Synthesis And Biological Evaluation Of 1-Deoxynojirimycin And Its Derivatives

1-Deoxynojirimycin（DNJ）has drawn much attentions because it has various biological activities such as anti-hyperglycemia,anti-obesity,and anti-cancers.In the future,the demand for DNJ will inevitably increase.Exploring an optimization synthesis process to obtain DNJ is of great significance.In addition,obtaining glycosidase inhibitors with higher selectivity and effectiveness against glycosidase by chemical modification of DNJ now has aroused general interest.The main work of this dissertation is as follows:（1）The target compound DNJ was obtained from methyl-α-D-glucopyranoside via seven steps reactions including benzylation,methyl hydrolysis,oxidative amination,oxidation of C-5 hydroxyl group,intramolecular reductive amination,reduction of lactam and debenzylation.（2）The optimized conditions for key steps in synthesis of DNJ such as oxidative amination,ring closure reaction and reduction of lactam were explored.The need of ammonia water was reduced by half,with the yield 88.00%which is higher than those in the literatures（78.00%-83.00%）,and the column chromatography operation was omitted;The optimization conditions of the ring closure step is as follows:DMSO and acetic anhydride as oxidant,the oxidation temperature was 5-10℃,1.00 g raw material using 2 ml formic acid,and when the feed amount was 10.00g,the yield was 54.70%,which is higher than those in the literatures（48.00%）.（3）Providing two methods to obtain multivalent DNJ derivatives:A new divalent DNJ derivatives 4.2 was synthesized using compound 2.6 and glutaraldehyde via reductive amination reaction;Compound 4.4 was obtained from 2.6 by nucleophilic substitution reaction with halides and hydrazinolysis;Compound 4.4 reacted with terephthaloyl chloride or trimesoyl chloride respectively provided divalent DNJ derivative 4.5 or trivalent DNJ derivative 4.6.Hydrogenation of compound 4.5 provided a new divalent DNJ derivative 4.7.The reaction conditions for debenzylation under atmospheric pressure were explored.（4）We investigated the inhibitory activities of compound 4.7 againstα-glucosidase,β-glucosidase andα-mannosidase in vitro.The IC₅₀ of the compound 4.7 forα-glucosidase was0.302±0.030 mmol/L.Compound 4.7 has no inhibitory activity againstβ-glucosidase,while DNJ showed inhibitory activities againstα-glucosidase andβ-glucosidase,the divalent DNJ derivatives 4.7 has increase selectivity forα-glucosidase overβ-glucosidase compared to DNJ.