Esters and lactones of phenolic amino carboxylic acids: prodrugs for iron chelation.
Esters and lactones of phenolic amino carboxylic acids: prodrugs for iron chelation.
复制标题
酚氨基羧酸的酯和内酯：铁螯合的前药。
DOI：
10.1021/jm00157a020
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发表时间：
1986
影响因子：
7.3
通讯作者：
Metterville,J
中科院分区：
文献类型：
--
作者：
Pitt,CG;Bao,Y;Thompson,J;Wani,MC;Rosenkrantz,H;Metterville,J
The new iron chelator N, JV'-bis (2-hydroxyphenyl) ethylenediamine-iV,. ZV'-diacetic acid (1), its dilactone 2, N, N'-bis (2-hydroxybenzyl)-2-hydroxypropylene-l, 3-diamine-lV, lV'-diacetic acid (3), andits methyl ester lactone 4 and a series of esters of iV, N-bis (2-hydroxybenzyl) ethylenediamine-iVJV,-diaceticacid (5) were prepared and their iron chelating efficacy and toxicity determined by using the hypertransfused mouse model of iron overload. The biological activities were compared with results obtained with use of the hypertransfusedrat. Esterification enhanced the oral iron chelating activitybut also increased toxicity. The diisopropyl ester of 5 exhibited the highest therapeutic index. In vitro measurements showed that the rate of ester hydrolysis at pH 7.5 increasedby a factor of 104 5in the presence of 5 X™ 4 M ferric ion, which may account for the utility of esters and lactones as prodrugs. Seventeen other chelating agents were screened but showed no intraperitoneal or oral activity.The recent discovery1 of a mouse model of/3-thalassemia offers greater hope that genetic manipulation may ulti-mately correct this fatal genetic disease, which arises from errant biosynthesis of the/3-chain of hemoglobin. Pres-ently, however,/3-thalassemia can only be treated by a regular, life-long transfusion regimen, which itself ulti-mately produces a fatal hemosiderotic condition associated with cardiotoxicity, hepatic cirrhosis, and pancreatic
