| With the improvement of people's living standard,the acceleration of life rhythm and the sharp increase of work and life pressure,the number of people with diabetes mellitus(DM)also increases rapidly.This kind of disease has a long course,high cost,and will cause a variety of complications.Make the patient is immersed in economic health more double menace,affect healthy life badly,make major health problem.Among them,type II diabetes patients are the main group.About 90%of patients with diabetes suffer from this type of diabetes.Type II diabetes(T2DM)is mainly a metabolic disease caused by insufficient insulin secretion and insulin resistance,which is mainly characterized by hyperglycemia.Persistent hyperglycemia will lead to a series of diabetic complications,including diabetic ketoacidosis coma,macrovascular disease,diabetic retinopathy,diabetic peripheral neuropathy,diabetic nephropathy,diabetic microvascular disease,etc.Protein tyrosine phosphatases 1B(PTP1B)is an important hypoglycemic drug target.PTP1B is one of the key members of the protein tyrosine phosphatase(PTPs)family.PTPs plays an important role in regulating a variety of cell signal transduction pathways and catalyzing protein tyrosine dephosphorylation.Protein tyrosine phosphorylation,as the main switch of protein function,plays an important role in biological system.A large number of studies have shown that the mouse model with PTP1B gene knockout can effectively resist the influence of hyperglycemia and hyperlipidemia.Therefore,the research on the development of drugs to treat diabetes based on PTP1B inhibitors is very effective and reliable.Kinsenoside is a polychiral glycoside compound isolated from the genus Anoectochilusroxburghii of the orchid family,HerbaAnoectochili.Its chemical name is 4-R-?-D-pyranoglucosyl-butyrate lactone.It has been reported that in vitro enzyme activity experiments showed that clematis aureus has a high inhibitory activity against PTP1B,and a strong specificity,while it has a small inhibitory effect on SHP,VHR,TCPTP and other homologous PTPs,In addition,clematis aureus has significant hypoglycemic activity in STZ sarcoma mice.Although gold lotus glycosides have better hypoglycemic activity,but its synthetic route is longer(the linear synthetic steps for step 12),low production rate and configurations are hard to break up(chiral center and more sugar ring of alpha and beta configuration split difficult),diversity of compounds is not high,compound type,cannot effectively filtering is more efficient specific PTP1B inhibitors.In this report,a series of new derivatives of clematis aureus were designed and synthesized by studying the structure of the glycogen and the partial structure of the glycogen.In structure design,we through to the gold lotus glycosides repletion the change of the part,synthesized based on glucose,galactose,rhamnose and mannose cross-linked with benzyl oxygen radicals imine esters glycogen donor,on the other hand,change the gold lotus quercetin glycosides yuan of parts,respectively,the introduction of S-and R-3-hydroxy butyrolactone configurations,and S-and R-configurations of 4-hydroxy-2-pyrrolidone and 4-hydroxy-l-benzyl-2-pyrrolidone as more receptors,with previous glycogen donor cross synthesis,respectively,21 compounds including kinsenoside and its epimer goodyeroside A were obtained,19 of which were derivatives of kinsenoside.The screening test of these derivatives in vitro enzyme activity,preliminary screening test results show that with mannose glucoside and R-3-hydroxy-gamma butyrolactone gold lotus nucleoside derivatives(36)has a gold lotus more efficient inhibit PTP1B biological activity,for the synthesis of nitrogen compounds and further putting forward the comparatively clear experimental animal experiment target,gives the preliminary gold lotus nucleoside derivatives of PTP1B structure-activity relationship,for subsequent PTP1B inhibitors and the design of the gold lotus nucleoside derivatives with more experimental basis and reference data. |
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