N,N'-BIS-DIBENZYL ETHYLENEDIAMINEDIACETIC ACID (DBED) - A SITE-SPECIFIC HYDROXYL RADICAL SCAVENGER ACTING AS AN OXIDATIVE STRESS ACTIVATABLE IRON CHELATOR IN-VITRO
Jb. Galey et al., N,N'-BIS-DIBENZYL ETHYLENEDIAMINEDIACETIC ACID (DBED) - A SITE-SPECIFIC HYDROXYL RADICAL SCAVENGER ACTING AS AN OXIDATIVE STRESS ACTIVATABLE IRON CHELATOR IN-VITRO, Free radical research, 22(1), 1995, pp. 67-86
During oxidative stress, iron traces are supposed to be released from
normal storage sites and to catalyse oxidative damage by Fenton-type r
eactions. This type of damage is difficult to prevent in vivo except b
y the use of strong iron chelators such as deferoxamine (affinity cons
tant for Fe(III): log K = 30.8). However, strong iron chelating agents
are also suspected to mobilize iron from various storage and transpor
t proteins thereby leading to toxic effects. In contrast, N,N'-bis-dib
enzyl ethylenediaminediacetic acid (DBED) is an iron chelator with rel
atively low affinity for iron (affinity constant for Fe(III): log K <
15). In the present paper, we show that, in situations mimicking oxida
tive stress in vitro, DBED is site-specifically oxidized into new spec
ies with strong iron binding capacity. Indeed, in the presence of asco
rbate as a reductant, the iron chelate of DBED reacts with H2O2 in aqu
eous solution to yield a purple chromophore with minor release of free
HO. in the medium, as measured by aromatic hydroxylation assay. The f
ormation of these purple species is not suppressed by the presence of
HO. scavengers at high concentration. The visible spectrum of these sp
ecies is consistent with a charge transfer band from a phenolate ligan
d to iron. N-2-hydroxybenzyl N'-benzyl ethylenediaminediacetic acid (H
BBED) was identified in the medium as one of the oxidation products of
DBED. Therefore, these results suggest that the iron chelate of DBED
undergoes an intramolecular aromatic hydroxylation by HO. leading to 2
-OH derivatives and hence that DBED is a site-specific HO. scavenger.
Moreover, since the measured affinity for Fe(III) of HBBED (log K = 28
) is at least 13 orders of magnitude higher than that of DBED and sinc
e ferric HBBED chelate is not a catalyst of Fenton chemistry, DBED may
be looked as an ''oxidative stress activatable'' iron chelator, e.g.
which increase in affinity for iron is triggered in the presence of H2
O2 and an electron donor. Therefore it is proposed that DBED and relat
ed derivatives may be interesting as protective compounds against oxyg
en radicals toxicity, especially for chronic use.