3-Hydroxy-4(1H)-Pyridinones Iron Chelators

Under the above title, here is an extract of my thesis for a PhD study I have undertaken between 1993-96 A.D. in the Department of Pharmacy, Chelsea, London, U.K.

ABSTRACT

Although iron is an essential element to all living cells, it is toxic when the level exceeds the tissue or blood binding capacity. An increased amount of iron is found in iron-loaded patients such as those suffering from b-thalassaemia. The conventional way to treat b-thalassaemia major is regular and frequent blood transfusion. Patients on hypertransfusion regimens may accumulate up to 8-10 g of iron per year. Thus iron must be removed from the tissues by the use of an effective chelating agent. Desferrioxamine has been successfully used to treat transfusional iron-overload, however, it suffers from being not orally active and has to be given by s.c. or i.v. infusion over 8-12 h periods, 5-7 days a week. Thus an orally active alternative is required to improve the quality of life for such patients, as well as providing a possible means of improving chelation efficiency. The 3-hydroxy-4(1H)-pyridinone (HPO) moiety has been identified as a suitable therapeutic iron(III) chelator. The aims of the present study are based on two different approaches designed to tackle certain disadvantages associated with the simple N-alkyl bidentate 3-hydroxy-4(1H)-pyridinones.

A) Tridentate concept;

This approach has been investigated in an attempt to diminish the toxicity associated with partially dissociated bidentate iron(III) complexes and the resulting free radical damage associated with such compounds. Eight 3-hydroxy-4(1H)-pyridinone compounds have been investigated for their potential as tridentate ligands. The physico-chemical properties of these ligands have been fully characterised. In order to establish whether this class of HPO behaves in a bidentate or tridentate fashion, a spectral study of the corresponding iron(III) complexes over a wide range of pH has been made. This study demonstrates that these prototype HPOs behave as bidentate ligands and therefore offer little advantage over the simple bidentate HPOs.

B) Prodrug concept;

The second approach was directed towards the design of HPOs to be targeted to the liver, a major iron storage organ in b-thalassaemia patients. In principle this property would diminish the toxicity typically associated with partially dissociated bidentate iron(III) complexes. 3-Hydroxy-4(1H)-pyridinone compounds have been prepared as prodrug ester derivatives of N-hydroxyalkyl-3-hydroxypyridin-4(1H)-ones. The physico-chemical properties of these new HPO ligands have been fully characterised.

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