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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具有生物活性和结构独特的三萜聚醚，它们被认为是生物生成的角鲨烯衍生的天然产物(氧杂奎烯)。其中对KB细胞有细胞毒性(IC_&lt；50&gt；=5.3μg/mL)的过氧化长环烯(1)，由Itokawa等人从长叶龙须草的木材中分离得到。虽然1的相对立体结构和构象已通过X射线晶体分析和光谱分析方法确定，但尽管该化合物和相关聚醚具有生物起源的兴趣，但到目前为止还没有确定其绝对构型。本研究首次从具有光学活性的C2对称双环氧化物出发，利用其固有的分子对称性，通过双向合成的概念，首次实现了(-)-长烯过氧化氢(1)的不对称全合成。因此，未知的过氧化己二烯的绝对构型为de…Glabresol(3)和环氧三氢呋喃(THF)二醇(2)是由Jacobs等人从牙买加特有植物光肩星天麻(Spatkelia toresens，Rutaceae)中分离得到的。虽然目前还没有关于这两种化合物的生物活性的报道，但这些含有五个或三个四氢呋喃环的聚醚可能会显示出离子传递功能和细胞毒性。目前已分离出许多类型的氧杂喹烯类化合物，但仅通过光谱分析很难确定它们的立体结构，特别是在含有非环四元碳中心的体系中。在这种情况下，预测和合成可能的立体异构体是有效的。虽然2的平面结构和部分相对构型也被核磁共振方法阐明，但还没有达到对化合物2的全部立体化学的确定。在本研究中，我们通过首次不对称全合成，完成了新的角鲨烯类环氧三四氢呋喃二醇(2)的立体结构的完全归属。较少