新型α-葡萄糖苷酶抑制剂类降血糖药的合成及其活性研究  

Synthesis of New Type α-Glucosidase Inhibitor Hypoglycemic Drugs and Its Activity Study

作　　者：王谦[1,2] 边晓丽[1] 樊向妮[1] 罗振吉[1] 赵桂兰[1] 

机构地区：[1]西安交通大学医学院,西安710061 [2]陕西科技大学生命科学与工程学院,西安710021

出　　处：《中国药房》2013年第1期19-22,共4页China Pharmacy

基　　金：国家自然科学基金资助项目(No.21172177)

摘　　要：目的:合成一种新型葡萄糖氮苷化合物,并对其α-葡萄糖苷酶抑制活性及降低餐后血糖活性进行初步研究,为寻找具有新型结构的α-葡萄糖苷酶抑制剂类降血糖药奠定基础。方法:取邻苯二甲酰亚胺经硝化、成盐得4-硝基酞酰亚胺钾盐,再与葡萄糖经乙酰化、溴化得到的溴代葡萄糖反应后去乙酰基得到目标化合物。以阿卡波糖为阳性对照药,对目标化合物进行酵母和小鼠肠来源的α-葡萄糖苷酶(麦芽糖酶、乳糖酶和淀粉酶)体外抑制活性[以半数抑制浓度(IC50)为指标]的测定,以及灌胃给药2h内小鼠餐后血糖水平变化的初步研究。结果:合成了目标化合物,其结构经质谱(MS)及核磁共振(1H-NMR)确证;目标化合物对4种酶的活性抑制强弱顺序为:酵母α-葡萄糖苷酶、麦芽糖酶、乳糖酶、淀粉酶(IC50分别为1.49、33.7、101.1、>200μmol/L);其可降低正常小鼠餐后血糖,其与阳性对照药、空白组餐后2h时血糖水平分别为(10.6±0.4)、(7.4±1.0)、(11.9±0.7)mmol/L。结论:合成了一种新的葡萄糖氮苷化合物5-硝基-2(-β-D-吡喃葡萄糖基)-1H-异吲哚-1,3二酮;其体外具有明显的α-葡萄糖苷酶抑制活性,体内具有降低正常小鼠餐后血糖的活性但不及阿卡波糖。OBJECTIVE：To synthesize new type glocosaminidase compound,and to study its activity of α-glucosidase and postprandial blood glucose,and to lay a foundation for the development of new type α-glucosidase inhibitor hypoglycemic drugs.METHODS：Phthalimide was nitrified and salified to produce 4-nitro phthalimidopotassium.Target product was obtained after 4-nitro phthalimidopotassium reacted with acetylized and bromized glucose,following by deacetylation.The IC50 of α-glucosidase（maltase,lactase and amylase）from yeast and mice intestines were determined using acarbose as positive control.Postprandial blood glucose was determined in mice within 2 h after i.g.administration.RESULTS：The target product was synthesized and its structure was confirmed by MS and 1H-NMR.It showed significant dose dependent inhibitory activity against yeast α-glucosidase with IC50 of 1.49 μmol/L,maltase with IC50 of 33.7 μmol/L,lactase with IC50 of 101.1 μmol/L and amylase with IC50200 μmol/L.Target product could reduce postprandial blood glucose of normal mice（11.9±0.7 mmol/L）,2 h postprandial blood glucose of mice given target product and positive control were（10.6±0.4）mmol/L and（7.4±1.0）mmol/L.CONCLUSIONS：New type glocosaminidase compound 5-nitro-2-（β-D-glucopyranosyl）-1H-isoindole-1,3-dione（NGID）is synthesized and the compound has obvious inhibition effect on α-glucosidase in vitro,but it is not as good as acarbose in reducing postprandial blood glucose.

关 键 词：5-硝基-2(-β-D-吡喃葡萄糖基)-1H-异吲哚-1 3二酮 Α-葡萄糖苷酶抑制剂 合成 体外抑制活性 小鼠 血糖水平 

分 类 号：R914.5[医药卫生—药物化学] R965[医药卫生—药学]