The Development of Hydroxypyridin‐4‐ones as Orally Active Iron Chelators

The obvious method of choice for the design of iron chelators is to model novel structures on natural siderophores, which possess extremely high affinities for iron(III).’ These structures are typically based on the hydroxamate and catechol moieties. Unfortunately, hydroxamates are susceptible to the acid environment of the stomach, and some are subject to enzyme-catalyzed cleavage. Consequently, they possess low oral activity. Although the catechol function is more stable, most natural catechol-containing siderophores are still hydrolyzed in the intestinal tract. In an attempt to overcome this difficulty, several research groups have designed nonhydrolyzable analogues of the natural sidcrophore enterobactin.2 Like enterobactin, these moleculcs possess an extremely high affinity for iron(1II) but are insoluble in water. Although this limitation can be avoided by the introduction of sulphonic acid functions, the resulting water-soluble derivatives are poorly absorbed. A further disadvantage associated with catechol siderophores is that they form highly charged iron(I1I) complexes which tend to trap iron in intracellular compartments. In addition to these problems many siderophore analogues are capable of donating iron to pathogenic organisms, and consequently neither hexadentate catechols or hydroxamates appear to be well suited to the task of scavenging and removing iron from iron-overloaded mammals. In order to design molecules which possess a high selectivity for iron(III), and yet lack the disadvantages of the catechol and hydroxamate moieties, a search was made for monoprotic bidentate iron(II1) ligands. There is a range of such aromatic nuclci which are capable both of co-ordinating iron(II1) with high affinity and of forming neutral complexes. These include tropolone, 8-hydroxyquinoline, hydroxypyran-4ones, hydroxypyridin-2-ones, and hydroxypyridin-4-ones. A systematic analysis of the