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. 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.
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