Study On The Synthesis And Hypoglycemic Activities Of 9-O-glycosyl-berberine Homologues

The isoquinoline alkaloids berberine, an important active component of Rhizoma Coptidis, is used in the treatment of bacterial gastrointestinal diseases such as diarrhea. Modern scientific research indicated that berberine has not only antimicrobial activity in vitro and in vivo, but also other important pharmacological activities such as lipid-modulating, antihyperglycemic, antitumor, antihypertension and antiarrhythmia. In order to increase the bioavailability of berberine,9-O-glycosyl-berberine homologues were synthesized in our laboratory by introducing different monosaccharide (glucose, arabinose and erythritol) at C9 position after demethylation of berberine. Some pharmacokinetic properties and in vitro hpyerglycemic activities of 9-O-glycosyl-berberine were studied according to corresponding methods. The methods and results are as follows:1. The synthesis of 9-O-glycosyl-berberine homologuesWith berberine as lead compound, common monosaccharide as substiuent groups, the synthesis approaches to 9-O-glycosyl-berberine were carried out according to solid-liquid phase transfer catalysis in different raction conditions, temperature, solvent and raction time. The results showed that the highest yields of the intermediates had been archieved when synthesized in DMF under 45℃, while the highest yields of the end products had been archieved with Na2CO3/NaHCO3 as hydrolysis reagent under 40℃. The structure of 9-O-glycosyl-berberine homologues synthesized were affirmed with Ultraviolet spectrum and 1H NMR. 2. The pharmacokinetic studies of 9-O-glycosyl-berberine homologuesThe pharmacokinetc profiles of 9-O-glycosyl-berberine were investigated after i.g. administration of rats via HPLC analysis of plasma and tissue, compared with berberine and 9-O-alkyl-berberine. The results showed that maximum concentration (Cmax) and area under concentration-time curve (AUC) of berberine which was metabolite of 9-O-glycosyl-berberine increased dramatically. The Cmax and AUC of 9-O-glucosyl-berberine were 9.3 and 13.5 times, i.e.63.42μg·L-1 and 268.94μg·L-1, respectively, higher than that of berberine and 9-O-alkly-berberine, which indicated that glycosylated modification could increase the hydrophilic activity and bioavailability of berberine. All derivatives could be transformed into proberberine derivatives in vivo, the concentrations of that were proportional and they would reach an equilibrium state at the end, which demonstrated the phenomena of "global systems biology".3. The hypoglycemic activity preliminary studies of 9-O-glycosyl-berberine homologues.To investigate the hypoglycemic effects of 9-O-glycosyl-berberine homologues, the glucose consumption of human hepatoma cell (HepG2) were analysized by automatic biochemistry analyzer and the cell survival rates were measured according to MTT assay. Further more, to evaluate the hypoglycemic ability of 9-O-glycosyl berberine in vivo, a hyperglycemic rats model were established by tail vein injection of alloxan and the FBG (fasting blood-glucose) were assaied after i.g. adminstration of 9-O-glucosyl-berberine upon hyperglycemic rats, compared with berberine and metformin. The results showed that 9-O-glycosyl-berberine homologues had no significant in vitro hypoglycemic activities in various glucose concentration either insulin concentration environment. However, The FBG results showed that after 15 days i.g. administration,9-O-glucosyl-berberine had significant in vivo hypoglycemic activity, the hypoglycemic rate was up to over 56%.