Preliminary Toxicity Data on New Ethylenediamine Derivatives Designed for Iron Chelation

Abstract

During development of iron chelators for the treatment of iron overload in Cooley's anemia, the opportunity arose to obtain some acute and subacute toxicity data on hydroxybenzyl-ethylenediamine (HBED) derivatives, hydroxyphenyl-ethylenediamine (HPED) congeners, and ethylenediamine-phenylacetic acid (EDHPA) compounds. Such data permitted correlations among structure, toxicity, and efficacy parameters useful for further syntheses. Young, adult male mice were used to perform acute intraperitoneal (IP) or oral (PO) LD50 studies, and hypertransfused groups were treated IP or PO with vehicle, Desferal, or test chelators once daily for 7 days. Changes in behavior, weights of spleen, liver, and feces, and urine volume and gross pathology were monitored. In the HBED series, esterification of acetic acid groups with or without acetylation of phenolic hydroxyl groups increased LD50 values, and the major behavioral change was decreased exploratory activity. Dimethylenephosphonate derivatives of HBED were more toxic. Single treatment with compounds in the EDHPA and HPED series yielded IP LD50 values between 175 and 325 mg/kg. After subacute treatment, active compounds were found in each series, and efficacy was related to toxicity. Chelation effectiveness was usually greater by the IP route than orally. The major toxic signs were reduction in organ weights and excreta output.