The design, synthesis, and evaluation of organ-specific iron chelators.
A series of iron chelators, three (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid (DADFT) and three (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-thiazolecarboxylic acid (DADMDFT) analogues are synthesized and assessed for their lipophilicity (log Papp), iron-clearing efficiency (ICE) in rodents and iron-loaded primates (Cebus apella), toxicity in rodents, and organ distribution in rodents. The results lead to a number of generalizations useful in chelator design strategies. In rodents, while log Papp is a good predictor of a chelator's ICE, chelator liver concentration is a better tool. In primates, log Papp is a good predictor of ICE, but only when comparing structurally very similar chelators. There is a profound difference in toxicity between the DADMDFT and DADFT series: DADMDFTs are less toxic. Within the DADFT family of ligands, the more lipophilic ligands are generally more toxic. Lipophilicity can have a profound effect on ligand organ distribution, and ligands can thus be targeted to organs compromised in iron overload disease, for example, the heart.
Bergeron
Raymond J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA. rayb@ufl.edu
Wiegand
Jan
J
McManis
James S
JS
Bharti
Neelam
N
D000818:Animals; D001646:Bile / Q000378:metabolism; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002428:Cebus; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007505:Iron-Dextran Complex / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014018:Tissue Distribution
D002264:Carboxylic Acids; D004095:Dihydropyridines; D007502:Iron Chelating Agents; D013844:Thiazoles; C477594:desazadesferrithiocin; D007505:Iron-Dextran Complex