具有肝损伤保护活性的五味子酚衍生物设计、合成及作用机制研究

Long-standing liver damage is always the most important initial factors leading to liver fibrosis, or even initiating cirrhosis, liver cancer, and other diseases, which seriously affect human health and quality of life. Therefore, the development of effective drugs for liver injury treatment is of extremely great importance. By way of seeking for effective component in Traditional Chinese Medicine as lead compound, under modern screening pharmacological activities and evaluating efficacy of drugs, and by using the molecular design ideas on rational molecular design of medicinal chemistry，the structure of lead compound optimized to provide a safe and efficient clinical candidate drug molecule，is still one of the important way to modern drug development. On the basis of the early discovery of halogenated schisanhenol derivatives with significant liver damage protective activity and their preliminary structure-activity relationships, the project is going to carried out by using modern structural optimization methods of lead compounds in pharmaceutical chemistry to improve the solubility of drug molecules and to promote drug absorption in body as a precondition. By continuing to study rational molecular design of schisanhenol derivatives, a series of new schisanhenol derivatives will be sythesised and prepared. Through evaluation and screening of activity in vivo and in vitro, the three-dimensional quantitative structure-activity relationship (3D-QSAR) of these schisanhenol derivatives will be explored, and the corresponding mechanism of the active derivative will be also studied. The project will provide a scientific basis for the derived dibenzocyclooctene lignans in preparation for the lead compounds of protecting liver injury or drug candidates.

肝损伤的长期存在往往是导致肝纤维化，甚至肝硬化、肝癌等疾病发生的最重要始动因素，严重影响人类健康和生活质量。因此，研发有效治疗肝损伤的药物具有极其重要的意义。以传统中药中明确的有效成分为先导物，在现代药理活性筛选评价的指导下，运用药物化学中合理化分子设计思想不断优化先导物的结构，为临床上提供安全高效的候选药物分子，仍是现代新药研发的重要途径之一。 本项目拟以前期发现的具有显著肝损伤保护活性的五味子酚卤代衍生物及其初步构效关系为基础，运用现代药物化学原理中先导化合物结构优化方法，以改善药物分子溶解性促进体内吸收为前提，继续进行五味子酚衍生物的合理化分子设计研究，合成制备系列五味子酚新衍生物，并通过体内外肝损伤保护活性的筛选对其进行综合评价，同时探讨其三维定量构效关系（3D-QSAR），选择活性衍生物进行相应作用机制的研究，为该类木脂素衍生作为肝损伤保护的先导物或候选药物分子提供科学依据。

肝损伤的长期存在往往是导致肝纤维化，甚至肝硬化、肝癌等疾病发生的最重要始动因素，严重影响人类健康和生活质量。因此，研发有效治疗肝损伤的药物具有极其重要的意义。以传统中药中明确的有效成分为先导物，在现代药理活性筛选评价的指导下，运用药物化学中合理化分子设计思想不断优化先导物的结构，为临床上提供安全高效的候选药物分子，仍是现代新药研发的重要途径之一。 本项目以前期发现的具有显著肝损伤保护活性的五味子酚卤代衍生物及其初步构效关系为基础，运用现代药物化学原理中先导化合物结构优化方法，以改善药物分子溶解性促进体内吸收为前提，继续进行了五味子酚衍生物的合理化分子设计研究，共合成制备了67个五味子酚新衍生物，并通过体内外肝损伤保护活性的筛选对其进行了综合评价，同时探讨了其三维定量构效关系（3D-QSAR），选择2个活性衍生物进行了相应作用机制的研究，为联苯环辛二烯类木脂素衍生物作为肝损伤保护的先导物或候选药物分子提供了科学依据。