Synthesis and evaluation of di-cationic sulfonium-type alpha-glucosidase inhibitors based on the structure of salacinol

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08377
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Kindai University
• Principal Investigator: Tanabe Genzoh 近畿大学, 薬学部, 教授 (40217104)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: salacinol / neokotalanol / α-glucosidase inhibitor / Salacia / SAR study / Diabetes

Outline of Final Research Achievements

A facile and highly diastereoselective approach toward the synthesis of potent salacinol-type α-glucosidase inhibitors, originally isolated from plants of the genus “Salacia”, was developed using the S-alkylation of thiosugars with epoxides in HFIP (約;90%, dr, α/β = 約 26/1). The dr ratio of the product was significantly improved by the protocol as compared to that of the conventional S-alkylation of thiosugars (dr, α/β = 約 8/1). The protocol could be used for gram scale synthesis of the desired compounds. The 3′-O-benzylated salacinol analogs, which are the most potent in vitro inhibitors to date, were synthesized and evaluated in vivo; all analogs suppressed blood glucose levels in maltose－loaded mice, at levels comparable to those of the antidiabetic agent, voglibose.

Free Research Field

有機合成、構造活性相関

Academic Significance and Societal Importance of the Research Achievements

サラシアは、世界的に糖尿病患者およびその予備軍に関心が持たれている天然薬物である。したがって、サラシアエキス品質管理用の標品としての活性成分の大量供給法を確立できたことは意義がある。糖尿病治療薬、アカルボース、ボグリボースには肝障害などの副作用を示すことが報告されているが、サラシア活性成分はそれとは全く異なるチオ糖スルホニウム塩構造をもつことから医薬品シードとして期待できる。その中で、in vivo で高活性を示す誘導体の合成に成功したことは、糖尿病予防・治療への貢献ができるものと考えている。