基于苝单酰亚胺-野尻霉素的自组装多效价糖苷酶抑制剂研究  

Self-assembled multivalent glycosidase inhibition effect based on perylene monoimide-deoxynojirimycin conjugates

作　　者：李仁风 杨建星 张慧妍 王克让[1,2] 李小六[1,2] Ren-Feng Li;Jian-Xing Yang;Hui-Yan Zhang;Ke-Rang Wang;Xiao-Liu Li(College of Chemistry and Environmental Science,Hebei University,Baoding 071002,China;Key Laboratory of Medicinal Chemistry and Molecular Diagnosis(Ministry of Education),Key Laboratory of Chemical Biology of Hebei Province,Baoding 071002,China;Department of Pharmacy,the Affiliated Hospital of Qingdao University,Qingdao 266700,China)

机构地区：[1]河北大学化学与环境科学学院,保定071002 [2]药物化学与分子诊断教育部重点实验室,河北省化学生物学重点实验室,保定071002 [3]青岛大学附属医院(平度)药剂科,青岛266700

出　　处：《中国科学：化学》2021年第9期1276-1282,共7页SCIENTIA SINICA Chimica

基　　金：国家自然科学基金(编号:21778013,22077024);河北省生物医药联合基金重点项目(编号:B2020201092);河北大学多学科交叉项目(编号:DXK202004)资助。

摘　　要：糖尿病是糖苷酶代谢异常导致的慢性疾病.近年来多效价糖苷酶抑制剂研究为新型降糖药物的研发开辟了新的途径和策略.如何构筑多效价糖苷酶抑制剂是多效价糖苷酶抑制剂研究存在的关键科学问题.本文合成了苝单酰亚胺-野尻霉素分子PMI-DNJ,经自组装构筑了多效价糖苷酶抑制剂,其对α-甘露糖苷酶的抑制活性为1.41μM,与米格列醇和单体相比分别提高24倍和65倍,具有多价效应.PMI-DNJ对α-葡萄糖苷酶的抑制活性为10.98μM,与米格列醇和单体相比分别提高1.88倍和5.6倍.小鼠体内降糖效果显示,给药量分别为0.5和1.0 mg/kg时,PMI-DNJ在30 min时的相对降糖率分别为27.36%和30.08%,折合摩尔降糖效果,比米格列醇具有更好的降糖作用,具有多价效应.Diabetes mellitus is a serious and chronic disease.Recently,multivalent glycosidase inhibitors were found and rapidly developed,but the key element for construction of multivalent glycosidase inhibitor remained a large challenge.In this article,a perylene monoimide derivative(PMI-DNJ)with 1-deoxynojirimycin conjugated was synthesized.Furthermore,its self-assembly behaviors and glycosidase inhibition effects were studied.PMI-DNJ showed very good glycosidase inhibition activity againstα-mannosidase(jack bean)with a Ki value of 1.41μM,increased approximately 24-fold and 65-fold compared with the control drugs(miglitol and DNJ-1).Moreover,the Ki value of PMI-DNJ againstα-glucosidase was 10.98μM,increased approximately 1.88-fold and 5.6-fold compared with the control drugs(miglitol and DNJ-1).In addition,PMI-DNJ exhibited potent hypoglycemic effects in mice with 27.36%and 30.08%decreases in blood glucose under the drug dose of 0.5 and 1.0 mg/kg.This article introduced a new means to develop antihyperglycemic agents in the field of multivalent glycomimetics.

关 键 词：苝单酰亚胺 自组装 1-脱氧野尻霉素 糖苷酶抑制剂 多效价 

分 类 号：R587.1[医药卫生—内分泌]