Study on total synthesis, stereochemical assignment, and biological assessment of amphidinolide N and its epimers

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K15270
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 33020:Synthetic organic chemistry-related
• Research Institution: Tohoku University
• Principal Investigator: Umemiya Shigenobu 東北大学, 理学研究科, 助教 (10802754)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: マクロリド / 有機触媒 / 不斉アルドール反応 / 構造決定 / 天然物 / 全合成

Outline of Final Research Achievements

The applicant has improved the synthetic route of the C7 epimer of amphidinolide N. An important intermediate C1-C13 fragment were successfully synthesized on a decagram scale via the present route. This synthetic route was also able to synthesize not only the C7 epimer but also the C10 epimer divergently. Namely, four isomers were successfully prepared on the gram scale by our synthetic strategy. The C7 epimer of amphidinolide N, which had already been synthesized and structurally determined by our group, was investigated for its biological activity in collaboration with Prof. Kubota, in Showa Pharmaceutical University. As a result, it was found that the C7 epimer exhibited IC50=6 μg/mL against KB cells and IC50=2.8 μg/mL against L1210 cells.

Free Research Field

有機合成化学

Academic Significance and Societal Importance of the Research Achievements

これまでamphidinolide Nは強力な生物活性を有している事が知られていたが、実際にその全体構造を合成し、活性評価をした例はなかった。今回初めて全体構造を有する化合物の活性評価を行う事に成功し、オリジナルと比べて弱いものの抗腫瘍活性を持つことを明らかとした。これにより、本化合物の立体が活性に与える影響が極めて大きい事が示唆された。本研究を通し、amphidinolide Nのような複雑なマクロリドを大量供給する手法が確立されたとともに、その生物活性試験を実施できたことは、有機合成化学のみならず、天然物化学や医学・生物学への波及効果があったとみなすことができる。