Copper biologically active chelates

A current area of interest is the use of AB cements as devices for the controlled release of biologically active species (Allen et al, 1984). AB cements can be formulated to be degradable and to release bioactive elements when placed in appropriate environments. These elements can be incorporated into the cement matrix as either the cation or the anion cement former. Special copper/cobalt phosphates/selenates have been prepared which, when placed as boluses in the rumens of cattle and sheep, have the ability to decompose and release the essential trace elements copper, cobalt and selenium in a sustained fashion over many months (Chapter 6). Although practical examples are confined to phosphate cements, others are known which are based on a variety of anions polyacrylate (Chapter 5), oxychlorides and oxysulphates (Chapter 7) and a variety of organic chelating anions (Chapter 9). The number of cements available for this purpose is very great. 

The role of Cu as an essential trace element has focused attention on possible roles for copper chelation of biologically active ligands, with subsequent interference of normal transport and distribution, as well as the role of the metal in redox reactions due to the accessible oxidation states of (I) and (II). Similarly, the physiological response of copper levels in disease conditions [50] and the overall role of trace metals in health and disease [51, 52] are relevant and of considerable importance. The increase in serum copper content in infections, arthritic diseases, and certain neoplasms is well documented and, in fact, the subsequent decrease in level upon treatment has been used successfully as an indicator of cancer remission [50]. Copper complexes may be effective in therapy due in part to their ability to mimic this physiological response of elevated copper [53] and, clearly, the interplay of introduced copper with pre-existent bound copper and effects on copper—protein mediated processes will affect the ultimate biological fate of the complex. Likewise, while the excess accumulation of free Cu, and indeed Fe and Zn, caused by malfunction or absence of normal metabolic pathways is extremely damaging to the body, the controlled release of such metals may be beneficially cytotoxic. The widespread pharmacological effects of copper complexes have been briefly reviewed [54]. 

Primary effect affinity precipitation is best suited for the purification of proteins showing multiple-point interaction with some of the above mentioned small affinity ligands. Typical target substances for primary effect affinity precipitation are, for example, enzymes, which interact with triazine dyes such as Cibacron blue, but also proteins rich in surface histidine residues, since these protein show strong interaction with immobilized (chelated) transition metal ions such as copper or zinc. The latter effect can be used in a very general manner since the introduction of so-called histidine-tags (i.e., multiple histidine sites) into recombinant proteins is a routine procedure, which normally has litde or no influence on the biological activity of the protein. ... 

Iron is transported in forms in which it is tightly complexed to small chelators called siderophores (microorganisms) or to proteins called transferrins (animals) or to citrate or mugeneic acid (plants). The problem of how the iron is released in a controlled fashion is largely unresolved. The process of mineral formation, called biomineralization, is a subject of active investigation. Vanadium and molybdenum are transported as stable anions. Zinc and copper appear to be transported loosely associated with peptides or proteins (plants) and possibly mugeneic acid in plants. Much remains to be learned about the biological transport of nonferrous metal ions. 

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). 

Scheme 4. Schiff-base superoxide dismutase models surriving biological chelators. Upper section Dibenzoy Imethane does not readily react with 2-(2-aminoethyl)-pyridine due to a keto-enol tautomery. Therefore only poorly active and instable complexes are obtained. In contrast, 2-pyridine-aldehyde and putrescine yield a highly active and stable copper

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