Search for Anticancer Drugs of Taxol Analogue

紫杉醇（Taxol）是1971年从紫杉科（Taxaceae）短叶红豆杉（Taxus brevifolia）中分离得到的一种功能性很强的二萜类化合物，被认为是目前癌症化疗中最令人兴奋的先导化合物，被誉为90年代的抗癌药物。紫杉烷类化合物具有良好的抗肿瘤活性、独特的结构特征、新颖的作用方式和独特的生物起源等特点，促使人们从分布广泛的红豆杉科植物和天然产物中寻找具有相似活性的新的相关二萜类化合物。本研究以云南红豆杉、云南红豆杉和南方红豆杉三种红豆杉科植物为研究对象。mairei被选为铅化合物的植物来源。从这些植物中分离得到20多个新的二萜类化合物，以及包括紫杉醇和10-去乙酰基浆果赤霉素III在内的16个已知的紫杉烷类化合物。 ...更多信息 具有新颖的5/7/6/碳骨架，四个为普通紫杉烷骨架。对于结构测定，一些2D NMR技术，如长程^<13>C-^1H COSY、ROESY、NOESY，被发现是非常有效的。通过X射线晶体学分析，对一些新的二萜化合物的结构进行了确证。特别令人感兴趣的是，前者的二萜类化合物在环境温度下作为溶液中构象异构体的混合物存在。该比率取决于B和C环上的取代模式。不幸的是，迄今为止还没有发现新的二萜类化合物对微管蛋白解聚的显著抑制活性。将紫杉醇抗肿瘤活性的重要结构单元苯基异丝氨酸引入新分离的5/7/6化合物的C13位，以及基于活性化合物构象分析和计算化学的人工设计化合物的合成，目前正在进行中。少

Taxol, a highly functional diterpene isolated in 1971 from the Pacific yew tree, Taxus brevifolia (Taxaceae), is currently considered the most exciting lead in cancer chemotherapy, hence called as the anticancer drug of '90s. Some aspects of taxoids, such as their promising antitumor activity, unique structural features, novel mode of action and unusual biogenesis, stimulated the search for new related diterpenoids having similar activity from the widely distributed species of the family Taxaceae as well as natural products. In this project, three Taxaceaes which grow at Yunnan in China, Taxus chinensis, Taxus Yunnansis and Taxus chinensis var. mairei, were chosen as a plant source for a lead compound. From these plants, more than twenty new diterpenes have been isolated in a pure form together with sixteen known taxoids including taxol and 10-deacetyl baccatin III.Among the new diterpenoids, the structures of totally sixteen compounds could be elucidated, in which twelve diterpenoids … More possesses novel 5/7/6/carbon framework and the four an ordinary taxoid skeleton. For structural determination, some 2D NMR techniques, such as Long Range ^<13>C-^1H COSY,ROESY,NOESY,were found to be extremely effective. The final proof on the structures of some new diterpenoids was afforded by X-ray crystallographic analyzes. Particular interest is that the diterpenoids of the former exist as a mixture of conformational isomers in a solution at an ambient temperature. The ratio depends upon the substitution pattern on the B and C ring. Unfortunately, no significant inhibitory activity of the new diterpenoids isolated against tublin depolymerization has been recognized so far. Introduction of the phenyl isoserine moiety, which is known as an essential structural unit for antitumor activity in taxol, into C13 position of the newly isolated 5/7/6 compounds as well as the synthesis of artificially designed compounds based on conformational analysis of active compounds and computationary chemistry, are currently in progress. Less