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

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.