摘要：

IntroductionRoles of metal ions in low molecular mass (l.m.m.) species2,3and in the active sites of metallo-enzymes such as copper–zinc superoxide dismutase (CuZnSOD)4,5have long been of biological interest. The elevation of the concentrations of l.m.m. copper(ii) complex species in the plasma and synovial fluids of rheumatoid arthritic (RA) patients is well documented, indicating some involvement of copper in this disease.2–4In addition, a number of Cu2+chelates have been shown to possess anti-inflammatory activity.2,3A further review of the literature has shown that Cu2+is unable to reach the ribosomes and therefore, fails to be incorporated into the relevant enzyme systems.6For RA sufferers, this is indicative of a defective Cu2+transport mechanism which may be attributed to a Cu2+‘carrier’ being absent within the plasma resulting in the metal ion being unable to partition across the plasma membrane barrier as an initial step into entering the cytosol.6It appears that a ‘carrier’ ligand, L, which can complex copper and enhance its transportation across a membrane, is required. However, for this ligand to be of potential application in the treatment of RA, it must be able to either compete with histidine for copper in plasma or form ternary complexes of the type Cu–His–L.Such a ligand must also be selective for copper over calcium(ii) and zinc(ii), as these two metal ions are present in plasma at much higher concentrations than copper(ii) and hence are potential competitorsin vivo.7,8Previously, we have shown that 3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioxime (L1) (Fig. 1) forms stable complexes with copper(ii).9The plasma mobilizing index (p.m.i.) was promising9but did not include the possibility of competition with zinc(ii) and calcium(ii). This is the essence of this paper in which competition by zinc(ii) and calcium(ii) had been considered. It is also part of a wider spectrum of investigations10–12aimed at developing copper(ii)-based anti-inflammatory complexes which can be administered orally, intravenously or even transdermally. Although copper(ii) complexes when administered orally and intravenously do increase available copper, it is difficult to move this coordinated metal ion through a series of body compartments without binding to proteins.8This study also considers percutaneous absorption of copper as another method of drug administration. Transdermal absorption, however, requires that the permeate should be reasonably lipophilic. We have, hence, investigated octan-1-ol/water partition coefficients of the copper complexes as the measure of their lipophilicity using the solvent mixture as a biophase analogue.13,14The superoxide dismutase mimic activity of the copper complex predominating at pH 7.8 was determined using the nitroblue tetraazolium (NBT) assay.15–17Molecular mechanics (MM) calculations and molecular dynamics (MD) simulations were used to assess the low energy conformations of the copper and zinc complexes.18Structures of ligands mentioned in this paper and those of predicted complex species in solution. For simplicity, the axial H2O ligands are omitted in these representations.A number of polyaminocarboxylates incorporating gadolinium(iii) are presently used or are under development as contrast agents in magnetic resonance imaging (MRI). Caravanet al.19have given an extensive review on the latest advances in contrast agents development. Taking advantage of the fact that all three divalent metal ions are competitors of gadoliniumin vivo, the formation constants of Gd3+with the ligand were investigated for possible use of the resulting complexes as contrast agents in MRI.

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