Partition-variant desferrithiocin analogues: Organ targeting and increased iron clearance
Partition-variant desferrithiocin analogues: Organ targeting and increased iron clearance
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DOI：
10.1021/jm049306x
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发表时间：
2005-02-10
影响因子：
7.3
通讯作者：
Brittenham, GM
中科院分区：
文献类型：
--
作者：
Bergeron, RJ;Wiegand, J;Brittenham, GM
改变去铁硫蛋白类似物的亲脂性(logP-APP)可以改变螯合剂的器官分布，并导致铁清除增强。例如，(S)-2-(2，4-dihydroxyphenyl)-4，5-dihydro-4-methyl-4-thiazolecarboxylic酸[(S)-4‘-(HO)-DADFT]及其类似物，如(S)-4，5-dihydro-2-(2-hydroxy-4-methoxyphenyl)4-methyl-4-thiazolecarboxylic酸[(S)-4’-(CH3O)-DADFT]的烷基化提供了配体，使心脏、肝脏、和胰腺(铁超载疾病风险最大的器官)。4‘-O-甲基化的化合物在啮齿类动物中被去甲基化为它们的羟基化的对应化合物；此外，这种O-去甲基化在啮齿动物和人的肝微粒体中都发生了。通过比较(S)-2-(2，3-dihydroxyphenyl)-4，5-dihydro-4-methyl-4-thiazolecarboxylic酸[(S)-3‘-(HO)-DADFT]与其3’-(CH3O)的清铁效率，进一步强调了螯合剂的亲脂性与铁的清除效果之间的关系。最后，这些DFT类似物被证明既是铁介导的抗坏血酸氧化的抑制剂，也是有效的自由基清除剂。
Altering the lipophilicity (log P-app) of desferrithiocin analogues can change the organ distribution of the chelators and lead to enhanced iron clearance. For example, alkylation of (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT] and its analogues to more lipophilic compounds, such as (S)-4,5-dihydro-2-(2-hydroxy-4-methoxyphenyl)4-methyl-4-thiazolecarboxylic acid [(S)-4'-(CH3O)-DADFT], provides ligands that achieved between a 3- and 8-fold increase in chelator concentrations in the heart, liver, and pancreas (the organs most at risk in iron-overload disease) of treated rodents. The 4'-O-methylated compounds are demethylated to their hydroxylated counterparts in rodents; furthermore, this O-demethylation takes place in both rodent and human liver microsomes. The relationship between chelator lipophilicity and iron-clearing efficacy in the iron-overloaded Cebus apella primate is further underscored by a comparison of the iron-clearing efficiency of (S)-2-(2,3-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [(S)-3'-(HO)-DADFT] and its 3'-(CH3O) counterpart. Finally, these DFT analogues are shown to be both inhibitors of the iron-mediated oxidation of ascorbate as well as effective radical scavengers.