番石榴叶中结构新颖的复杂倍半萜的发现及其抗糖尿病活性研究

It is one of the major research directions for antidiabetic agents to obtain candidates from natural products by systematic pharmaceutical research. The hypoglycemic activity and in-vitro α-glucosidase activity of the leaves of Psidium guajava has been found from our previous studies. By fast identification and recognition method of chemical ingredients, we have obtained ten novel sesquiterpene derivatives, three of which represented the new skeleton with inhibitive activity to protein tyrosine phosphatase 1B (PTP1B), especially one of them was bis-sesquiterpene derivatives. Comprahensive activity studies of the novel compounds were not performed due to limited amount obtained. So, this project will focus on the studies of novel sesquiterpene derivatives: to obtain compounds of the same category effectively by the established fast identification and enrichment method, and evaluate their antidiabetic activities on different targets, perform structure-activity relationship research and structure-based virtual screening. For those compounds with strong activities, we will make biomimetic synthetic to accumulate to enough amounts, so that the mechanism research, preliminary toxic research etc can be performed, and finally the lead compounds with exact antidiabetic activity.

从天然药物中寻找具有抗糖尿病活性的化合物或活性组分，并通过系统的药学研究得到候选药物是国内外抗糖尿病新药研发的方向之一。前期研究发现番石榴叶有降血糖和体外α-葡萄糖苷酶抑制活性，经化学成分的快速识别和发现研究，从中得到了10个结构新颖的复杂倍半萜类化合物，有3个为新骨架化合物并且显示了PTPIB酶的抑制活性，其中一个化合物为少见的二聚倍半萜复合物。由于分离得到的量较少，没有对新颖结构化合物进行深入的活性评价。本课题拟对番石榴叶中新颖复杂倍半萜类成分进行研究：利用建立的复杂倍半萜的快速获取和富集方法，高效获取番石榴叶中该类成分并对其进行多靶点的抗糖尿病活性评价和构效关系、计算机虚拟筛选等研究。对活性强的化合物开展仿生合成研究积累化合物的量，从而进行作用机制、初步毒性等研究，最终得到活性确切的抗糖尿病先导化合物。

本课题对番石榴[Psidium guajava L.(Myrtaceae)]叶和果实的95%乙醇提取物进行了系统的微量成分分离，共得到了132个化合物。通过结构鉴定发现，混源萜类化合物53个，甾体、三萜及其苷类化合物23个，黄酮、苯甲酮及其苷类化合物27个，醌类化合物2个，其它类型化合物27个。其中新化合物30个，包括9个新骨架化合物。通过体外活性筛选，首次发现部分混源萜类化合物表现出了显著的肾小管上皮细胞保护活性；部分化合物表现出显著的神经细胞保护活性及PTP1B酶抑制活性等。通过三步反应，实现了新骨架混源萜类化合物(±)-Psiguamer A及(±)-Psiguamer B的首次全合成。在此基础上，以(±)-Psiguamer A及(±)-Psiguamer B为先导化合物，通过Diels-Alder环化、甲基化、氧化、还原及还原胺化等反应，对其进行结构优化，设计并合成了10个类似物，并发现化合物G-8具有显著的抗肾炎活性，具有深入研究价值。