Phenolic ethylenediamine derivatives: a study of orally effective iron chelators.
Of 35 potential iron chelators screened for in vivo activity in rats, a group of phenolic compounds with excellent chelating properties were identified. These included N,N'-ethylene-bis(o-hydroxyphenylglycine) (EHPG), N,N'-Bis(o-hydroxybenzyl)-ethylenediamine diacetic acid (HBED), and their respective dimethyl esters (dmEHPG and dmHBED). All four phenolic compounds produced a marked increase in the fecal excretion of hepatocellular radioiron. This amounted to 42% of total body radioactivity with dmEHPG, 58% with EHPG, 63% with HBED, and 80% with dmHBED after a single injection of 40 mg/animal. At a dose of 5 mg/animal, EHPG, HBED, and dmHBED were 9, 12, and 15 times more potent, respectively, than deferoxamine. Both dimethyl esters showed significant oral activity; oral dmEHPG retained 1/3 and dmHBED retained 2/3 of the effect of the same dose given by intramuscular injection. The ester dmHBED combines oral effectiveness with superior chelating ability, selective hepatocellular action, and low apparent toxicity. It may represent a significant advance in the development of new iron chelating drugs.
D000284:Administration, Oral; D000818:Animals; D002614:Chelating Agents; D003676:Deferoxamine / Q000008:administration & dosage / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005029:Ethylenediamines / Q000008:administration & dosage*; D005243:Feces / Q000032:analysis; D005293:Ferritins / Q000378:metabolism; D007501:Iron / Q000032:analysis; D007504:Iron Radioisotopes; D008099:Liver / Q000378:metabolism; D010636:Phenols / Q000008:administration & dosage; D051381:Rats; D011919:Rats, Inbred Strains
D002614:Chelating Agents; D005029:Ethylenediamines; D007504:Iron Radioisotopes; D010636:Phenols; D005293:Ferritins; D007501:Iron; D003676:Deferoxamine