微小管凝集阻害とトポイソメラ-セ阻害活性発現の分子構造論的基礎

微管聚集抑制的分子结构基础和拓扑异构酶抑制活性表达

• 批准号: 07229231
• 负责人: 富岡 清
• 金额: $ 1.22万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 无数据
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-07229231/
• 关键词: 抗腫瘍性; 天然物; 合成物; 不斉合成; 微小管; リグナン; ペプチド; チアゾール

本研究では、ドラスタチン10及びその誘導体の大量確保が必須である。特に改良が必要となるDoe部分の合成法をL-Pheの修飾法からイミンとチアゾールの不斉カップリング法への転換を、われわれが開発した外部キラル配位子法を用いて行った。その結果、81%eeと比較的高い不斉収率で目的物を得ることに成功した。本合成法をと生かして、各種の人工誘導体を設計・合成したい。さらに、それらの生物活性の比較検討と物理化学的手法から活性発現の、立体因子、電子的因子、さらに三次元構造因子を明らかにする段階である。また、我々の開発した抗腫瘍性非天然型リグナンが極めて高い活性を有し、しかもトポイソメラーゼ阻害活性をも示すことが分かった。これらをDoeの同族体として捉え、Doe部に置換して結合させると、微小管結合部位の転換、もしくは全く新しい結合特性を有する化合物に変換できる可能性がある。従って、ドラスタチン10と非天然型リグナンとのハイブリッドを合成し、その結合部位の確定及び抗腫瘍活性を測定する。さらに非天然型リグナン部位のトポイソメラ-セ阻害型への構造修飾を行いdual actionを可能とするハイブリッドを創製する計画である。

In this study, a large number of people are required to make sure that a large number of people are required to ensure that they do not need to be protected. It is necessary to improve the Doe part of the synthesis method, the L-Phe method, the method of synthesis, the method of partial synthesis, the method of synthesis, the method of partial synthesis, the method of synthesis, the method of partial synthesis, the method of synthesis, the method of partial synthesis, the method of synthesis, the method of partial synthesis, the method of synthesis, the method of partial synthesis, the method of synthesis, the method of partial synthesis, the method of synthesis, the method of partial synthesis, the method of synthesis, the method of partial synthesis, the method of synthesis, the method of partial synthesis, the method of synthesis, the method of partial synthesis, the method of synthesis, the method of partial synthesis, the method of synthesis, the method of partial synthesis, the method of synthesis, the method of partial synthesis, the method of synthesis, the method of partial synthesis, the method of The result of the experiment and the high success rate of the 81%ee comparison show that the target is successful. The synthetic method is used to design the synthetic equipment of all kinds of artificial materials. The biological activities of antioxidants and antioxidants are compared with those of physical chemistry. The three-dimensional factors, stereo factors, electronic factors and three-dimensional factors show that there are significant differences in the biological activity of physics and chemistry. The antiviral activity of non-natural antiviral drugs is very high, and the anti-toxic activity of non-natural antiviral agents is very high. The new combination properties of the same family of Doe, Doe, microtubule, microtubule and microtubule have the potential to affect the possibility of binding. The synthesis, the determination of the binding site and the determination of the activity of anti-tumor were determined in the presence of non-natural drugs. This is a non-natural model, and the parts are not natural. There are some problems in the construction and repair of the dual action.

项目成果

Motomu Kanai: "Catalytic Asymmetric Conjugate Addition of Grignard Reagents Controlled by Copper(I)-Chiral Bidentate Phosphine Complex" Tetrahedron Letters. 36(24). 4275-4278 (1995)

Motomu Kanai：“由铜(I)-手性双齿膦配合物控制的格氏试剂的催化不对称共轭加成”四面体字母。

Motomu Kanai: "Asymmetric Conjugate Addition of Organomagnesium Cuprates Controlled by Stoichiometric Amount of Chiral Phosphine" Tetrahedron Letters. 36(24). 4273-4274 (1995)

Motomu Kanai：“手性膦化学计量控制有机镁铜酸盐的不对称共轭加成”四面体字母。

Isao Inoue: "Enantioselective Reaction of An Imine With Methyllithium CataLyzed by A Chiral Ligand" Tetrahedron Asymmetry. 6(10). 2527-2533 (1995)

Isao Inoue：“手性配体催化亚胺与甲基锂的对映选择性反应”四面体不对称性。

Motomu Kanai: "Conformational Preference and Diastereoselectivity of (S)-N-(α, β-Unsaturated Carbonyl)-γ-trityloxymethyl-γ-butyrolactam" Tetrahedron Letters. 36(51). 9349-9352 (1995)

Motomu Kanai：“(S)-N-(α, β-不饱和羰基)-γ-三苯甲氧基甲基-γ-丁内酰胺的构象偏好和非对映选择性”四面体快报 36(51) 9349-9352。

Kiyoshi Tomioka: "Diastereoselective Thiophenol Addition to (S) -N-α,β-Unsaturated Carbonyl-γ-triyloxymethyl-γ-butyrolactams" J. Org. Chem.60(19). 6188-6190 (1995)

Kiyoshi Tomioka：“(S)-N-α,β-不饱和羰基-γ-三酰氧基甲基-γ-丁内酰胺的非对映选择性苯硫酚加成”J. Org.60(19)。