9-O-小檗碱糖苷同系物的合成与降糖药理活性
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摘要
小檗碱属异喹啉类生物碱,为黄连等传统中药的主要活性成分,在临床上被广泛用于治疗细菌感染引起的胃肠道疾病。现代科学研究显示,小檗碱不但具有良好的体内外抗菌作用,而且还表现出很好的调脂,降血糖,抗肿瘤,降血压,抗传染性原虫和抗心率失常等多种药理活性。本实验以小檗碱为先导化合物,通过小檗碱分子C9位去甲基后引入单糖分子发生糖苷化反应的方法制备了不同单糖取代的9-O-小檗碱糖苷同系物,并采用相应的实验方法研究了它们的药代动力学特性和体外降糖活性。实验方法与结果如下：
1.9-O-小檗碱糖苷同系物的合成
以常见的单糖作为取代基,借鉴7-羟基黄酮糖苷合成方法采用固-液相转移催化法,在小檗碱C9位进行亲水性结构修饰,合成了9-O-小檗碱糖苷同系物,并研究了不同反应条件(温度、反应溶剂、反应时间)对中间体9-O-乙酰小檗碱糖苷及终产物9-O-小檗碱糖苷合成产率的影响。结果发现以DMF为溶剂、45℃下反应3h为最优中间体生成工艺,以Na2CO3/NaHCO3为水解试剂、在40℃下反应1h为最优终产物生成工艺。合成化合物的分子结果分别通过紫外光谱和核磁共振分析等方法进行了确认。
2.9-O-小檗碱糖苷同系物的药代动力学及组织分布研究
用合成的9-O-小檗碱糖苷同系物对SD大鼠进行灌胃给药,通过采集大鼠血浆、组织器官,采用HPLC测定大鼠血浆中血药浓度、组织器官中药物分别,并对比小檗碱、9-O-辛基小檗碱药代动力学数据,结果显示9-O-小檗碱糖苷同系物在口服生物利用度方面与小檗碱、9-O-烷基小檗碱相比有显著优势,9-O-小檗碱葡萄糖苷的Cmax与AUC分别为小檗碱的9.3和13.5倍,达到63.421μg·L-1与268.945μg·L-1·h,提示亲水性糖苷化修饰有助于提高小檗碱生物利用度。同时发现小檗碱与9-O-小檗碱糖苷同系物在大鼠血液中经过代谢可以转化为其他小檗碱同系物,并可在体内各组织器官中检测出,验证了“网通虹势”理论。
3.9-O-小檗碱糖苷同系物降糖活性初步研究
通过一系列细胞实验,利用全自动生化分析仪和全自动酶标仪,研究了9-O-小檗碱糖苷同系物对人肝癌细胞HepG2的葡萄糖消耗量及对细胞存活率的影响,结果显示在不同葡萄糖浓度、不同胰岛素浓度环境中,9-O-小檗碱糖苷同系物并无明显降糖活性,但小檗碱的降糖活性非常明显,在中浓度条件下(1mg·L-1)即表现有效降糖活性,优于二甲双胍。继而通过对SD大鼠尾静脉注射四氧嘧啶获得实验性高血糖大鼠模型,分组对大鼠灌胃给药9-O-小檗碱葡萄糖苷、小檗碱与二甲双胍阳性对照药15天,并检测期间空腹血糖值。结果显示9-O-小檗碱葡萄糖苷具有明显体内降血糖与调节葡萄糖代谢异常能力,给药15天后高血糖大鼠血糖下降超过56%,优于小檗碱。
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 homologues
With 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 homologues
The 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%.
1.9-O-小檗碱糖苷同系物的合成
以常见的单糖作为取代基,借鉴7-羟基黄酮糖苷合成方法采用固-液相转移催化法,在小檗碱C9位进行亲水性结构修饰,合成了9-O-小檗碱糖苷同系物,并研究了不同反应条件(温度、反应溶剂、反应时间)对中间体9-O-乙酰小檗碱糖苷及终产物9-O-小檗碱糖苷合成产率的影响。结果发现以DMF为溶剂、45℃下反应3h为最优中间体生成工艺,以Na2CO3/NaHCO3为水解试剂、在40℃下反应1h为最优终产物生成工艺。合成化合物的分子结果分别通过紫外光谱和核磁共振分析等方法进行了确认。
2.9-O-小檗碱糖苷同系物的药代动力学及组织分布研究
用合成的9-O-小檗碱糖苷同系物对SD大鼠进行灌胃给药,通过采集大鼠血浆、组织器官,采用HPLC测定大鼠血浆中血药浓度、组织器官中药物分别,并对比小檗碱、9-O-辛基小檗碱药代动力学数据,结果显示9-O-小檗碱糖苷同系物在口服生物利用度方面与小檗碱、9-O-烷基小檗碱相比有显著优势,9-O-小檗碱葡萄糖苷的Cmax与AUC分别为小檗碱的9.3和13.5倍,达到63.421μg·L-1与268.945μg·L-1·h,提示亲水性糖苷化修饰有助于提高小檗碱生物利用度。同时发现小檗碱与9-O-小檗碱糖苷同系物在大鼠血液中经过代谢可以转化为其他小檗碱同系物,并可在体内各组织器官中检测出,验证了“网通虹势”理论。
3.9-O-小檗碱糖苷同系物降糖活性初步研究
通过一系列细胞实验,利用全自动生化分析仪和全自动酶标仪,研究了9-O-小檗碱糖苷同系物对人肝癌细胞HepG2的葡萄糖消耗量及对细胞存活率的影响,结果显示在不同葡萄糖浓度、不同胰岛素浓度环境中,9-O-小檗碱糖苷同系物并无明显降糖活性,但小檗碱的降糖活性非常明显,在中浓度条件下(1mg·L-1)即表现有效降糖活性,优于二甲双胍。继而通过对SD大鼠尾静脉注射四氧嘧啶获得实验性高血糖大鼠模型,分组对大鼠灌胃给药9-O-小檗碱葡萄糖苷、小檗碱与二甲双胍阳性对照药15天,并检测期间空腹血糖值。结果显示9-O-小檗碱葡萄糖苷具有明显体内降血糖与调节葡萄糖代谢异常能力,给药15天后高血糖大鼠血糖下降超过56%,优于小檗碱。
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 homologues
With 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 homologues
The 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%.
引文
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