权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Search for Medicinal Leads Inhibiting Nuclear Export of NES-containing Protein

寻找抑制含 NES 蛋白核输出的药物先导物

基本信息

批准号：
16590007
负责人：
MURAKAMI Nobutoshi
金额：
$ 2.24万
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

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590007/
关键词：
nuclear export signal (NES)1'-acetoxychavicol acetate inhibitor for nuclear export medicinal leads anti-HIV agents anti-tumor agents CRM1 molecular orbital calculation 1)-acetoxychavicol acetate

项目摘要

1'-Acetoxychavicol acetate (ACA), a NES-antagonistic inhibitor against nuclear export of NES containing protein, was suggested to be readily hydrolyzed in vivo because of its two acetyl moieties. Thus, some carbamate and carbonate analogs were prepared to be analyzed for its activity and stability in the medium containing serum. This analysis clarified that the functional group, which is difficult to be hydrolyzed, on phenolic hydroxyl portion extremely reduced the inhibitory activity for nuclear export of NES containing protein. Additionally, reactants of ACA and N-acetyl-L-cyctein methyl ester established 1-acetoxy-2-ene moiety as the binding site of cystein-529 in CRM1 and presumed the hydrolysis of ester linkage at 4-OH followed by formation of p-quininemethide intermediate to be essential for potent activity. Under this circumstance, molecular orbital calculation for each energy barrier based on the plausible mechanism of action of ACA disclosed the hydrolysis energy of acetyl group at 4-OH in ACA to be a rate-determining step. Furthermore, 2,3-difluoro-ACA analog with lower E1 was shown to exhibit 50 fold more potent activity than that of ACA. On the other hand, homology model of human CRM1 was built by means of a fold recognition method. Through the docking study of the analogs and the constructed homology model, the correlation between interaction energy and biological activity was obserbed.

1′-Acetoxychavicol acetate （ACA）是一种抑制含有NES蛋白核输出的NES拮抗剂，由于其含有两个乙酰基，因此很容易在体内被水解。因此，制备了一些氨基甲酸酯和碳酸盐类似物，以分析其在含血清的培养基中的活性和稳定性。这一分析表明酚羟基部分难以水解的官能团极大地降低了含NES蛋白的核输出抑制活性。此外，ACA和n-乙酰- l- cytein甲酯的反应物在CRM1中建立了1-乙酰氧基-2-烯片段作为半胱氨酸-529的结合位点，并推测4-OH上酯链的水解随后形成对奎宁甲胺中间体是有效活性的必要条件。在这种情况下，根据ACA的合理作用机理对每个能垒进行分子轨道计算，发现ACA中4-OH处乙酰基的水解能是一个决定速率的步骤。此外，具有较低E1的2,3-二氟ACA类似物的活性比ACA强50倍。另一方面，利用折叠识别方法建立了人类CRM1的同源性模型。通过对类似物与构建的同源性模型的对接研究，观察了相互作用能与生物活性之间的关系。

项目成果

期刊论文数量（44）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

1'-アセトキシシャピコールアセテートの立体選択的化学合成法

1-乙酰氧基沙皮醇醋酸酯的立体选择性化学合成方法

DOI：
发表时间：
2005
期刊：
影响因子：
0
作者：
通讯作者：

Kola acuminata proanthocyanidins:: a class of anti-trypanosomal compounds effective against Trypanosoma brucei

DOI：
10.1016/j.ijpara.2004.10.019
发表时间：
2005-01-01
期刊：
INTERNATIONAL JOURNAL FOR PARASITOLOGY
影响因子：
4
作者：
Kubata, BK;Nagamune, K;Urade, Y
通讯作者：
Urade, Y

Enhancement of anthocyanin content in red radishes (Raphanus sativus L.) by γ-ray irradiation

γ射线辐照提高红萝卜（Raphanus sativus L.）花青素含量

DOI：
发表时间：
2005
期刊：
Jpn.J.Food Chem. 12(3)
影响因子：
0
作者：
藤田博己;(SADI組織委員会編);N.Murakami et al.;高田伸弘;藤田博己;N.Murakami et al.;矢野泰弘;夏秋優;N.Murakami et al.;岩崎博道;N.Murakami et al.;田原研司;N.Murakami et al.
通讯作者：
N.Murakami et al.

Exploration for new anti-malarial leads using ingredients from medicinal plants as scaffolds

使用药用植物成分作为支架探索新的抗疟疾先导化合物