若干天然石蒜科生物碱和番杏科生物碱的不对称全合成及其生物活性研究

The synthesis of natural Amaryllidaceae and Aizoaceae alkaloids has received great attention because of their good biological activities, motivating researchers designed different ways for the fabrication of such kind of alkaloids. However, the asymmetric syntheses were rarely reported, and almost all of those limited asymmetric syntheses ways were dependent on chiral substrates or auxiliaries. Moreover, the study of their biological activities is extremely limited, to the best of our knowledge, there are even no reports yet about the intrinsical relationship between chemical structure and their activity. In view of the above analysis, this proposal focuses on the following three aspects: (1) The all-carbon quaternary stereocenters in Amaryllidaceae and Aizoaceae alkaloids is produced directly by the novel enantioselective Michael addition based on achiral materials instead of chiral substrates or auxiliaries. In order to optimize the reactivity and enantioselectivity of the key step mentioned above, synthetic methodology is applied on it; (2) Based on the key asymmetric Michael addition, asymmetric synthesis of several Amaryllidaceae and Aizoaceae alkaloids is realized through an relatively simple and diversity synthetic route; (3) The evaluation antitumor activities of those alkaloids is evaluated which targets the mechanism of their anticancer activity, and the structure-activity relationship is investigated, providing a theoretical basis for the development and synthesis of new anticancer drugs.

天然石蒜科和番杏科生物碱具有良好的生物活性，化学家们对此类生物碱的合成表现出了浓厚的兴趣，报道了很多合成策略，但是，在不对称合成方面，报道非常有限。现有的不对称合成路线中，绝大多数都依赖手性原料或手性辅基的使用。另外，对其生物活性的研究也比较局限，且分子结构与生物活性的内在联系还未见报道。基于上述分析，本项目主要研究以下三个方面的内容：（1）避免手性试剂的使用，从廉价的非手性原料出发，通过催化的对映选择性 Michael 加成反应，一步直接构建石蒜科和番杏科生物碱分子中的关键手性季碳，并对此关键步进行详细的方法学研究，优化其反应性和对映选择性；（2）利用我们发展的方法学，以一条较为简洁的多样性合成路线，完成若干石蒜科和番杏科生物碱的不对称全合成；（3）对合成得到的天然生物碱进行抗癌活性测试，探索其抗癌活性的作用机制，并分析此类生物碱的构效关系，为新型抗癌药物的开发与合成提供理论依据。

在以往文献中，天然石蒜科生物碱和番杏科生物碱的不对称合成研究已经有很多报道，但是以廉价的非手性化合物为原料，通过催化的对映选择性反应构建这些天然产物中的关键手性中心，进而高效完成其不对称全合成的工作鲜有报道。本资助项目设计了通过催化的对映选择性Michael加成反应构建天然石蒜科生物碱和番杏科生物碱的关键手性中心，并对该关键反应进行了优化，在最佳反应条件下对映选择性为60%，尚待进一步提高。但是该实验结果为基于此合成策略的手性合成工作奠定了基础。目前，该反应的不对称催化研究仍在进行中。基于此，我们以一条较为简洁的发散性合成路线，完成了多个天然生物碱的合成。本资助项目首次报道了若干天然药物衍生的手性药物分子设计、合成及生物活性研究，所有新化合物均进行了充分的结构表征，数据翔实可靠，多个化合物的体外抗肝癌活性优于一线抗肝癌药物长春新碱和阿糖胞苷，且对肝癌细胞毒性远远超过对良性肝细胞系的毒性，这些结果为抗癌新药的开发提供了重要的参考价值，预期将在抗癌药物研发中获得应用。