Partition-Variant Desferrithiocin Analogues:  Organ Targeting and Increased Iron Clearance

• Published in: Journal of medicinal chemistry Vol. 48; no. 3; pp. 821 - 831
• Main Authors: Bergeron, Raymond J, Wiegand, Jan, McManis, James S, Weimar, William R, Park, Jeong-Hyun, Eiler-McManis, Eileen, Bergeron, Jennifer, Brittenham, Gary M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10-02-2005
• Subjects: Animals; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacokinetics; Ascorbic Acid - chemistry; Catechols - chemical synthesis; Catechols - chemistry; Catechols - pharmacokinetics; Cebus; Dihydropyridines - chemical synthesis; Dihydropyridines - chemistry; Dihydropyridines - pharmacokinetics; Free Radical Scavengers - chemical synthesis; Free Radical Scavengers - chemistry; Free Radical Scavengers - pharmacokinetics; Humans; In Vitro Techniques; Iron - chemistry; Iron - pharmacokinetics; Iron Chelating Agents - chemical synthesis; Iron Chelating Agents - chemistry; Iron Chelating Agents - pharmacokinetics; Liver - metabolism; Male; Myocardium - metabolism; Oxidation-Reduction; Pancreas - metabolism; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacokinetics; Tissue Distribution
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049306x

Altering the lipophilicity (log P app) of desferrithiocin analogues can change the organ distribution of the chelators and lead to enhanced iron clearance. For example, alkylation of (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [(S)-4‘-(HO)-DADFT] and its analogues to more lipophilic compounds, such as (S)-4,5-dihydro-2-(2-hydroxy-4-methoxyphenyl)-4-methyl-4-thiazolecarboxylic acid [(S)-4‘-(CH3O)-DADFT], provides ligands that achieved between a 3- and 8-fold increase in chelator concentrations in the heart, liver, and pancreas (the organs most at risk in iron-overload disease) of treated rodents. The 4‘-O-methylated compounds are demethylated to their hydroxylated counterparts in rodents; furthermore, this O-demethylation takes place in both rodent and human liver microsomes. The relationship between chelator lipophilicity and iron-clearing efficacy in the iron-overloaded Cebus apella primate is further underscored by a comparison of the iron-clearing efficiency of (S)-2-(2,3-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [(S)-3‘-(HO)-DADFT] and its 3‘-(CH3O) counterpart. Finally, these DFT analogues are shown to be both inhibitors of the iron-mediated oxidation of ascorbate as well as effective radical scavengers.