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A Chemical Biosynthesis Design for an Antiatherosclerosis Drug by Acyclic Tocopherol Intermediate Analogue Based on “Isoprenomics”

  • Yoshihiro Uto
  • Daisuke Koyama
  • Mamoru Otsuki
  • Naoki Otomo
  • Tadashi Shirai
  • Chiaki Abe
  • Eiji Nakata
  • Hideko Nagasawa
  • Hitoshi Hori
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 645)

Abstract

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 α- (TX-2254) and ß- (TX-2247) phytyl quinol as an unnatural intermediate, other γ- (TX-2242) and δ- (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-a-tocopherol were very similar. Radical reactivity of TX-2231 was equal to dl-α-tocopherol, whereas TX-2254, TX-2247, and TX-2231 showed lower reactivity than dl-α-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.

Keywords

Molecular Orbital Free Radical Scavenge Activity Methyl Cellulose Molecular Orbital Energy Silicon Ring 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Yoshihiro Uto
    • 1
  • Daisuke Koyama
    • 1
  • Mamoru Otsuki
    • 1
  • Naoki Otomo
    • 1
  • Tadashi Shirai
    • 1
  • Chiaki Abe
    • 1
  • Eiji Nakata
    • 1
  • Hideko Nagasawa
    • 2
  • Hitoshi Hori
    • 1
  1. 1.Department of Life System Institute of Technology and Science Graduate SchoolThe University of TokushimaMinamijosanjimacho-2Japan
  2. 2.Laboratory of Pharmaceutical ChemistryGifu Pharmaceutical UniversityMitahorahigashi-5Japan

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