神经营养因子是神经元功能的调控因子，与神经系统疾病的发病机制和治疗有着十分密切的关系，开发类似神经营养活性的化合物已成为国际上神经退行性疾病药物研发的新方向。在前期工作基础中，发现部分石蒜科生物碱具有良好抑制胆碱酯酶活性；类似物15不仅具有抑制胆碱酯酶活性和NGF诱导的PC12细胞分化活性，而且能够显著延长秀丽隐杆线虫寿命；实验表明该类化合物具有潜在开发价值。本课题拟全合成石蒜科生物碱Clivonine、Narseronine、Augustamine和Hamayne及类似物，利用细胞生物学、线虫突变株等技术手段，开展药物作用靶点和作用机制研究，进而有针对性地进行结构优化和构效关系研究，以期开发出新结构、低毒性的抗神经退行性疾病先导化合物。本课题的实施对神经退行性疾病药物开发及其机制的深入研究具有重要的理论和实际意义。

Neurotrophic factors are best known for their roles in both development and continued maintenance of the nervous system. Their strong potential to elicit pro-survival and pro-functional responses in neurons of the peripheral and central nervous system make them good drug candidates for treatment of neurodegenerative disorders. Developing low molecular natural products having a typical neurotrophic property has become one of the hot topics in modern drug development. The preliminary work has shown that some amaryllidaceae alkaloids have good AChE and BuChE inhibition, good differentiated PC12 cells activity and can significantly extend the lifespan of adult Caenorhabditis elegans. This project mainly focuses on the total synthesis of a library of amaryllidaceae alkaloids Clivonine, Narseronine, Augustamine, Hamayne and their derivatives, and the study of their biological activities and their neuroprotective mechanism through Cell Biology, C. elegans mutants and other technical tools. The drug target and the structural optimization of these compounds based on their structure-activity relationships will be investigated. This ambitious yet feasible multidisciplinary project will create a practical synthetic route to synthesize a few amaryllidaceae alkaloids and their bioactive analogues. It will be of great potential benefits to the development of more efficient low or even non-toxic drug candidates for the treatment of neurodegenerative disorders. It is expected that this project will have a significant impact on neurodegenerative disorder drug discovery and mechanism of action.

本研究合成了一系列clivonine，erythrinine 、N-取代苯并咪唑和吡唑并[1,5-a]嘧啶衍生物。部分clivonine和erythrinine化合物具有良好的抑制胆碱酯酶活性和NGF诱导的PC12细胞分化活性；N-取代苯并咪唑和吡唑并[1,5-a]嘧啶衍生物对于瞬时受体电位通道4和6（TRPC4，TRPC6）有良好的抑制作用。研究表明TRPC6抑制剂具有良好的抗肿瘤活性,TRPC4相关蛋白已经被证明与AD的晚期发病有关，研究发现合成的部分N-取代苯并咪唑化合物具有乙酰胆碱酯酶抑制活性，对AChE和BuChE良好的抑制活性，且对丁酰胆碱酯酶表现出很高的选择性，细胞毒性测试显示所得衍生物均没有细胞毒性。其中部分化合物具有良好的TRPC4 抑制作用，对治疗AD等神经疾病具有重要的指导意义。