【作者】 雍智全；

【导师】 翁玲玲；

【作者基本信息】 四川大学 ， 药物化学， 2006， 博士

【摘要】 Combretastatin A-4(简称CA4)是Pettit小组从南非Combretum caffrum树干中提取分离的具有抗肿瘤活性的二苯乙烯类化合物。与传统的直接作用于癌细胞的化合物不同，CA4是靶向作用于肿瘤的血管，引起内皮细胞在形态学上的许多改变，从而阻塞肿瘤微血管。药理试验表明CA4在多种实体肿瘤模型中均能靶向作用于肿瘤微血管系统并快速减小肿瘤血流量。由于CA4在天然植物中含量极少，在我国还没有发现有植物含有该成分，同时溶解性极差，造成了不仅资源短缺而且难以充分发挥其药理药效作用。解决CA4的原料来源问题和改善CA4的溶解性问题成为众多药学工作者近年研究的焦点之一。其中在增加溶解性方面具有代表性的是经磷酸化修饰合成的前药combretastatin A-4磷酸酯二钠(CA4P)，其体内抗肿瘤活性大大提高，在国内、外均已作为新药申报，且国外已经进入三期临床试验。由此，全合成CA4及其可溶性类似物也就成为本课题研究的主要核心。 本论文在这一背景下，首先完成了对CA4、CA4P的全合成工艺研究并对各步反应进行了筛选与优化；并就合成工艺中涉及的相关中间原料的合成工艺进行筛选和优化；进而引入具有优良亲水性的磷酸酯胆碱基团，设计并合成出CA4磷酸酯胆碱系列类似物，并对它们抗肿瘤活性和稳定性进行了初步研究。课题具体完成了： 1．CA4的全合成 作者在参考文献的启发下，通过和Wittig反应系列对比实验，完成了用Perkin缩合立体选择性合成CA4工艺研究。研究中解决并完成了中间体2-(3,4,5-三甲氧基苯基)-3’-羟基-4’-甲氧基-(E)苯乙烯酸合成实验条件，如：两种关键原料的配料比为醛要比苯乙酸过量20％反应收率最高，杂质最少；反应产生的是3`-羟基乙酰化产物，要通过水解才能得到2-(3,4,5-三甲氧基苯基)-3`-羟基-4`-甲氧基-(E)苯乙烯酸，而不是文献中的直接得到该中间体；完成对该产物的熔点、MS、NMR数据的确定，而文献没有任何质量和结构确证数更多还原

【Abstract】 Combretastatin A-4 (11) is a natural product isolated from the bark of a South African tree Combretum caffrum. This substance can strongly inhibit the polymerization of tubulim by binding to the colchicine-binding site. CA4 exhibits excellent cytotoxity against various human cancer cells including multidrug resistant (MDR) cancer cell lines. However, CA4 itself was prevented from entering clinical trial due to the poor solubility in pharmaceutically acceptable solvents. In order to create a prodrug with such property, several groups have reported the synthesis of the prodrugs of CA4 with increased aqueous solubility. The most important one is disodium phosphate prodrug of CA4 (CA4P), which is currently undergoing the phase II/III clinical trials. As a tumor vascular targeting agent, CA4P displays potent antivuscular/anticacer activity while causing no significant blood flow retention in normal tissues.On the other hand, phosphoryl choline (PC) is an essential part of cell membrane bounding phospholipids, and contributes to the hydrophicity of such amphiphiles. Over the past years PC have been widely applied to produce biomimetic, hemocompatible and biodegradable polymers. However, to the best of our knowledge, there is no specific report about PC as water-soluble moiety for the synthesis of prodrugs. We speculate that a prodrug containing a PC structure would not only have better aqueous solubility, but also be biodegradable and biocompatible with living environment.Since the amount of CA4 in the bark of Combretum caffrum is very low, the isolation of this compound is quite difficult. Therefore, the development of efficient methods for the total synthesis of CA4 has triggered intensive interests over the past更多还原