N,N'-BIS-(3,4,5-TRIMETHOXYBENZYL) ETHYLENEDIAMINE N,N'-DIACETIC ACID AS A NEW IRON CHELATOR WITH POTENTIAL MEDICINAL APPLICATIONS AGAINST OXIDATIVE STRESS

N,N'-bis-(3,4,5-trimethoxybenzyl) ethylenediamine N,N'-diacetic acid d ihydrochloride (OR10141) is a member of a recently described series of ''oxidative stress activatable iron chelators.'' These chelators have a relatively low affinity for iron but can be site-specifically oxidi zed, in situations mimicking oxidative stress in vitro, into species w ith strong iron-binding capacity. It is hoped that this local activati on process will minimise toxicity compared to strong iron chelators th at may interfere with iron metabolism. The present paper describes the results of experiments aimed at characterising oxidative reactions be tween iron-OR10141 complexes and hydrogen peroxide. Incubation of asco rbate and hydrogen peroxide with the ferric chelate of OR10141 in neut ral aqueous solution yields a purple solution with a chromophore at 56 0 nm, which is consistent with an o-hydroxylation of one of the trimet hoxybenzyl rings. Oxidation of OR10141 also takes place, although more slowly, by incubating hydrogen peroxide with ferric OR10141 complex i n the absence of reductant. HPLC analysis shows that OR10141 is consum ed during the reaction and transformed principally into N-(2-hydroxy 3 ,4,5-trimethoxybenzyl) N'-(3,4,5-trimethoxybenzyl) ethylenediamine N,N '-diacetic acid. Minor products are also formed, some of which were id entified by mass spectrometry. The protective effect of OR10141 in vit ro against DNA single strand breaks, protein damage, and lipid peroxid ation induced by Fenton chemistry suggests that this compound is able to compete for iron with biological molecules and, thus, that this str ategy of protection against oxidative stress is feasible. In addition, preliminary results showing protective effects of OR10141 dimethyl es ter against toxicity induced by hydrogen peroxide in cell culture are described. It is concluded that OR10141 and related prodrugs might be useful in vivo in chronic situations involving oxidative stress.