Synthesis of 2-amido-3-hydroxypyridin-4(1H)-ones:: Novel iron chelators with enhanced pFe3+ values
Synthesis of 2-amido-3-hydroxypyridin-4(1H)-ones:: Novel iron chelators with enhanced pFe3+ values
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DOI：
10.1016/s0968-0896(00)00273-x
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发表时间：
2001-03-01
影响因子：
3.5
通讯作者：
Hider, RC
中科院分区：
文献类型：
--
作者：
Liu, ZD;Piyamongkol, S;Hider, RC
描述了作为具有口服给药潜力的双齿铁（III）螯合剂的一系列2-氨基-3-羟基吡啶-4-酮的合成。配体的pKa值连同其铁（III）络合物的稳定常数已被确定。结果表明，在2-位上引入酰胺基取代基导致pFe（3+）值的明显提高。使用Fe-59-铁蛋白负载的大鼠模型研究了这些新的3-羟基吡啶-4-酮促进胆汁中铁排泄的能力。用N-甲基氨基衍生物15 b观察到最佳效果，其具有21.7的相关pFe（3+）值，比去铁酮（1，2-二甲基-3-羟基吡啶-4-酮）1a（pFe（3+）= 19.4）高两个数量级以上。剂量反应研究表明，与简单的二烷基取代羟基吡啶酮相比，具有高pFe（3+）值的螯合剂在较低剂量下更有效地螯合铁。(C)2001爱思唯尔科技有限公司版权所有。
The synthesis of a range of 2-amido-3-hydroxypyridin-4-ones as bidentate iron(III) chelators with potential for oral administration is described. The pKa values of the ligands together with the stability constants of their iron(III) complexes have been determined. Results indicate that the introduction of an amido substituent at the 2-position leads to an appreciable enhancement of the pFe(3+) values. The ability of these novel 3-hydroxypyridin-4-ones to facilitate the iron excretion in bile was investigated using a Fe-59-ferritin loaded rat model. The optimal effect was observed with the N-methyl amido derivative 15b, which has an associated pFe(3+) value of 21.7, more than two orders of magnitude higher than that of deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one) 1a (pFe(3+) = 19.4). Dose response studies suggest that chelators with high pFe(3+) values scavenge iron more effectively at lower doses when compared with simple dialkyl substituted hydroxypyridinones. (C) 2001 Elsevier Science Ltd. All rights reserved.