Esters and lactones of phenolic amino carboxylic acids: prodrugs for iron chelation.
The new iron chelator N,N'-bis(2-hydroxyphenyl)ethylenediamine-N,N'-diacetic acid (1), its dilactone 2, N,N'-bis(2-hydroxybenzyl)-2-hydroxypropylene-1,3-diamine-N,N'- diacetic acid (3), and its methyl ester lactone 4 and a series of esters of N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (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 hypertransfused rat. Esterification enhanced the oral iron chelating activity but 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 increased by a factor of 10(4) in the presence of 5 X 10(-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.
D000818:Animals; D001803:Blood Transfusion; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000378:metabolism; D017707:Erythrocyte Transfusion; D004952:Esters / Q000138:chemical synthesis / Q000378:metabolism; D006868:Hydrolysis; D007202:Indicators and Reagents; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000138:chemical synthesis*; D007783:Lactones / Q000138:chemical synthesis / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D013055:Spectrophotometry, Infrared; D013154:Spleen / Q000378:metabolism; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D004952:Esters; D007202:Indicators and Reagents; D007502:Iron Chelating Agents; D007783:Lactones; D007501:Iron