N,N'-BIS-(3,4,5-TRIMETHOXYBENZYL) ETHYLENEDIAMINE N,N'-DIACETIC ACID AS A NEW IRON CHELATOR WITH POTENTIAL MEDICINAL APPLICATIONS AGAINST OXIDATIVE STRESS
Jb. Galey et al., N,N'-BIS-(3,4,5-TRIMETHOXYBENZYL) ETHYLENEDIAMINE N,N'-DIACETIC ACID AS A NEW IRON CHELATOR WITH POTENTIAL MEDICINAL APPLICATIONS AGAINST OXIDATIVE STRESS, Biochemical pharmacology, 51(2), 1996, pp. 103-115
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.