新規な構造を持つアセトゲニン類をリード化合物とする新しいがん細胞認識分子の探索

使用具有新颖结构的acetogenins作为先导化合物寻找新的癌细胞识别分子

• 批准号: 03671005
• 负责人: SASAKI Shigeki
• 金额: $ 1.34万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-03671005/
• 关键词: Acetogenin; Bullatacin; Antitumor Activity; Tumor cell recognition molecule; Cell growth inhibition; Stereoselective Synthesis

Selective discrimination of tumor cells from normal cells has been a central concern in development of potent therapeutic agents for cancer.A number of studies have been directed to seek tumor-specific molecular targets which exist only in tumor cells not in normal cell.Biochemical investigations on antitumor activity of naturally occurring materials with quite high potency may contribute to such a research.Bullatacin(1),a representative of natural products called annonaceae acetogenins with neighboring bistetrahydrofuran,has impressibly potent antitumor activity with ED_<50>=10^<-15> mug/ml for 9PS,1)and was expected to be a suitable lead compound with which biochemical studies may facilitate to search tumor-specific molecular targets.As the first step for such an approach,we studied versatile chiral synthesis of Bullatacin(1)and its enantiomer which is applicable to the synthesis of other members of this group.In a preliminary investigation on its function,it was found that a model compound(2)has cation transport ability selective to potassium cation,as illustrated in Fig 1,although cation binding ability has not yet been correlated to antitumor activity of 1. We expect that biochemical studies with the synthetic as well as radiolabelled compounds would reveal a molecular target of 1.

肿瘤细胞与正常细胞的选择性识别一直是开发有效的癌症治疗药物的核心问题。许多研究旨在寻找仅存在于肿瘤细胞中而不存在于正常细胞中的肿瘤特异性分子靶点。对具有相当高效力的天然物质的抗肿瘤活性的生化研究可能有助于这方面的研究。布拉他星(1)是一种天然产物，与邻近的双四氢呋喃一起被称为番荔枝属乙酰基，具有显著的抗肿瘤活性，其ED_&lt；50&gt；=10^&lt；-15&gt；作为这种方法的第一步，我们研究了布拉塔星(1)及其对映体的多用途手性合成。在对其功能的初步研究中，发现一个模型化合物(2)对钾离子具有选择性，如图1所示。虽然阳离子结合能力尚未与1的抗肿瘤活性相关。我们预计合成的化合物以及放射性标记化合物的生物化学研究将揭示1的分子靶点。

项目成果

Hiroyuki NAITO: "Metal Cation Selective Binding Ability of Bistetrahydrofuran Derivatives"

Hiroyuki NAITO：“双四氢呋喃衍生物的金属阳离子选择性结合能力”

内藤 博之: "Metal Cation Selective Binding Ability of Bistetrahydrofuran Derivatives"

Hiroyuki Naito：“双四氢呋喃衍生物的金属阳离子选择性结合能力”

河原 英治: "Chiral Synthesis of Natural Product,Bullatacin,With Potent Antitumor Activity"

Eiji Kawahara：“天然产物布拉他星的手性合成，具有有效的抗肿瘤活性”

Eiji KAWAHARA: "Chiral Synthesis of Natural Product,Bullatacin,with Potent Antitumor Activity"

Eiji KAWAHARA：“具有有效抗肿瘤活性的天然产物布拉他星的手性合成”