Mobilization of Iron by Chiral and Achiral Anionic 3-Hydroxypyrid-4-ones

• Published in: Journal of medicinal chemistry 1994-12, Vol.37 (25), p.4363-4370
• Main Authors: Molenda, John Josef, Jones, Mark M, Johnston, David S, Walker, Ernest M, Cannon, Donald J
• Format: Article
• Language: English
• Subjects: Animals; Anions; Bile - metabolism; Biological and medical sciences; Chemistry; Circular Dichroism; Crystallography, X-Ray; Exact sciences and technology; Female; General and cellular metabolism. Vitamins; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Iron - metabolism; Iron - urine; Iron Chelating Agents - chemical synthesis; Iron Chelating Agents - pharmacology; Medical sciences; Models, Molecular; Molecular Structure; Organic chemistry; Pharmacology. Drug treatments; Preparations and properties; Pyridones - chemistry; Pyridones - pharmacology; Rats; Rats, Sprague-Dawley; Spectrophotometry, Ultraviolet; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00051a014

In the search for 3-hydroxypyrid-4-ones with enhanced iron-mobilizing ability, seven chiral, anionic amino acid derivatives of maltol (3-hydroxy-2-methyl-4-pyrone) have been synthesized, utilizing L-methionine, L-serine, L-leucine, L-phenylalanine, L-glutamic acid, and the D- and L-isomers of alanine. Two achiral, aromatic compounds were also synthesized and compared with the phenylalanine derivative. The biliary iron excretion following iv injection and the urinary iron excretion following po administration were measured using female Sprague-Dawley rats and compared to that of the standard, 1,2-dimethyl-3-hydroxypyrid-4-one (L1). While none of the compounds was as effective as L1 in enhancing the urinary excretion of iron, all monoanionic chelators increased excretion relative to the controls. All monoanionic compounds were at least equivalent to L1 in enhancing the biliary excretion of iron, with the methionine, leucine, and benzoate derivatives surpassing the standard and the other aromatic compounds also showing strong activity. The dianionic glutamate derivative showed low activity relative to the controls for both urinary and biliary iron excretion. No significant difference in iron excretion was observed due to variation in chirality; molecular weight and the number of negative charges appeared to have the greatest influence on the ability of the various derivatives to enhance iron excretion. In order to evaluate the relative purity of the stereoisomers, the alanine derivatives were analyzed by circular dichroism. Further characterization was provided by UV/vis spectroscopy for all compounds and X-ray crystallography for the novel dianionic derivative.