Development of drug discovery chemistry centered on cyclodepsipeptide natural products
| Project/Area Number |
26282208
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Partial Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Biomolecular chemistry
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| Research Institution | Tohoku University |
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Principal Investigator |
Doi Takayuki 東北大学, 薬学研究科, 教授 (90212076)
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| Project Period (FY) |
2014-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
Fiscal Year 2016: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2015: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2014: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
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| 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 / 有機合成 / 三次元構造 / 立体配座解析 / 細胞毒性 |
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| 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.
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Report
(5 results)
Research Products
(24 results)
