N,N'-bis-dibenzyl ethylenediaminediacetic acid (DBED): a site-specific hydroxyl radical scavenger acting as an "oxidative stress activatable" iron chelator in vitro.
During oxidative stress, iron traces are supposed to be released from normal storage sites and to catalyse oxidative damage by Fenton-type reactions. This type of damage is difficult to prevent in vivo except by the use of strong iron chelators such as deferoxamine (affinity constant for Fe(III): log K = 30.8). However, strong iron chelating agents are also suspected to mobilize iron from various storage and transport proteins thereby leading to toxic effects. In contrast, N,N'-bis-dibenzyl ethylenediaminediacetic acid (DBED) is an iron chelator with relatively low affinity for iron (affinity constant for Fe(III): log K < 15). In the present paper, we show that, in situations mimicking oxidative stress in vitro, DBED is site-specifically oxidized into new species with strong iron binding capacity. Indeed, in the presence of ascorbate as a reductant, the iron chelate of DBED reacts with H2O2 in aqueous solution to yield a purple chromophore with minor release of free HO. in the medium, as measured by aromatic hydroxylation assay. The formation of these purple species is not suppressed by the presence of HO. scavengers at high concentration. The visible spectrum of these species is consistent with a charge transfer band from a phenolate ligand to iron. N-2-hydroxybenzyl N'-benzyl ethylenediaminediacetic acid (HBBED) 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 since 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 H2O2 and an electron donor. Therefore it is proposed that DBED and related derivatives may be interesting as protective compounds against oxygen radicals toxicity, especially for chronic use.
Galey
J B
JB
L'Oréal Basic Research Center, Aulnay sous bois, France.
Dumats
J
J
Beck
I
I
Fernandez
B
B
Hocquaux
M
M
D001205:Ascorbic Acid / Q000737:chemistry; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D016166:Free Radical Scavengers / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D017665:Hydroxyl Radical; D007502:Iron Chelating Agents / Q000737:chemistry*; D015394:Molecular Structure; D018384:Oxidative Stress
D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; C092592:N,N'-bis(dibenzyl)ethylenediaminediacetic acid; D017665:Hydroxyl Radical; D004492:Edetic Acid; D001205:Ascorbic Acid