Fox, Raymond Charles; (1996) The synthesis and characterisation of hydroxypyranones and hydroxypyridinones. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A number of bidentate and oligodentate metal(III) ion chelators based on the 3-hydroxy-4H- pyranone, 3-hydroxy-2(1H)-pyridinone and 3-hydroxy-4(1H)-pyridinone moieties have been synthesised and characterised. The prototype carbon-carbon bond forming reaction, the Mannich reaction was employed in the synthesis of 3-hydroxy-2(1H)-pyridinone and 3- hydroxy-4(1H)-pyridinone bidentate ligands to furnish suitable synthons for the development of oligodentate chelators. Directed aminomethylation is discussed in relation to the synthesis of a number of derivatives whose properties may affect their efficacy as potential oral chelation agents. A number of novel tetradentate chelators are also described. The determination of the ionisation (pKn) and the gallium(III) and indium(III) stability (log Kn) constants of a representative number of ligands have been performed using spectrophotometric and potentiometric techniques. Biological studies have indicated that one of the novel tetradentate chelators described approaches the efficacy exhibited by the clinically approved drug, Deferiprone for the in vitro mobilisation of ferritin-bound iron. It is hoped to develop an orally active chelation agent to replace Desferal (the methane sulphonate salt of Desferrioxamine B) for the treatment of pathologies associated with transfusion-induced iron overload. Iron chelation agents may also find application in the treatment of other disease states including asthma, malaria and rheumatoid disease.

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