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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Bergeron RJ,Wiegand J,Bharti N,McManis JSdoi
10.1021/jm300509ysubject
Has Abstractpub_date
2012-08-23 00:00:00pages
7090-103issue
16eissn
0022-2623issn
1520-4804journal_volume
55pub_type
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