Synthesis and Functional Analysis of Cell Adhesion Inhibitory Polyketides

从浅水加勒比海海绵Forcepia sp.中分离得到的海洋天然产物Lasonolide A，在一项新发展的全细胞检测信号转导药物的实验中，显示出抑制A-549人肺癌细胞体外增殖和抑制细胞黏附的作用。我们计划合成这一天然产物，并发现一种新的有效的先导化合物用于新药的开发。(1)C_1-C_1；17&gt；片段的合成：Lasonolide A分为三个片段。其中，C_1-C_(17)链段是对映体选择性合成的。(2)C_&lt；18；C_&gt；25&gt；链段的合成：C_&lt；18；-C_&gt；25&gt；链段是利用二恶二环[3.2.1]辛烷手性构筑块的结构特征，对映体选择性合成的，是制备难度最大的链段。(3)C_&lt；26&gt；C_&lt；35&gt；链段的合成：C_&lt；26&gt；-C_&&lt；35&gt；以戊醛和(S)-苹果酸为原料合成。从而成功地合成了拉索内酯A全合成所需的三个链段。由于合成路线灵活高效，有助于寻找对新药开发有用的先导化合物。(4)雷索内酯A合成中间体的生物学评价：为了探索对新药开发有用的先导化合物，我们利用正常细胞和一些癌细胞对几种合成中间体进行了生物活性测定。因此，有趣的是，一种简单的内酯中间体显示出细胞毒性和类凋亡活性

Polyketide-derived marine natural product lasonolide A, which was isolated from the shallow water Caribbean marine sponge, Forcepia sp., was shown to inhibit the in vitro proliferation of A-549 human lung carcinoma cells as well as to inhibit cell adhesion in a newly developed whole cell assay that detects signal transduction agents. We planned to synthesize this natural product and to discover a new and efficient lead compounds for the development of new drugs(1 ) Synthesis of the C_1-C_<17> segment : Lasonolide A was divided into three segments. Of these, the C_1-C_<17> segment was prepared enantioselectively(2) Synthesis of the C_<18> C_<25> segment : The C_<18>-C_<25> segment, which is the most difficult segment for the preparation, was enantioselectively synthesized by using the characteristic structural feature of dioxabicyclo [3.2.1] octane chiral building block. The synthetic route is also efficient and flexibe(3) Synthesis of the C_<26>C_<35> segment : The acyclic segment C_<26>-C_<35> was prepared starting from valeraldehyde and (S)-malic acid. Thus the three segments required for the total synthesis of lasonolide A were synthesized successfully. Since the synthetic routes for the segments are efficient and flexible, they would contribute to find useful lead compound for the development of new drugs(4) Biological evaluations of the synthetic intermediates of lasonolide A : To explore the useful lead compounds for the development of new drugs, the biological assay for several kinds of synthetic intermediates of lasonolide A was investigated by using normal cell and some cancer cells. As a result, interestingly, a simple lactone intermediate exhibited cytotoxicity and apoptosis-like activity