一枝蒿酮酸衍生物的合成及初步的抗流感病毒药效学研究

Influenza shows strong infectivity, high incidence and high mortality rate and has caused great threat to human survival. The currently existing anti-influenza virus drugs play a very important role in influenza prevention and treatment, but they showed some disadvantages. Artemisia rupestris L. (Chinese name is Yizhihao) is one kind of traditional Chinese medicines, long been used in Xinjiang, China. Rupestonic acid is one of the sesquiterpenes with mutifunctional groups, which was isolated from Artemisia rupestris L. In this project, Rupestonic acid will be choosen as the research object and synthesis of derivatives and preliminary in vivo and in vitro pharmacodynamics as the key content. The two functional groups including 3-carbonyl and C=C double bond in rupestonic acid will be modified and 40 rupestonic acid ester and ether derivatives and analogues will be synthesized according to classic organic synthesis methods. All the derivatives will be tested for their activities in vitro against influenza A and B. Combined with previous research results, the structure-activity relationship of all the compounds will be further explored. Meanwhile, the in vivo preliminary activity of screened active compounds against influenza virus will be studied to further discovery the candidate compounds with better activity and lower toxicity. All the results will provide a sufficient theoretical basis for the independent intellectual property rights of anti-influenza innovative drug development and transformation and effective use of local advantage resources.

流感具有传染性强、发病率高和死亡率高等特点，对人类的生存造成了很大的威胁。目前已有的抗流感病毒药物在流感的预防和治疗方面发挥着重要的作用，但存在一定的局限性。本项目拟选择新疆道地药材一枝蒿中的代表性倍半萜类化合物—一枝蒿酮酸（Rupestonic acid）作为研究对象，以衍生物的合成和初步的体内外药效学研究为重点内容，利用酯类、醚类和胺类的常规有机合成方法，对分子中的3-位羰基和环外C=C双键两个官能团进行结构改造，拟合成40个结构新颖的一枝蒿酮酸衍生物及类似物，测试它们的体外抗A、B型流感病毒活性；结合前期的研究结果，进一步分析探讨一枝蒿酮酸衍生物的构效关系，并对筛选出的活性化合物进行耐药性和初步的体内抗A、B型流感病毒活性研究，以期发现活性高、毒性小的抗流感病毒候选化合物。预期取得的成果将为自主知识产权抗流感病毒创新药物的开发及当地优势资源的转化和利用提供充分的理论依据.

流感具有传染性强、发病率高和死亡率高等特点，对人类的生存造成了很大的威胁。目前已有的抗流感病毒药物在流感的预防和治疗方面发挥着重要的作用，但存在一定的局限性。本项目选择新疆道地药材一枝蒿中的代表性倍半萜类化合物—一枝蒿酮酸（Rupestonic acid）作为研究对象，以衍生物的合成和初步的体内外药效学研究为重点内容，利用酯类和醚类的常规有机合成方法，对分子中的3-位羰基、2-位亚甲基和羧基三个官能团进行结构改造，共合成了67个结构新颖的一枝蒿酮酸衍生物及类似物，测试它们的体外抗A、B型流感病毒活性，结果发现与母核化合物相比，大部分化合物表现出较好的抗流感病毒活性；进一步分析探讨了一枝蒿酮酸衍生物的构效关系；对候选化合物YZH-106进行了抗流感病毒药效学和作用机制研究，结果表明YZH-106通过上调HO-1从而激活宿主细胞的Ⅰ型干扰素系统抑制流感病毒的复制。研究成果为自主知识产权抗流感病毒创新药物的开发及当地优势资源的转化和利用提供了充分的理论依据。