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PI3キナーゼ阻害剤ワ-トマンニンの合成と生物有機化学的展開

PI3激酶抑制剂渥曼青霉素的合成及生物有机化学开发

基本信息

批准号：
07772088
负责人：
中田雅久
金额：
$ 0.7万
依托单位：
Waseda University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Encouragement of Young Scientists (A)
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

项目摘要

本研究では、PI3キナーゼの強力な阻害剤、ワ-トマンニンをバイオロジカルツールとして利用する研究展開を目指した。バイオロジカルツールとしては、(1)ワ-トマンニンをリガンドとしたアフィニティクロマトグラフィー(2)放射性同位体を導入したワ-トマンニン誘導体(標識化合物)を考えた。これらの合成には、PI3キナーゼの阻害活性を保持しているワ-トマンニン誘導体が必要であった。そこで既存の構造活性相関のデータから、ワ-トマンニンの17位のカルボニル基周辺に構造修飾を施せば、その目的に合った誘導体が得られると我々は予想した。この予想のもとに幾つかのワ-トマンニン誘導体を合成し、それらのPI3キナーゼ阻害活性をin vitroで測定したところ(東京大学薬学部堅田教授に測定を依頼)、いずれにおいても2〜3桁の活性低下が観察された。この結果は、既存の構造活性相関とは異なる傾向にあり、新たな知見を得たと言える。ワ-トマンニンは反応性に富んだフラン環を有し、実際その部位で速やかに化学反応を起こして開環体を与えことより、その部位でPI3キナーゼと共有結合を生成すると思われる。本研究で得られたワ-トマンニン誘導体をリガンドとするアフィニティークロマトグラフィーを使用すれば、2〜3桁の活性低下を見込んでも、ワ-トマンニンPI3キナーゼ複合体が形成され、PI3キナーゼに結合する未発見のタンパク質を単離精製可能であるので、アフィニティークロマトグラフィーの作成を現在検討中である。また、放射活性なヨウ素を含む誘導体の合成に成功し、その標識体を利用してPI3キナーゼの触媒ユニットを初めて標識できたこと、従来のPI3キナーゼのサブユニットとは、制御様式等の異なる新たなサブタイプを確認できたことは特筆すべき成果である。

The purpose of this study is to use the PI3 research to carry out the research on the purpose of this study. In the first place, (1) the radioisotope was introduced into the body (identification compound). It is necessary to keep the activity of PI3 synthesis, synthesis and inhibition of toxicity. In order to improve the performance of the system, we need to know that there are many factors in the system, such as the active phase, the active phase, the active phase I don't think so. I don't think so. I don't want to know about the synthesis of the body, the inhibition activity, the in vitro test, the in vitro test, the test, the low activity, the low activity, the low activity. The results show that the existing products are similar to each other, and that the new information can be obtained from each other. The chemical reaction between the environment and the PI3 environment of the environmental protection system, the environmental protection environment and the chemical reaction of the environmental protection environment, the environmental protection environment and the environmental protection environment have been combined to form a chemical reaction system. In this study, we found that there was no significant difference between the use of PI3 and the formation of complex in this study. The results showed that there was no significant difference between the two groups in this study. in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study were as follows: in this study, the results of this study showed that the use of I don't know. I don't know. The radiation activity factor contains the PI3, the radiation activity, the synthesis, and so on.