两种中国特有八角属植物中新颖结构抗柯萨奇病毒活性化合物的研究

Based on the important discovery of dioxaspiro novel skeleton compounds , prenylated C6-C3 compounds with unique structures, as well as 6/6/3 tricyclic skeleton sesquiterpene with significant anti-coxsackie viral activities from Illicium oligandrum, we will apply the method and technology of fast and efficient chemical screening (HPLC-DAD/MSn,HPLC-RI,HPLC-ELSD) andpharmacological activity screening to rapidly find and obtain anti-coxsackie viral prenylated C6-C3 compounds, sesquiterpene, and analogue metabolic components in little amount from two species of Illicium endemic to China, I. oligandrum and I. fargrsii. 100-120 compounds of these two types of compounds will be obtained by integrating multi-channel flash chromatography and preparative HPLC, and their structures will be determined by spectral and chemical methods. Through the evaluation of activity, some new compounds with anti-coxsackie viral activities will be found. and the role and structure-activity relationships of these compounds could be clarified, and 1-2 candidate novel compounds with strong activities could be obtained for the development of new type broad-spectrum anti-coxsackie virus drug.

本课题前期研究中发现从少药八角中获取的二氧杂螺环新骨架结构化合物、新颖结构异戊烯基取代的C6-C3类化合物，以及6/6/3三环骨架倍半萜类成分具有显著抗柯萨奇病毒活性。在此基础上，采用高效快速的化学筛选(HPLC-DAD/MSn等)和药理活性筛选集成应用的方法与技术，识别与锁定两种我国特有八角属（Illicium）有毒药用植物（少药八角和华中八角）活性部位中异戊烯基取代的C6-C3类化合物和倍半萜类成分（特别是活性部位中的微量成分），整合多通道闪式色谱和制备型HPLC，定向地获取这两类化合物100-120个，利用波谱和化学方法测定它们的结构。通过活性评价，发现具有抗柯萨奇病毒新颖结构活性化合物，阐明其作用特点和构效关系，优选出1-2个结构新颖、活性强的先导化合物，为创制新型广谱抗柯萨奇病毒新药奠定基础。

采用高效快速的化学筛选和活性筛选集成应用的方法与技术，识别与锁定两种我国特有八角属（Illicium）有毒药用植物（少药八角和华中八角）活性部位中异戊烯基取代的C6-C3类化合物和倍半萜类成分。从中分离获取了129个化合物（其中新化合物61个），包括86个异戊烯基取代的C6-C3类化合物，25个倍半萜类化合物。活性评价发现15个化合物具有抗柯萨奇病毒活性，8个化合物具有神经细胞保护活性。.针对从少药八角中发现1个含有6个手性中心的5/6/6/6/7五环新骨架化合物（1）具有较好的抗柯萨奇B3病毒活性（IC50 = 2.14 µmol/L），基于该化合物6/6/6/7四环高度线性稠合的结构特点，采用化学仿生合成策略，合成了含有6个手性中心的5/6/6/6/7五环新骨架抗病毒活性化合物（SYBJ-F10-3）的32个异构体，通过构效关系研究，优选出2个抗柯萨奇病毒的先导化合物。同时发现分子结构中D环为关键药效团，这一重要研究结果对该复杂结构活性天然产物的下一步结构简化研究具有重要的科学价值和指导意义。