逆转肿瘤耐药性的Aspidofractine型吲哚生物碱的普适性合成研究

Cancer is the second most deadly disease in the world. Multidrug resistance, by which cells resist many structurally and functionally unrelated drugs, is a serious problem in chemotherapeutic management of cancer. Thus, it is very importance to develop new compounds that can reverse multidrug resistance in the treatment of cancers. Aspidofractinine is considered the parent compound of a large family of related indole alkaloids isolated from the genus Kopsia that are widely found throughout Southeast Asia. Many members of this family were found to reverse multidrug resistance in vincristine-resistant KB cells. However, the amount of this alkaloids isolated from Kopsia was very limited, thus it rendered further biological research impossible. This type kopsane alkaloids have an unusually strained carbon skeleton with six rings and at least three quaternary centers, more than two of which are contiguous, which is riddled with interesting synthetic challenges. In this research propose, we have designed a novel cascade to build the C-ring and E-ring of these type alkaloids. Based on this cascade, asymmetric total synthesis of about six kopsane alkaloids should be accomplished, as well as nine analogues. After that, we will evaluate all these aspidofractinine-type compounds for their potential in reversing multidrug resistance in the hope that new lead compound could be found in this project. Through the research in this program, it is not only of very important academic significance on the total synthesis of complex natural products, but also it can provide material support on new drug development.

癌症是全球第二大致死疾病，多药耐药性的出现是癌症化疗期间最大的治疗障碍。从东南亚蕊木属植物中分离得到的Aspidofractinine型吲哚生物碱被发现：对长春新碱具有耐药性的人口腔表皮样癌细胞具有显著的耐药性的逆转作用。然而，由于该类生物碱在蕊木属植物中的含量有限，大大限制了该类化合物进一步的生理活性研究。该类化合物具有非同寻常的刚性六环骨架，每个分子中至少包括三个手性季碳，其中至少有两个是连续手性季碳，在合成上极具挑战性。本项目设计了一种新颖的串联关环反应，一步实现目标分子的C环和E环的构建。基于此串联反应，本项目拟合成6个左右Aspidofractinine型蕊木碱和8个左右的骨架类似物，并对合成的所有化合物进行肿瘤细胞多药耐药性逆转活性的筛选，以期发现活性更好的化合物。本项目无论是在天然产物的合成方法学上，还是在肿瘤多药耐药性逆转活性化合物的发现上，都具有非常好的学术意义。

本项目以Aspidofractine型蕊木生物碱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。在合成方法学方面，本项目发展了Heathcock/aza-Prins串联环化反应和Pummerer重排/aza-Prins串联环化反应，分别可以一步构建Aspidosperma型吲哚生物碱和Aspidofractine型蕊木生物碱的C环和E环，此外，还发展了合成δ-氨基酸衍生物、2-氯吖啶和2-吲哚螺环己基化合物的新方法。在天然产物全合成方面，本项目完成了1个Aspidofractine型蕊木生物碱的全合成，还完成了16个复杂天然吲哚生物碱的全合成，结构类型包括Aspidosperma型、Sarpagine型、Ajamaline型、Taberpsychine型和Koumine型，共计完成Aspidofractine型吲哚生物碱及其生物同源的天然产物达7个以上。在类天然产物合成与生物活性评价方面，本项目完成了5个Aspidofractine型蕊木生物碱骨架类似物以及33个类天然产物的合成，并进行了体外的抗肿瘤活性筛选和构效关系分析，发现了多个具有进一步研究价值的化合物。

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