Synthetic Studies of the Marine Alkaloids, Madangamines with Anti Tumor Activities

具有抗肿瘤活性的海洋生物碱马达加明的合成研究

• 批准号: 15590025
• 负责人: YAMAZAKI Naoki
• 金额: $ 1.66万
• 依托单位: Tokyo University of Pharmacy and Life Sciences
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590025/
• 关键词: marine alkaloid; madangamine; macrocyclization; cross-coupling reaction; N, O-acetalization; hydrogenation of bridge head iminium ion; intramolecular reductive amination; anti tumor activities; 天然物化学; 還元的アミノ化; 環状N,O-アセタール; 2-アザビシクロノナン; 閉環メタセシス

Madangamine A is a pentacyclic alkaloids that was isolated from the marine sponge Xestospongia ingens by Andersen in 1994. Soon after, new constituents of this alkaloid type, madangamines B-E, were isolated from the same organism. Madangamine A exhibits cytotoxic activities against P388, A549, U373, and MCF-7 tumor cell lines. In this research project, I have accomplished the construction of the ABC and ACE-ring frameworks of madangamines. N, O-Acetalization of the keto-aminophenol allows rapid construction of the 2-azabicyclo[3.3.1]nonane skeleton with a quaternary carbon center at C4. This strategy enabled the stereoselective construction of the central diazatricyclic core (ABC-ring) of the madangamine alkaloids. In the next stage of our investigation, an efficient construction of the madangamine tricyclic ring, 4-azatricyclo[11.2.2.0^<4.14>]heptadec-12-ene, including an 11-membered macrocycle (ACE-ring) has been accomplished via construction of the 2-azabicyclo[3.3.1]nonane skeleton by N, O-acetalization of a cyclohexanone derivative, geometry-retained cross-coupling reaction, and intramolecular reductive amination. From the results obtained above, my future studies will be focused on the construction of a 15-membered macrocycle (D-ring) for the total synthesis of madangamines.

Madangamine A是一种五囊生物碱，是Andersen于1994年与Andersen隔离的典型生物碱。不久之后，这种生物碱类型的新成分Madangamines B-E被与同一生物体分离出来。 Madangamine A针对P388，A549，U373和MCF-7肿瘤细胞系具有细胞毒性活性。在这个研究项目中，我完成了Madangamines的ABC和ACE环框架的建设。 n，酮氨基苯酚的O-乙醇化可以快速构建与C4的第四纪碳中心的2-氮杂[3.3.1]非骨架。该策略使Madangamine生物碱的中央二氮杂核（ABC环）的立体选择性结构。在下一个调查阶段，通过构建2- Zazabicyclo [3.3.1] nonhane noane sheleton n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n N.衍生物，几何固定的交叉偶联反应和分子内还原性胺化。从上面获得的结果来看，我的未来研究将集中于建造15元的大环（D-RIR），以用于Madangamines的总合成。

项目成果

環状N,O-アセタールを利用するアルカロイド合成

使用环状 N,O-缩醛合成生物碱

• 发表时间: 2003
• 期刊: 有機合成化学協会誌 61・9
• 作者: 山崎直毅;樹林千尋
• 通讯作者: 樹林千尋

Synthesis of the Diazatricyclic Core of the Marine Alkaloids Madangamines

海洋生物碱 Madangamines 的二氮杂三环核心的合成

• 发表时间: 2004
• 期刊: Tetrahedron Letters 45
• 作者: Naoki Yamazaki;Takahiko Kusanagi;Chihiro Kibayashi
• 通讯作者: Chihiro Kibayashi

山崎直毅, 樹林千尋: "環状N, O-アセタールを利用するアルカロイド合成"有機合成化学協会誌. 61・9. 868-881 (2003)

Naoki Yamazaki，Chihiro Jubayashi：“使用环状N，O-缩醛的生物碱合成”有机合成化学学会杂志61・9（2003）。

Synthesis of the 11-Membered Ring of the Marine Alkaloids, Madangamines

海洋生物碱 Madangamines 11 元环的合成

• 发表时间: 2006
• 期刊: Tetrahedron Letters 47
• 作者: Yoshimura;Y.; Inoue;J.; Yamazaki;N.; Aoyagi;S.; Kibayashi;C.
• 通讯作者: C.