Middle-size cyclic peptides containing unnatural amino acids enable the control of higher cell function

2019 Fiscal Year Final Research Report

• Project Area: Middle molecular strategy: Creation of higher bio-functional molecules by integrated synthesis.
• Project/Area Number: 15H05837
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: Tohoku University
• Principal Investigator: DOI TAKAYUKI 東北大学, 薬学研究科, 教授 (90212076)
• Co-Investigator(Kenkyū-buntansha): 塚本 裕一 横浜薬科大学, 薬学部, 教授 (70323037)
• Project Period (FY): 2015-06-29 – 2020-03-31
• Keywords: 中分子 / 環状ペプチド / 非天然型アミノ酸 / フロー合成 / 反応集積化 / 固相合成 / 環化反応

Outline of Final Research Achievements

We have developed a method for efficiently synthesizing cyclic peptide natural products and their analogues exhibiting biological activities. Their three-dimensional structures were clarified by X-ray crystal structure analysis and/or a distance geometry method based on NMR studies. We found that it is important to consider the membrane permeability of the cyclic peptides. Generally, cyclic peptides have a large polar surface area and low membrane permeability. In cyclic peptides that exhibit biological activity, however, the polar surface area decreases due to the intramolecular hydrogen bond between the amide bonds, resulting in sufficient membrane permeability. In addition, we have developed an asymmetric aldol reaction and Mannich reaction utilizing a flow system and have realized reaction integration that can efficiently supply starting materials required for the synthesis of middle-size molecules.

Free Research Field

有機合成化学

Academic Significance and Societal Importance of the Research Achievements

ガン細胞の増殖を抑制する活性、骨を溶かす破骨細胞を抑制する活性を有するなど、天然から発見された創薬シーズである環状ペプチド化合物は、従来の低分子量の化合物とは異なり中分子量（500から2,000程度）であり、難解な構造をもつ。我々はこれら中分子環状ペプチド化合物とその周辺化合物を効率良く合成する手法を確立し、活性評価、三次元構造解析を行って、その有用性、および活性発現に必要な構造情報を明らかにした。この際、フロー合成法により、合成の出発物質を効率良く供給できる反応集積化を実現した。