Construction of focused library and the development of protein tyrosine phosphatase inhibitor

重点文库构建及蛋白酪氨酸磷酸酶抑制剂的开发

• 批准号: 15310144
• 负责人: SODEOKA Mikiko
• 金额: $ 10.05万
• 依托单位: TOHOKU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15310144/
• 关键词: focused library; protein tyrosine phosphatase; inhibitor; tetronic acid; RK-682; Ascorbic acid; heparanase; protein kinase C; ライブラリー; テロン酸

Aiming at developing PTP (protein tyrosine phosphatase), a "focused-library" (compounds having a "core" structure that can interact with the conserved catalytic site of PTP as a phosphate mimic and having "various" substituents that may interact with the unique region of each enzyme) was synthesized. Construction of a new library having L-ascorbic acid as a "core" structure was examined. We have already developed an efficient method for carbamate synthesis using a polymer-supported N-hydroxysuccinimide (NHS). Using this method an ascorbic acid-carbamate library was synthesized. The carbamate derivatives were prepared either from 6-amino-ascorbic acid and various alcohols, or from 5-dehydroxy-ascorbic acid and various amines. The inhibitory activity of these compounds (about 80 compounds) toward PTP1B (PTP) was tested, and several compounds showed the moderate inhibitory activity.The 4-O-alkyated tetronic acid derivatives as second generation library was synthesized, and 4-benzyl-RK-682 has been found to possess a selective inhibitory activity for heparanase. 4-Benzyl-RK-682 also inhibited the invasion and migration of human fibrosarcoma HT 1060 cells.The isobenzofuranone library was also synthesized, and among them we have found the strong PKCα activators.

以开发蛋白酪氨酸磷酸酶（PTP）为目标，合成了一个“聚焦文库”（具有“核心”结构的化合物，可以与PTP的保守催化位点作为磷酸盐模拟物相互作用，并且具有“各种”取代基，可以与每种酶的独特区域相互作用）。研究了以l -抗坏血酸为“核心”结构的新文库的构建。我们已经开发了一种利用聚合物负载的n -羟基琥珀酰亚胺（NHS）合成氨基甲酸酯的有效方法。用该方法合成了抗坏血酸-氨基甲酸酯文库。由6-氨基抗坏血酸和各种醇或5-去羟基抗坏血酸和各种胺制备氨基甲酸酯衍生物。这些化合物（约80个）对PTP1B （PTP）的抑制活性进行了测试，其中一些化合物表现出中等的抑制活性。合成了4- o -烷基化四烯酸衍生物作为第二代文库，发现4-苄基rk -682对肝素酶具有选择性抑制活性。4-苄基- rk -682还能抑制人纤维肉瘤HT 1060细胞的侵袭和迁移。我们还合成了异苯并呋喃酮文库，并在其中发现了PKCα强激活剂。

项目成果

Y.Baba, S.Mayumi, G.Hirai, H.Kawasaki, Y.Ogoshi, T.Yanagisawa, Y.Hashimoto, M.Sodeoka: "Evaluation of Series of Isobenzofuranone Dimers as PKCa Ligands : Implication for the Distance between the Two Ligand Binding Sites"Bioorg.Med.Chem.Lett.. Vol.14(In Pr

Y.Baba、S.Mayumi、G.Hirai、H.Kawasaki、Y.Ogoshi、T.Yanagisawa、Y.Hashimoto、M.Sodeoka：“一系列异苯并呋喃酮二聚体作为 PKCa 配体的评估：对两者之间距离的影响

An efficient catalytic enantioselective fluorination of β-ketophosphonates using chiral palladium complexes

• DOI: 10.1016/j.tetlet.2005.01.018
• 发表时间: 2005-02
• 期刊: Tetrahedron Letters
• 影响因子: 1.8
• 作者: Y. Hamashima;Toshiaki Suzuki;Yuta Shimura;Tadashi Shimizu;N. Umebayashi;Toshihiro Tamura;Naoki Sasamoto;M. Sodeoka

Design, synthesis, and structure-activity relationship of new isobenzofuranone ligands of protein kinase C

• DOI: 10.1016/j.bmcl.2004.02.097
• 发表时间: 2004-06-07
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• 影响因子: 2.7
• 作者: Baba, Y;Ogoshi, Y;Sodeoka, M
• 通讯作者: Sodeoka, M

Y.Baba, Y.Ogoshi, G.Hirai, T.Yanagisawa, K.Nagamatsu, S.Mayumi, Y.Hashimoto, M.Sodeoka: "Design, Synthesis, and Structure-Activity Relationship of New Isobenzofuranone Ligands of Protein Kinase C."Bioorg.Med.Chem.Lett.. Vol.14(In Press). (2004)

Y.Baba、Y.Ogoshi、G.Hirai、T.Yanagisawa、K.Nagamatsu、S.Mayumi、Y.Hashimoto、M.Sodeoka：“蛋白激酶 C 新型异苯并呋喃酮配体的设计、合成和构效关系

Structure-based design of a selective heparanase inhibitor as an antimetastatic agent.

• DOI: 10.1158/1535-7163.1069.3.9
• 发表时间: 2004-09
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: K. Ishida;Go Hirai;K. Murakami;T. Teruya;S. Simizu;M. Sodeoka;H. Osada