中国悬钩子果实中 Ursane 型三萜的蛋白酪氨酸磷酸酶 1B 抑制活性。
Protein tyrosine phosphatase 1B inhibitory activities of ursane-type triterpenes from Chinese raspberry, fruits of Rubus chingii.
机构信息
Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Faculty of Pharmaceutical Sciences, Toho University, Chiba 274-8510, Japan.
出版信息
Chin J Nat Med. 2019 Jan;17(1):15-21. doi: 10.1016/S1875-5364(19)30004-4.
Protein tyrosine phosphatase 1B (PTP1B) has led to an intense interest in developing its inhibitors as anti-diabetes, anti-obesity and anti-cancer agents. The fruits of Rubus chingii (Chinese raspberry) were used as a kind of dietary traditional Chinese medicine. The methanolic extract of R. chingii fruits exhibited significant PTP1B inhibitory activity. Further bioactivity-guided fractionation resulted in the isolation of three PTP1B inhibitory ursane-type triterpenes: ursolic acid (1), 2-oxopomolic acid (2), and 2α, 19α-dihydroxy-3-oxo-urs-12-en-28-oic acid (3). Kinetics analyses revealed that 1 was a non-competitive PTP1B inhibitor, and 2 and 3 were mixed type PTP1B inhibitors. Compounds 1-3 and structurally related triterpenes (4-8) were further analyzed the structure-activity relationship, and were evaluated the inhibitory selectivity against four homologous protein tyrosine phosphatases (TCPTP, VHR, SHP-1 and SHP-2). Molecular docking simulations were also carried out, and the result indicated that 1, 3-acetoxy-urs-12-ene-28-oic acid (5), and pomolic acid-3β-acetate (6) bound at the allosteric site including α3, α6, and α7 helix of PTP1B.
蛋白酪氨酸磷酸酶 1B（PTP1B）作为抗糖尿病、抗肥胖和抗癌药物，其抑制剂的开发引起了人们的浓厚兴趣。悬钩子属（Rubus）植物的果实被用作一种传统的中药。悬钩子属植物果实的甲醇提取物表现出显著的 PTP1B 抑制活性。进一步的基于生物活性的分段分离得到了三种 PTP1B 抑制性五环三萜：熊果酸（1）、2-氧代齐墩果酸（2）和 2α，19α-二羟基-3-氧代乌苏-12-烯-28-酸（3）。动力学分析表明，1 是非竞争性 PTP1B 抑制剂，而 2 和 3 是混合性 PTP1B 抑制剂。进一步分析了化合物 1-3 和结构相关的三萜（4-8）的构效关系，并评估了它们对四种同源蛋白酪氨酸磷酸酶（TCPTP、VHR、SHP-1 和 SHP-2）的抑制选择性。还进行了分子对接模拟，结果表明 1、3-乙酰氧基-12-烯-28-乌苏酸（5）和齐墩果酸-3β-乙酸酯（6）结合在 PTP1B 的变构位点，包括α3、α6 和α7 螺旋。
Zotero 插件