Modificating The Glucose Ring Of Dapagliflozin And Its Bioactivity

Objectives:Sodium-dependent glucose cotransporter 2(SGLT2)inhibitors are new diabetes mellitus therapeutic drugs.Selectively inhibiting the activity of SGLT2 can cause the decline of blood glucose by accelerating the excretion of urine sugar.Combined literatures research with analyzing the molecular structure of SGLT2 inhibitors we synthesized early,we can draw a conclusion that the glucose ring of SGLT2 inhibitors can be used as a transformation target.But there is much difficulty in modifying hydroxyls of glucose and have little available literatures,because four hydroxyls have similar chemical environment.In order to know the effect of glucose ring on the hypoglycemic activity of SGLT2 inhibitors and better understand the structure-activity relationship of SGLT2 inhibitors,we modified the glucose ring of newly marketed drug dapagliflozin,screened by activity test.In this way,we can also orientate modificatory targets and lay a better base on novel SGLT2 inhibitors design.Method:Based on the results got earlier,we design three kinds of methods to modificate glucose ring,they are(1)6-OH deoxygenated.We first synthesized the 6-deoxylated glucose moiety,and then coupled it with compound i-5 to synthesized 6-deoxyglucose SGLT2 inhibitor(1-1).(2)3-OH carbonylated.In considerations of industrial need and patents,we carried out the construction of the 3-oxoglucose before C-glycosidation and employed the convergent route to synthesis 3-oxo-dapagliflozin(Ⅱ-1).(3)3,6-dehydrated.After analyzing and compareing with the results obtained earlier,we found that the 3-OH and 6-OH of dapagliflozin are not necessary for the SGLT2 inhibitory activity perhaps.When the 3-OH or 6-OH was reduced respectively,the individual corresponding products still had the same SGLT2 inhibitory activity to dapagliflozin.In order to investigate the effects of 3-OH and 6-OH on structure-activity of SGLT2 inhibitors,we design a new compound,3,6-anhydrodapagliflozin.Result:We synthesized the 6-deoxyglucose C-glycosides bearing trans-cyclohexane moieties,3-oxo C-glycosides and 3,6-anhydrodapagliflozin successfully.The structures of them were confirmed by 1H-NMR,13C-NMR,HR-MS and IR.At the same time,we screened the reaction condition of debenzylation,and found a synthetic route with high yield,good operability and high reproducibility.The hypoglycemic activity of Ⅰ-1、Ⅱ-1、Ⅲ-1 was evaluated in in vitro model and rat UGE test.The IC50 values of each of product are 290 nM、1.4 nM、1.0 nM(IC50 dapagliflozin:1.3 nM).Conclusion:All the experimental results suggest that:(1)6-OH of glucose has little effect on SGLT2 inhibitory activity.(2)Saturated cyclic substituted aglycone can be a potential modificatory target in future.(3)3-OH of glucose is another modificatory target.(4)The stereoscopic structure of SGLT2 inhibitors has significant business with its inhibitory activity and should be taken into serious consideration when do the molecular model design.The synthetic route of Ⅱ-1 represents a general method to synthesis various kinds of 3-oxoglycosides,which developed a synthetic route of saccharides derivatives.The new synthetic technology has good stability and full intellectual property,which provides a guarantee for the further development and utilization ofⅡ-1.We got a further understanding of the structure-activity relationship of SGLT2 inhibitors and laided a theoretical foundation for new drugs development.