Inhibition of the iron-catalysed formation of hydroxyl radicals by nitrosouracil derivatives: protection of mitochondrial membranes against lipid peroxidation.
A new series of metal ligands containing the 1,3-dimethyl-6-amino-5- nitrosouracil moiety has been synthesized and they have been studied as potential inhibitors of iron-dependent lipid peroxidation. For this purpose, these new derivatives have been tested in the Fenton induced deoxyribose degradation assay, which allows a quantitative measurement of their inhibitory effect towards hydroxyl radical generation. When iron(II) is complexed by these ligands, a strong inhibition of deoxyribose degradation is observed, especially in the case of tris-[2-(1,3-dimethyl-5-nitrosouracil-6-yl)aminoethyl] amine (5). This inhibitory effect is clearly related to a specific complexation of iron(II) and is not due to the direct scavenging of hydroxyl radical by the ligand. Inhibition of the iron mediated Fenton reaction presumably results from inactivation of the reactivity of the metal center towards hydrogen peroxide. These derivatives, as well as long alkyl chain substituted nitrosouracils were evaluated in the protection of biological membranes against lipid peroxidation (induced by iron(II)/dihydroxyfumaric acid and determined with the 2-thiobarbituric acid test). Ligand 5 inhibited lipid peroxidation at a rate similar to Desferal (desferrioxamine B) and slightly higher than bathophenanthroline sulphonate (BPS), which are respectively good iron(III) and iron(II) chelators. When covalently bound with a long alkyl chain, the increase of lipophilic character of the ligand allows its location near the mitochondrial membrane, where lipid peroxidation occurs. Lower concentrations (IC50 = 4 microM) are then necessary to inhibit lipid peroxidation. This IC50 concentration should be compared to those obtained for Trolox (IC50 = 3 microM) or the 21-aminosteroid U74500A (IC50 = 1 microM) described previously.
Rabion
A
A
Laboratoire de Chimie Organique et Organométallique, URA 35 CNRS, Université Bordeaux I, Talence, France.
Verlhac
J B
JB
Fraisse
L
L
Roche
B
B
Seris
J L
JL
D000818:Animals; D002374:Catalase / Q000378:metabolism; D002417:Cattle; D003855:Deoxyribose / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism*; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D015227:Lipid Peroxidation; D008929:Mitochondria, Heart / Q000648:ultrastructure*; D009603:Nitroso Compounds / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014498:Uracil / Q000378:metabolism*; D019820:Xanthine; D014969:Xanthine Oxidase / Q000378:metabolism; D014970:Xanthines / Q000378:metabolism
C045076:Fenton's reagent; D009603:Nitroso Compounds; D017392:Thiobarbituric Acid Reactive Substances; D014970:Xanthines; D019820:Xanthine; D017665:Hydroxyl Radical; D003855:Deoxyribose; D014498:Uracil; D006861:Hydrogen Peroxide; D007501:Iron; D002374:Catalase; D014969:Xanthine Oxidase; D010100:Oxygen