SELECTION AND EVALUATION OF NEW CHELATING-AGENTS FOR THE TREATMENT OF IRON OVERLOAD

Abstract

A large-scale systematic evaluation of potential Fe chelators for the treatment of hemosiderosis was conducted. The compounds were identified and evaluated using a hypertransfused mouse screen in which deferrioxamine B was a standard. This screen was designed to measure Fe depletion in the tissues as well as Fe excretion. Groups of 10 previously hypertransfused BDF1 male mice received a single daily i.p. injection of either vehicle, standard, or test compound for 7 days. Fe in daily urine pools and individual spleen and liver homogenates was determined by atomic absorption. More than 70 chelators were evaluated, including natural and synthetic hydroxamic acids, phenols, catechols and tropolones known to have a high affinity for iron (III) in vitro. Ethylenediamine-N,N''-bis(2-hydroxyphenylacetic acid) was shown to be considerably more effective than deferrioxamine B (i.p.) and, in addition, was orally active. Factors determining the efficacy of this and other chelating agents are discussed.