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Studies toward Determination of Absolute Stereochemistry and Total Synthesis of Stereochemically Undefined Bioactive Natural Polyether Macrolides

绝对立体化学测定及立体化学未定义生物活性天然聚醚大环内酯的全合成研究

基本信息

批准号：
16510152
负责人：
FUJIWARA Kenshu
金额：
$ 2.56万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Toward development of an efficient methodology for determination of the absolute stereochemistry of undefined bioactive natural polyether macrolides, goniodomin A and caribenolide I were investigated in view of organic synthetic chemistry. Goniodomin A was isolated from dinoflagellate Alexandrium hiranoi as an antifungal agent by Murakami in 1988. Later, its particular bioactivities, such as modulation of actomyosin ATPase activities, increasing the filamentous actin content of human astronoma cells, and antiangiogenic activity via inhibition of actin reorganization in endothelial cells, were found. Although its detailed NMR data and unique planer structure featured by a 32-membered macrolactone including 5- and 6-membered cyclic ethers (the A-,D- and E-ring parts), a spirocyclic acetal (the BC-ring part), and a 6-membered cyclic hemiacetal (the F-ring part) were reported, the stereochemistry of goniodomin A was unclear. Caribenolide I was isolated from dinoflagellate Amphidinium sp.S1 … More -36-5 as a cytotoxic agent, which showed strong cytotoxicity against HCT116 with 1.6 nM of IC_<50>, by Shimizu in 1995. While its planer structure, characterized by a 26-membered macrolactone with an oxolane, a 6-membered cyclic hemiacetal, an epoxide, and 5 hydroxy groups (including a hemiacetal hydroxy group), was elucidated, its relative and absolute configurations were not determined. From this research project, determination of partial stereochemistry and partial synthesis of goniodomin A have been achieved as follows : (1)the relative configurations of the A-,BC-,D-,E-, and F-ring parts were predicted from the NMR data of goniodomin A reported by Murakami ; (2)the A-,D-,E-, and F-ring segments possessing the predicted stereochemistries were synthesized ; (3)NMR data of natural goniodomin A agreed well with those of synthetic A-,D-,E-, and F-ring segments ; (4)relative stereochemistry of the DE-ring part was determined by comparison of NMR data of natural goniodomin A with the synthetic DE-ring included in a macro ring ; (5)the proper stereochemistry of the BC-ring part was elucidated by synthetic assessment of the predicted structure from the NMR data of goniodomin A. Some synthetic analogues of caribenolide I were also designed in order to determine its relative stereochemistry. Less

为了建立一种有效的测定未知生物活性天然聚醚大环内酯类化合物绝对立体化学的方法，从有机合成化学的角度出发，对高碘甲素和卡里本内酯I进行了研究。Goniodomin A是1988年村上从甲藻亚历山大藻中分离得到的抗真菌药物。后来，发现了其独特的生物活性，如调节肌动蛋白ATPase活性，增加人类天文细胞的丝状肌动蛋白含量，以及通过抑制内皮细胞肌动蛋白重组而抗血管生成活性。虽然其详细的核磁共振数据和独特的平面结构被报道为32元大内酯，包括5元和6元环醚(A环、D环和E环部分)、螺环缩醛(BC环部分)和6元环半缩醛(F环部分)，但其立体化学尚不清楚。从甲藻Amphiddium sp.S1…中分离得到Caribenolide IMore-36-5作为一种细胞毒剂，对HCT116表现出很强的细胞毒作用，其IC_50和GT；在1995年由清水公司发现。其平面结构为26元大内酯与氧杂环己烷、6元环状半缩醛、环氧化物和5个羟基(包括半缩醛羟基)，但其相对和绝对构型尚未确定。(1)根据村上刚碘甲素的核磁共振数据预测了A-、BC-、D-、E-和F-环段的相对构型；(2)合成了具有预测立体化学结构的A-、D-、E-和F-环段；(3)合成了具有预测立体化学特征的A-、D-、E-和F-环段；(4)通过比较天然De环和大环中合成的De环的核磁共振数据，确定了De环部分的相对立体化学；(5)通过对Gongiodon A的核磁共振数据预测的结构的合成评估，确定了BC环部分的合适的立体化学。较少