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 dihydrochloride (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 oxidized, in situations mimicking oxidative stress in vitro, into species with strong iron-binding capacity. It is hoped that this local activation process will minimise toxicity compared to strong iron chelators that may interfere with iron metabolism. The present paper describes the results of experiments aimed at characterising oxidative reactions between iron-OR10141 complexes and hydrogen peroxide. Incubation of ascorbate and hydrogen peroxide with the ferric chelate of OR10141 in neutral aqueous solution yields a purple solution with a chromophore at 560 nm, which is consistent with an o-hydroxylation of one of the trimethoxybenzyl rings. Oxidation of OR10141 also takes place, although more slowly, by incubating hydrogen peroxide with ferric OR10141 complex in the absence of reductant. HPLC analysis shows that OR10141 is consumed 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 identified by mass spectrometry. The protective effect of OR10141 in vitro against DNA single strand breaks, protein damage, and lipid peroxidation induced by Fenton chemistry suggests that this compound is able to compete for iron with biological molecules and, thus, that this strategy of protection against oxidative stress is feasible. In addition, preliminary results showing protective effects of OR10141 dimethyl ester 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.
Galey
J B
JB
L'Oréal Research Center, Aulnay Sous Bois, France.
Dumats
J
J
Genard
S
S
Destree
O
O
Pichaud
P
P
Cctroux
P
P
Marrot
L
L
Beck
I
I
Fernandez
B
B
Barre
G
G
D001205:Ascorbic Acid / Q000737:chemistry; D002460:Cell Line / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004249:DNA Damage / Q000187:drug effects; D004277:DNA, Single-Stranded / Q000187:drug effects; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005949:Glucose Oxidase; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000633:toxicity; D007502:Iron Chelating Agents / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D013053:Spectrophotometry
D004277:DNA, Single-Stranded; D007502:Iron Chelating Agents; C097359:N,N'-bis(3,4,5-trimethoxybenzyl)ethylenediamine N,N'-diacetic acid; D004492:Edetic Acid; D006861:Hydrogen Peroxide; D005949:Glucose Oxidase; D001205:Ascorbic Acid