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

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 polyeth...

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Bibliographic Details
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm300509y