著作: [堀 均]/[宇都 義浩]/Koyama Daisuke/Otsuki Mamoru/Otomo Naoki/Shirai Tadashi/Abe Chiaki/[中田 栄司]/[永澤 秀子]/A chemical biosynthesis design for antiatherosclerosis drug by acyclic tocopherol intermediate analogue based on ``isoprenomics''/ISOTT2007 (2007 International Society on Oxygen Transport to Tissue Conference)
(英) A chemical biosynthesis design for antiatherosclerosis drug by acyclic tocopherol intermediate analogue based on ``isoprenomics''
(英) Tocopherols constitute members of the vitamin E group and act as a potent lipid peroxidation inhibitor against for cell membrane such as blood vessels. Phytyl quinols, namely acyclic tocopherols, are key intermediate of tocopherol biosynthesis, but their biological activities remain unclear. We therefore investigated the structure-activity relationship of phytyl quinols to apply chemical biosynthesis design for an antiatherosclerosis drug. We have achieved the biosynthesis-oriented design and synthesis of alpha- (TX-2254) and beta- (TX-2247) phytyl quinol as an unnatural intermediate, other gamma- (TX-2242) and delta- (TX-2231) phytyl quinol as a natural one. Free radical reactivity was determined by using DPPH radical. Inhibitory activity of human low density lipoprotein (LDL) oxidation was measured by TBARS assay. Free radical reactivity of TX-2242 (EC50 = 24.6 microM) and TX-2231 (24.2 microM) were equal with DL-alpha-tocopherol (22.3 microM), whereas TX-2254 (38.0 microM) and TX-2247 (30.2 microM) showed lower reactivity than DL-alpha-tocopherol. TX-2242 (IC50 = 61 microM) and TX-2231 (69 microM) also showed almost same LDL antioxidant activity as DL-alpha-tocopherol (64 microM), while TX-2254 (149 microM) and TX-2247 (254 microM) showed lower antioxidant activity than DL-alpha-tocopherol. We suggested from these results that the cyclization of phytyl quinol to tocopherol is not indispensable for the appearance of the potent antioxidant activity. We also have found an interesting negative correlation between methylation and antioxidant activity of phytyl quinols. We will present ex vivo antioxidant activity for blood vessels in the chick embryo chorioallantoic membranes (CAM) as an alternative in vivo model.
(英) ISOTT2007 (2007 International Society on Oxygen Transport to Tissue Conference)
|都市||必須||(英) Uppsala, Sweden|
|年月日||必須||2007年 8月 28日|