新颖的环新木脂烷型抗AD先导化合物的发现和基于抑制小胶质细胞过度活化的作用机制研究

阿尔茨海默病（AD），是老年人的第四大杀手。中国的AD患者数目居全球之首。小胶质细胞过度活化介导的神经炎症是AD发病的关键机制和治疗靶点。针对这一靶点的AD临床治疗药物主要是NASIDs和雌激素，缺乏针对性、长期服用副反应大。基于此，申请人以抑制小胶质细胞活化为切入点，从天然药物中寻找低毒高效的抗AD 先导化合物。前期研究中，油桐属植物中一类新骨架木脂素——9, 9′环氧-7, 9′-环-8, 1′-新木脂烷，因其独特的结构和显著的抗神经炎症活性脱颖而出。本项目旨在进一步利用ODS/ Ph-CD /IF三重色谱分离和生物转化的方法丰富这一新骨架结构库；以LPS诱导活化的BV2细胞模型和神经炎症小鼠模型系统评价系列环新木脂烷的抗神经炎症活性，和其基于LPS/IKK/NF-κB信号通路调控的作用机制。构建其定量三维构效和基于受体的药效团，探索性尝试结构修饰和得到新颖的抗AD先导化合物。

Alzheimer's disease is the fourth killer for the aged. The number of AD patients in China is highest in the world. Neuroinflammation, mediated by over-activation of microglia, plays key roles in the development of AD. Now, therapeutic drugs targeted on neuroinflammation are NASIDs and estrogens, which are unsatisfactory because of their efficacy and side effects. So, we have concentrated on finding out novel natural neuroinflammation inhibitors as leading compounds for therapeutic agents of AD. In our previous work, a kind of novel cycloneolignanes--9, 9′-epoxy-7, 9′-cyclo-8, 1′-neolignane attracted our attention because of its distinctive structure and significant anti-neuroinflammation activities. Based on above, further research would be carried out to enrich the novel structures by means of selective separation and biotransformation. Then LPS-induced BV2 microglia cell and neuroinflammation mice were employed to evaluate the anti-neuroinflammation effects of cycloneolignanes in vitro and in vivo. The preliminary mechanism would be discussed on LPS/IKK/NF-κB signal pathway. Moreover, quantitative structure and activity relationship and pharmacophore could be built up. Finally, a kind of novel leading compounds for AD therapy might be afforded.