Chemical Synthetic Approach towards Clarifying Mechanism of Action for Cytotoxicity of Squalene-Derived Polyethers

澄清角鲨烯衍生聚醚细胞毒性作用机制的化学合成方法

基本信息

批准号：
13640594
负责人：
MORIMOTO Yoshiki
金额：
$ 2.11万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

Recently, biologically active and structurally unique triterpene polyethers, which are thought to be biogenetically squalene- derived natural products (oxasqualenoids), have been isolated from both marine and terrestrial plants. Among them is cytotoxic (IC_<50> = 5.3 μg/mL against KB cells) longilene peroxide (1), isolated from the wood of Eurycoma longifolia by Itokawa et al. Although the relative stereostracture and conformation of 1 have been elucidated by X-ray crystallographic analysis and spectroscopic methods, the absolute configuration had not hitherto been determined in spite of the biogenetic interest in the compound as well as the relevant polyethers. In this research, the first asymmetric total synthesis of (-)-longilene peroxide (1) has been achieved starting from the optically active C_2-symmetric diepoxide through the concept of two-directional synthesis utilizing its intrinsic molecular symmetry. Thus, the unknown absolute configuration of longilene peroxide has been de … More termined by this synthesis.Glabrescol (3) and an epoxy tri-tetrahydrofuran (THF) diol (2) biogenetically related to each other were isolated from the endemic Jamaican plant Spatkelia glabrescens (Rutaceae) by Jacobs et al. Although there is no report on the biological activities of both compounds, these polyethers containing five or three THF rings may be expected to exhibit ionophoric functions as well as cytotoxicities. Many types of oxasqualenoids have been isolated; however, it is often difficult to determine their stereostructures only by spectroscopic analysis, especially in systems including acyclic quaternary carbon centers. In such cases, it is effective to predict and synthesize the possible stereoisomers. Although the planar structure and partial relative configuration of 2 were also elucidated by NMR methods, determination of the entire stereochemistry of compound 2 has not been reached. In this research, we have accomplished complete assignment of the stereostmcture of the new squalene-derived epoxy tri-THF diol (2) through its first asymmetric total synthesis. Less

最近，从海洋和陆地植物中分离出了生物活性和结构上独特的三萜聚乙烯聚乙烯（被认为是生物基因降异形的天然产物（Oxqualenoid））。其中包括细胞毒性（IC_ <50> =5.3μg/ml针对Kb细胞）长氧化二硅烷（1），由Itokawa等人从Eurycoma longifolia的木材中分离出来。尽管通过X射线晶体学分析和光谱方法阐明了1的相对定位和构象，但尽管在化合物中具有生物遗传学意义，但迄今尚未确定绝对构型。在这项研究中，从光学活跃的C_2对称二氧化二氧化碳开始，通过使用其固有分子对称性的二个方向合成的概念，已经实现了（ - ） - 多氧化过氧化物（1）的第一个不对称总合成。这就是说，longilene过氧化物的绝对构型已被这种合成所称为……glabrescol（3）和环氧三氢呋喃（THF）二醇（2）生物遗传学（2）在彼此之间隔离了彼此之间的相关性。尽管没有关于两种化合物的生物学活性的报道，但这些含有五个或三个THF环的聚乙烯可以观察到离子化功能以及细胞毒性。已经分离出了许多类型的黄甲苯；但是，通常很难仅通过光谱分析来确定其立体结构，尤其是在包括环状四级碳中心在内的系统中。在这种情况下，预测和合成可能的立体异构体是有效的。尽管还通过NMR方法阐明了2的平面结构和部分相对构型，但尚未达到化合物2的整个立体化学的测定。在这项研究中，我们通过其第一个不对称的总合成完成了新的衍生山毛环氧氧基三二醇（2）的立体结构的完整分配。较少的