Effects of C-4 stereochemistry and C-4' hydroxylation on the iron clearing efficiency and toxicity of desferrithiocin analogues

Article abstract of DOI:10.1021/jm990058s

Additional structure-activity studies of desferrithiocin analogues are carried out. The effects of stereochemistry at C-4 on the ligands' iron clearing efficiency are reviewed and assessed using the enantiomers 4,5- dihydro-2-(2,4-dihydroxyphenyl)thiazole-4(R)-carboxylic acid and 4,5-dihydro- 2-(2,4-dihydroxyphenyl)thiazole-4(S)-carboxylic acid. The utility of 4'- hydroxylation as a method of reducing the toxicity of desazadesferrithiocin analogues is also examined further with the synthesis and in vivo comparison of 4,5-dihydro-2-(2-hydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid, which is the natural product 4-methylaeruginoic acid, and 4,5-dihydro-2- (2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid. The stereochemistry at C-4 is shown to have a substantial effect on the iron clearing efficiency of desferrithiocin analogues, as does C-4'-hydroxylation on the toxicity profile. All of the compounds are evaluated in a bile-duct- cannulated rodent model to determine iron clearance efficiency and are carried forward to the iron-overloaded primate for iron clearing measurements. On the basis of the results of the present work, although 4,5- dihydro-2-(2,4-dihydroxyphenyl)thiazole-4(S)-carboxylic acid is still the most promising candidate for clinical evaluation, 4,5-dihydro-2-(2,4- dihydroxyphenyl)4-methylthiazole-4(S)-carboxylic acid (4'- hydroxydesazadesferrithiocin) also merits further preclinical assessment.