Synthesis, Physicochemical Characterization, and Biological Evaluation of 2-(1‘-Hydroxyalkyl)-3-hydroxypyridin-4-ones:  Novel Iron Chelators with Enhanced pFe3+ Values

• Published in: Journal of medicinal chemistry 1999-11, Vol.42 (23), p.4814-4823
• Main Authors: Liu, Zu D, Khodr, Hicham H, Liu, Ding Y, Lu, Shu L, Hider, Robert C
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Medical sciences; Pharmacology. Drug treatments
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm991080o

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 pFe3+ 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 (pFe3+ = 21.4) and 1,6-dimethyl-2-(1‘-hydroxyethyl)-3-hydroxypyridin-4-one (pFe3+ = 21.5) where an enhancement on pFe3+ values in the region of two orders of magnitude is observed, as compared with Deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one) (pFe3+ = 19.4). The ability of these novel 3-hydroxypyridin-4-ones to facilitate the iron excretion in bile was investigated using a [59Fe]ferritin-loaded rat model. Chelators and prodrug chelators possessing high pFe3+ values show great promise in their ability to remove iron under in vivo conditions.