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PubMed1987

Antiarthritic gold compounds effectively quench electronically excited singlet oxygen.

Although certain gold [Au(I)] compounds have been used effectively in the treatment of rheumatoid arthritis for some years, the molecular basis for such therapeutic action has been unclear. One possible mechanism of the action of Au(I) compounds is that they protect unsaturated membrane lipids and proteins against oxidative degradation caused by activated phagocytes that are not properly regulated. In this study it has been shown that superoxide ion (O-2.), a product of activated phagocytes, can be oxidized to electronically excited singlet oxygen (O1(2)delta g), an agent that is capable of peroxidation of unsaturated fatty acid derivatives. It has also been shown that antiarthritic Au(I) compounds are effective deactivators of O1(2)delta g with quenching constants on the order of 10(7) M-1 sec-1.

Arthritis, Rheumatoid↗
PubMed2000

Gold(III) complexes as potential antitumor agents: solution chemistry and cytotoxic properties of some selected gold(III) compounds.

Gold(III) complexes generally exhibit interesting cytotoxic and antitumor properties, but until now, their development has been heavily hampered by their poor stability under physiological conditions. To enhance the stability of the gold(III) center, we prepared a number of gold(III) complexes with multidentate ligands - namely [Au(en)(2)]Cl(3), [Au(dien)Cl]Cl(2), [Au(cyclam)](ClO(4))(2)Cl, [Au(terpy)Cl]Cl(2), and [Au(phen)Cl(2)]Cl - and analyzed their behavior in solution. The solution properties of these complexes were monitored by visible absorption spectroscopy, mass spectrometry, and chloride-selective potentiometric measurements; the electrochemical properties were also studied by cyclic voltammetry and coulometry. Since all the investigated compounds exhibited sufficient stability under physiological conditions, their cytotoxic properties were tested in vitro, via the sulforhodamine B assay, on the representative human ovarian tumor cell line A2780, either sensitive or resistant to cisplatin. In most cases the investigated compounds showed relevant cell-killing properties with IC(50) values falling in the 0.2-10 microM range; noticeably most investigated gold(III) complexes were able to overcome, to a large extent, resistance to cisplatin when tested on the corresponding cisplatin-resistant cell line. The cytotoxic properties of the free ligands were also determined under the same solution conditions. Ethylenediamine, diethylenetriamine, and cyclam were virtually nontoxic (IC(50) values > 100 microM) so that the relevant cytotoxic effects observed for [Au(en)(2)]Cl(3) and [Au(dien)Cl]Cl(2) could be quite unambiguously ascribed to the presence of the gold(III) center. In contrast the phenanthroline and terpyridine ligands turned out to be even more cytotoxic than the corresponding gold(III) complexes rendering the interpretation of the cytotoxicity profiles of the latter complexes less straightforward. The implications of the present findings for the development of novel gold(III) complexes as possible cytotoxic and antitumor drugs are discussed.

Antineoplastic Agents↗
PubMed1985

Modulation of macrophage-lymphocyte interactions by the antiarthritic gold compound, auranofin.

Auranofin (AF), a new oral gold agent effective for treating rheumatoid arthritis (RA) was evaluated for its ability to alter macrophage and lymphocyte functions of immune mediated chronic inflammation. AF (2 microM) inhibited antigen presentation by splenic macrophages to sensitized (DNFB) lymph node cells in vitro and also inhibited production of IL-2 and IL-1 by lymphocytes and macrophages, respectively. When AF suppressed Con-A induced mitogenesis in vitro, there were no inhibitory effects on Con-A induced suppressor T cell functions. AF administered orally to normal mice did not affect antigen presentation. DNFB contact sensitivity or Con-A induced mitogenesis. High concentrations of topical AF inhibited local immune responses to contact sensitizing agents and enhanced the induction of antigen specific suppressor T cells. Optimally, in vitro or in vivo AF inhibited macrophage and helper T cell functions with impairing the induction of suppressor T cells. After chronic treatment, similar effects could contribute to the efficacy of AF in humans with RA.

Animals↗
PubMed1989

Inhibition of several enzymes by gold compounds. II. beta-Glucuronidase, acid phosphatase and L-malate dehydrogenase by sodium thiomalatoraurate (I), sodium thiosulfatoaurate (I) and thioglucosoaurate (I).

Bovine liver beta-D-glucuronide glucuronohydrolase, EC 3.2.1.32), wheat germ acid phosphatase (orthophosphoric monoesterphosphohydrolase, EC 3.1.3.2) and bovine liver L-malate dehydrogenase (L-malate: NAD oxidoreductase, EC 1.1.1.37) were inhibited by a series of gold (I) complexes that have been used as anti-inflammatory drugs. Both sodium thiosulfatoaurate (I) (Na AuTs) and sodium thiomalatoraurate (NaAuTM) effectively inhibited all three enzymes, while thioglucosoaurate (I) (AuTG) only inhibited L-malate dehydrogenase. The equilibrium constants (K1) ranged from nearly 4000 microM for the NaAuTM-beta-glucuronidase interaction to 24 microM for the NaAuTS-beta-glucuronidase interaction. The rate of covalent bond formation (kp) ranged from 0.00032 min-1 for NaAuTM-beta-glucuronidase formation to 1.7 min-1 for AuTG-L-malate dehydrogenase formation. The equilibrium data shows that the gold (I) drugs bind by several orders lower than the gold (III) compounds, suggesting a significantly stronger interaction between the more highly charged gold ion and the enzyme. Yet the rate of covalent bond formation depends as much on the structure of the active site as upon the lability of the gold-ligand bond. It was also observed that the more effective the gold inhibition the more toxic the compound.

Acid Phosphatase↗
PubMed2004

Superconductivity in copper, silver, and gold compounds.

High-temperature superconductivity exists in layered, square-planar cuprates, but is almost absent in most other Cu(II) compounds and in most Ag(II) and Au(II) compounds. Valence state II is quite unusual in silver and gold and often disproportionates to valence states I and III ("negative-U compounds"). The two-electron difference in oxidation state is suggestive of electron pairing, a prerequisite for superconductivity. In the present paper the connection between disproportionation and geometrical structure on one hand and superconductivity on the other is discussed by using the accepted theory for mixed valence complexes. It is concluded that absence of superconductivity in gold and silver compounds can be connected to the instability of oxidation state II and the large difference in equilibrium geometry between oxidation states I and III.

Journal Article↗
PubMedDate not supplied

The modulation of interleukin 1 production by interferon gamma, and the inhibitory effects of gold compounds.

We have studied the in vitro effects of gold sodium thiomalate (GST) and auranofin (Auf) on the production of interleukin 1 (IL1) expressed as thymocyte co-stimulatory activity (TCSA), and interleukin 1 beta (IL1 beta) as modulated by interferon gamma (IFN gamma). Adherent cells (ADC), of which 80% were monocytes, were obtained from human peripheral blood, and stimulated with lipoprotein polysaccharide (LPS) for 24-48 h. TCSA and IL1 beta production by fresh ADC (0-24 h) was significantly higher than that of aged ADC (24-48 h). The addition of IFN gamma to ADC cultures, however, maintained the capacity of aging ADC to respond optimally to LPS. The addition of GST or Auf inhibited this modulatory effect of IFN gamma, resulting in a marked reduction of TCSA and IL1 beta production. The effects of IFN gamma on the production of IL1 may be important in the pathogenesis of rheumatoid arthritis (RA). The inhibition by GST and Auf of IFN gamma modulation may contribute to the therapeutic efficacy of these drugs in RA.

Auranofin↗
PubMed1983

The pharmacological profile of auranofin, an orally active gold compound.

Auranofin (AF; ' Ridaura '), an oral chrysotherapeutic agent, parenteral gold sodium thiomalate (GST) and gold thioglucose (GTG) were evaluated in order to compare their preclinical profiles. AF was found to be more effective than GST and GTG in suppressing inflammation and stimulating cell-mediated immunity. In contrast to GST, AF inhibited cellular release of lysosomal enzymes, antibody-dependent cellular cytotoxicity, production of antibodies in adjuvant arthritic rats, and antibodies involved in cytotoxicity reactions. In pharmacokinetic studies, plasma gold in rats following AF administration, exhibited greater cell association than after GST administration. In conclusion, the pharmacological profile of AF is markedly different from those of GST and GTG and this suggests potential for improvements in chrysotherapy.

Absorption↗
PubMed1986

Induction of mammalian stress proteins by a triethylphosphine gold compound used in the therapy of rheumatoid arthritis.

In vitro exposure of cultured human, murine and rat cells to pharmacologic concentrations (10(-8) to 10(-6) M) of auranofin, 2,3,4,6,-tetra-O-acetyl-1-thio-beta-D-glucopyranosato-S- triethylphosphine gold(I) (Ridaura), a gold containing compound approved for the treatment of rheumatoid arthritis, results in the induction of several stress proteins. The enhanced synthesis of two polypeptides, p32 and p34, was particularly prominent. A similar response was observed in freshly collected human monocytes challenged with auranofin. In addition, oral administration of auranofin to rats induced enhanced synthesis of a 32-kDa protein in peritoneal exudate cells analyzed ex vivo at various times following drug treatment. These data suggest that increased synthesis of p32 and p34 might participate in mediating certain aspects of auranofin pharmacology.

Animals↗
PubMed2005

Tris(mercaptoimidazolyl)borate complexes of the coinage metals: syntheses and molecular structures of the first gold compounds and related copper and silver derivatives.

The first tris(mercaptoimidazolyl)borate complexes of gold, Au(Tm(tBu)) and (Tm(tBu))Au(PPh3), have been prepared and structurally characterized. Together with their copper and silver analogues M(Tm(tBu)) and (Tm(tBu))M(PPh3)(M = Cu, Ag), these compounds constitute the first two complete series of Tm(R) derivatives to be isolated for the coinage metals. In order to evaluate the steric and electronic effects of the bulky tert-butyl substituents in these species, comparative structural analyses with the known methyl-substituted analogue Ag(Tm(Me)) and various (Tm(Me))M(PR3) derivatives (M = Cu, Ag) are also presented.

Journal Article↗
PubMedDate not supplied

Comparative pharmacology and biological effects of different gold compounds.

Auranofin's (AF) physical, chemical, pharmacological, and pharmacokinetic properties differ from those of gold sodium thiomalate (GSTM). AF is lipid soluble, monomeric, nonconductive and is not a potent sulfhydryl reagent. In further contrast to GSTM, AF gold is orally absorbed, exhibits protracted blood levels, is bound to cellular elements of the blood, excreted mainly in the feces, and exhibits less tissue retention. AF is more effective in acute inflammatory models and is a potent inhibitor of lysosomal enzyme release, antibody-dependent cellular cytotoxicity, and superoxide production. AF can suppress antibodies produced in adjuvant arthritic rats and those involved in cytotoxicity reactions; whereas, GSTM is ineffective or immunoenhancing. AF is more effective in stimulating abnormalized cell-mediated immunity. In conclusion, AF is a unique oral chrysotherapeutic agent which can affect cellular and immunopathological events involved in the perpetuation of inflammation and tissue damage.

Animals↗