基于麦冬植物中高异黄酮的骨架跃迁设计及其抗帕金森分子作用机制研究

Parkinson’s disease which has become a common disease in modern society is seriously threatening physical and psychological health of people, and the limitation of synthetic drugs in treatment of Parkinson’s disease is obvious. Hence, R & D of anti-Parkinson’s disease drugs from traditional Chinese medicine has great theoretical significance and practical application value. Our previous study revealed that natural product-like compounds based on scaffold hopping of sappanin-type homoisoflavonoids from ophiopogon japonicas showed strong neuroprotective activities as well as excellent safety. On the basis of our previous study, this project will design a series of analogues based on scaffold hopping of sappanin-type homoisoflavonoids with the adoption of preliminary structure-activity relationship study and classic drug design theory. Then with the help of the evaluation of the in vitro and in vivo anti-Parkinson activity of these derivatives, the more detailed structure-activity relationships of these compounds may be obtained and anti-Parkinson lead compound with high efficacy and low toxicity will be found rapidly. Besides, further study will focus on the anti-Parkinson mechanism of homoisoflavonoid derivatives. With the adoption of small molecule bioactive probes, the cellular targets of the active compounds will be identified. And eventually, novel anti-Parkinson drug candidates with independent intellectual property rights will be obtained.

帕金森病已成为现代社会的常见病，严重威胁着人们的身心健康，但是合成抗帕金森病药物在治疗上有一定的局限性，因此从传统中药开发研究抗帕金森病药物具有重要的理论意义和实际应用价值。在前期工作中，本课题组基于麦冬植物sappanin型高异黄酮化合物进行骨架跃迁设计，获得数个具有显著神经保护活性的类天然产物，兼具较高的安全性。本项目在前期研究工作的基础上，参考初步构效关系和经典药物设计理论，拟对sappanin型高异黄酮进行全面深入的骨架跃迁设计，突破高异黄酮母核结构，并结合体内外神经保护药理活性筛选，快速发现高效低毒，兼具较好类药性的抗帕金森先导化合物，在此基础上总结出较清晰的构效关系。并采用基于生物探针的化学蛋白质组学技术探究优选化合物的作用靶标，优化设计出具有自主知识产权的抗帕金森候选药物。

帕金森病已成为现代社会的常见病，严重威胁着人们的身心健康，但是合成抗帕金森病药物在治疗上有一定的局限性，因此从传统中药开发研究抗帕金森病药物具有重要的理论意义和实际应用价值。本课题参考初步构效关系和经典药物设计理论，基于天然来源麦冬植物sappanin型高异黄酮化合物进行骨架跃迁设计，突破高异黄酮母核结构，得到100多个类天然产物，并结合体内外神经保护药理活性筛选，获得数个具有显著神经保护活性的类天然产物，兼具较高的安全性。并在此基础上总结出较清晰的构效关系。此外我们利用分子对接（反向对接技术）对优选化合物的作用靶标进行探索，实验结果表明该类天然产物（及其衍生物）可能作用于I类 PI3K 信号通路，从而诱导自噬发挥神经保护作用。