虎杖苷及其衍生物抑制SGLT2降血糖活性研究

Study of Antihyperglycemic Activity by Inhibiting SGLT2 of Polydatin and Its Derivatives

关键词:  虎杖苷  衍生物  SGLT2  降血糖  口服糖耐量  促尿糖

Key words:  polydatin  derivatives  SGLT2  antihyperglycemic  OGTT  UGE

摘要:

目的 揭示虎杖苷及其衍生物抑制钠-葡萄糖协同转运体2（sodium-glucose cotransporter 2，SGLT2）活性的构效关系。方法 以虎杖苷为起始物，经S_N2取代反应、催化氢化获得5个衍生物，以¹H-NMR和HR-ESI-MS进行结构表征。采用荧光标记的1-脱氧葡萄糖{1-[N-（7-nitrobenz-2-oxa-1，3-diazol-4-yl）amino]-1-deoxy-D-glucose，1-NBDG}作为底物对虎杖苷及其衍生物进行体外抑制SGLT2活性测试，对衍生物1b进行体内活性测试，大鼠口服糖耐量实验及促尿糖实验。结果 获得5个虎杖苷衍生物，¹H-NMR和HR-ESI-MS表征结构正确，体外实验显示虎杖苷及其衍生物能较好地抑制SGLT2活性，且化合物1b在10^-5 mol·L^-1时对SGLT2的抑制率达98.6%，但是大鼠体内实验显示1b在120 mg·kg^-1时抑糖率只有11%，尿糖量只有122 mg每200 g，其活性远远低于阳性对照药达格列净。结论 虎杖苷及其衍生物作为O-芳基糖苷化合物具有较弱的抑制SGLT2降血糖活性，其分子结构对后续设计新的C-芳基糖苷SGLT2抑制剂具有一定的指导意义。

Abstract:

OBJECTIVE To disclose the structure-activity relationships of polydatin and its derivatives by inhibiting SGLT2. METHODS Five compounds were synthesized through S_N2 substitution reaction and catalytic hydrogenation in the presence of Pd (OH)₂/C. The compounds were characterized by ¹H-NMR and HR-ESI-MS. The antihyperglycemic activity of the compounds were performed in vitro test taking 1-NBDG as the substrate in the uptake assay to evaluate the Na⁺-dependent glucose transport activities of SGLT2 and operated oral glucose tolerance test and urinary glucose excretion in vivo test. RESULTS Obtained 5 polydatin derivatives, characterized by ¹H-NMR and HR-ESI-MS. Polydatin and derivatives exhibited reasonable inhibition for SGLT2 in vitro test, especially 1b showed the best inhibitory activities in this series derivatives (the inhibition was 98.6% at the dose of 10^-5 mol·L^-1 against SGLT2). However, 1b played a rather weak activity of oral glucose tolerance test (OGTT) with only 11% at 120 mg·kg^-1 dose and urinary glucose excretion (UGE) with 122 mg per 200 g in diabetic SD rats, which was much lower than that in dapagliflozin. CONCLUSION Polydatin and its derivatives as O-aryl glycoside compounds have weaker inhibition of SGLT2 hypoglycemic activity, and its molecular structure has certain guiding significance for the subsequent design of new C-aryl glycoside SGLT2 inhibitors.