Department of Medicinal Chemistry, University of Florida, Box 100485 JHMHC, Gainesville, Florida 32610-0485, USA.
J Med Chem. 2012 Aug 23;55(16):7090-103. doi: 10.1021/jm300509y. Epub 2012 Aug 13.
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.
地拉罗司（DFT，1）口服时是一种非常有效的铁螯合剂。然而，它具有严重的肾毒性。用 1 进行的构效关系研究表明，去除芳族氮以提供去甲地拉罗司（DADFT，2），并在芳环上引入羟基或聚醚片段，得到了口服活性的铁螯合剂，其毒性远小于 1。本研究的目的是确定通过对 1 本身进行相同的结构操作是否可以达到类似的降低肾毒性的效果。因此，合成了三种 DFT 类似物。在大鼠和灵长类动物中评估了其清除铁的效率和铁动力学；在啮齿动物中进行了毒性评估。结果表明，这些 DFT 配体的毒性降低与 DADFT 类似物相当，且具有良好的清除铁的特性。
