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Substituent effects on desferrithiocin and desferrithiocin analogue iron-clearing and toxicity profiles.

ABSTRACT: 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.

SUBMITTER: Bergeron RJ

PROVIDER: S-EPMC3583384 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Substituent effects on desferrithiocin and desferrithiocin analogue iron-clearing and toxicity profiles.

Bergeron Raymond J RJ Wiegand Jan J Bharti Neelam N McManis James S JS

Journal of medicinal chemistry 20120813 16

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 toxic ...[more]

PMID: 22889170

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