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

肿瘤细胞与正常细胞的选择性区分一直是开发有效癌症治疗剂的核心问题。许多研究都是为了寻找只存在于肿瘤细胞而不存在于正常细胞中的肿瘤特异性分子靶点。对天然高效物质的抗肿瘤活性进行生化研究可能有助于这方面的研究。Bullatacin(1)是一种与邻体双四氢呋喃（bistetrahydrofuran）相结合的天然产物，具有显著的抗肿瘤活性，其ED_<50>=10^<-15>杯/ml (9PS,1)，有望成为一种合适的先导化合物，通过生化研究可以方便地寻找肿瘤特异性分子靶点。作为该方法的第一步，我们研究了布拉他星(1)及其对映体的多用途手性合成，这适用于该基团其他成员的合成。在对其功能的初步研究中，发现模型化合物(2)具有选择性钾离子的阳离子转运能力，如图1所示，尽管阳离子结合能力尚未与1的抗肿瘤活性相关。我们期望通过对合成和放射性标记化合物的生化研究将揭示1的分子靶标。

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.