Substituent Effects on Desferrithiocin and Desferrithiocin Analogue Iron-Clearing and Toxicity Profiles

• Published in: Journal of medicinal chemistry 2012-08, Vol.55 (16), p.7090-7103
• Main Authors: Bergeron, Raymond J, Wiegand, Jan, Bharti, Neelam, McManis, James S
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Cebus; Coordination Complexes - chemistry; Coordination Complexes - metabolism; Dihydropyridines - chemistry; Dihydropyridines - metabolism; Dihydropyridines - pharmacology; Dihydropyridines - toxicity; Ethers - chemistry; Ethers - metabolism; Ethers - pharmacology; Ethers - toxicity; Ferric Compounds - chemistry; Ferric Compounds - metabolism; Hydroxylation; Iron Chelating Agents - chemistry; Iron Chelating Agents - metabolism; Iron Chelating Agents - pharmacology; Iron Chelating Agents - toxicity; Iron Overload - metabolism; Kidney - drug effects; Kidney - physiopathology; Ligands; Male; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship; Thiazoles - chemistry; Thiazoles - metabolism; Thiazoles - pharmacology; Thiazoles - toxicity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300509y

Desferrithiocin (DFT, 1) is a very efficient iron chelator when given orally. However, it is severely nephrotoxic. Structure–activity studies with 1 demonstrated that removal of the aromatic nitrogen to provide desazadesferrithiocin (DADFT, 2) and introduction of either a hydroxyl group or a polyether fragment onto the aromatic ring resulted in orally active iron chelators that were much less toxic than 1. The purpose of the current study was to determine if a comparable reduction in renal toxicity could be achieved by performing the same structural manipulations on 1 itself. Accordingly, three DFT analogues were synthesized. The iron-clearing efficiency and ferrokinetics were evaluated in rats and primates; toxicity assessments were carried out in rodents. The resulting DFT ligands demonstrated a reduction in toxicity that was equivalent to that of the DADFT analogues and presented with excellent iron-clearing properties.