title: Partition-variant desferrithiocin analogues: organ targeting and increased iron clearance.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA. bergeron@mc.cop.ufl.edu
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Bergeron
authors.forename: Jan
authors.initials: J
authors.lastname: Wiegand
authors.forename: James S
authors.initials: JS
authors.lastname: McManis
authors.forename: William R
authors.initials: WR
authors.lastname: Weimar
authors.forename: Jeong-Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Eileen
authors.initials: E
authors.lastname: Eiler-McManis
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bergeron
authors.forename: Gary M
authors.initials: GM
authors.lastname: Brittenham
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D001205:Ascorbic Acid / Q000737:chemistry; D002396:Catechols / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002428:Cebus; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D007501:Iron / Q000737:chemistry / Q000493:pharmacokinetics*; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: C497148:2-(2,3-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid; D000975:Antioxidants; D002396:Catechols; D004095:Dihydropyridines; D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D013844:Thiazoles; D007501:Iron; D001205:Ascorbic Acid; C050223:desferrithiocin