8-烷基黄连碱同系物的合成与药理活性
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摘要
黄连碱属异喹啉类生物碱,为黄连等传统中药的活性成分之一,黄连碱在临床上的应用极少,现代科学研究显示,黄连碱表现出很好的降血糖,降血压,抗传染性原虫和保护胃粘膜等等多种药理活性。本实验以黄连碱为先导化合物,通过在黄连碱分子C8位引入直链烷基的方法制备了不同碳链取代的8-烷基黄连碱同系物(Cop-C8-n, n= 4,6,8,10,12,),并采用相应的实验方法研究了Cop-C8-n的体外抗菌活性,体内外降糖活性和体内毒性。实验方法与结果如下：
1.利用黄连中黄连碱硫酸盐溶解度的差异,通过一系列处理,反复在乙醇中重结晶,成功制备了黄连碱单体,利用聚酰胺成功分离了药根碱和表小檗碱。
2.8-烷基黄连碱同系物的合成与鉴定
采用格氏试剂引入烷基的方法进行中间体8-烷基二氢黄连碱的合成,对反应溶剂进行优选,最后以THF为溶剂顺利制备了不同碳数烷基特别是长链烷基取代的cop-C8-n。合成化合物的分子结构分别通过1H NMR和13C NMR等方法进行了确认。
3.8-烷基黄连碱同系物的体外抗菌活性
抑菌圈法研究了5种微生物(包括G+菌,G-菌和真菌)对Cop-C8-n的敏感性,并采用比浊法测定了5种敏感微生物的MIC值。实验结果显示,G+菌和真菌对Cop-C8-n敏感性明显强于G-菌；Cop-C8-n的抗菌活性规律为：在黄连碱C8位接入烷基后抗菌活性随烷基碳数的增加而提高,但当烷基碳数>8时,cop-C8-n的抗菌活性则随烷基碳数的增加而下降,即8-辛基黄连碱(Cop-C8-8)在同系物中表现出最高抗菌活性。
4.8-烷基黄连碱同系物与溶菌酶的作用机制进行研究
应用荧光猝灭法对8-烷基黄连碱同系物与溶菌酶的作用机制进行研究。研究发现,黄连碱同系物对溶菌酶的内源性荧光产生了极强的猝灭作用,通过测定不同温度下的猝灭常数,表明猝灭作用过程既有静态猝灭又有动态猝灭,同时热力学参数通过计算得出黄连碱同系物与溶菌酶的结合作用力主要为疏水作用力。随着烷基链的增长溶菌酶的紫外吸收逐渐下降,而在荧光分析中,室温下溶菌酶与Cop-C8-8的结合位点为2以及结合常数为206.3×105,都显著高于其它物质,与抑菌结果一致
4.8-烷基黄连碱的体外和体内降糖活性
采用与人肝细胞表型相似的HepG2细胞,检测24 h后培养液中葡萄糖消耗量,用MTT法监测细胞增殖的情况,研究了8-烷基黄连碱同系物在体外对细胞糖代谢和细胞增殖的影响。8-烷基黄连碱同系物在葡萄糖浓度(10 mmol/L)状态下可使HepG2细胞的葡萄糖消耗量有不同程度的增加,其中以8-已基黄连碱最为显著。8-烷基黄连碱同系物对HepG2细胞的增殖有显著的抑制作用。通过对昆明小鼠尾部静脉注射四氧嘧啶获得实验性糖尿病模型,将糖尿病小鼠分为若干组,黄连碱及8-烷基黄连碱及二甲双胍灌胃治疗15天,并检测其血糖值、糖耐量、血清中SOD和MDA等含量变化。结果显示,经过黄连碱及其同系物和二甲双胍的治疗后,小鼠的血糖值和糖耐量得到改善。模型小鼠在治疗前,其血清中MDA含量高于正常水平,SOD活力低于正常水平,经15天黄连生物碱灌胃治疗后,药物组的血清SOD活性明显升高,MDA含量明显下调。说明黄连生物碱及其同系物可提高糖尿病小鼠机体SOD活性,清除自由基,抑制脂质过氧化。8-己基黄连碱是具有一定潜力的降糖先导化合物。
5.8-烷基黄连碱同系物的体内毒性。
昆明种小鼠为实验动物模型,采用改良寇氏法测定了8-烷基黄连碱同系物的LDso值,并以昆明小鼠为实验动物,经小鼠皮下注射,初步确定了8-烷基黄连碱同系物的急性毒性,实验结果表明,接入短链烷基后8－烷基黄连碱同系物的LD50值与其先导化合物盐酸黄连碱比较大幅度减小,即毒性大幅增加。但随着接入烷基碳数的增加,8－烷基黄连碱同系物的LD50值随之增加,即毒性逐步下降。8-月桂基黄连碱有几乎和黄连碱的毒性相当。
The isoquinoline alkaloids coptisine, is an important active component of Rhizoma Coptidis, and seldom used in clinic. Modern scientific research indicated that coptisine has not only antimicrobial activity in vitro and in vivo, has hypoglycemic antioxidant, Gastric-Mucous Membrane Protection anti-diabetic and Antibacteria Activity To increase the pharmaceutica activity of coptisine 8-alkylcoptisine homologues with seriate different lipophilic property were synthesized in our laboratory by introducing different length alkyl at C8 position, some pharmacological effects of 8-alkyl-coptisine homologues were studied including the antimicrobial activity, glucose consumption effect and toxicity. The methods and results are as follows:
1. The synthesis and molecular structure identification of 8-alkyl-berberine homologues
The synthesis approaches to 8-alkyl-dihydro coptisine were carried out in tetrahydrofuran. The result showed that the highest recovery of the compound had been achieved when synthesized in tetrahydrofuran. The structure of 8-alkyl-coptisine homologues synthesized was affirmed with,1H NMR and 13C NMR.
2. The antimicrobial activity of 8-alkyl- coptisine homologues in vitro
The sensitivity of 5 microorganism come from G+ bacteria, G- bacteria and fungus to 8-alkyl- coptisine homologues respectively were evaluated by inhibition zone method and MICs of 8-alkylcoptisine homologues against 5 sensitive microorganisms were determined by turbidimetric method respectively.
The result showed that G+ bacteria and fungus were more sensitive than G- bacteria. The antimicrobial activity increased as the length of aliphatic chain elongated and then decreased gradually when the alkyl chain exceeded 8 carbon atoms.8-octyl- coptisine showed the highest antimicrobial activity among all compounds.
3. The antimicrobial mechanism of 8-alkyl-berberine homologues in vitro
The mechanism of the interactions of coptisine analogues with lysozyme was studied by fluorescence quenching method. The result had revealed that there was a strong fluorescence quenching effect of coptisine analogues binding to lysozyme. The quenching constants of the synthesized compounds with lysozyme were measured and calculated at different temperatures. The data had indicated both dynamic and static quenchings were involved in the quenching process. The thermodynamic parameters of Gibbs free energy change(ΔG), Enthalpy change(ΔH), Entropy change(ΔS) were calculated. NegativeΔG value(ΔG<0) had found the interactions were spontaneous; PositiveΔH value(ΔH>0) had showed the benefit to the binding. UV absorption of lysozyme was more negatively affected by a longer alkyl chain. Cop-C8 had the highest binding constant which is 206.3×105 and two binding sites which is higher than othersbility to whole cells of B. subtilis (G+) and E. coli (G-) is nearly same while same compound.
4. investigate the glycometabolism of 8-Alkylberberine in vitro
To investigate the glycometabolism of 8-Alkyl coptisine in vitro. HepG2 cell s similar to human hepatic cells were used to test the glucose consumption (GC), MTT assay was used to monitor the proliferation of the HepG2 cells, The results indicated that In moderate high glucose concentration (10 mmol/L), the amounts of Glucose consumption of 8-hexyl coptisine is the highest by Glucose- consumption test in vitro. Glucose-Lowering Effect increased as the length of the aliphatic chain increased and we discovered the Glucose-Lowering Effect decreased when the length of the aliphatic chain exceeded six atoms,while a long aliphatic chain is beneficial for Glucose-Lowering Effect of HepG2. 8-hexyl Coptisine is a potential Hypoglycemic leading compound
8-Alkyl coptisine could effectively decrease the blood glucose of the mouse t rel. It could aslo improve the glucose tolerance, body weight and food intake of diabetes rats. Moreover, 8-Alkyl coptisinein had ability to regulate the level of SOD, MDA and GSH-Ps in the secrum.
5. Preliminary study on toxicity of 8-alkyl coptisine homologues in vivo
With kuming mouse o rats as animal model, the LD50 was determined to evaluate the toxicity of8-alkylcoptisine according to Karber, The route of administration is aintraperitoneal injection..inject 4ml drug one mouse every day according to different concentrations and groups, Result showed that the toxicity of 8-alkyl coptisine derivatives was stronger than that of coptisine. However, by elongating the aliphatic chain, toxicity decreased gradually.
1.利用黄连中黄连碱硫酸盐溶解度的差异,通过一系列处理,反复在乙醇中重结晶,成功制备了黄连碱单体,利用聚酰胺成功分离了药根碱和表小檗碱。
2.8-烷基黄连碱同系物的合成与鉴定
采用格氏试剂引入烷基的方法进行中间体8-烷基二氢黄连碱的合成,对反应溶剂进行优选,最后以THF为溶剂顺利制备了不同碳数烷基特别是长链烷基取代的cop-C8-n。合成化合物的分子结构分别通过1H NMR和13C NMR等方法进行了确认。
3.8-烷基黄连碱同系物的体外抗菌活性
抑菌圈法研究了5种微生物(包括G+菌,G-菌和真菌)对Cop-C8-n的敏感性,并采用比浊法测定了5种敏感微生物的MIC值。实验结果显示,G+菌和真菌对Cop-C8-n敏感性明显强于G-菌；Cop-C8-n的抗菌活性规律为：在黄连碱C8位接入烷基后抗菌活性随烷基碳数的增加而提高,但当烷基碳数>8时,cop-C8-n的抗菌活性则随烷基碳数的增加而下降,即8-辛基黄连碱(Cop-C8-8)在同系物中表现出最高抗菌活性。
4.8-烷基黄连碱同系物与溶菌酶的作用机制进行研究
应用荧光猝灭法对8-烷基黄连碱同系物与溶菌酶的作用机制进行研究。研究发现,黄连碱同系物对溶菌酶的内源性荧光产生了极强的猝灭作用,通过测定不同温度下的猝灭常数,表明猝灭作用过程既有静态猝灭又有动态猝灭,同时热力学参数通过计算得出黄连碱同系物与溶菌酶的结合作用力主要为疏水作用力。随着烷基链的增长溶菌酶的紫外吸收逐渐下降,而在荧光分析中,室温下溶菌酶与Cop-C8-8的结合位点为2以及结合常数为206.3×105,都显著高于其它物质,与抑菌结果一致
4.8-烷基黄连碱的体外和体内降糖活性
采用与人肝细胞表型相似的HepG2细胞,检测24 h后培养液中葡萄糖消耗量,用MTT法监测细胞增殖的情况,研究了8-烷基黄连碱同系物在体外对细胞糖代谢和细胞增殖的影响。8-烷基黄连碱同系物在葡萄糖浓度(10 mmol/L)状态下可使HepG2细胞的葡萄糖消耗量有不同程度的增加,其中以8-已基黄连碱最为显著。8-烷基黄连碱同系物对HepG2细胞的增殖有显著的抑制作用。通过对昆明小鼠尾部静脉注射四氧嘧啶获得实验性糖尿病模型,将糖尿病小鼠分为若干组,黄连碱及8-烷基黄连碱及二甲双胍灌胃治疗15天,并检测其血糖值、糖耐量、血清中SOD和MDA等含量变化。结果显示,经过黄连碱及其同系物和二甲双胍的治疗后,小鼠的血糖值和糖耐量得到改善。模型小鼠在治疗前,其血清中MDA含量高于正常水平,SOD活力低于正常水平,经15天黄连生物碱灌胃治疗后,药物组的血清SOD活性明显升高,MDA含量明显下调。说明黄连生物碱及其同系物可提高糖尿病小鼠机体SOD活性,清除自由基,抑制脂质过氧化。8-己基黄连碱是具有一定潜力的降糖先导化合物。
5.8-烷基黄连碱同系物的体内毒性。
昆明种小鼠为实验动物模型,采用改良寇氏法测定了8-烷基黄连碱同系物的LDso值,并以昆明小鼠为实验动物,经小鼠皮下注射,初步确定了8-烷基黄连碱同系物的急性毒性,实验结果表明,接入短链烷基后8－烷基黄连碱同系物的LD50值与其先导化合物盐酸黄连碱比较大幅度减小,即毒性大幅增加。但随着接入烷基碳数的增加,8－烷基黄连碱同系物的LD50值随之增加,即毒性逐步下降。8-月桂基黄连碱有几乎和黄连碱的毒性相当。
The isoquinoline alkaloids coptisine, is an important active component of Rhizoma Coptidis, and seldom used in clinic. Modern scientific research indicated that coptisine has not only antimicrobial activity in vitro and in vivo, has hypoglycemic antioxidant, Gastric-Mucous Membrane Protection anti-diabetic and Antibacteria Activity To increase the pharmaceutica activity of coptisine 8-alkylcoptisine homologues with seriate different lipophilic property were synthesized in our laboratory by introducing different length alkyl at C8 position, some pharmacological effects of 8-alkyl-coptisine homologues were studied including the antimicrobial activity, glucose consumption effect and toxicity. The methods and results are as follows:
1. The synthesis and molecular structure identification of 8-alkyl-berberine homologues
The synthesis approaches to 8-alkyl-dihydro coptisine were carried out in tetrahydrofuran. The result showed that the highest recovery of the compound had been achieved when synthesized in tetrahydrofuran. The structure of 8-alkyl-coptisine homologues synthesized was affirmed with,1H NMR and 13C NMR.
2. The antimicrobial activity of 8-alkyl- coptisine homologues in vitro
The sensitivity of 5 microorganism come from G+ bacteria, G- bacteria and fungus to 8-alkyl- coptisine homologues respectively were evaluated by inhibition zone method and MICs of 8-alkylcoptisine homologues against 5 sensitive microorganisms were determined by turbidimetric method respectively.
The result showed that G+ bacteria and fungus were more sensitive than G- bacteria. The antimicrobial activity increased as the length of aliphatic chain elongated and then decreased gradually when the alkyl chain exceeded 8 carbon atoms.8-octyl- coptisine showed the highest antimicrobial activity among all compounds.
3. The antimicrobial mechanism of 8-alkyl-berberine homologues in vitro
The mechanism of the interactions of coptisine analogues with lysozyme was studied by fluorescence quenching method. The result had revealed that there was a strong fluorescence quenching effect of coptisine analogues binding to lysozyme. The quenching constants of the synthesized compounds with lysozyme were measured and calculated at different temperatures. The data had indicated both dynamic and static quenchings were involved in the quenching process. The thermodynamic parameters of Gibbs free energy change(ΔG), Enthalpy change(ΔH), Entropy change(ΔS) were calculated. NegativeΔG value(ΔG<0) had found the interactions were spontaneous; PositiveΔH value(ΔH>0) had showed the benefit to the binding. UV absorption of lysozyme was more negatively affected by a longer alkyl chain. Cop-C8 had the highest binding constant which is 206.3×105 and two binding sites which is higher than othersbility to whole cells of B. subtilis (G+) and E. coli (G-) is nearly same while same compound.
4. investigate the glycometabolism of 8-Alkylberberine in vitro
To investigate the glycometabolism of 8-Alkyl coptisine in vitro. HepG2 cell s similar to human hepatic cells were used to test the glucose consumption (GC), MTT assay was used to monitor the proliferation of the HepG2 cells, The results indicated that In moderate high glucose concentration (10 mmol/L), the amounts of Glucose consumption of 8-hexyl coptisine is the highest by Glucose- consumption test in vitro. Glucose-Lowering Effect increased as the length of the aliphatic chain increased and we discovered the Glucose-Lowering Effect decreased when the length of the aliphatic chain exceeded six atoms,while a long aliphatic chain is beneficial for Glucose-Lowering Effect of HepG2. 8-hexyl Coptisine is a potential Hypoglycemic leading compound
8-Alkyl coptisine could effectively decrease the blood glucose of the mouse t rel. It could aslo improve the glucose tolerance, body weight and food intake of diabetes rats. Moreover, 8-Alkyl coptisinein had ability to regulate the level of SOD, MDA and GSH-Ps in the secrum.
5. Preliminary study on toxicity of 8-alkyl coptisine homologues in vivo
With kuming mouse o rats as animal model, the LD50 was determined to evaluate the toxicity of8-alkylcoptisine according to Karber, The route of administration is aintraperitoneal injection..inject 4ml drug one mouse every day according to different concentrations and groups, Result showed that the toxicity of 8-alkyl coptisine derivatives was stronger than that of coptisine. However, by elongating the aliphatic chain, toxicity decreased gradually.
引文
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[1]吴立军.天然药物化学[M].北京：人民卫生出版社,2004,365-366.
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[1]Ye XL, Li XG, Yuan LJ, He HM Effect of the surface activityon the antibacterial activity of octadecanoyl acetal sodium sulfiteseries. Colloids Surf A Physicochem Eng Aspects 2005,268:85-89
[2]Yang Y, Ye XL, Li XG, Zhen J, Zhang BS, Yuan LJ Synthesis and antimicrobial activity of 8-alkylberine derivatives with a long aliphatic chain. Planta Medica 2007,73:602-604
[3]Wang LJ, Ye X. L, Chen Z, Li XG, Sun QL, Zhang BS, Cao XG, Yu G (2009) Synthesis and antimicrobial activity of 3-octyloxy-8-alkyljatrorrhizine, derivatives. Journal of Asian Natural Products Research.2009,11:365-370
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[2]Kong WJ,Zhao YL, Xiao XH,Li ZL. Investigation of the anti-fungal activity of coptisine onCandida albicans growth by microcalorimetry combinedwith principal component analysis.Journal of Applied Microbiology2009,107:1072-1080
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[1]吴立军.天然药物化学[M].北京：人民卫生出版社,2004,365-366.
[2]应懿,何志红,周世文,汤建林,杨雪,王璐,测定黄连中5种生物碱含量的高效液相色谱法[J].第三军医大学学报,2007,5：843
[3]游元元,王天志,陈 璐,吴维碧 草连生物碱成分的研究[J]华西药学杂志2005,20(6)：505·506
[4]杨异卉黄连化学成分的分离与鉴定[J]黑农江中医药2009,22,(4)56
[5]李峰黄连的化学成分及质量标准研究[C].四川大学硕士论文2004,17
[6]杨义芳,孔德云中药提取分离手册[M]化学工业出版社,北京2008,5,189
[7]薛杨,吴唯,聚酰胺树脂的层析分离应用[J].化工新型材料,2005,4,50
[8]冯艳明,徐康明,从生产盐酸黄连素的母液中提取分离盐酸药根碱[J].中国中药杂志,1989,14(1)：
[9]李峰,黄连的化学成分及质量标准研究[C].四川大学硕士论文2004,17
[10]陶剑虹,张晓琦,叶文才,等.苏元胡的生物碱成分研究[J].中药材,2005,28(7)：556-557
[11]马兆堂,杨秀伟,钟国跃黄连解读汤中1个新的黄酮苷[J].中国中药杂志,2009,5(34) 156
[1]Ye XL, Li XG, Yuan LJ, He HM Effect of the surface activityon the antibacterial activity of octadecanoyl acetal sodium sulfiteseries. Colloids Surf A Physicochem Eng Aspects 2005,268:85-89
[2]Yang Y, Ye XL, Li XG, Zhen J, Zhang BS, Yuan LJ Synthesis and antimicrobial activity of 8-alkylberine derivatives with a long aliphatic chain. Planta Medica 2007,73:602-604
[3]Wang LJ, Ye X. L, Chen Z, Li XG, Sun QL, Zhang BS, Cao XG, Yu G (2009) Synthesis and antimicrobial activity of 3-octyloxy-8-alkyljatrorrhizine, derivatives. Journal of Asian Natural Products Research.2009,11:365-370
[4]Iwasa K., Nishiyama Y, Ichimaru M, Moriyasu M, Kim HS, and WatayaY etal. structure-activity relationships of Quaternary Protoberberinealkaloids having an antimalarial activity Eur. J. Med. Chem.1999.34:1077.
[5]杨勇,叶小利,郑静,张保顺,等.8-烷基小檗碱的合成[J].有机化学,2007,11,1438.
[6]Park K S, Kang K C, Kim K Y, et al. HWY-289, a novel semi-synthetic protoberberine derivative with multiple target sites in Candida albicans[J]. J. Antimicrob. Chemother.,2001,47(5):513～519.
[1]杨勇叶小利李学刚4种黄连生物碱的抑菌作用时珍国医国药[J].2007,12,3013-3014
[2]Kong WJ,Zhao YL, Xiao XH,Li ZL. Investigation of the anti-fungal activity of coptisine onCandida albicans growth by microcalorimetry combinedwith principal component analysis.Journal of Applied Microbiology2009,107:1072-1080
[3]Iwasa K, Lee DU, Kang SI, et al. Antimicrobial activity of 8-alkyl-and 8-phenyl-substituted berberines and their 12-bromo derivatives [J]. J Nat Prod,1998,61(9):1150-1153.
[4]Iwasa K, Kamigauchi M, Sugiura M, and Nanba H.Antimicrobial activity of some 13-alkyl substituted protoberberinium salts.Planta Medica.1997.63:196
[5]Iwasa K,Lee DU,Kang SI, and Wiegrebe W. (.Antimicrobial activity of 8-alkyl- and 8-phenyl-substituted berberines and their 12-bromo derivatives .J.Nat. Prod.1998 61:1150
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