女贞子中调控mGluR5蛋白的裂环环烯醚萜类成分研究

Plaque of amyloid-β and neurofibrillary tangles are the distinct pathology of Alzheimer’s disease (AD). mGluR5 has been proposed as an key protein in Aβ toxicity transmitting and NTFS formation. Accordingly, mGluR5 has been proved to be an important target for neural drug. Our previous study of fruits of Ligustrum lucidum leads to the isolation of numbers of new secoiridoids with 1α-OH, and the preliminary activities experiments showed that secoiridoids could significantly suppress apoptosis of differenced PC12 cells, which was confirmed to be associated with mGluR5 protein. While the promotion activity between the stereoisomers were different, which suggested the mechanism and structure-activity relationship still need to be explored. Accordingly, this project aims to the advanced chemical research of secoiridoids from the fruits of Ligustrum lucidum, and will further examined the ability of these compounds in mGluR5 regulation, and the mechanism and QSAR in it. It is supposed to be a scientific basis for the development of anti-AD Drugs as mGluR5 targeted.

淀粉样蛋白沉积和神经纤维缠结是AD患者的主要病理特征。mGluR5蛋白是一种介导淀粉样蛋白聚合物的神经毒性和神经纤维缠结形成的关键蛋白，已成为重要的新型神经药物靶点。我们在前期工作中对女贞子的裂环环烯醚萜类化合物进行了系统的研究，首次发现天然来源的1α-氧代裂环环烯醚萜类成分；初步的活性测试结果显示，该类化合物可显著的抑制Aβ25-35诱导的PC12细胞凋亡，并首次发现其抗凋亡活性与mGluR5蛋白相关。不同构型的裂环环烯醚萜类化合物表现出来的活性差异，提示其作用机制和构效关系尚有待探索。本项目拟在前期工作基础上，进一步对女贞子中的裂环环烯醚萜类成分进行分离和鉴定，评价该类成分调控mGluR5蛋白的生物活性、作用机制和构效关系，为研究和开发高效低毒的以mGluR5为靶标的抗AD药物提供科学依据。

淀粉样蛋白沉积和神经纤维缠结是AD患者的主要病理特征。mGluR5蛋白是一种介导淀粉样蛋白聚合物的神经毒性和神经纤维缠结形成的关键蛋白，已成为重要的新型神经药物靶点。我们在前期工作基础上，继续开展了女贞子中裂环环烯醚萜类成分研究，从中共分离并鉴定25个列环烯醚萜类化合物，包括16个新化合物，其中ligureside B (L-3)、ligureside C (L-4)、1-epi-Gl 3 A (L-9)、1-epi-Gl 3 B (L-10)、liguside A (L-13)和liguside B (L-14)为6个新的裂环环烯醚萜苷二聚体，ligureside A (L-1)、ligureside D (L-2)、ligureside B (L-3)、ligureside C (L-4)和ligureside E (L-16)为5个C1/C8重排的新裂环环烯醚萜苷，5R, 8R, 9S,-elenolic acid acetal (L-5)、8(Z)-oleonin (L-6)和1-epi-oleonin (L-7)为3个苷元形式的裂环环烯醚萜，以及1个无环列换环烯醚萜苷（L-15，liguside C）。此外对24个单体化合物对Aβ损伤的PC12细胞的保护作用，其中3个化合物显示较强的保护作用。最后对活性最好的化合物L-14与mGluR5的相互作用模型进行了研究，结果显示其结合位点主要为9个氢键相互作用。以上研究为女贞子中该类成分的神经保护作用提供了科学依据，并为进一步开发提供参考。