2β-Acetoxyferruginol去醋酸基骨架衍生物抑制α-葡萄糖苷酶活性研究

α-Glucosidase Inhibition Research of Derivatives Based on 2β-Acetoxyferruginol Scaffold Excluding Acetic Acid Group

合成了系列2β-acetoxyferruginol去醋酸基骨架衍生物(1~24),并测定了其α-葡萄糖苷酶抑制活性.结果表明:化合物1~24均有较好的α-葡萄糖苷酶抑制作用.其中(3R,4aS,10aS)-6-羟基-1,1,4-三甲基-1,2,3,4,4a,9,10,10-八氢邻蒽3-基-4-(三氟甲基)苯甲酸酯(15)抑制α-葡萄糖苷酶活性最强[IC_(50)=(23.91±2.34)μmol/L],是阿卡波糖抑制活性的23.6倍.构效关系分析表明三氟甲基的引入更有利于提高化合物的活性.动力学结果显示化合物15为可逆非竞争性的α-葡萄糖苷酶抑制剂.3D荧光结果表明化合物15与α-葡萄糖苷酶的结合可改变α-葡萄糖苷酶的构象.分子对接结果显示化合物15与α-葡萄糖苷酶Asp68,Arg312,Tyr313形成了氢键,与Phe177和Phe300形成疏水作用.

In this study,a series derivatives based on 2β-acetoxyferruginol scaffold excluding acetic acid group(1~24)were synthesized and their inhibitory activities onα-glucosidase were determined.The results showed that all compounds 1~24 had goodα-glucosidase inhibitory activities.Among them,(3R,4aS,10aS)-6-hydroxy-1,1,4a-trimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-3-yl 4-(trifluoromethyl)benzoate(15)had the strongest inhibitory activity[IC_(50)=(23.91±2.34)μmol/L],about 23.6-fold more active than acarbose.The structure activity relationship analysis showed that the introduction of trifluoromethyl was more conducive to enhance its activity.The kinetic results showed that compound 15 was a reversible and non competitiveα-glucosidase inhibitor.The 3D fluorescence results indicated that the binding ofα-glucosidase with compound 15 could change the conformation ofα-glucosidase.The molecular docking results showed that compound 15 made hydrogen bonds with Asp68,Arg312,and Tyr313,and formed hydrophobic interactions with Phe177 and Phe300.