高抗肿瘤活性的Stephacidin A及其相关吲哚生物碱的合成研究

Natural products represent a highly significant source of inspiration in the drug discovery as well as development process. Stephacidins A and B with potent in vitro cytotoxicity against various human tumor cell lines were isolated from Aspergillus ochraceus WC76466. The half-maximum inhibitory concentration of Stephacidin A against testosterone-dependent prostate LNCaP cell line is 1.00 μM, and Stephacidin B, a dimer of oxidized Stephacidin A, shows the half-maximum inhibitory concentration to be 60 nM against the same cell line. However, the amount of these alkaloids isolated from biological source was very limited, thus it rendered further antitumor research impossible. This type monomeric alkaloids have seven rings with a bicyclo[2.2.2]diazaoctane framework and three chiral centers, two of which are quaternary centers, which is riddled with interesting synthetic challenges. In this research project, we have designed a catalytic asymmetric aza-Diels-Alder reaction and a novel cationic cascade sequence to construct the bicyclo[2.2.2]diazaoctane and the key polycyclic framework of Stephacidin A and its related alkaloids, respectively. Based on these two key reactions, asymmetric total synthesis of Stephacidin A and more than three related alkaloids should be accomplished, as well as more than ten analogues. Then, we will evaluate these Stephacidin A-type analogues for their potential in cytotoxic activities toward a series of human tumor cell lines in the hope that new lead compound could be found in this propose. To summarize, this program is not only of very important academic significance on enantioselective total synthesis of complex prenylated indole alkaloids, but also can provide material support to drug discovery.

天然产物是人类药物创新的源泉，基于天然产物成功开发的新药屡见不鲜。从海洋真菌Aspergillus ochraceus次生代谢产物中分离得到的Stephacidin A及其氧化二聚产物Stephacidin B均具有显著抗癌活性。但该类化合物的天然来源有限，限制了抗肿瘤活性的进一步研究。Stephacidin A包含7个环系，具有一个典型的双环[2.2.2]二氮杂辛烷结构以及两个季碳中心，在合成上具有一定的挑战性。本项目设计了催化不对称Aza-Diels-Alder环加成反应和新颖的正离子串联环化拟高效构建该类天然产物的多环骨架。基于这两个反应，本项目拟合成4个以上Stephacidin A及其相关吲哚生物碱和10个以上的衍生物，并对合成的衍生物进行体外抗癌活性筛选，以期发现活性更好的化合物。本项目具有很好的合成方法学意义，同时也可为基于Stephacidin A的新药研发提供物质基础。

本项目以Stephacidin A及其相关吲哚生物碱的全合成及其骨架类似物的合成为研究目标，在合成方法学、天然产物全合成和类天然产物合成与生物活性评价等三个层面开展研究工作。在合成方法学上，本项目发展了新颖的Mannich型串联环化反应构建含氮桥的八元环结构单元、Pummerer重排/吲哚亲核性环化/aza-Prins串联环化反应构建四环螺吲哚啉结构单元、新颖的正离子引发的环化合成含芳基的二氢化萘结构单元以及形式上的Michael加成反应合成2-吲哚螺环化合物等新4种合成新方法。在天然产物合成上，本项目完成了Stephacidin A的五环骨架的构建、3个Aspidofractine 型蕊木吲哚生物碱的全合成、18个Sarpagine-Ajamaline-Koumine型吲哚生物碱的集群式全合成和3个苯基萘类木脂素内酯的全合成，共计完成了24个复杂天然产物的全合成，其中有12个复杂吲哚生物碱是首次全合成。在类天然产物设计、合成与生物活性评价上，完成了40余个含二酮哌嗪环的Stephacidin A类天然产物的合成，化合物正在进行抗肿瘤、抗流感病毒和抗HIV等活性筛选。