Design and Synthesis of 4,6-Di-tert-butyl-2,3-dihydro-5-benzofuranols as a Novel Series of Antiatherogenic Antioxidants
| Autor: | Etsuo Niki, Tatsuhiko Kodama, Mitsutaka Yoshida, Yoshiaki Takashima, Osamu Cynshi, Yoshiki Kawabe, Yoshiaki Kato, Tsukasa Suzuki, Motomu Himori, Makoto Shimizu, Akira Ishikawa, Yasuharu Kato, Kunio Tamura |
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| Rok vydání: | 2003 |
| Předmět: |
Vitamin
Antioxidant Free Radicals Arteriosclerosis medicine.medical_treatment alpha-Tocopherol Probucol Antioxidants Linoleic Acid Lipid peroxidation Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Animals Benzofurans Autoxidation Vitamin E Lipoproteins LDL chemistry Biochemistry Luminescent Measurements Molecular Medicine Rabbits Oxidation-Reduction medicine.drug Lipoprotein |
| Zdroj: | Journal of Medicinal Chemistry. 46:3083-3093 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Antioxidants have been considered as potential antiatherogenic agents by inhibiting oxidation of low-density lipoprotein (LDL), albeit vitamin E, a natural antioxidant, has failed to show reduction on atherosclerosis in clinical trials. We have rationally designed and synthesized a novel series of antioxidants, 4,6-di-tert-butyl-2,3-dihydro-5-benzofuranols, to overcome the clinical limitation of vitamin E. In vitro, the compounds showed a potent inhibitory effect on lipid peroxidation detected as 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1,2-a]pyrazin-3-one (MCLA)-dependent chemiluminescence in linoleic acid autoxidation. They also inhibited the LDL oxidation induced by Cu(2+), and the inhibition is more potent than that of vitamin E and probucol. In vivo, 4,6-di-tert-butyl-2,3-dihydro-2,2-dipentyl-5-benzofuranol (BO-653, 1f), an optimal compound, showed the highest concentration in plasma and LDL fraction in Watanabe heritable hyperlipidemic rabbits, due to its high affinity to LDL. The isolated LDL samples from the 1f-treated rabbits showed potent resistibility to LDL oxidation. Compound 1f has been taken into clinical trials. |
| Databáze: | OpenAIRE |
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