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Iron overload is a serious clinical condition which can be largely prevented by the use of iron-specific chelating agents. Desferrioxamine-B, the most widely used iron chelator in haematology over the past 30 years, has a major disadvantage of being orally inactive. Consequently, the successful design of an orally active, nontoxic, selective iron chelator has become a much sought after goal. In order to identify an ideal iron chelator for clinical use, a range of specifications must be considered such as metal selectivity and affinity, kinetic stability of the complex, bioavailability and toxicity. A wide range of chelator types bind iron(III) and of these, hexa-, tri-, and bidentate are capable of providing iron(III) with the favoured octahedral environment. In this review, the comparative properties of such ligands are discussed, examples being selected from hydroxamates, aminocarboxylates, hydroxypyridinones, orthosubstituted phenols and triazoles.

The synthesis of a range of 2-(1'-hydroxyalkyl)-3-hydroxypyridin-4-ones as bidentate iron(III) chelators with potential for oral administration is described. The pK(a) values of the ligands and the stability constants of their iron(III) complexes have been determined. Results indicate that the introduction of a 1'-hydroxyalkyl group at the 2-position leads to a significant improvement in the pFe(3+) values. Such an effect was found to be greater with the hydroxyethyl substituent than with the hydroxymethyl substituent, particularly in the cases of 1-ethyl-2-(1'-hydroxyethyl)-3-hydroxypyridin-4-one (pFe(3+) = 21.4) and 1,6-dimethyl-2-(1'-hydroxyethyl)-3-hydroxypyridin-4-one (pFe(3+) = 21.5) where an enhancement on pFe(3+) values in the region of two orders of magnitude is observed, as compared with Deferiprone (1, 2-dimethyl-3-hydroxypyridin-4-one) (pFe(3+) = 19.4). The ability of these novel 3-hydroxypyridin-4-ones to facilitate the iron excretion in bile was investigated using a [(59)Fe]ferritin-loaded rat model. Chelators and prodrug chelators possessing high pFe(3+) values show great promise in their ability to remove iron under in vivo conditions.

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