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Development of Systematic Synthesis of Antitumor Annonaceous Acetogenins and Evaluation of Biological Activity

抗肿瘤番荔枝苷的系统合成及生物活性评价

基本信息

批准号：
16590006
负责人：
MAEZAKI Naoyoshi
金额：
$ 1.34万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

We have investigated a synthesis of Annonaceous acetogenins possessing a potent cytotoxicity against various human cancer cell lines as well as a development of highly potent derivatives. As a result, a first total synthesis of representative mono- and bis-THF acetogenins, murisolin and longimicin D, respectively, was accomplished. Furthermore, by applying our systematic synthesis of the poly-THF cores, two diastereomeric murisolin congeners were synthesized and their biological activity was evaluated.1)Synthesis of Murisolin Derivatives and Evaluation of Biological activityWe have already developed systematic synthesis of the poly-THF cores. As an extension of the research, we applied the methodology to a first total synthesis of mono-THF acetogenin, murisolin. We established a method for a connection of the THF segment and the γ-lactone segment that is important process for a synthesis of Annaceous acetogenins. As a result, first total synthesis of murisolin was accomplished. In addi … More tion, two diastereomeric isomers of murisolin were synthesized in a similar manner. Three murisolins were evaluated by the cell-growth inhibition profile and COMPARE analysis. Their finger prints against 39 kinds of human cancer cell lines were collected. These finger prints were statistically compared with each other as well as with known anti-cancer drugs having different action mechanisms.2)First Total Synthesis of Longimicin DWe investigated a total synthesis of bis-THF Annonaceous acetogenins, longimicin D, which possesses a potent cytotoxicity against human pancreatic cancer call. The bis-THF ring cores having congested stereogenic centers were constructed with high diastereoselectivity by applying previously developed systematic synthesis of the poly-THF cores. Then, we examined appropriate linker segment to connect the bis-THF and γ-lactone segments. Consequently, (3R)-10-benzyloxy-3-(methoxymethoxy)dec-1-yne was found to be the most suitable linker segment. Finally, three segments were efficiently assembled and a first total synthesis of longimicin D was achieved. Less

我们研究了对多种人类癌细胞系具有有效细胞毒性的番荔枝乙酰苷的合成，以及高效衍生物的开发。结果，分别完成了代表性单-和双-THF acetogenins、murisolin 和 longimicin D 的首次全合成。此外，通过应用我们的聚-THF核心的系统合成方法，合成了两种非对映异构体murisolin同源物并评估了它们的生物活性。1）Murisolin衍生物的合成和生物活性评价我们已经开发了聚-THF核心的系统合成。作为研究的延伸，我们将该方法应用于单-THF acetogenin Murisolin 的首次全合成。我们建立了一种连接THF片段和γ-内酯片段的方法，这是合成Annaceous acetogenins的重要过程。结果，首次完成了 murisolin 的全合成。此外，以类似的方式合成了 murisolin 的两种非对映异构体。通过细胞生长抑制曲线和比较分析评估了三种 murisolins。收集了他们针对 39 种人类癌细胞系的指纹。这些指纹图谱相互之间以及与具有不同作用机制的已知抗癌药物进行了统计比较。2)长米星D的首次全合成我们研究了双-THF番红花苷元长米星D的全合成，它对人类胰腺癌具有有效的细胞毒性。通过应用先前开发的聚-THF核心的系统合成，以高非对映选择性构建具有拥挤的立体中心的双-THF环核心。然后，我们检查了适当的接头片段来连接双-THF 和γ-内酯片段。因此，发现(3R)-10-苄氧基-3-(甲氧基甲氧基)癸-1-炔是最合适的连接片段。最终，三个片段被高效组装，实现了长米星D的首次全合成。较少的

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

First total synthesis of longimicin D

DOI：
10.1002/ejoc.200500850
发表时间：
2006-03
期刊：
European Journal of Organic Chemistry
影响因子：
2.8
作者：
Hiroaki Tominaga;N. Maezaki;Minori Yanai;N. Kojima;D. Urabe;R. Ueki;Tetsuaki Tanaka
通讯作者：
Hiroaki Tominaga;N. Maezaki;Minori Yanai;N. Kojima;D. Urabe;R. Ueki;Tetsuaki Tanaka

Total Synthesis of Murisolins and Evaluation of Tumor‐Growth Inhibitory Activity.

Murisolins 的全合成和肿瘤生长抑制活性的评价。

DOI：
10.1002/chin.200615211
发表时间：
2006
期刊：
影响因子：
0
作者：
N. Maezaki;Hiroaki Tominaga;N. Kojima;Minori Yanai;D. Urabe;R. Ueki;Tetsuaki Tanaka;T. Yamori
通讯作者：
T. Yamori

First Total Synthesis of Murisolin

Murisolin 的首次全合成