Synthesis and Structure-Function Relationship Studies of Polycyclic Ether Natural Products

多环醚天然产物的合成及构效关系研究

• 批准号: 16310145
• 负责人: SASAKI Makoto
• 金额: $ 9.86万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16310145/
• 关键词: Polycyclic ethers; Gambierol; Gymnocin-A; Gymnocin-B; Brevenal; Structural Revision; Gambieric acids; Structure-activity relationship; 構造改訂; 神経毒; 蛍光プローブ; 電依存性カリウムチャネル; 機能解析

1.We have synthesized 18 structural variants of gambierol, potent neurotoxic polycyclic ether, and evaluated their biological activity. The structure-activity relationship (SAR) studies revealed the crucial structural elements necessary for exhibiting potent neurotoxicity.2.The structural features required for cytotoxicity of gymnocin-A were investigated by the total synthesis and evaluation of the structural analogues. The SAR studies indicated that the enal functionality of the side chain as well as the molecular length were necessary for cytotoxicity of gymnocin-A. A synthetic route to the LMNOring fragment of gymnocin-B was also established.3.Total synthesis of the proposed structure of brevenal was achieved. However, the ^1H and ^<13>C NMR spectra did not match those for the natural sample. The revised structure, the C26-epmier, was proposed based on the detailed NMR analysis along with the proposed biosynthetic pathway of marine polycyclic ethers and finally validated through total synthesis. The present studies also led to determination of the absolute configuration.4.A highly convergent synthesis of the nonacyclic polyether skeleton of gambieric acids A and C, potent antifungal polycyclic ethers, was accomplished for the first time. Stereoselective synthesis of the AB-ring fragment of gambieric acid A was also achieved.

1.我们合成了18个具有神经毒性的多环醚化合物甘比洛尔的结构变体，并对其生物活性进行了评价。构效关系（SAR）研究揭示了裸霉素A具有神经毒性的关键结构要素。2.通过全合成和结构类似物的评价，研究了裸霉素A细胞毒性所需的结构特征。SAR研究表明，侧链的烯醛官能度以及分子长度是裸霉素A细胞毒性所必需的。并建立了裸子菌素-B的LMNOring片段的合成路线。3.实现了短叶芹醛的全合成。然而，^1H和13 <13>C NMR谱与天然样品的谱不匹配。通过沿着详细的核磁共振分析，结合海洋多环醚的生物合成途径，提出了新的结构，即C26-epsilon，并通过全合成验证。4.首次实现了有效抗真菌多环醚化合物冈比亚酸A和冈比亚酸C的九环聚醚骨架的高度收敛合成。还实现了冈比亚酸A的AB环片段的立体选择性合成。

项目成果

Convergent synthesis of the BCDEFGHIJ-ring polyether core of gambieric acids, potent antifungal polycyclic ethers

强效抗真菌多环醚 BCDEFGHIJ 环聚醚核心冈比亚酸的收敛合成

• 发表时间: 2007
• 期刊: Tetrahedron 63
• 作者: S. Oshita;A. Matsumoto;Kazushi Sato
• 通讯作者: Kazushi Sato

Stereoselective synthesis of the AB-ring fragment of gambieric acid A

• DOI: 10.3987/com-06-s(k)30
• 发表时间: 2007-04-13
• 期刊: HETEROCYCLES
• 影响因子: 0.6
• 作者: Fuwa, Haruhiko;Suzuki, Akihiro;Sasaki, Makoto
• 通讯作者: Sasaki, Makoto