A chemical biosynthesis design for an antiatherosclerosis drug by acyclic tocopherol intermediate analogue based on "isoprenomics".
Phytyl quinols, namely acyclic tocopherols, are key intermediates of tocopherol biosynthesis, but their biological activities remain unclear. We therefore investigated the structure-activity relationship of phytyl quinols to apply a chemical biosynthesis design for an antiatherosclerosis drug based on isoprenomics. 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. Geometry optimization and Molecular orbital (MO) calculation of TX-2254 showed a unique right-angle structure; however, MO energy of TX-2254 and d-alpha-tocopherol were very similar. Radical reactivity of TX-2231 was equal to dl-alpha-tocopherol, whereas TX-2254, TX-2247, and TX-2231 showed lower reactivity than dl-alpha-tocopherol. All four phytyl quinols showed almost the same moderate inhibitory activity against low-density lipoprotein (LDL) oxidation instead of their different degree of C-methylation with character different from tocopherols. In vivo toxicities of phytyl quinols against chick embryo chorioallantoic membrane (CAM) vasculature were hardly observed. We proposed phytyl quinols were possible antioxidants in plants and animals, like vitamin E.
Uto
Yoshihiro
Y
Department of Life System, Institute of Technology and Science, Graduate School, The University of Tokushima, Minamijosanjimacho-2, Tokushima, 770-8506 Japan.
Koyama
Daisuke
D
Otsuki
Mamoru
M
Otomo
Naoki
N
Shirai
Tadashi
T
Abe
Chiaki
C
Nakata
Eiji
E
Nagasawa
Hideko
H
Hori
Hitoshi
H
D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D050197:Atherosclerosis / Q000188:drug therapy; D002623:Chemistry Techniques, Analytical; D002642:Chick Embryo; D015195:Drug Design; D006801:Humans; D007536:Isomerism; D008958:Models, Molecular; D015394:Molecular Structure; D024505:Tocopherols / Q000737:chemistry* / Q000378:metabolism* / Q000627:therapeutic use
D000975:Antioxidants; D024505:Tocopherols