Action of Copper Complexes

As with all antiarthritic drugs, the situation is not clear. Biochemical effects of copper are general, and no one target, such as a particular protein, is recognizable. The copper complexes are presumably a means of further increasing the copper content, because the species are expected to be rather labile. The introduction of exogenous copper will also affect thiol content and redox state of the cell, and some biochemical responses listed above may be a consequence of this altered state. Besides ceruloplasmin and albumin, major binding sites of Cu(II) are histidine and cysteine [94, 95] and some possibilities for the mechanism of action have been summarized [64]. 

Since lysyl oxidase, the enzyme responsible for tissue repair, is copper-dependent, the possibility exists that lysyl oxidase activity could be induced by copper. The SOD-like activity of many active copper complexes, and the antiinflammatory effects of SOD itself, offer another possibility. Modulation of prostaglandin synthesis by Cu salts [96, 97] stabilization of lysosomal membrane by membrane thiol oxidation [98], stabilization of globulin [89], and alteration of histaminic activity and T-lymphocyte responses have been invoked [64]. 

The immunosuppressant activity of cisplatin, as with most antitumour agents which inhibit nucleic acid synthesis, suggests application in alteration of the immune system associated with arthritis, and platinum complexes have been shown to improve some signs of inflammation [103, 104], Osmium tetroxide, as an intraarticular injection, is essentially of historical interest [105,106], 

The rationale for the use of zinc is that serum zinc levels are lowered in arthritis sufferers, zinc promotes wound healing, and that zinc is necessary for maintenance of some immune responses [107—109]. Some benefit has been observed but with no dramatic improvements, and efficacy is unconfirmed. Despite the logic of the arguments used for zinc, it has been classed as of unlikely benefit , along with other attempts such as acupuncture and prayer [110]. In this respect, taking heart from the traditional use of copper bracelets, we can say that the use of metals probably outdates that of prayer. 

Copper complexes also have demonstrated potential utility in treatment of arthritis. Copper salicylate (permalon) has been marketed but presently no other metal salts besides those of gold are in clinical use. The 

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A large variety of codimerization reactions under the catalytic action of copper complexes is known. Usually, these reactions proceed via carbene intermediates and provide substituted ethenylcyclopropanes. Most of the catalysts for these reactions consist of copper(I) chloride and a phosphorus ligand, such as triphenylphosphane or triphenyl phosphite. Under the influence of these catalysts, carbenes are presumably formed from various substituted cyclopropenes at temperatures ranging from —40 to - -20°C, and these carbenes can be trapped by reaction with alkenes. ... 

A computer study has identified the critical chemical feature required in an AI agent to exploit serum albumin bound copper. Although the mechanism of action of copper complexes is unknown, stimulation of superoxide dismutase has been proposed as a contributing factor. ... 

Table 7.23 Antimicrobial action of copper complexes containing paper sheets on some microorganisns...

Thrombin (MW 39,000) is a proteolytic enzyme of the serine protease group. It is derived from prothrombin, a circulating plasma protein, through the proteolytic action of a complex consisting of the proteolytic enzyme factor X (or factor Xa), another protein called factor V (accelerator protein), calcium, and phospholipid. Factor V has recently been identified as the plasma copper protein ceruloplasmin or a similar protein (see Chapter 6). 

The current theory on the mode of action of copper compounds is that the copper ion, Cu, is the active component, which is released from the different salts on the leaf surfaces. The copper ions in the presence of CO2 from the air and the organic acids excreted from the plant and/or fungal spores interact together to produce the resultant activity. The copper ions and complex-bound copper are capable of penetrating the spores and lead to the inhibition of enzyme reactions. This can occur by the removal of other important metals from their compounds by chelation and also by blocking or interacting with the sulfhydryl groups of the spore enzymes. 

McCallan and Wilcoxon (1936) were the first to report that fungal spores can solubilise copper. In the bathing medium of Neurospora sitophilus spores they detected malic acid and certain amine acids which were able to dissolve copper even from dry deposits of Bordeaux mixture. In this case, complex compounds of the copper(II) ions are formed and, as shown already by the investigations of Bodnar and Terenyi (1930), the fungicidal action of copper(II) complexes proved to be superior to that of copper(II) ions. Horsfall et al. (1937) made similar observations. This phenomenon can be explained by the much higher lipoid solubility of copper(II) complexes (Horsfall, 1957 Durkee, 1958) which allows them to penetrate the cell more easily. They dissociate in the cell, and copper(II) ions are liberated. Thus, complex-forming compounds seem to aid the transport of the... 

The inhibition of the autoxidation of ascorbic acid in the presence of sucrose, dextrose, levulose, and corn sirup, has been studied by various workers (47, 50, 60, 77, 91, 96, 97,109). The autoxidation can be reduced by 10 to 90%, depending upon the concentration of sugar, the pH, and the amount of copper present. Shamrai 97) and Joslyn and Miller (50) attribute the reduced rate of the autoxidation of ascorbic acid at pH of 4 and above to the complexing action of copper by sugars. Copper is an effective oxidation catalyst even at concentrations as low as 1 p.p.m. 

BIOCHEMICAL AND PHYSIOLOGICAL ASPECTS OF COPPER COMPLEXES THAT SUPPORT POSSIBLE MECHANISMS OF ACTION 525... 

Another possible biochemical mechanism of action for copper complex action is based upon the report that copper decreased the permeability of human synovial lysosomes obtained from arthritic patients by oxidizing membrane thiols to disulphides and, as a result, decreased the release of free lysosomal enzymes [80]. Membrane stabilization as opposed to lysosomal enzyme inhibition is also consistent with the observation that many copper complexes, with the exception of Cu(II)(niflumate)2, failed to inhibit cathepsin-D, a lysosomal proteinase [647]. 

An increase in the rate of oxidation of hydroquinone and pyrocatechol by the action of Cu(II), Co(II), Fe(Il), and Mn(II) metal complexes with PEI has been observed [94]. The rate of quinone accumulation depends on the type of metal ion entering the coordination sphere and increases in the following order Cu(II)>Co(II)>Fe(II)>Mn(II). Furthermore, the oxidation of hydroquinone catalyzed by Cu(II) complexes with PVI, PEI and vinyl-amine-vinyl acetate copolymer has been studied in an aqueous solution at 25 °C [95]. In addition, the oxidation of hydroquinone by PVI-Cu(II) and vinylimidazole-vinyl sulfide Vl-VS/Cu(II) complexes has exibited somewhat a typical behavior of copper complexes with copolymers [96]. For example, in respect of VI-VS/Cu(lI) complexes, hydroquinone is oxidized quite rapidly only during the initial phase of the reaction. However, thereafter it changes only slightly. Deviation from linearity has been observed on increasing the content of vinyl sulfide units in the VI-VS copolymer. 

Our current knowledge of the functional relationships between the hypothalamus and the anterior pituitary gland is discussed in Chapter 4. The chemistry, actions and control of hypophysiotropic hormones are well covered. Much controversy exists over the value of copper complexes in the treatment of rheumatic disorders, although these compounds are active in many animal models of inflammation. Chapter 5 surveys this problem and should stimidate medicinal chemists to attempt the preparation of less toxic and more effective and stable complexes. 

The copper(II) complexes of 1-thio-a- and -i8-D-glucopyranose and 2-amino-2-deoxy-l-thio- -D-glucopyranose and their peracetates have been synthesised by action of copper(II) acetate on the respective sodium thiolates, followed by acid catalysed acetylation, for an investigation of their anti-inflammatory activity The mesogenic properties of the C4 - dialkyl dithioacetals of ten standard pentoses and hexoses have been examined. Most of them form thermotropic liquid crystals with the notable exception of all L-rhamnose derivatives. A model has been proposed to correlate carbohydrate configuration and melting behaviour. Despite the intrinsic chirality of all carbohydrate mesogens no evidence for chiral mesophases was detected. 

The action of redox metal promoters with MEKP appears to be highly specific. Cobalt salts appear to be a unique component of commercial redox systems, although vanadium appears to provide similar activity with MEKP. Cobalt activity can be supplemented by potassium and 2inc naphthenates in systems requiring low cured resin color lithium and lead naphthenates also act in a similar role. Quaternary ammonium salts (14) and tertiary amines accelerate the reaction rate of redox catalyst systems. The tertiary amines form beneficial complexes with the cobalt promoters, faciUtating the transition to the lower oxidation state. Copper naphthenate exerts a unique influence over cure rate in redox systems and is used widely to delay cure and reduce exotherm development during the cross-linking reaction. 

Fast sulphon black F ( C.I.26990). This dyestuff is the sodium salt of 1-hydroxy-8-( 2-hydroxynaphthylazo) -2- (sulphonaphthylazo) -3,6-disulph onic acid. The colour reaction seems virtually specific for copper ions. In ammoniacal solution it forms complexes with only copper and nickel the presence of ammonia or pyridine is required for colour formation. In the direct titration of copper in ammoniacal solution the colour change at the end point is from magenta or [depending upon the concentration of copper(II) ions] pale blue to bright green. The indicator action with nickel is poor. Metal ions, such as those of Cd, Pb, Ni, Zn, Ca, and Ba, may be titrated using this indicator by the prior addition of a reasonable excess of standard copper(II) solution. 

Figure 8.3 A model of iron transport across the intestine. Reduction of ferric complexes to the ferrous form is achieved by the action of the brush border ferric reductase. The ferrous form is transported across the brush border membrane by the proton-coupled divalent cation transporter (DCT1) where it enters an unknown compartment in the cytosol. Ferrous iron is then transported across the basolateral membrane by IREG1, where the membrane-bound copper oxidase hephaestin (Hp) promotes release and binding of Fe3+ to circulating apotransferrin. Except for hephaestin the number of transmembrane domains for each protein is not shown in full. Reprinted from McKie et al., 2000. Copyright (2000), with permission from Elsevier Science.

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