Jb. Galey et al., PROTECTION OF U937 CELLS AGAINST OXIDATIVE INJURY BY A NOVEL SERIES OF IRON CHELATORS, Free radical biology & medicine, 25(8), 1998, pp. 881-890
A new series of iron chelators designed to protect tissues against iro
n-catalysed oxidative damage is described. These compounds are aminoca
rboxylate derivatives bearing pendant aromatic groups. They were desig
ned to have a relatively low affinity for both ferrous and ferric iron
and to be site-specifically oxidizable by hydrogen peroxide through i
ntramolecular aromatic hydroxylation into species with strong iron bin
ding capacity which do not catalyse hydroxyl radical formation. Thus,
at the cellular level, oxidative injury is used to convert weak iron c
helators 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 v
iew of their capacity to undergo intramolecular hydroxylation and to p
rotect 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 monoh
ydroxylation product of N,N'-dibenzylethylenediamine N,N'-diacetic aci
d, protects cells against both H2O2 and tBuOOH toxicity with IC50's of
12 and 60 mu M, respectively, in agreement with the oxidative activat
ion concept. These results represent the first step toward the develop
ment of a new strategy to safe iron chelation for the prevention of ox
idative damage. (C) 1998 Elsevier Science Inc.