Synthesis And Biological Evaluation Of 1-deoxynojirimycin Derivatives

Type 2 diabetes mellitus（T2DM）is a common chronic metabolic disease characterized by high blood-glucose levels which result from insulin resistance and impaired insulin secretion,which has become one of the most important chronic diseases affecting human health.1-Deoxynojirimycin（DNJ）,a strongα-glucosidase inhibitor,can significantly decrease the intestinal absorption of carbohydrates and lower postprandial blood glucose levels.In order to findα-glucosidase inhibitors with better selectivity and inhibitory activity,36 novel compounds were designed and synthesized by modifying at 6-O-and N-position of DNJ.The structure of the target compounds was confirmed by NMR and HRMS.All compounds were investigated against a panel of glucosidases.Part of compounds were evaluated including in vitro anticancer activity,cytotoxicity,kinetics of enzyme inhibition and molecular docking simulation.1.Synthesis and biological evalution of C-6-OMe DNJ as a potentα-glucosidase inhibitor.A facile and efficient synthesis of C-6-OMe DNJ from commercially available methyl?-D-glucopyranoside in 10 steps and 25%overall yield was reported.The structure of the target compound was confirmed by NMR and HRMS.The target compound(IC₅₀=72.65 mg/L)showed improved inhibitory activity againstα-glucosidase compared DNJ(IC₅₀=192.74 mg/L)and Acarbose(IC₅₀=105.42 mg/L).2.Synthesis and bioactivity of N-alkylated DNJ derivatives connected to a terminal tertiary amine were studied.A series of target compounds containing C₂ and C₄ linker were synthesized from cheap commercial 2,3,4,6-tetra-O-benzyl-D-glucose.N-morpholinoethyl-DNJ(IC₅₀=0.052±0.004 m M)showed improved and selective inhibitory activity againstβ-glucosidase compared to DNJ(IC₅₀=0.648±0.036 m M).In addition,analysis of the kinetics of enzyme inhibition by using Lineweaver-Burk plots indicated that this compound inhibitedβ-glucosidase in a competitive manner.N-pyrrolidinobutyl-DNJ and N-piperidinobutyl-DNJ were found to be moderate and selective inhibitors ofα-glucosidase.3.N-substituted guanidine modified and DNJ-triazole hybrid derivatives were prepared and tested against a panel of glycosidases for their inhibitory properties.DNJ-phenyltriazole 4.5f(IC₅₀=0.063±0.006 m M)containing the amyl on the 4-position of the phenyl exhibited improved inhibitory potency againstα-glucosidase compared to DNJ(IC₅₀=0.155±0.015 m M).Moreover,analysis of the kinetics of enzyme inhibition by using Lineweaver-Burk plots indicated that 4.5f inhibitedα-glucosidase in a competitive manner.The structure-activity relationships indicated that introduction of the phenyl group and the lengthening of alkyl chain on the 4-position of the phenyl could further enhance the inhibitory potency ofα-glucosidase.4.Synthesis and bioactivity of a series of DNJ-phenyltriazole derivatives containing C₄ and C₆ linkers were further studied,and linear alkyl substituents（H,C₁-C₆）of different lengths were introduced at the 4-position of the phenyl.Compared with DNJ,most target compounds were strongα-glucosidase inhibitors.The results of in vitro cytotoxicity showed that compounds showed no cytotoxicity at low concentrations.When the concentration reached 50μM,only compound 6.4k showed cytotoxicity,and the cell survival rate was only 20.89%.Molecular docking studies revealed that compound 6.4i bound to the active site pocket ofα-glucosidase via hydrogen bonds,hydrophobic and van der Waals interactions withα-glucosidase.