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2023 Fiscal Year Final Research Report

Structural Control and Generation of New Functional Molecules Using a Solid-Phase Library Strategy for Peptidic Natural Products

Research Project

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Project/Area Number 21K05286
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
Research InstitutionThe University of Tokyo

Principal Investigator

Itoh Hiroaki  東京大学, 大学院薬学系研究科(薬学部), 准教授 (20758205)

Project Period (FY) 2021-04-01 – 2024-03-31
Keywords天然物有機化学 / 化合物ライブラリー / 固相合成 / 構造活性相関 / 全合成
Outline of Final Research Achievements

The aim of this study is the generation of new functional molecules through the structural modification of natural products targeting FoF1-ATP synthase. A complex peptidic natural product efrapeptin C was adopted as the structural basis, and the introduction of a methyl group, the smallest aliphatic substituent, was conducted to enhance the biological activity by controlling its three-dimensional structure.
First, an efficient strategy for the solid-phase total synthesis of efrapeptin C was established. Using this synthetic strategy, six methylated analogues were constructed, and their biological activities and molecular functions were evaluated. As a result, a promising new analogue was discovered. This new analogue exhibited more potent growth inhibitory activity against cancer cells and higher proteolytic stability compared to the parent efrapeptin C.

Free Research Field

有機合成化学、天然物有機化学

Academic Significance and Societal Importance of the Research Achievements

メチル基導入は、医薬品候補化合物の特性を最適化するために広く用いられているが、柔軟かつ分子量の大きい鎖状分子においては、導入する位置や立体化学の生物活性に与える総合的影響を正確に予測することは困難であり、応用例が限られてきた。また、一般的に自然選択を経た生物活性天然物よりも優れた性質を示す類縁体を得ることは容易ではない。強力な活性と高い安定性を持つ新規エフラペプチンC類縁体の創出に成功した本成果は、鎖状分子を対象とした機能向上の方法論として、メチル基導入による構造制御が有効であることを実証する重要なものである。また、得られた類縁体は、新規抗がん活性分子創出のために有用な構造基盤である。

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Published: 2025-01-30  

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