N,N'-Bis-Dibenzyl Ethylenediaminediacetic Acid (Dbed): a Site-Specific Hydroxyl Radical Scavenger Acting as an “Oxidative Stress Activatable” Iron ChelatorIn Vitro

Abstract

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.

Cardioprotective effects of iron chelator HAPI and ROS-activated boronate prochelator BHAPI against catecholamine-induced oxidative cellular injury

“…However, classical powerful Fe chelators may not be suitable for long-term treatment of oxidative stress-associated conditions without systemic Fe overload due to chelator-induced deregulation of physiological Fe homeostasis (Galey 2001). Therefore, an “ideal” Fe chelator to be used in oxidative stress-related conditions should not affect Fe homeostasis, but rather “strategically” chelate Fe only in oxidative cellular environment (Galey et al 1995). Recently, boronate-masked prochelators have been introduced and evaluated (Bureš et al 2015).…”

The Potential Role of Iron Chelators in the Treatment of Parkinson's Disease and Related Neurological Disorders

“…4a) (Hasinoff et al 1994) and decreases anthracycline-induced radical formation (Hershko et al 1993). Galey et al (1995) introduced an iron chelator which is triggered by oxidative stress. In vitro, the prodrug N,N"-bis-dibenzylethylenediaminediacetic acid (DBED), is converted into the active compound N-(Zhydroxybenzy1)-N'-benzylethylenediaminediacetic acid (HBBED) by treatment with H202 ( fig.…”

“…Chronic treatment of rats with the neuroleptics chlorpromazine and haloperidol weakens the bloodbrain barrier and facilitates the uptake of Fe3+ into the brain (Ben-Shachar et al & 1994Leenders et al 1994). As iron may play a major role in neuroleptic-induced dopamine D2 receptor supersensitivity (Ben-Shachar et al inhibition (Galey et al 1995) I ) N-r2-hydroxybenzyl)-N'-benzylethylenediaminediacetic acid, generated in situ from N,N'-bis-dibenzylethylenediaminediacetic acid (DBED) and HzOz. (Morel et al 1995) 1985), this can provide a key to the pathophysiology of tardive dyskinesia and related extrapyramidal motor defects caused by antischizophrenic treatment.…”

Nanoparticles for the Treatment ofAlzheimer's Disease: Theoretical Rationale, Present Status and Future Perspectives

“…These agents include some antibiotics, antineoplastic drugs and central nervous system-active therapeutics, especially neuropeptides [99,100]. To overcome this obstacle, various strategies have been developed, which include osmotic opening of the brain endothelial cell tight junctions [120], prodrug preparation [121,122], and utilization of carrier-mediated transporter systems such as antibodies [123][124][125], carbohydrate conjugation [126][127][128][129], viral and nonviral gene delivery vectors [130][131][132], peptide vectors [133,134], liposomes [135][136][137], micelles [138,139], and nanoparticles [100,102,103,[140][141][142]. While these studies have shown promise, most of these methods have been of limited use [133,140].…”

“…For example, a prochelator has been designed for the purpose of easily entering the BBB. The functional groups of the prochelator are then activated by enzymatic or nonenzymatic reactions after they have entered the target organ [121]. Another example is to use simple inorganic silicate that can form very stable complexes with many metals and probably has the ability to enter the BBB [348].…”