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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

为了开发一种有效的方法来确定未定义的生物活性天然聚醚大环内酯的绝对立体化学，从有机合成化学的角度对 goniodomin A 和 caribenolide I 进行了研究。 Murakami 于 1988 年从甲藻平井亚历山大藻中分离出 Goniodomin A 作为抗真菌剂。后来，人们发现了其特殊的生物活性，如调节肌动球蛋白 ATP 酶活性、增加人天文学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具有抗血管生成活性。尽管报道了其详细的NMR数据和独特的平面结构，其特征为32元大环内酯，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goniodomin A的立体化学尚不清楚。 Caribenolide I 是 Shimizu 于 1995 年从甲藻 Amphidinium sp.S1 … 更多 -36-5 中分离出来的一种细胞毒剂，对 HCT116 表现出很强的细胞毒性，IC_<50> 为 1.6 nM。而其平面结构的特点是 26 元大环内酯和四氢呋喃（一种 6 元环状半缩醛），环氧化物和5个羟基（包括半缩醛羟基）已被阐明，但其相对和绝对构型尚未确定。本研究项目实现了goniodomin A的部分立体化学测定和部分合成：(1)根据Murakami报道的goniodomin A的NMR数据预测了A-、BC-、D-、E-和F-环部分的相对构型； (2)合成了具有预测立体化学的A-、D-、E-和F-环片段； (3)天然goniodomin A的NMR数据与合成的A-、D-、E-和F-环片段的NMR数据吻合良好； (4)通过比较天然goniodomin A与包含在大环中的合成DE-环的NMR数据确定DE-环部分的相对立体化学； (5)通过对goniodomin A的NMR数据预测的结构进行综合评估，阐明了BC环部分的正确立体化学。还设计了caribenolide I的一些合成类似物，以确定其相对立体化学。较少的