bo-653 and 2-2--azobis(2-4-dimethylvaleronitrile)

To develop a novel potent radical-scavenging antioxidant, the ideal structure of a phenolic compound was designed considering the factors that determine antioxidant potency. 2,3-Dihydro-5-hydroxy-2,2-dipentyl-4, 6-di-tert-butylbenzofuran (BO-653) was thus synthesized and its antioxidant activity was evaluated against lipid peroxidations in vitro. The electron spin resonance study showed that the phenoxyl radical derived from BO-653 was more stable than alpha-tocopheroxyl radical. BO-653 reduced alpha-tocopheroxyl radical rapidly, but alpha-tocopherol did not reduce the phenoxyl radical derived from BO-653. However, the chemical reactivity of BO-653 toward peroxyl radical was smaller than that of alpha-tocopherol. This was interpreted as the steric effect of bulky tert-butyl groups at both ortho positions which hindered the access of peroxyl radical to the phenolic hydrogen. However, the tertbutyl substituents increased the stability of BO-653 radical and also lipophilicity, and its antioxidant potency against lipid peroxidation in phosphatidylcholine liposomal membranes was superior to that of alpha-tocopherol. Ascorbic acid reduced the phenoxyl radical derived from BO-653 and spared BO-653 during the oxidation of lipid in the homogeneous solution. On the other hand, ascorbic acid did not spare BO-653 in the oxidation of liposomal membranes. It was concluded that BO-653 is a potent novel radical-scavenging antioxidant.

Topics: Antioxidants; Ascorbic Acid; Azo Compounds; Benzhydryl Compounds; Benzofurans; Chromatography, High Pressure Liquid; Drug Design; Electron Spin Resonance Spectroscopy; Free Radical Scavengers; Kinetics; Linoleic Acids; Lipid Peroxidation; Liposomes; Molecular Structure; Nitriles; Oxidation-Reduction; Peroxides; Phenols; Phosphatidylcholines; Spin Labels; Vitamin E

2,3-Dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butyl-benzofuran (BO-653) is a novel antioxidant synthesized by theoretical designing based on the previous experimental findings and consideration. The antioxidant activities of BO-653 against the oxidative modification of low-density lipoprotein (LDL) induced by free radicals were studied. BO-653 was consumed faster than endogenous alpha-tocopherol and inhibited the formation of lipid hydroperoxides, which was observed during the consumption of alpha-tocopherol. Doxyl stearic acids incorporated into LDL as spin probes competed with the antioxidants in scavenging radicals. It was found that the efficacy of radical scavenging by alpha-tocopherol became smaller as the radical went deeper into the interior of LDL particle, whereas that by BO-653 did not change. Ascorbic acid in the aqueous phase spared alpha-tocopherol efficiently during oxidation. On the other hand, the sparing effect of ascorbic acid for BO-653 was not remarkable, unlike that for alpha-tocopherol, which implied different locations of radicals derived from BO-653 and alpha-tocopherol within the LDL particle. It was concluded that BO-653 protected LDL from oxidative modification efficiently by scavenging peroxyl radicals and by reducing alpha-tocopheroxyl radicals and that this novel antioxidant might act as a potent inhibitor of development of atherosclerosis.

Topics: Amidines; Animals; Antioxidants; Apolipoproteins B; Arteriosclerosis; Ascorbic Acid; Azo Compounds; Benzofurans; Cyclic N-Oxides; Drug Design; Free Radical Scavengers; Humans; Kinetics; Lipid Peroxidation; Lipid Peroxides; Lipoproteins, LDL; Nitriles; Oxidants; Oxidation-Reduction; Peroxides; Rabbits; Vitamin E