【作者】 林海霞；

【导师】 陈建民；

【作者基本信息】 复旦大学 ， 环境科学， 2005， 博士

【摘要】 紫杉醇是从红豆杉属植物中分离得到的一种二萜化合物,其结构新颖,抗癌机制独特,是近年来国际上公认的最好的抗癌药物之一。但它天然含量甚微,远远不能满足临床及基础研究的需要。于是紫杉醇及其类似物的新资源和替代资源的研究倍受关注。本文对紫杉醇伴生物1-去羟基巴卡亭Ⅵ紫杉烷资源的开发利用进行了研究。 本文研究重点主要包括三个部分。第一部分为1-去羟基巴卡亭Ⅵ的分离和结构的确认。在对福建产的美丽红豆杉树根提取物的分离研究中,我们发现了该化合物的存在且含量高,通过常规硅胶柱和反相液相制备色谱联合分离即可得到高纯度的1-去羟基巴卡亭Ⅵ:通过常规硅胶柱分离再经重结晶提纯也可得到纯度达97%以上的1-去羟基巴卡亭Ⅵ。后者提供了一种操作简单、成本低廉、环境友好的清洁生产新工艺。用X-射线单晶衍射方法研究1-去羟基巴卡亭Ⅵ的立体结构,它的固态构象研究表明7-羟基、9-羟基、10-羟基的乙酰化和C1位脱氧对紫杉烷中四环的构象几乎不产生影响。 第二部分为1-去羟基巴卡亭Ⅵ新衍生物的合成和结构的确认。我们对1-去羟基巴卡亭Ⅵ的选择性去酰化反应和羟基的选择性保护进行了研究,合成了十个新的衍生物,通过¹H NMR、、¹³C NMR、¹H-¹H COSY、¹H-¹³C COSY、MS以及X-射线单晶衍射法确证了它们的结构。 第三部分为1-去羟基巴卡亨Ⅵ新衍生物精细立体结构的研究。用X-射线单晶衍射方法研究其中七个新衍生物的精细立体结构。研究了晶态下母环上不同取代基对分子立体结构的影响,晶体学数据分析的结果证明C4-C5-C20四元氧环、C4取代基以及C2取代基对该类化合物活性的重要性,它们为紫杉醇类化合物与受体的结合提供了合适的空腔。从晶体学角度给出6/8/6/4骨架与抗癌活性的关系。 本文从分子水平上研究了紫杉醇类化合物的构效关系,并进行分子结构修饰,得到了一系列新衍生物,为合理利用该类紫杉烷资源,变废为宝,开发具有抗癌活性的新药打下了坚实的基础。更多还原

【Abstract】 A naturally occurring diterpenoid Paclitaxel (Taxol?, known also in the literature as taxol). isolated from the bark of the Pacific yew (Taxus brevifolia), has proved to be one of the most important new anticancer drug introduced in the last decades, owing to its great potential in the successful treatment of wide types of cancer, a unique antitumor mechanism of action, and complex molecular architecture. However, this source is neither abundant nor rapidly renewable, and it has been in short supply. Huge research efforts have been devoted to the search for sustainable alternatives. The most promising approach in terms of ecology and economy is at present the semi-synthesis of Paclitaxel. We report here studies on the exploitation of 1-dehydroxybaccatin VI resources.In the first section, 1-dehydroxybaccatin VI, corresponding to the diterpenoid core of Paclitaxel and available in relatively high yield (up to 0.08%), was isolated from roots of Taxus chinensis, Rehd. var. mairei. C18-silica gel reversed phase chromatography, column chromatography on silica gel and recrystallization were used to purify 1-dehydroxybaccatin VI. The operation conditions of chromatography were optimized. The structural assignments of the compound were based on their spectral data, including 2D NMR experiments and chemical correlation. The X-ray crystallographic analysis of 1-deoxy-baccatin VI provided unambiguous characterization for the structures. The solid-state conformation of 1-dehydroxybaccatin VI showed that both esterification of the 7-hydroxyl, 9-hydroxyl, 10-hydroxyl and removal of oxygen functionality at 1-position had little effect on the conformation of tetracyclic system.The second part of this thesis is study on synthesis of novel 1-dehydroxybaccatin VI derivatives. The use of potassium carbonate, hydrazine monohydrate and magnesium in methanol for the selective deacylation on 1-deoxybaccatinVI was described, and Montmorillonite K10 provided a method suitable for effective, selective ketalization occurring predominantly at C 9 and C 10 hydroxyl group of its derivatives. These protocols should prove to be of utility to more efficient semisyntheses of taxol analogs. Their structures were elucidated using extensive spectroscopic techniques (IR, 1HNMR, DEPT, COSY and MS). In addition, the conformations for these compounds were obtained by X-ray diffraction methods.In the final section, The crystal structures of 7 1-dehydroxybaccatin VI derivatives were analyzed. The effects of the induction by different substitution on the更多还原