Inhibition of oxidation of low-density lipoprotein by a novel antioxidant, BO-653, prepared by theoretical design.
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.
Noguchi
N
N
Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, 4-6-1 Komaba, Meguro, 153, Japan.
Okimoto
Y
Y
Tsuchiya
J
J
Cynshi
O
O
Kodama
T
T
Niki
E
E
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001055:Apolipoproteins B / Q000378:metabolism; D001161:Arteriosclerosis / Q000188:drug therapy; D001205:Ascorbic Acid / Q000494:pharmacology; D001391:Azo Compounds / Q000378:metabolism / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000378:metabolism; D015195:Drug Design; D016166:Free Radical Scavengers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects*; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000378:metabolism / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D010545:Peroxides / Q000494:pharmacology; D011817:Rabbits; D014810:Vitamin E / Q000494:pharmacology
C106512:2,3-dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butylbenzofuran; D000578:Amidines; D000975:Antioxidants; D001055:Apolipoproteins B; D001391:Azo Compounds; D001572:Benzofurans; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D008054:Lipid Peroxides; D008077:Lipoproteins, LDL; D009570:Nitriles; D016877:Oxidants; D010545:Peroxides; C055792:2,2'-azobis(2,4-dimethylvaleronitrile); D014810:Vitamin E; C037404:12-doxylstearic acid; C046728:2,2'-azobis(2-amidinopropane); D001205:Ascorbic Acid