三种杜鹃花属植物中新型二萜类成分的发现及其镇痛活性研究

Previous research on R. molle resulted in the isolation of 79 new diterpenoids including two novel skeletons. In the analgesic assay, two diterpenoids were 5-8 folds more potent than morphine, and 35 compounds showed moderate analgesic activity. Based on these results, we selected three Rhododendron medicinal plants (R. micranthum, R. decorum, R. latoucheae) which showed solid analgesic activity in bioactive screen. HPLC-MS/MS based chemical screen proved that these plants contain abundant diterpenoids and were structurally different from those discovered in R. molle. Therefore, there is a great chance to identify novel structures with analgesic activity from these three plants. In this project, we will locate the analgesic fraction and separate the bioactive compounds with novel structure from the three medicinal plants by integrated application of chemical and bioactive screen and determine the structures by modern spectrum and chemical method. We expect to obtain 85-100 new compounds including 4-8 novel skeletons. By screening the isolated diterpenoids on in-vitro/in-vivo analgesic models, we expect to obtain 20-30 analgesic compounds. Based on these data, the structure-activity relationship (SAR) will be studied. Finally, we expect to obtain 1-2 promising lead compounds with both strong activity and novel structures which would contribute the drug discovery and the study of the molecular mechanism.

前期研究从杜鹃花属植物羊踯躅中发现了79个结构新颖的二萜类化合物，包括2种新的骨架类型。活性筛选发现： 2个化合物镇痛作用强度是吗啡的5-8倍，35个化合物具有中等强度的镇痛作用。在此基础上，通过镇痛活性筛选，从12种杜鹃花科植物中遴选出照山白、大白杜鹃和鹿角杜鹃等三种具有良好镇痛活性的药用植物。初步的化学筛选显示其中蕴含大量结构新颖的二萜类化合物，且结构较前期发现的化合物有较大差异。本课题拟集成化学筛选和活性筛选技术，从三种药用植物中快速识别、锁定活性部位中的二萜类成分，进而针对性地获取其中具有新颖结构的化合物，并确定结构。预期发现新颖结构化合物85-100个，新骨架化合物4-8个。通过体内外活性研究，发现具有显著镇痛作用的化合物20-30个，并根据药理活性结果和化合物的结构特征，分析构效关系，优选出1-2 个活性强、结构新颖的先导化合物，为新型镇痛药物的创制和分子机制研究奠定基础。

课题组前期通过活性筛选从12种民间镇痛药用植物中遴选出三种具有良好镇痛活性的药用植物（照山白、大白杜鹃和鹿角杜鹃）开展深入研究。为了阐明照山白、大白杜鹃和鹿角杜鹃等三种药用植物的药效物质，从中发现结构新颖的活性化合物，课题组集成化学筛选和活性筛选技术，从三种药用植物中快速识别、锁定活性部位，并对其中新颖活性成分进行针对性地获取。通过研究，共分离鉴定化合物231个，其中新颖结构化合物100个，包括新骨架化合物4个。通过体内外活性研究，发现镇痛活性化合物19个，抗炎活性化合物12个，抗病毒活性化合物9个。其中两个化合物镇痛活性与阳性对照药吗啡相当，具有进一步开发的价值。研究完善了木藜芦烷型二萜镇痛作用的构效关系，并且为阐明三种药用植物镇痛、抗炎作用的科学内涵奠定了基础。研究共发表SCI 论文9篇，其中一篇IF>5。培养研究生3名。