| Diabetes is a complex,chronic and multifactorial disease characterized by hyperglycemia.Gliflozins（Sodium-glucose cotransporter 2 inhibitors）are one of the most recently approved clinical antidiabetic drugs.C-glycosides,as a class of sodium-dependent glucose cotransporter 2（SGLT2）inhibitors,are the most extensively studied.The formation of C-C bonds is the key step in the synthesis of these C-glycosides.This reaction usually involved harsh conditions such as ultra-low temperature,leading to moderate yield,which greatly increased the difficulty and cost of synthesis.In comparison with C-glycosides,S-glycosides are easy to synthesize and resistant to acid/alkali and enzymatic hydrolysis so that they are also commonly used O-glycoside mimics.Therefore,the S-glycoside analogs of C-glycoside SGLT2 inhibitors（Thioglucoside analogs of gliflozin）were designed and synthesized in this thesis,and their biological activites were evaluated.Per-O-acetylated glycosyl 1-thioacetates and glycosyl 1-thiols are precursor compounds for thiosugar synthesis,and per-O-acetylated 1-thioglycosides are the most commonly used glycosyl donors for oligosaccharide synthesis.In the traditional synthetic approachs,they were prepared either by a one-step reaction of per-O-acetylated sugars with malodorous thioacetic acid/thiols,or by a two-step reaction where bromosugars were prepared from per-O-acetylated sugars in the first step,followed the reaction of bromosugars with an odorless thioacetate or in the second step.However,the reaction between per-O-acetylated sugars and thioacetates or thiolates had never been investigated.In this thesis,we have developed improved methods for the synthesis of per-O-acetylated 1-thiosugars/1-thioglycosides.Furthermore,six thioglucoside gliflozin analogues were synthesiszed starting from per-O-acetylated glycosyl 1-thiol as the starting materials,and their biological activities were evaluated through cell experiments.The specific work is as follows:（1）The synthesis of per-O-acetylated 1-thioacetates was improved:per-O-acetylated sugars were allowed to react with KSAc in the presence of BF3.Et2O in Et OAc to obtain per-O-acetylated 1-thioacetates with high yields in a one-step reaction.The green solvent Et OAc can be recycled by simple distillation operation.Based on this,one-pot strategies were further developed for the efficient synthesis of per-O-acetylated glycosyl 1-thiols and per-O-acetylated glycosyl disulfides,which has been applied in the synthesis of auranofin.（2）The synthesis of per-O-acetylated 1-thioglycosides was improved:per-O-acetylated sugars were allowed to react with alkylthiolates in the presence of BF3.Et2O with or without dichloromethane as solvent to obtain per-O-acetylated 1-thioglycosides with high yields in a one-step reaction.Furthermore,it was found that 1,2-trans-β-thioglycosides could be converted into corresponding 1,2-cis-α-thioglycosides in the presence of Tf OH in nonpolar solvents under mild conditions.This provided a simple and efficient new approach to synthesize challenging 1,2-cis-α-thioglycosides.（3）The total synthesis of six thioglucoside gliflozin analogues was completed using per-O-acetylated 1-thiol as the starting material:three iodo derivatives of aglycone moieties（m-I-Ar）,which were also used in the synthesis C-glycolide gliflozin,were purchased from Reagent Company;the other three iodo derivatives of aglycone moieties（o-I-Ar）were prepared from iodobenzoic acid or iodobenzoyl chloride drrivatives.With Pd G3-Xant Phos as the catalyst and tetrahydrofuran as the solvent,the coupled reaction of per-O-acetylated1-thiol and iodo derivatives of aglycone moieties was allowed to occur at room temperature.The deprotection of the coupled products led to six thioglucoside gliflozin analogues in high yields.These six thioglucoside gliflozin analogues were further tested for their stability to inβ-glucosidase hydrolysis,cytotoxicity,and ability to inhibit SGLT2.Preliminary results showed that all six analogues had good stability to enzymatic hydrolysis and low cytotoxicity.Three thioglucoside gliflozin analogues where the glycosyl 1-S groups were attached to the meta-position of the alkyl group on the phenyl ring for the aglycone moieties showed low inhibitory activity against SGLT2.The other three thioglucoside gliflozin analogues where the glycosyl 1-S groups were attached to the ortho-position of the alkyl group on the phenyl ring for the aglycone moieties showed similar inhibitory activity to SGLT2 as their corresponding C-glycolide gliflozins. |
