John R. J. Sorenson

Characterization of a mononuclear copper carboxylate complex: Bis(acetylsalicylato)bis(pyridine)copper(II)

Abstract The preparation, spectral properties, and crystal structure of a mononuclear copper(II) complex of acetylsalicylate and pyridine are reported. The complex exists as bis(acetylsalicylato)bis(pyridine)copper(II) both in the solid state and in chloroform solution. The crystal is monoclinic, space group P21/n, with a = 17.823(5), b = 10.903(4), c = 6.598(2) A, β = 95.74(2)°. The final refinement used 1472 observed reflections and gave an R of 0.046. The copper atom is surrounded by four atoms in a trans square planar arrangement with two short CuO distances of 1.949(3) A and two CuN distances of 2.003(4) A. Two longer CuO distances of 2.623(3) A are made with the remaining oxygen atoms of the aspirin carboxylate groups.

Low-temperature (180 K) crystal structure, electron paramagnetic resonance spectroscopy, and propitious anticonvulsant activities of CuII2(aspirinate)4(DMF)2 and other CuII2(aspirinate)4 chelates.

The purpose of this research was to characterize by X-ray crystallography the ternary dimethylformamide (DMF) Cu(II) complex of acetylsalicylic acid (aspirin), in an effort to compare the structure-activity relationships for the anticonvulsant activity of this and other Cu(II)aspirinate chelates. The ternary DMF Cu(II) complex of aspirin was synthesized and crystals grown from a DMF solution were characterized by single crystal X-ray diffraction. This crystalline material was analyzed for anticonvulsant activity in the Maximal Electroshock (MES) Grand Mal and subcutaneous Metrazol (scMET) Petit Mal models of seizure used to detect anticonvulsant activity. The ternary DMF complex was found to be a monomolecular binuclear complex, tetrakis-mu-(acetylsalicylato)bis(dimethylformamido)dicopper(II) [Cu(II)(2)(aspirinate)(4)(DMF)(2)] with the following parameters: monoclinic, space group P2(1)/n, a=12.259 (1), b=10.228 (1), c=16.987 (1) A, beta=92.07 (1) degrees; V=2128.5 (3) A(3); Z=2. The structure was determined at 180 K from 2903 unique reflections (I>1sigma(I)) to the final values of R=0.030 and wR=0.033 using F. This binuclear complex contains four acetylsalicylate bridging ligands which are related to each other in a two by two symmetry center. The four nearest O atoms around each Cu atom form a closely square planar arrangement with the square pyramidal coordination completed by the dimethylformamide oxygen atom occupying an apical position at a distance of 2.154 (1) A. Each Cu atom is displaced towards the DMF ligand by 0.187 A from the plane of the four O atoms. Electron paramagnetic resonance (EPR) spectra of [Cu(II)(2)(aspirinate)(4)(DMF)(2)] crystals show a strong antiferromagnetic coupling of the copper atoms, similar to that observed with other binuclear copper(II)salicylate compounds. Studies used to detect anticonvulsant activity revealed that [Cu(II)(2)(aspirinate)(4)(DMF)(2)] was an effective anticonvulsant in the MES model of seizure but ineffective against scMET-induced seizures. The monomolecular ternary binuclear [Cu(II)(2)(aspirinate)(4)(DMF)(2)] complex is more effective in inhibiting MES-induced seizures than other binuclear or mononuclear Cu(II) chelates of aspirin including: binuclear polymeric [Cu(II)(2)(aspirinate)(4)], [Cu(II)(2)(aspirinate)(4)(H(2)O)], which is anticipated to be less polymeric, and monomolecular ternary [Cu(II)(2)(aspirinate)(4)(DMSO)(2)] and [Cu(II)(aspirinate)(2)(Pyr)(2)]. These and other chelates appear to be more effective in the scMET model of seizure than [Cu(II)(2)(aspirinate)(4)(DMF)(2)]. These structure-activity relationships support the potential efficacy of Cu chelates of aspirin in treating epilepsies.

Copper complexes of non-steroidal antiinflammatory agents: Analgesic activity and possible opioid receptor activation

Cu(II)2(acetylsalicylate)4, Cu(II)(anthranilate)2, Cu(II)2[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetate]4, Cu(II)(3,5-diisopropylsalicylate)2, Cu(II)(salicylate)2, Cu(II)2{2-[3-(trifluoromethyl)-phenyl]aminonicotinate}4, Cu(II)(l-alaninate)2, Cu(II)(l-cystinate)2, and Cu(II)(glycinate)2 were generally found to be more effective analgesics than their parent ligands, Cu(II)(chloride)2, and Cu(II)2(acetate)4 in the Writhing Mouse and Adjuvant Arthritic Rat pain models following subcutaneous and oral administration. Comparison of the time course of analgesia for salicylic acid and Cu(II)(salicylate)2 in the adjuvant arthritis pain model revealed that this complex had more sustained activity in addition to being more potent than salicylic acid. Cu(II)2(indomethacin)4 was also found to be as effective as morphine in both pain models. These data and pertinent literature are discussed in support of the hypothesis that copper complexes activate copper-dependent opioid receptors.

Treatment of rheumatoid and degenerative diseases with copper complexes: a review with emphasis on copper-salicylate.

This review presents a historical account of the treatment of rheumatoid and other degenerative diseases with copper complexes. Clinical data obtained from 1940 to 1971 are provided for about 1500 patients with rheumatoid arthritis (acute or chronic), rheumatic fever, ankylosing spondylitis, staphlococcal spondylitis, gonococcal arthritis, chronic gouty arthritis, polyarticular synovitis, coxitis, disseminated spondylitis, arthritis with psoriasis, Reiters syndrome, lupus erythematosus, sarcoidosis, arthrosis deformans, erythema nodosum, sciatica (with and without lumbar involvement), cervical spine-shoulder syndrome or lumbar spine syndrome. The drugs used in these studies were Dicuprene, Alcuprin, Cuprimyl, and Permalon, a coppersalicylate preparation. A detailed presentation of toxicities associated with the use of these copper complexes is included.

Mononuclear and binuclear copper(II) complexes of 3,5-diisopropylsalicylic acid

Abstract Several copper(II) complexes of 3,5-diisopropylsalicylic acid and a variety of ligating solvents have been prepared and studied by elemental analysis, and by infrared, electronic, and EPR spectroscopy. In the solid state, all of the compounds are binuclear, carboxylate-bridged Cu2(3,5-DIPS)4(L)2, where L may be a vacant site or a coordinating ligand. In non-coordinating solvents such as hexane and dichloromethane, the binuclear structure is retained in solution, but in polar coordinating solvents the dimer dissociates into monomers where the copper is coordinated to two solvent molecules and to two bidentate diisopropylsalicylate ligands through their carboxylic and phenolic oxygen atoms.

Copper complexes: a physiological approach to the treatment of ‘inflammatory diseases’

Abstract Plasma concentrations of low molecular weight copper-containing components are known to increase in response to arthritis, epilepsy, and cancer. Each of these diseases are recognized as having inflammatory components. Evidence is provided to show that administration of low molecular weight copper complexes produce antiinflammatory effects in animal models of inflammation, anticonvulsant effects in animal models of seizure, and anticancer effects in animal models of cancer. These data are reviewed in support of the hypothesis that the elevation of plasma copper-containing components represents a physiologic response which may lead to remission. Promotion of this physiologic response would appear to be a valid approach to the treatment of arthritis, epilepsy, cancer, and other diseases with inflammatory components.

Anticancer activity of metal compounds with superoxide dismutase activity

LARRY W. OBERLEY I, S.W.C. LEUTHAUSER l, ROBERT F. PASTERNACK 2, TERRY D. OBERLEY 3, LOREN SCHUTT J and JOHN R. J. SORENSON 4 JRadiation Research Laboratory, 14 Medical Laboratories, The University of Iowa, Iowa City, Iowa 52242, USA 2Department of Chemistry, Ithaca College, Ithaca, New York 14850, USA, 3Department of Pathology and Immunobiology Research Center, University of Wisconsin, 470 North Charter Street, Madison, Wisconsin 53706, USA, and 4College of Pharmacy, University of Arkansas Medical Sciences Campus, 4301 West Markham Street, Little Rock, Arkansas 72201, USA

Pharmacologic Activities of Copper Compounds in Chronic Diseases

Copper complexes have been shown to be effective antiinflammatory, antiulcer, anticonvulsant, anticancer, and antidiabetic agents. This seemingly diverse variety of pharmacologic effects is unified by the hypothesis that copper complexes facilitate or promote tissue repair processes involving copper-dependent enzymes and that arthritis, ulcers, seizures, neoplasia, and diabetes are diseases of specific tissues in disrepair. The corollary to this hypothesis is that the loss or reduction of copper-dependent enzyme-mediated processes leads to tissue dysfunction that may be reversed with copper complex therapy.

Effect of nutritional copper deficiency on adjuvant arthritis and immunocompetence in the rat

Both severe and marginal copper deficiency were produced in male Sprague Dawley rats prior to induction of adjuvant arthritis. Degree of copper deficiency was confirmed by analysis of plasma, liver, and brain samples prior to adjuvant injection. Incidence of adjuvant arthritis was the same in both copper deficient and control animals although the severity was slightly but not statistically less in the former. However, recovery from foot edema was impaired in copper-deficient animals, while marginally copper-deficient animals recovered at the same rate as did controls. Plasma copper concentration increase in response to the injection of adjuvant and the increase was directly related to dietary copper content. Plasma zinc concentration was decreased in arthritic animals and the decrease was inversely correlated to paw edema. Liver copper, zinc, and iron concentrations in arthritic animals remained unchanged or increased slightly in comparison to the corresponding non-injected controls. Copper-deficient rats were immunosuppressed as demonstrated by impaired responsiveness to the T-cell dependent contact sesitizing agent oxazolone and diminshed capacity to respond to the T-cell independent antigen Type III pneumococcal polysaccharide. Although a statistical difference in paw volumes was not found for group of animals fed diets differing in copper content, it is postulated that copper deficiency may alter the severity and kinetics of adjuvant arthritis by impairing aspects of the immune response and the tissue repair processes subsequent to injury.

Low-temperature crystal structures of Tetrakis-μ-3,5-diisopropylsalicylatobis-dimethylformamidodicopper(II) and Tetrakis-μ-3,5-diisopropylsalicylatobis-diethyletheratodicopper(II) and their role in modulating polymorphonuclear leukocyte activity in overcoming seizures

Two binuclear copper(II) complexes of 3,5-diisopropylsalicylic acid were characterized by single crystal X-ray diffraction methods and examined for anti-inflammatory activity using activated polymorphonuclear leukocytes and for anticonvulsant activities using electroshock and metrazol models of seizures. These complexes were crystallized from dimethylformamide (DMF) or diethylether. Tetrakis-mu-3,5-diisopropylsalicylatobis-dimethylformamidodicop per(II) [Cu(II)2(3,5-DIPS)4(DMF)2] I is in space group P 1; a = 10.393 (2), b = 11.258 (2), c = 12.734 (2) A, alpha = 96.64 (2), beta = 92.95 (2), gamma = 94.90 (2) degrees; V = 1471.7 (4) A3; Z = 1. Tetrakis-mu-3,5-diisopropylsalicylatobis-etheratodicopper(II ) [Cu(II)2(3,5-DIPS)4(ether)2] II is in space group P 1; a = 10.409 (3), b = 11.901 (4), c = 12.687 (6) A, alpha = 91.12 (5), beta = 90.84 (5), gamma = 100.90 (4) degrees; V = 1542 (1) A3; Z = 1. The structure of I was determined at 140 K from 4361 unique reflections (I > 2sigma(1)) and refined on F2 to R1 = 0.04 and wR2 = 0.09. The structure of II was determined at 180 K from 4605 unique reflections (I > 2sigma(I)) and refined on F2 to R1 = 0.05 and wR2 = 0.13. Each compound is a crystallographically centrosymmetric binuclear complex with Cu atoms bridged by four 3,5-diisopropylsalicylate ligands related by a symmetry center [Cu-Cu(i): 2.6139 (9) A in I and 2.613 (1) in II]. The four nearest O atoms around each Cu atom form a nearly rectangular planar arrangement with the square pyramidal coordination completed by the dimethylformamide (or diethylether) oxygen atom occupying an apical position, at a distance of 2.129 (2) A in I and 2.230 (3) A in II. Each Cu atom is displaced towards the DMF (or diethylether) ligand, by 0.189 A in I and 0.184 A in II, from the plane of the four O atoms. The crystal structures of I and II are essentially similar to each other, except for the DMF or diethylether accommodation. Many disorder phenomena were found in the crystal structure of I. Copper(II)2(3,5-DIPS)4(DMF)2 inhibited polymorphonuclear leukocyte (PMNL) oxidative metabolism in vitro. This effect was concentration related and significant for concentrations higher than 10 microg or 0.68 nmol/ml. Copper(II)2(3,5-DIPS)4(DMF)2 was more active than the parent ligand, 3,5-DIPS, as has been demonstrated with copper complexes of other non-steroidal anti-inflammatory drugs. The DMF and diethylether ternary complexes of Cu(II)2(3,5-DIPS)4 were found to have anticonvulsant activity in the maximal electroshock model of grand mal epilepsy in doses ranging from 26 to 258 micromol/kg of body mass following intraperitoneal, subcutaneous, or oral treatment. The DMF ternary complex was also found to be effective in the subcutaneous injection of metrazol model of petit mal epilepsy. We conclude that both ternary copper complexes are lipophilic and bioavailable, capable of facilitating the inflammatory response to brain injury and causing the subsidence of this response in bringing about remission of these disease states.