两种杜鹃花科有毒植物中新颖结构二萜类化合物的发现及其生物活性研究

This project will be to study on the diterpenoids with analgesic and ion channel bioactivities from two toxic medicinal plants(Rhododendron molle and Rhododendron mariae) belonging to family Ericaceae.First of all, the plant extracts will be screened chemically and biologically to identify and lock the fractions containing the bioactive diterpenoids before any further purification.The obtained bioactive fractions will then be isolated to yield novel bioactive diterpenoids by using advanced chromatographic methods. The structures of the diterpenoids isolated will then be elucidated by using spectroscopic techaniques. And also, the biosynthesic pathway of the new diterpenoids will be proposed. For the bioactivities of the diterpenoids, they will also be assayed for their analgesic and ion channel effects to discover the compounds with strong bioactivity in vivo or in vitro system. Based on the bioassay results, their structure activity relationship (SAR) will be deeply studied. The mechanism of action of the compounds with strong bioactivities will then be further studied. Since some of the isolates could be toxic,the research on their toxic effects will be considered. The goal of this project is to discover 60-90 diterpenoids, including 30-40 new ones, 10-15 ones with strong bioactivity, and 1 or 2 lead compounds for the development of new medicine.

对杜鹃花科有毒植物羊踯躅（Rhododendron molle）果实、根和岭南杜鹃(Rhododendron mariae)的茎规范提取物进行镇痛、离子通道活性测定，遴选出含有二萜的活性提取物或组分；多种色谱检测和分离手段相结合从活性提取物或组分中快速获取新颖结构二萜类化合物，确定它们的化学结构，并对新颖结构化合物进行生源途径的探讨。对获得的二萜类化合物采用离子通道模型进行体外活性筛选；对活性强的二萜类化合物进行体内镇痛药效实验；并对体内外活性强的化合物进行构效关系和作用机制研究；对强活性结构新颖的二萜成分进行初步的毒性研究。发现二萜类化合物 60-80个，其中新颖结构化合物30-40个，活性显著的化合物10-15个，有研发前景的创新镇痛药物先导物1-2个。

采用活性筛选的方法，以化学筛选为指导，通过多种色谱检测和分离手段相结合，从杜鹃花科有毒植物羊踯躅的根、果实和岭南杜鹃的茎中共分离得到169个化合物并确定了结构，其中新化合物56个，新骨架化合物4个。15个化合物具有显著的镇痛活性，其中有两个化合物的镇痛活性是吗啡的5-8倍，而且这两个化合物同时对炎症和慢性神经性疼痛也具有显著的作用。阐明了羊踯躅临床上广泛应用于风湿性关节炎、跌打损伤、偏头疼、神经性头痛和牙痛等多种疼痛的物质基础，为进一步开发新型镇痛新药奠定了基础。. 本项目研究工作已在国际期刊发表SCI收录的论文5篇，目前已撰写完成待发表文章3篇，申请中国发明专利1项，培养研究生1名。