Penicillamine, copper complex

Table 6.16. COMPARISON OF ORAL ANTIULCER ACTIVITIES OF PENICILLAMINE COPPER COMPLEXES, COPPER CHLORIDE AND COPPER ACETATE, IN THE SHAY...

The somewhat paradoxical situation of having enhanced copper levels in advanced arthritis, and the moderate advantages of using copper complexes in treatment, is mirrored by the apparent contradiction of D-penicillamine efficacy, despite its clinical use for treatment and excretion of excess copper in Wilson s disease [46]. There is little evidence that penicillamine copper complexes have any relevance in vivo. Ceruloplasmin copper is unavailable for chelation and, indeed, D-penicillamine is not particularly effective at scavenging Cu(II) from BSA [84]. 

A very large number of copper compounds have been tested for antiinflammatory activity, and various copper complexes of antiarthritic drugs have been found to be more effective than the parent drugs alone (including aspirin, D-penicillamine, ketoprofen and gold thiomalate).25... 

Fig. 19.30 Molecular structure of copper complex of D-penicillamine. The [CuiCu" peniciI aminate)i2CI] ion (a) the central cluster of Cu and ligating atoms only (b) the entire ion with the central cluster oriented as in (a). [From Birker. P. J. M. W. L. Freeman, H. C. Chem. Commun. 1976. 312. Reproduced with permission.]...

The list of compounds presented in Table 6.4 includes copper complexes of well-known antiarthritic drugs, including salicylic acid, aspirin, diflunisal, niflumic acid, D-penicillamine, hydrocortisone, dexamethasone, dimethyl-sul-phoxide, clopirac, ketoprofen, ibuprofen, (+ )-naproxen, indomethacin, me-fenamic acid, thiomalic acid, phenylbutazone, lonazolac, isoxicam and azo-propazone. While there has been much discussion concerning the qualitative and quantitative activities of these complexes [136, 152-156, 164, 187], it is... 

Patents have issued for the use of amino-acid complexes [253], copper-metallothioneins [254], compositions of copper compounds mixed with fatty acids [253], copper complexes of D-penicillamine, alkylcysteines [256, 257] and copper complexes offatty acids alone or mixed with metallic copper [258]. Compositions of copper compounds mixed with fatty acids were also claimed to be useful in the treatment of other inflammatory disorders, including cardiovascular and thrombotic disorders, menstrual cycle disorders, diabetes, endometriosis, nutritional deficiencies and malignancies [255]. Scheinberg has also obtained a Food and Drug Administration approved Investigational New Drug application for the treatment of RA with the mixed-valence copper penicillamine complex (personal communication). Preparations of Cu(II)-(oleate) are currently being sold in Europe for topical treatment of RA and other inflammatory disorders under the trade names of Kupfer and Kupfer Forte, which contains fine particles of metallic copper [258]. 

Copper blue proteins, 721 Copper complexes, 533-750 imidazole, 592 D-penicillamine, 592 salicylaldimine, 942 triazole, 592... 

I. Pharmacology. Penicillamine is a derivative of penicillin that has no antimicrobial activity but effectively chelates some heavy metals such as lead, mercury, and copper. It has been used as adjunctive therapy after initial treatment with calcium EDTA (see p 440) or BAL (dimercaprol p 413), although its use has largely been replaced by the oral chelator sucdmer (DMSA, p 501) because of its poor safety profile. Penicillamine is well absorbed orally, and the penicillamine-metal complex is eliminated in the urine. No parenteral form is available. 

Penicillamine is apotent chelator for copper which forms even in vivo very stable copper complexes In contrast to all other complexes described above, copper penicillamine is resistant to EDTA and cyanide treatment. A considerable superoxide dismutase activity of the (Cu(II)6Cu(I -(D-penicillamine)i2Cl) -complex was found employing indirect and direct assay systems jjjgse observations were chal-... 

Concerning the catalytic superoxide dismutase activity of low molecular mass copper complexes, some general comments are neccessary. Firstly, it should be emphasized, that apart from the inactive Cu-penicillamine, all complexes described above do not survive high concentrations of biological chelators in aqueous solutions. For example, bovine serum albumine is able to remove most of the copper from these complexes (Fig. 14). 

Penicillamine also undergoes reactions with copper(ii) peptide complexes which might act as models for the therapeutic effect of penicillamine in the removal of copper in Wilson s disease. A number of species could be identified by e.p.r. and visible absorption techniques, including 1 1 and 1 2 penicillamine-copper(n) complexes, in the binary system although in the ternary systems there was no e.p.r.-detectable ternary complex. The results are consistent with the scheme shown, in... 

Penicillamine is known to form complexes of varying stability with several metal ions. In neutral solution, penicillamine complexes with mercury, lead, nickel, and copper are relatively more stable than those of zinc, iron, and manganese. The three functional groups of penicillamine may be engaged in the formation of metal complex, and the resultant compounds may be polymeric in structure. 

The (n)-enantiomer of penicillamine is used clinically in man either as the hydrochloride or as the free amino acid [1], although the (L)-enantiomer also forms chelation complexes. Penicillamine is an effective chelator of copper, mercury, zinc, and lead, and other heavy metals to form stable, soluble complexes that are readily excreted in the urine [2,3]. 

The use of chelating or complexing agents to treat metabolic dysfunction. The classical example is the use of D-penicillamine to treat Wilson s disease, which is caused by an inability of the body to metabolize copper in the normal way. Another example is the use of desferrioxamine for iron overload in Cooley s anemia, which is caused by a fault in hemoglobin synthesis. 

The kinetics of reaction of a number of A-nitrosothiols (334) in water with mercury(II) salts have been reported. Reaction is first order in both reactants and the products are nitrous acid and the corresponding thiol-Hg2+ complex. The mechanism involves slow attack by water at the nitrogen atom in the complex.300 The same group has also studied the copper(II)-catalysed decomposition of the, -nitrosothiols derived from penicillamine, cysteamine, thiomalic acid, A -acetylpenicillaminc, and cysteine.301... 

In in vitro studies penicillamine inhibited angiotensin-con-verting enzyme (ACE) and carboxypeptidase (930). Penicillamine interferes with the functions of the copper-containing enzyme ceruloplasmin, and some of the penicillamine- and copper-containing complexes formed in vivo have a superoxide dismutase effect (931). In patients with scleroderma, penicillamine normalized collagen metabolism, by inhibiting beta-galactosidase activity (932). 

Mixture of D-penicillamine (pen, Fig. 22) and copper(II) chloride forms a complex of the formula [Cu(I)8Cu(II)6pen12]5-. The Ri value of this complex at 300 MHz and 23°C is 0.586 mM 1 s-1 [178]. The carboxylate groups on the cluster have been shown to react with aziridines such as XAMA-7 (Fig. 23) which in turn can be reacted with biotin [179]. The copper clusters can then be attached to antibodies or other biotinylated proteins via an avidin linker molecule. 

Cellulose was the first sorbent for which the resolution of racemic amino acids was demonstrated [23]. From this beginning, derivatives such as microcrystalline triacetylcellulose and /3-cyclodextrin bonded to silica were developed. The most popular sorbent for the control of optical purity is a reversed-phase silica gel impregnated with a chiral selector (a proline derivative) and copper (II) ions. Separations are possible if the analytes of interest form chelate complexes with the copper ions such as D,L-Dopa and D.L-penicillamine [24], Silica gel has also been impregnated with (-) brucine for resolving enantiomeric mixtures of amino acids [25] and a number of amino alcohol adrenergic blockers were resolved with another chiral selector [26]. A worthwhile review on enantiomer separations by TLC has been published [27],... 

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