Synthesis Of 1-Deoxynojirimycin Derivatives And Its Inhibition On ?-Glucosidase

1-deoxynojirimycin?1-DNJ?is a polyhydroxy alkaloid isolated from the mulberry leaves.This compound can competitively bind the active center of?-glucosidase,and its affinity is stronger than sucrose and other disaccharides.In vitro experiments showed that 1-DNJ can effectively inhibit disaccharide hydrolysis catalyzed by?-glucosidase.The structure of the material is very similar to glucose,studies have shown that its absorption and metabolism in the body is fast,half-life is short,so the inhibition of postprandial hyperglycemia activity is not outstanding.In recent years,DNJ derivatives have attracted the attention of researchers,such as Miglitol?N-?2-hydroxyethyl?-DNJ?and Zavesca?N-butyl-DNJ?have been used for the treatment of type 2 diabetes and Gaucher's disease respectively in clinical.In this paper,a series of N-benzyl DNJ and hybrids of DNJ and oleanolic acid were synthesized and characterized by?-glucosidase inhibitory activity.Several compounds with high activity were founded,in which the inhibitory activity of II-15 was stronger than that of acarbose.The details are as follows:?1?Preparation of 1-deoxynojirimycin:Tetrabenzyl D-glucopyranose as raw material,adopted ring hydrogenation of lithium aluminum hydride into alcohol,Swern oxidation of aldehyde,sodium cyanoborohydride and ammonium reductive amination,and finally hydrogen palladium Carbon to remove the benzyl group to get 1-deoxynojirimycin.?2?Synthesis and activity screening of N-Benzyl deoxynojirimycin derivatives:19compounds were prepared by utilizing 1-deoxynojirimycin as a primer and introducing benzyl compounds at their amino positions.The results showed that the activity of compound II-15 was higher than acarbose through?-glucosidase-PNPG activity in vitro,and the half inhibitory constant of?-glucosidase was 0.207mM,and IC50 value of acarbose was0.353mM.The results of kinetic test showed that the inhibitory constant of?-glucosidase was 0.101mM,which was lower than that of positive control acarbose?Ki=0.115mM?.?3?Synthesis and ativity seening of hybrids of DNJ and Oleanolic Acid:7 kinds of1-deoxynojirimycin derivatives were synthesized by introducing the active group-oleanolic acid.IC50 was 0.786 mM for alpha-glucosidase,although higher than that of positive control acarbose?IC50=0.353 mM?was lower than that of Oleanolic Acid.The results of kinetic test showed that the inhibitory constant of?-21 to?-glucosidase was 0.85mM,which was a mixed inhibitor.?4?The mechanism of?-15 and?-21 inhibiting?-glucosidase was studied by molecular docking method.The mechanism of?-15 and?-21 inhibition of?-glucosidase was compared with that of acarbose.The binding of acarbose to?-glucosidase mainly depends on the hydrogen bond and?-?interaction.The binding of II-15 and III-21 to?-glucosidase is similar.However,the structure of?-15 is more simple than acarbose,the resistance of the compound into the active cavity is relatively small,so the inhibition activity is better,and steric hindrance of?-21 is strong,the inhibitory activity is relatively poor.In this paper,26 novel 1-deoxynojirimycin derivatives were synthesized and the compound?-15(IC₅₀=0.203 mM)with high activity were screened by in vitro?-glucosidase-PNPG detection model.The value of IC₅₀ was lower than acarbose(IC₅₀=0.353mM)and the value of K_i was 0.101 mM,which was a mixed inhibitor.The results of molecular docking analysis showed that the binding of compound II-15 to?-glucosidase mainly depends on the hydrogen bond and?-?accumulation interaction formed between the amino-linked glucose analogue with the enzyme activity center.