Essential and beneficial metals

Calcium Cobalt

Bone deformities (Rickets), tetany Anaemia, anorexia

Atherosclerosis, cataracts, gall stones Cardiomyopathy, hypothyroidism, polycythaemia, cancer Wilson's disease, intestinal and liver inflammation, haemolysis, hyperglycaemia Contact dermatitis, allergy, lung cancer

Copper

Anaemia, Menke's "kinky hair" syndrome

Chromium

Defective glucose metabolism, hyperlipidaemia, corneal opacity Anaemias

Iron

Haematochromatosis, siderosis, cardiac failure, cancer

Lithium Manic depression

Magnesium Convulsions

Molybdenum Growth depression,

None yet recognised Anaesthesia

Anaemia, "gout-like" lesions, persistent keratinization defects, hyperpurinaemia dysentery (sheep and cattle)

Manganese Skeletal deformities, testicular dysfunction

Ataxia, liver cirrhosis, psychiatric disorders

Selenium

Zinc

Liver necrosis, endemic cardiomyopathy (Kesham disease), osteoarthropathy (Kashin's Beck disease), muscular dystrophy (sheep and cattle), membrane malfunction Anorexia, dwarfism, anaemia, hypogonadism, hyperkeratosis, acrodermatitis enteropathica, depressed immune response, teratogenic effects.

Non-essential, non-beneficial elements

Aluminium None yet recognised

Antimony Beryllium Cadmium

Lead Mercury

Thallium

None yet recognised None yet recognised Reduced growth

None yet recognised None yet recognised

None yet recognised

Radioelements e.g. None yet recognised radium uranium, thorium, plutonium and radioisotopes__

Teratogenesis, foetal toxicity, hepatic and renal damage, cancer, blind staggers in cattle.

Hyperchronic anaemia, metal fume fever at high doses

Bone disorders, encephalopathy, dialysis dementia

Hepatic and cardiac damage, cancer Skin and lung irritation, granuloma, cancer Renal, hepatic, cardiac, skeletal and haematological disorders Anaemia, encephalitis, renal damage Encephalitis, neuropsychiatric disorders, renal damage Central nervous system damage, loss of vision or hearing

Cancer induction, genetic effects, cataract of essential and beneficial elements

• Several metals play important roles through redox reactions in facilitating electron flow to enable high speed transport of signals in nerves, and in storing energy or information.

13.3 METAL COORDINATION CHEMISTRY

13.3.1 General aspects

Since many biochemicals and pharmaceuticals are often near ideal ligands for transition metal ions it is appropriate here to summarise briefly the basic aspects of the chemistry of metal complexation. For a full discussion of this topic the reader is referred to the works given in the references (Huheey 1978; Stenlake 1979; Taylor and Williams 1995). A ligand may be defined as a chemical which has a pair of electrons that can be donated to a vacant orbital in a metal ion. Important biochemical/pharmacological donor groups are RS-, -NH2, -COO- and -O-, in addition other groups such as -PO43-, -NO3- etc. can form dative covalent bonds by donating electrons into vacant orbitals in a metal ion. Metal coordination is biochemically important because it may mask the normal chemical properties of the metal or alter the properties of the ligand. The classic example of this phenomenon is the relatively non toxic substance potassium ferrocyanide (K4Fe(CN)6), (see Figure 13.3) which is made by mixing together two very toxic solutions of potassium cyanide and ferrous cyanide. The underlying chemistry of this was explained more than a century ago by Werner, who postulated the following principles.

Figure 13.3 Werner's complex.

Metals have two types of valency; first, a primary and ionizable valency, that is satisfied by negative ions such as Cl-, NO3-, SO42-, CN-, and a secondary and non-ionizable (covalent) one. For each metal there is a fixed number of secondary valencies—called the coordination number; for Fe2+ the coordination number is 6, while for Cu2+ it may be either 4 or 6, and coordination numbers ranging up to 8 are found with other metals. The secondary valencies are directional in nature radiating out from the central metal ion towards the corners of a regular tetrahedron or a regular octahedron with coordination numbers or 4 and 6, respectively. In potassium ferrocyanide the complex iron-cyanide moiety, [Fe(CN)6]4-, ionises as a complete unit and no highly toxic CN- ions are produced.

Large ligands can be attached to the metal ion by two or more bonds providing that their spacing is sufficient to accommodate the spatial distribution of the secondary valencies of the metal ion. The terms bi-, tri-, hexa- or polydentate are used to describe ligands with 2,3,6, or many points of attachment. Often rings are formed which are called chelate rings, 5- and 6- membered rings are most stable and hence are those most commonly encountered. Chelation may increase bond strengths by factors even as great as one millionfold; such polydentate ligands as the porphyrin rings in haemoglobin or vitamin B12, form exceptionally stable complexes which fix Fe2+ and Co2+, respectively, in their lower oxidation states and facilitate the biochemical functions of the molecules. The directional nature of the secondary bonds of a metal ion enables them to act as templates to hold specific configurations; such templates probably played a major role in biochemical evolution and they are important to-day in, for example, the production of chiral isomers.

In biochemistry and pharmacology complexing ligands can be used to hold a metal in an unfavourable valence state, to neutralize a charge to enable a metal complex to pass through a cell membrane, to produce exceptionally stable bonding by multiple chelation and to assist in the development of ligand drugs designed to react with a specific ion in vivo, for example to detoxify and remove a polluting metal.

13.3.2 Metal-ligand specificity

13.3.2.1 Complex stability

Metal ions and ligands show a definite order of affinity for each other. One method of quantifying the degree of tightness of the binding is to use mass-action equilibrium data for the reactions between the metal and a ligand, or ligands, to calculate a formation constant, K or p. Thus for the reaction of one atom of a metal M with one molecule of a ligand L the equilibrium is:

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