Total synthesis and stereochemical elucidation of natural products leading to the development of new hypoglycemic drugs and reduction of side effects of existing agents

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K15756
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 38040:Bioorganic chemistry-related
• Research Institution: The University of Tokyo
• Principal Investigator: Yusuke Ogura 東京大学, 大学院農学生命科学研究科(農学部), 准教授 (50750139)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: PPAR / 骨芽細胞 / 天然物合成

Outline of Final Research Achievements

A trace natural product isolated from dinoflagellate cultures, amphirionin-5, shows osteoblast proliferative activity that may lead to a new treatment for osteoporosis, but its chemical structure has not been fully determined. In this study, we have achieved a complete chemical synthesis of amphirionin-5, and now that the planar structure has been synthesized, we will determine the steric configuration to elucidate the structure of this compound.
We also carried out a comprehensive synthetic study of amorfrutin, a PPARγ antagonist related to hypoglycemic action and a natural product derived from licorice, and succeeded in establishing a synthetic route for them. Since a quantitative supply of amorfrutin will be realized, the foundation for future applied research has been established.

Free Research Field

農芸化学

Academic Significance and Societal Importance of the Research Achievements

糖尿病の理想的治療法の確立は世界規模で喫緊の課題であり、血糖降下薬はその有効な治療手段の一つである。 インスリン抵抗性改善剤は血糖降下薬の一種であるが、骨密度の低下や心不全等の副作用を伴うことから国内承認はpioglitazoneの1例に留まっており, それに加えて膀胱癌のリスクが指摘されている。そこで本問題の解決方針として, 骨密度低下等の副作用を抑える、あるいは副作用を低減した血糖降下薬の開発につながる微量天然物の量的供給を試み、実際の化学合成に成功した。今後これらの天然物を用いた応用研究が進展することが期待される。