Protection of U937 cells against oxidative injury by a novel series of iron chelators

A new series of iron chelators designed to protect tissues against iron-catalysed oxidative damage is described. These compounds are aminocarboxylate derivatives bearing pendant aromatic groups. They were designed to have a relatively low affinity for both ferrous and ferric iron and to be site-specifically oxidizable by hydrogen peroxide through intramolecular aromatic hydroxylation into species with strong iron binding capacity which do not catalyse hydroxyl radical formation. Thus, at the cellular level, oxidative injury is used to convert weak iron chelators into strong iron chelators in order to promote cell survival. The purpose of this local activation process is to minimise toxicity compared to strong iron chelators which may interfere with normal iron metabolism. Compounds within this series were evaluated in vitro in view of their capacity to undergo intramolecular hydroxylation and to protect cultured cells against oxidative injury. Results show that the intramolecular aromatic hydroxylation capacity is critically dependent upon the amino carboxylate chelating moieties and the substituents of the aromatic rings. Cell protection against oxidative injury is only observed with compounds possessing sufficient lipophilicity. The monohydroxylation product of N,N'-dibenzylethylenediamine N,N'-diacetic acid, protects cells against both H2O2 and tBuOOH toxicity with IC50's of 12 and 60 microM, respectively, in agreement with the oxidative activation concept. These results represent the first step toward the development of a new strategy to safe iron chelation for the prevention of oxidative damage.