847355-89-9Relevant academic research and scientific papers
Partition-variant desferrithiocin analogues: Organ targeting and increased iron clearance
Bergeron, Raymond J.,Wiegand, Jan,McManis, James S.,Weimar, William R.,Park, Jeong-Hyun,Eiler-McManis, Eileen,Bergeron, Jennifer,Brittenham, Gary M.
, p. 821 - 831 (2005)
Altering the lipophilicity (log Papp) 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′-(CH 3O)-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.
