基于PTP1B靶点的新型T2DM抑制剂—江西两种刺桐属植物中特异性异戊烯基化紫檀烷类成分及构效关系和作用机制研究

Protein tyrosine phosphatase 1B (PTP1B) is an important negative regulator of insulin signal transduction in vivo. In various tissue cells, overexpression of PTP1B results in a decrease in the activity of protein tyrosine kinase, which blocks interactions of insulin receptor with insulin and further lead the individual to insulin resistance. Finally, the metabolism of glucose and lipid is also disturbed, resulting in the pathogenesis of type 2 diabetes mellitus (T2DM). Therefore, it is of great significance to discover new anti-T2DM drug targeting PTP1B with high efficiency, low toxicity, and high selectivity.. 11 Novel prenylated pterocarpans characteristic of the plants of the genus Erythrina, which exhibited selective and potent PTP1B inhibitory activity, have been isolated from Erythrina crista-galli in our previous experiments. This project will deal with the discovery of natural product-based on PTP1B inhibitors from two plants of the genus Erythrina (E. corallodendron and E. subumbrans) distributed in Jiangxi on the basis of these findings. The aim of this research is to search for characteristic prenylated pterocarpans from the Erythrina genus, to evaluate for PTP1B inhibitory activity, hypoglycemic effect in vivo, structure-activity relationship, and mechanism of action of this type of compounds, and to obtain several lead compounds for new anti-T2DM drugs targeting PTP1B. This research will be to afford more theoretic and experimental data for investigation of rich source of the Chinese Erythrina plants ande to provide certain scientific data for the discovery of new anti-T2DM drugs targeting PTP1B.

蛋白酪氨酸磷酸酶1B(PTP1B)在胰岛素信号调节中起重要的负调节作用，组织细胞中PTP1B过表达会降低蛋白酪氨酸激酶的活性，使胰岛素受体无法与胰岛素结合，进而发生糖脂代谢紊乱，最终导致2型糖尿病(T2DM)。因此，寻找和发现高效、低毒、高选择性的PTP1B抑制剂作为抗T2DM药物具有重要意义。. 本项目在已从鸡冠刺桐中分离鉴定出11种刺桐属植物特征性、具明显选择性抑制PTP1B的异戊烯基化紫檀烷类新颖结构化合物的基础上，拟对江西两种刺桐属植物龙牙花和翅果刺桐中的异戊烯基化紫檀烷类成分进行定向分离和结构鉴定，并对该类化合物进行体外PTP1B抑制活性、体内降糖作用、构效关系和作用机制研究，以期获得一些可明显抑制PTP1B的新型抗T2DM药物先导化合物。本课题的开展将为开发利用我国刺桐属药用植物资源积累一定的资料，为PTP1B抑制类抗T2DM药物的研究与开发提供一定的科学依据。

本项目在国家自然科学基金（No. 81860616）的资助下，运用正反相硅胶柱、凝胶Sephadex LH-20及反相高校液相(RP-HPLC)等多种层析方法对两种刺桐属植物—龙牙花和翅果刺桐进行了系统的化学成分研究，从中共发现了33种异戊烯基化紫檀烷类化合物，其中新结构化合物16种。此外，从两种刺桐属植物中还发现了98种其它类型的化合物，包括46个异黄酮类、15个黄烷类、3个肉桂基苯酚、4个黄酮醇类、6个苯骈呋喃类、2个生物碱类、7个三萜类、6个倍半萜类、2个甾体类以及7个芳香类小分子化合物，其中新化合物15种。在体外生物活性筛选中，对分离得到的部分单体化合物进行了PTP1B抑制及抗炎等体外活性测试。结果显示，12种异戊烯基化紫檀烷类化合物具有明显的PTP1B抑制活性，并且还发现了23个异黄酮类、4个黄烷（醇）类、1 个肉桂基苯酚、4个环戊烷并苯呋喃/苯吡喃类及2个三萜类PTP1B抑制剂。此外，30个单体化合物还显示了显著的抗炎活性。本项目研究结果目前已正式发表5篇SCI收录论文，获国家发明专利授权13项，已培养10 名硕士研究生。研究结果可以为合理开发利用我国丰富的刺桐属植物资源积累资料，为PTP1B 抑制类抗糖尿病药物的研究开发提供一定的科学依据。