INHIBITION OF THE IRON-CATALYZED 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-ni trosouracil moiety has been synthesized and they have been studied as potential inhibitors of iron-dependent lipid peroxidation. For this pu rpose, these new derivatives have been tested in the Fenton induced de oxyribose degradation assay, which allows a quantitative measurement o f their inhibitory effect towards hydroxyl radical generation. When ir on(II) is complexed by these ligands, a strong inhibition of deoxyribo se degradation is observed, especially in the case of -[2-(1,3-dimethy l-5-nitrosouracil-6-yl)aminoethyl] amine (5). This inhibitory effect i s clearly related to a specific complexation of iron(II) and is not du e to the direct scavenging of hydroxyl radical by the ligand. Inhibiti on of the iron mediated Fenton reaction presumably results from inacti vation of the reactivity of the metal center towards hydrogen peroxide . These derivatives, as well as long alkyl chain substituted nitrosour acils were evaluated in the protection of biological membranes against lipid peroxidation (induced by iron(II)/ dihydroxyfumaric acid and de termined with the 2-thiobarbituric acid test). Ligand 5 inhibited lipi d peroxidation at a rate similar to Desferal (desferrioxamine B) and s lightly higher than bathophenanthroline sulphonate (BPS), which are re spectively good iron(III) and iron(II) chelators. When covalently boun d with a long alkyl chain, the increase of lipophilic character of the ligand allows its location near the mitochondrial membrane, where lip id peroxidation occurs. Lower concentrations (IC50 = 4 mu M) are then necessary to inhibit lipid peroxidation. This IC50 concentration shoul d be compared to those obtained for Trolox (IC50 = 3 mu M) or the 21-a minosteroid U74500A (IC50 = mu M) described previously.