulmonary function tests may be enough to diagnose gold-related pneumopathy. This avoids the need for bronchoscopic examination or transfer of the patient for computed tomography. Attention must be paid to this complication because the outcome and functional prognosis are better when pulmonary involvement is gold related: in our case steroid therapy was life-saving and induced complete recovery of the lung damage.

Aged↗
PubMedDate not supplied

Inhibitory effects of gold sodium thiomalate on DNA polymerase alpha.

The usefulness of gold compounds in the therapy of rheumatoid arthritis is well established, however, the pharmacological mechanisms of the compounds are still unclear. In this report, effects of gold compounds on DNA synthesis were examined. Gold sodium thiomalate inhibited DNA synthesis in the HeLa "nuclei system" as well as in the enzyme reaction using DNA polymerase alpha. More precisely, gold sodium thiomalate inhibited the activity of DNA polymerase alpha using activated DNA, poly[d(A-T)] or poly[d(G-C)] for the template, but did not inhibit the activity of DNA polymerase I with each template. The compound had also no inhibitory effect on DNA polymerase beta or gamma. On the other hand, auranofin inhibited the incorporation of [3H]thymidine into HeLa DNA but did not inhibit DNA synthesis in the HeLa "nuclei system". The inhibition of DNA polymerase alpha activity by gold sodium thiomalate was competitive with poly(dA).oligo(dT) for template but noncompetitive with dTTP. Thus, gold sodium thiomalate is a potent and specific inhibitor of DNA polymerase alpha and this inhibitory effect could play an important role in the therapeutic and pharmacological effects of gold sodium thiomalate.

Auranofin↗
PubMed1988

Inhibition of production of macrophage-derived angiogenic activity by the anti-rheumatic agents gold sodium thiomalate and auranofin.

We have investigated the effect of gold sodium thiomalate and auranofin, gold compounds employed in the treatment of rheumatoid arthritis, on production of macrophage-derived angiogenic activity. Elicited mouse peritoneal macrophages were cultured in the presence or absence of gold compounds or thiomalic acid, and the macrophages or their conditioned media were then assayed for their angiogenic activity in rat corneas. Control macrophage conditioned medium was potently angiogenic. In contrast, conditioned medium from gold or thiomalic acid treated macrophages was not. Addition of gold compounds or thiomalic acid to control macrophage conditioned medium did not inhibit its angiogenic activity. Drug treatments did not significantly affect macrophage lactate dehydrogenase release, lysozyme release, or protein synthesis. We conclude that gold sodium thiomalate and auranofin potently reduce the detectable angiogenic activity produced by macrophages.

Animals↗
PubMed1980

Action of gold salts in some inflammatory and immunological models.

Several gold salts were compared in kaolin-induced rat paw oedema, u.v. erythema in guinea pigs, delayed type hypersensitivity and humoral immunity in mice, and adjuvant-induced arthritis in the rat. In the latter the additional parameters of serum gold and copper levels and lysosomal enzyme activity were determined. In addition, the in vitro inhibition of several lysosomal enzymes derived from mouse macrophages was studied. The gold compounds examined were aurothiomalate, aurothioglucose, triethylphosphine gold chloride (SK & F 36914) and its glucopyranoside derivative (SK & F D-39162), triphenylphosphine gold chloride and sodium gold chloride dihydrate. SK & F 36914 and SK & F D-39162 has significant activity after oral dosage upon paw kaolin and u.v. erythema in rats and guinea pigs, respectively. Gastric swelling also occurred. In Wistar rats, adjuvant arthritis was little affected by the gold salts but in the Lewis rats there was suppression. In both strains there was less elevation in serum copper levels with treatment by SK & F 36914 and SK & F D-39162, but not by aurothiomalate. None of the compounds had any measurable effect on delayed hypersensitivity or humoral antibody levels in mice. The in vitro activities of cathepsin B1 and cathepsin D were inhibited by all the gold compounds. Reactivity of gold compounds with glutathione and cysteine in vitro was dependent on compound solubility and the nature of the gold ligand. Considerable differences exist between the profiles of activity for the different gold salts evaluated. These observations indicate that some gold salts do possess anti-inflammatory activity with a potency similar to that of indomethacin.

Animals↗
PubMed1992

[Phagocytic activity in rheumatoid arthritis].

The phagocytic activity of leukocytes was studied in 41 patients with active rheumatoid arthritis, 24 of whom were treated with gold compounds and the remaining 17 with non-steroidal anti-inflammatory drugs. The control group comprised 137 patients with no signs of inflammatory rheumatic diseases. The mean age of patients was 54.8 years (range: 32-75) and that of the controls, 53.5 years (range: 32-75). Spontaneous mobility (P < 0.001), phagocytic activity (P < 0.001) and antibody-dependent cytotoxicity (P < 0.001) of leukocytes were significantly lower in patients with rheumatoid arthritis compared to the control group. No significant differences were observed between patients treated with gold compounds and those receiving nonsteroidal anti-inflammatory drugs with respect to mean spontaneous mobility (U = 198, P = 0.44), phagocytic activity (U = 185, P = 0.31) and antibody-dependent cytotoxicity (U = 183, P = 0.29) of leukocytes. Among patients treated with gold compounds phagocytic activity was significantly lower in those receiving TauredonR compared to those receiving AuropanR (U = 33.5, P = 0.05). The antibody-dependent cytotoxicity was comparable in patients receiving Tauredon and Auropan, respectively (U = 58.5, P = 0.48).

Adult↗
PubMed1983

Association of HLA antigens, toxic reactions and therapeutic response to auranofin and aurothioglucose in patients with rheumatoid arthritis.

To investigate the possible relation between HLA antigens and either favourable clinical response or toxic reaction to two different gold compounds, aurothioglucose and auranofin, a new orally absorbable gold compound, we studied 50 patients with rheumatoid arthritis prospectively. Of the 25 aurothioglucose-treated patients, response to treatment could not be evaluated in four patients because of early toxicity. Nine patients showed an excellent response, while 12 were moderate or non-responders. Four of the 9 excellent responders were HLA-DR3 positive, but none of the 12 moderate or non-responders possessed this antigen (P less than 0.025). In accordance with previous reports HLA-DR3 was found more frequently in patients developing toxicity on aurothioglucose than in those who did not (RR = 5.6). No association was found between HLA antigens and favourable clinical response in 25 auranofin-treated patients. Two of them showed a severe adverse reaction, neither of them being DR3-positive. HLA-DR3 positivity is associated not only with drug toxicity, but also with excellent respondership to aurothioglucose treatment.

Arthritis, Rheumatoid↗
PubMed2005

Gold-induced reactive oxygen species (ROS) do not mediate suppression of monocytic mitochondrial or secretory function.

UNLABELLED: The toxicity of anti-rheumatic gold compounds has limited their use and development, yet both the toxicological and therapeutic actions of these compounds remain unclear. In the current study, we tested the hypothesis that intracellular reactive oxygen species (ROS) induced by Au(I) or Au(III) compounds mediate their ability to suppress mitochondrial activity. METHODS: Human THP1 monocytes were exposed to HAuCl(4) x 3H(2)O (Au(III)), or the anti-rheumatic compounds auranofin (AF) or gold sodium thiomalate (GSTM) for 6-72 h, after which mitochondrial activity (succinate dehydrogenase) was measured. To assess the role of cellular redox status as a mediator of mitochondrial suppression, monocytes were pre-treated with a pro-oxidant (t-butyl hydroquinone, t-BHQ) or antioxidant (N-acetyl cysteine, NAC ). ROS levels were measured 0-24h post-gold addition to determine their role as mediators of mitochondrial activity suppression. RESULTS: AF was the most potent inhibitor of mitochondrial activity, followed by Au(III) and GSTM. Only Au(III) induced intracellular ROS; no ROS formation was observed in response to AF or GSTM exposure. Although anti- and pro-oxidants had some effects on mitochondrial suppression of Au compounds, collectively the data do not support redox effects or ROS formation as major mediators of Au-compound mitochondrial suppression. CONCLUSIONS: Our results do not indicate that ROS and redox effects play major roles in mediating the cytotoxicity of AF, GSTM or Au(III).

Auranofin↗
PubMed2001

Effect of gold(I) compounds on the virulence of an amyocarditic strain of coxsackievirus B3.

Coxsackieviruses, especially B strains (CVB), are known etiological agents of myocarditis. Both amyocardititc and myocarditic strains exist and at least one amyocarditic strain, CVB3/0, can convert to virulence when passaged through selenium or vitamin E-deficient mice. Gold(I)-containing compounds, such as aurothiomalate (ATM) and aurothioglucose (ATG), can act as selenium antagonists. In this study, we examined the effect of intraperitoneal administration of equal doses of ATM or ATG on the virulence of CVB3/0. ATM but not ATG increased mortality in CVB3/0-infected mice. CVB3/0-infected mice treated with ATM had total necrosis of the pancreatic exocrine tissue. Heart damage also occurred in ATM-treated mice but did not correlate with mortality. Increased viral titers and persistence were observed in ATM-treated mice and, to a lesser extent, in ATG-treated mice. Thus, under our conditions, only ATM increased the virulence of CVB3/0, whereas ATG did not. On the other hand, both ATG and ATM inhibited thioredoxin reductase activity in heart and pancreas, but neither affected glutathione peroxidase activity. In contrast, dietary selenium deficiency reduces both enzyme activities. Thus, it is unlikely that these compounds affect virulence by acting as selenium antagonists.

Animals↗
PubMedDate not supplied

Tartrate-resistant acid phosphatase: a potential target for therapeutic gold.

Gold compounds are disease-modifying agents for the treatment of rheumatoid arthritis. They act on the immune system but the mechanism is not fully understood. Gold has been shown to affect antigen processing by T-cells and also reduces expression of cytokines in macrophages. Tartrate-resistant acid phosphatase (TRAP), expressed by osteoclasts, macrophages and dendritic cells is an enzyme with roles in skeletal metabolism and the immune response. TRAP is able to degrade skeletal phosphoproteins including osteopontin, identical to the T-cell cytokine, Eta-1; we thus propose that TRAP regulates the Eta-1 pathway common to the immune system and skeleton. We compared the distribution of osteopontin and TRAP in sections of 18-day-old embryonic mice by immunohistochemistry. Both proteins occurred in the same locations. To determine whether gold compounds exert their effects by modification of TRAP activity, we examined the action of gold chloride and the prodrugs, aurothioglucose and aurothiomalate on the dephosphorylation of osteopontin by TRAP. Aurothioglucose and aurothiomalate had little effect on phosphatase activity; gold chloride was a potent non-competitive inhibitor (Ki < 47 x 10(-9) M). These findings indicate a possible molecular mechanism for the action of therapeutic gold and further implicate TRAP in the control of immunity.

Acid Phosphatase↗
PubMed1996

Contact allergy to gold in dental patients.

Gold sodium thiosulphate (GSTS) in patch test series commonly yields positive reactions. In this study of dental patients, the clinical relevance of these positive reactions, the suitability of gold compounds as patch test materials, and value of the lymphocyte proliferation test in gold contact allergy, were evaluated. The frequency of positive patch test reactions to GSTS was 12.4% in the dental series. Fifty-two patients, only two of whom were male, were studied. Thirteen (25%) had had symptoms from jewellery or dental restorations. However, in most cases gold allergy was subclinical. A 10% aqueous solution of gold sodium thiomalate (GSTM) was almost as good as 0.5% GSTS in petrolatum as a marker of gold contact allergy, but 0.001% potassium dicyanoaurate (PDCA) yielded a high percentage of false-negative results. Seventy-three per cent of the subjects with positive patch tests to GSTS responded to gold compounds in vitro in the lymphocyte proliferation test, whereas 13 controls without gold contact sensitivity were negative. Consistent results in skin and lymphocyte proliferation tests provide support for the concept that gold salt-induced 'allergic-like' reactions are truly allergic in nature.

Adolescent↗
PubMed2001

Facilitated electrochemical oxidation of NADH and its model compound at gold electrode modified with terminally substituted electroinactive self-assembled monolayers.

The electrochemical oxidation of NADH and its model compound, N-benzyl-1,4-dihydronicotinamide (DHN), has been studied at gold electrode modified with self-assembled monolayer of terminally substituted thiols/disulfide, i.e., cystamine (CYST), mercaptopropionic acid (MPA) and mercaptoethanol (ME). A substantial decrease in the overpotential (approximately 250 mV) when compared to the bare electrode has been observed for the oxidation of NADH at the monolayer-modified electrodes, containing no so-called redox mediator. The bare electrode shows an ill-defined voltammetric peak for the oxidation of DHN, whereas the monolayer-modified electrodes showed a well-defined voltammetric peak. The monolayer assembly on the gold electrode prevents the fouling of electrode surface by the oxidation products, which favors the oxidation at the less positive potential. The square-wave voltammograms showed a sharp voltammetric signal for the oxidation of NADH at all the monolayer-modified electrodes. All the monolayer-modified electrodes showed a linear current response to change in the NADH concentration in its range of 25-300 microM and their sensitivities were found to be 0.005+/-0.0003, 0.0063+/-0.0002 and 0.0052+/-0.0003 microA/microM for CYST-Au, ME-Au and MPA-Au electrodes, respectively. The hydrodynamic voltammograms obtained at the rotating CYST-Au electrode for the oxidation of NADH and DHN were used to estimate the diffusion coefficient of DHN, and the number of electrons involved in the oxidation process of NADH.

Electrochemistry↗