Development of Systematic Synthesis of Antitumor Annonaceous Acetogenins and Evaluation of Biological Activity

我们研究了番荔枝内酯类化合物的合成及其高效衍生物的开发，该类化合物对多种人类癌细胞具有较强的细胞毒性。因此，首次完成了具有代表性的单-和双-四氢呋喃内酯的全合成，分别为小鼠李索林和长米星D。此外，应用我们系统合成的聚四氢呋喃核，合成了两个非对映异构体鼠李索林同系物，并对它们的生物活性进行了评价：1)鼠李索林衍生物的合成及生物活性评价我们已经系统合成了多四氢呋喃核。作为这项研究的延伸，我们将该方法应用于首次全合成单-四氢呋喃-乙酸生长素，Mursolin。我们建立了一种连接四氢呋喃片段和γ-内酯片段的方法，这是合成环节中的重要步骤。首次实现了小鼠李素的全合成。在ADI…中此外，还以类似的方法合成了小鼠李素的两个非对映异构体。通过细胞生长抑制谱和比较分析对3种小鼠孤素进行评价。收集了他们对39种人类癌细胞株的指纹图谱。将这些指纹图谱与已知作用机制不同的抗癌药物进行统计学比较。2)长米星的首次全合成研究了一种对人胰腺癌CALL具有较强细胞毒作用的双四氢呋喃类内酯类化合物长米星D的全合成。应用先前开发的多聚四氢呋喃环核的系统合成，构建了具有拥挤立体中心的双四氢呋喃环核，具有高的非对映选择性。然后，我们研究了连接bis-Thf和γ-内酯片段的合适连接子片段。因此，(3R)-10-苄氧基-3-(甲氧基甲氧基)DEC-1-yne是最合适的连接基段。最后，对三个片段进行了高效组装，实现了长米星D的首次全合成。较少

We have investigated a synthesis of Annonaceous acetogenins possessing a potent cytotoxicity against various human cancer cell lines as well as a development of highly potent derivatives. As a result, a first total synthesis of representative mono- and bis-THF acetogenins, murisolin and longimicin D, respectively, was accomplished. Furthermore, by applying our systematic synthesis of the poly-THF cores, two diastereomeric murisolin congeners were synthesized and their biological activity was evaluated.1)Synthesis of Murisolin Derivatives and Evaluation of Biological activityWe have already developed systematic synthesis of the poly-THF cores. As an extension of the research, we applied the methodology to a first total synthesis of mono-THF acetogenin, murisolin. We established a method for a connection of the THF segment and the γ-lactone segment that is important process for a synthesis of Annaceous acetogenins. As a result, first total synthesis of murisolin was accomplished. In addi … More tion, two diastereomeric isomers of murisolin were synthesized in a similar manner. Three murisolins were evaluated by the cell-growth inhibition profile and COMPARE analysis. Their finger prints against 39 kinds of human cancer cell lines were collected. These finger prints were statistically compared with each other as well as with known anti-cancer drugs having different action mechanisms.2)First Total Synthesis of Longimicin DWe investigated a total synthesis of bis-THF Annonaceous acetogenins, longimicin D, which possesses a potent cytotoxicity against human pancreatic cancer call. The bis-THF ring cores having congested stereogenic centers were constructed with high diastereoselectivity by applying previously developed systematic synthesis of the poly-THF cores. Then, we examined appropriate linker segment to connect the bis-THF and γ-lactone segments. Consequently, (3R)-10-benzyloxy-3-(methoxymethoxy)dec-1-yne was found to be the most suitable linker segment. Finally, three segments were efficiently assembled and a first total synthesis of longimicin D was achieved. Less