Development and mechanistic study of novel anti- Alzheimer's disease drugs with PKC-ε selective activation

选择性激活PKC-ε的新型抗阿尔茨海默病药物的开发及机制研究

• 批准号: 22790120
• 负责人: SHIMIZU Tadashi
• 金额: $ 2.5万
• 依托单位: Hyogo University of Health Sciences
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22790120/
• 关键词: 医薬品化学; PKC-ε; 認知症治療剤; DCP-LA; 構造活性相関; ターゲット探索; PKC-e; 認知症治療; 生理活性脂肪酸; 光学分割

We have already synthetic route for the preparation of all of the four isomers of enantiomerically pure DCP-LA employing lipase-mediated resolution method, and found the most active stereoisomers. However, first synthetic route was difficult for gram-scale synthesis of optically active DCP-LA. In this research, we have developed synthetic route for gram-scale preparation of all of the four isomers of enantiomerically pure DCP-LA, and found the most active stereoisomers in vivo system. In addition, we found that novel free fatty acid derivative HUHS2002 activated α7 ACh receptor responces. Fuethemore, we identified some candidates of target protein of DCP-LA with affinity chromatography methods.

我们已经采用脂肪酶介导的拆分方法合成了四种对映体纯的DCP-LA的异构体，并找到了活性最高的立体异构体。然而，第一条合成路线对于光学活性DCP-LA的克级合成是困难的。在本研究中，我们开发了克级制备对映体纯的DCP-LA的所有四种异构体的合成路线，并找到了体内系统中最具活性的立体异构体。此外，我们发现新型游离脂肪酸衍生物HUHS 2002可激活α7 ACh受体反应。此外，我们还通过亲和层析的方法鉴定了DCP-LA的一些候选目的蛋白。

项目成果

Effects of Newly Synthesized DCP-LA-Phospholipids on Protein Kinase C and Protein Phosphatases

• DOI: 10.1159/000350076
• 发表时间: 2013-01-01
• 期刊: CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
• 作者: Kanno, Takeshi;Tsuchiya, Ayako;Nishizaki, Tomoyuki
• 通讯作者: Nishizaki, Tomoyuki

Selective elution of target protein from affinity resins by a simple reductant with a thiol group.

通过带有硫醇基团的简单还原剂从亲和树脂上选择性洗脱目标蛋白。

• 发表时间: 2010
• 期刊: Bioorganic & Medicinal Chemistry Letters
• 影响因子: 2.7
• 作者: Miyuki Mabuchi;M. Haramura;Tadashi Shimizu;T. Nishizaki;A. Tanaka
• 通讯作者: A. Tanaka

Cyclooctanone synthesis via a formal [6+2] cycloaddition reaction of a dicobalt acetylene complex

通过二钴乙炔配合物的正式[6 2]环加成反应合成环辛酮

• DOI: 10.1016/j.tetlet.2010.05.120
• 发表时间: 2010
• 期刊: Tetrahedron Letters
• 影响因子: 1.8
• 作者: Katsuhiko Mitachi;Tadashi Shimizu;M. Miyashita;K. Tanino
• 通讯作者: K. Tanino

Indomethacin enhances learning and memory potential by interacting with CaMKII

• DOI: 10.1002/jcp.22800
• 发表时间: 2012-03-01
• 期刊: JOURNAL OF CELLULAR PHYSIOLOGY
• 影响因子: 5.6
• 作者: Kanno, Takeshi;Yaguchi, Takahiro;Nishizaki, Tomoyuki
• 通讯作者: Nishizaki, Tomoyuki

Synthetic Route to Optically Pure Norcantharidin Analog NCA-01, a Highly Selective Protein Phosphatase 2B inhibitor, and Its Derivatives

高选择性蛋白磷酸酶 2B 抑制剂、光学纯去甲斑蝥素类似物 NCA-01 及其衍生物的合成路线

• DOI: 10.1002/asia.201200077
• 发表时间: 2012
• 期刊: Chemistry-An Asian Journal
• 影响因子: 4.1
• 作者: Tadashi Shimizu