结构多样性导向合成苦参碱类衍生物、杀虫/螨活性及3D-QSAR研究

By using matrine, a quinolizidine alkaloid isolated from the roots of Sophora flavescens (Kushen), as the lead compound, we will carry out the extensive structural modifications as follows: (1) N-1 and C-13,14,15 positions; (2) N-1 and 16 positions, side-chain, and carboxyl group after opening the lactam of matrine. The insecticidal and acaricidal activities of a series of matrine derivatives will be evaluated against pre-third-instar larvae of Mythimna separata and the female adults of Tetranychus cinnabarinus. Furthermore, their quantitative structure−activity relationships (QSARs) will be investigated. Based upon the above results, we would want to know which parts of matrine, such as N-1 and C-13,14,15 positions, and N-1 and 16 positions, the length of side-chain, and carboxyl group after opening the lactam of matrine, are the important factors to the insecticidal and acaricidal activities. Then we hope that the suitable and important modification locations of matrine will be found, and the most promising and potent matrine derivatives will be discovered. Additionally, 3D-QSAR model of matrine derivatives will be developed and obtained. Finally, the optimization model for matrine derivatives bearing excellent insecticidal/acaricidal activities will be constructed, and it will pave the way for further design, structural modification, and development of matrine derivatives as pesticidal agents in the future.

本申请拟以从苦参根皮分离到的苦参碱为先导化合物，对其N-1位及C-13,14,15位进行结构改造，及其内酰胺开环后对其N-1,16位、碳链与羧基上进行结构改造，制备出系列苦参碱类衍生物；用3龄初期东方粘虫幼虫及朱砂叶螨雌成螨来评价其杀虫/螨活性。同时进行三维定量构效关系的研究。从而确证苦参碱N-1位及C-13,14,15位对其杀虫/螨活性的影响；确证苦参碱开环后其N-1,16位、碳链长短及羧基对其杀虫/螨活性的影响；找到苦参碱及苦参酸分子骨架上关键的结构修饰位点；发现高杀虫/螨活性的苦参碱类衍生物；构建出苦参碱类化合物具高杀虫/螨活性的理想结构模型，为今后开发利用苦参碱类化合物作为天然产物农药提供理论依据。

为了提高苦参碱的农用活性，本项目以苦参碱为先导化合物，对其内酰胺环、N-1,16位及C-14,15位的进行了结构多样性导向的优化合成，建立从苦参碱类衍生物顺利制备氧化苦参碱类衍生物的简便方法；建立了从苦参碱制备苦参酸/醇/酯类衍生物的方法；找到了一条超声辅助的环境友好、快速合成苦参碱–单糖类复合物的新方法；建立了合成14-甲醛基-15-氯取代苦参碱及15-氯-18-肟取代苦参碱的方法；建立在苦参碱C-15位引入五元螺杂环分子骨架的新方法。其次，获得具有较高农用活性的化合物，并建立了构效关系：发现氧化苦参碱胺类化合物、苦参碱酯类衍生物、苦参碱–单糖类复合物、15-氯-18-肟酯/醚类衍生物具有较好的杀虫/螨活性，与母体化合物相比，其中杀螨活性提高到7倍多，杀虫活性提高到2-3倍。发现苦参碱内酰胺开环，在其N-1,16及C-14,15位引入适当基团，是可以获得具有较高杀虫/螨活性的化合物。最后，通过对苦参碱类化合物杀虫/杀螨活性的作用机理初步研究，发现苦参碱和胆固醇可能是苹果黄蚜HMG-CoA还原酶的的抑制剂；发现苦参碱的内酰胺环对于作用于朱砂叶螨VGSC必要；发现苦参碱的内酰胺及羧基等官能团对于作用于朱砂叶螨nAChR的α2, α4, α5 和 β3亚基很重要； N-苯磺酰基取代苦参酸类化合物可能是朱砂叶螨nAChR及乙酰胆碱酯酶的抑制剂；发现苦参碱内酰胺环打开与侧链烷基羰基化，以及其C-15 和C-18位上的肟醚基团对于作用于朱砂叶螨nAChR的 α1, α2和 α4亚基很重要；15-氯-18-肟正丁基醚类化合物可能作用于朱砂叶螨nAChR的α1, α2, α4 和β3亚基。上述研究结果发表在农药学重要刊物Journal of Agricultural and Food Chemistry及Industrial Crops and Products、Bioorganic & Medicinal Chemistry Letters、Bioorganic Chemistry等11篇SCI论文（第一标注项目批准号）上。为进一步结构优化苦参碱及制备苦参碱类衍生物，以及研究其杀虫/杀螨活性与作用机理等奠定了基础。