Synthesis and Functional Analysis of Cell Adhesion Inhibitory Polyketides

细胞粘附抑制聚酮化合物的合成及功能分析

• 批准号: 14370722
• 负责人: SHISHIDO Kozo
• 金额: $ 9.66万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370722/
• 关键词: polyketide; lasonolide A; cell adhesion molecules; enantioselective synthesis; cytotoxicity; apoptosis; intramolecular Michael reactions; ring closing metathesis; エナンチオ選択的合成; ヒドロピラン

Polyketide-derived marine natural product lasonolide A, which was isolated from the shallow water Caribbean marine sponge, Forcepia sp., was shown to inhibit the in vitro proliferation of A-549 human lung carcinoma cells as well as to inhibit cell adhesion in a newly developed whole cell assay that detects signal transduction agents. We planned to synthesize this natural product and to discover a new and efficient lead compounds for the development of new drugs(1 ) Synthesis of the C_1-C_<17> segment : Lasonolide A was divided into three segments. Of these, the C_1-C_<17> segment was prepared enantioselectively(2) Synthesis of the C_<18> C_<25> segment : The C_<18>-C_<25> segment, which is the most difficult segment for the preparation, was enantioselectively synthesized by using the characteristic structural feature of dioxabicyclo [3.2.1] octane chiral building block. The synthetic route is also efficient and flexibe(3) Synthesis of the C_<26>C_<35> segment : The acyclic segment C_<26>-C_<35> was prepared starting from valeraldehyde and (S)-malic acid. Thus the three segments required for the total synthesis of lasonolide A were synthesized successfully. Since the synthetic routes for the segments are efficient and flexible, they would contribute to find useful lead compound for the development of new drugs(4) Biological evaluations of the synthetic intermediates of lasonolide A : To explore the useful lead compounds for the development of new drugs, the biological assay for several kinds of synthetic intermediates of lasonolide A was investigated by using normal cell and some cancer cells. As a result, interestingly, a simple lactone intermediate exhibited cytotoxicity and apoptosis-like activity

聚酮衍生的海洋天然产物拉索诺内酯 A 是从浅水加勒比海洋海绵 Forcepia sp. 中分离出来的，在新开发的检测信号转导剂的全细胞测定中，它被证明可以抑制 A-549 人肺癌细胞的体外增殖，并抑制细胞粘附。我们计划合成这种天然产物，并发现一种新的、高效的先导化合物，用于新药的开发。 (1)C_1-C_<17>片段的合成：Lasonolide A分为三个片段。其中，C_1-C_<17>片段是对映选择性制备的。(2)C_<18>C_<25>片段的合成：利用二氧杂双环[3.2.1]辛烷手性构件的特征结构特征，对映选择性合成了最难制备的片段C_<18>-C_<25>片段。该合成路线也是高效且灵活的。(3)C_ 26 C_ 35 链段的合成： 从戊醛和(S)-苹果酸开始制备无环链段C_ 26 -C_ 35 。至此，成功合成了拉索内酯A全合成所需的三个片段。由于该片段的合成路线高效且灵活，将有助于寻找用于新药开发的有用的先导化合物。(4)拉索内酯A合成中间体的生物学评价：为了探索用于新药开发的有用的先导化合物，利用正常细胞和一些癌细胞对拉索内酯A的几种合成中间体进行了生物学测定。结果，有趣的是，简单的内酯中间体表现出细胞毒性和凋亡样活性

项目成果

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M.Shindo: "Diastereoselective 1,3-Dipolar Cycloaddition of Ynolates with Chiral Nitrones"Synthesis. 1441-1445 (2003)

M.Shindo：“Ynolates 与手性硝酮的非对映选择性 1,3-偶极环加成”合成。

M.Shindo: "Electrophilic Cleavage of One Silicon-Carbon Bond of Pentacoordinate Tetraorganosilanes : Synthesis of Silalactones"Angew.Chem.Int.Ed.. 43-1. 104-106 (2004)

M.Shindo：“五配位四有机硅烷的一个硅碳键的亲电断裂：硅内酯的合成”Angew.Chem.Int.Ed. 43-1。

T.Kamei: "An Alternative Total Synthesis of (-)-Heliannuol E"Synlett. 2003・15. 2395-2397 (2003)

T.Kamei：“(-)-Heliannuol E 的替代全合成”Synlett 2003・15 (2003)。