Development of drug discovery chemistry centered on cyclodepsipeptide natural products

2017 Fiscal Year Final Research Report

• Project/Area Number: 26282208
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Biomolecular chemistry
• Research Institution: Tohoku University
• Principal Investigator: Doi Takayuki 東北大学, 薬学研究科, 教授 (90212076)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Keywords: 環状デプシペプチド / 天然物 / 全合成 / コンビナトリアル合成 / 三次元構造解析 / 構造活性相関 / ミメティクス / 創薬

Outline of Final Research Achievements

We have achieved efficient synthetic methods for the synthesis of various analogues of naturally occurring cyclodepsipeptides, apratoxin A and destruxin E, through a solid-phase peptide synthesis and macrocyclization in solution. Based on the three-dimensional analysis of apratoxin A using a distance geometry method, we designed sixteen mimetics without having a modified thiazoline moiety that would cause non-specific interaction. We discovered apratoxin M16 that exhibited similarly high level of growth inhibitory activity against 8 of 10 cancer cell lines as apratoxin A. We also achieved the combinatorial synthesis of 18 and 64 analogues of destruxin E and destruxin B. It was revealed that two intramolecular hydrogen bondings in destruxin regulate the three-dimensional conformation that is crucial to the induction of morphological changes in osteoclast-like multinuclear cells. In addition, we prepared an azido-containing molecular probe to identify a target molecule of destruxins.

Free Research Field

有機合成化学