CN101148437A - 碳碳方式连接的双青藤碱衍生物、制备方法及其应用 - Google Patents
碳碳方式连接的双青藤碱衍生物、制备方法及其应用 Download PDFInfo
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Abstract
本发明公开了一种碳碳方式连接的青藤碱衍生物,制备方法及其抗炎抗肿瘤作用。本发明青藤碱衍生物是以青藤碱为母体,通过生物转化技术和/或化学合成方法在1位通过碳碳连接方式生成双青藤碱衍生物,本发明青藤碱衍生物在抗炎、抗肿瘤等药效实验中具有较好的生物活性,具有潜在的药物应用前景。
Description
一、技术领域
本发明涉及一种化合物及其制备方法,具体地说是一种碳碳方式连接的双青藤碱衍生物及应用微生物转化和(或)化学合成制备该青藤碱衍生物的方法。本发明还提供的化合物在抗炎抗肿瘤领域具有潜在的药物应用前景。
二、背景技术
青藤碱(sinomenine)是从防己科植物青风藤及毛青藤的根茎中提取的临床上被应用于治疗风湿和类风湿关节炎,关节肿胀等疾病的最有效的生物碱类药物,具有显著的抗炎、镇痛、降压及抗脑缺血等药理作用。
通过对青藤碱的结构进行改造,寻找结构新颖的、活性更高效的青藤碱衍生物是目前的研究热点,而对青藤碱C环的结构改造更是研究重点。姚祝军(CN.1687070A,CN.1687065A)合成出C环连接有吡嗪环和五元杂环的青藤碱衍生物。叶仙蓉等(药学学报,2004,39(3),180-183)对青藤碱C环进行了修饰得到了系列化合物,并采用小鼠醋酸扭体法进行动物活性试验,发现化合物7-甲氧基-二氢青藤碱镇痛活性优于青藤碱。CN.1800164A同样对青藤碱C环结构进行修饰并得到一系列衍生物,该衍生物具有较强的抗炎镇痛活性,可用于制备治疗风湿性关节炎及心率失常方面的药物。
青藤碱结构改造同样发生在D环,中国专利CN.1785976A、CN.1785977A和CN1962638A分别报道了一类N-烃基青藤碱及其制备方法,一类17-磺酰基青藤碱及其制备方法以及一类具有右旋C环缺失吗啡喃骨架的青藤碱化合物及制法。
最新的研究出现在对青藤碱A环1-位碳的修饰,CN.1948291A合成了一类1-取代胺甲基青藤碱衍生物,专利CN.187634A在A环1位分别引入醛基及羟乙基。
纵观上述文献,对青藤碱中A环进行结构改造的研究较少,而利用微生物转化的方法对青藤碱进行结构改造的报道至今没有报道。
三、发明内容
本发明的第一个目的在于公开一类碳碳键连接的双青藤碱衍生物;本发明的第二个目的在于公开此类衍生物的制备方法;本发明的第三个目的在于公开此类化合物在抗炎和抗肿瘤方面的药物用途。
本发明目的是通过以下技术方案实现的:
本发明中青藤碱衍生物为一类A环以C-C键连接的双青藤碱衍生物,并具有立体选择性。结构式如下:
式中:R4=H,OH(α和β);
(I)当R2,R3=
R1=乙基,丙基,丁基,异丙基,烯丙基等直链烃基;或是环戊基,环己基,环庚基等环状烃基;或是β-氟乙基,环丙基甲基,环丁基甲基,苯甲基,吡啶甲基,呋喃甲基,β-苯基乙基,α-甲基苄基,烷氧基甲基,吡唑甲基等取代基。或者是R1=R5S(OO)-其中R5=甲基,乙基,丙基,三氟甲基的烃基及取代烃基,苯基及取代基;
(II)当R2,R3=
R1=CH3,H,R5为羰基或者羟基;
(III)当R2,R3=
R1=CH3,
R5,R6=R7,R8,R9,R10=H,C1-14的饱和及不饱和烷烃基,F,Cl,Br,I,-OH,-NH2,-OCH3,-OC2H5,-NO2,-CN,-CF3,COOCH3,COPh,COOH,Ph为苯基;
(IV)当R2,R3=
R1=CH3,R6,R7=C1-14的烷烃及不饱和烷烃基,R5=H,O,S,C1-10的烷基,带有1-3个取代基或者不带取代基的五元或者六元的芳环,含氮杂环,含氧杂环和含硫杂环,所述的取代基是C1-10的烃基,卤素,C1-14的烷基或含氟烷基,硝基,腈基,甲氧基或烃基,代表双键或者单键;
(V)当R2,R3=
R3=H,CH3,酰胺,磺酰胺,杂环等;R5=C1-20的饱和或不饱和烃基)
(VI)当R2,R3=
R3=H,CH3,酰胺,磺酰胺,杂环等;R5=O,-OH,-NH2,NHCONH2,NHCOPh,C1-20芳烃或者脂肪烃基,R6=C1-20的饱和或不饱和烃基;
(VII)当R2,R3=
R3=H,CH3,酰胺,磺酰胺,杂环等;R5=C1-20的饱和或不饱和烃基;
上述碳碳方式连接双青藤碱衍生物制备方法,其制备步骤如下:
1)菌株分离:野外采样,稀释涂布分离,选择性筛选,菌种斜面0℃保藏。
2)生物转化产物的制备:活化7天的斜面菌种,转接到发酵培养基中,在25℃,150r/min的摇床上培养4天,加入青藤碱盐酸盐,终浓度≤400μg/ml,同样条件下继续培养1天后加入第二种底物,终浓度≤400μg/ml,相同条件下继续培养4天,停止培养;将发酵液过滤,滤液用NH4OH调节pH值8~9,用二氯甲烷多次萃取,合并二氯甲烷萃取液,无水NaSO4干燥,过滤,旋转蒸干溶剂,得转化产物;
3)生物转化产物的分离:采用填充的层析柱为硅胶柱,层析液为100∶0~50∶50V/V氯仿-甲醇混合液。
上述步骤1)中的生物转化菌株包括:霉菌菌株Antrodiella semisupina及其同属菌株、单色云芝Coriolus unicolor及其同属菌株、过氧化物酶Peroxidase或漆酶Laccase。
本发明还提供了碳碳方式连接双青藤碱衍生物的化学制备方法,其特征在于在反应瓶中加入青藤碱,溶于甲醇中,加入过量二氧化锰,室温搅拌反应,离心分离,取上清液减压浓缩,得棕色油状物,经硅胶柱色谱以氯仿-甲醇15∶1V/V分离得到产物;
或者:在反应瓶中加入青藤碱盐酸盐,溶于水中,加入过量高锰酸钾溶液,室温搅拌,TLC检测反应进程,反应终止时,加入氨水调节pH值为8.0-9.0,用二氯甲烷萃取,有机相用无水硫酸钠干燥,减压干燥,得黄色油状物。经硅胶柱色谱以氯仿-甲醇15∶1V/V分离得产物。
本发明还要求保护碳碳方式连接双青藤碱衍生物在制备治疗炎症药物的应用,以及在制备抗肿瘤药物的应用。
本发明所述的有机溶剂包括但不限于甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、正戊醇、异戊醇、环己醇、卞醇、二氯甲烷、氯仿、1,2-二氯乙烷、四氯化碳、乙醚、四氢呋喃、苯、甲苯、二甲苯、丙酮、丁酮、乙氰、N,N-二甲基甲酰胺、乙酸乙酯等。
四、说明书附图
图1是毛细管微反应器。
五、具体实施方式
下述实验和实施例用于进一步说明但不限于本发明。
实施例1:
碳碳连接双青藤碱的立体选择性生物合成,其合成路线是:
菌株Antrodiella semisupina在斜面培养基上,于25℃培养7天后,接种到灭过菌的2L转化培养基内,摇床上培养4天(25℃,150r/min),通过0.1μm微孔滤膜加入青藤碱盐酸盐,添加浓度为250μg/ml,同样条件下继续培养4天。转化液经过过滤,菌丝用少量pH 6.0的蒸馏水淋洗,合并后共得滤液2100ml,用氨水调节pH值8~9,并用二氯甲烷多次萃取,合并二氯甲烷萃取液,无水硫酸钠干燥,过滤,旋转蒸干溶剂,得固体粉末450mg。转化产物经硅胶柱(300-400目)分离,淋洗液为氯仿∶甲醇=2∶1,得双青藤碱100mg,产率20%。双青藤碱A(1):熔点220-222℃,[α]25 D=+12.9°(c=0.45,CH3OH).UV(λmax,CH3OH):252nm(ε,16626).EI-MS m/z:656[25.1%,M+],641[100.0%,],598[17.4%],192[12.1%]。
氢谱(溶剂为Chloroform-d):6.00(1H,s,2-H),3.75(3H,s,3-OCH3),2.49(1H,d,J=15.6Hz,5-H),4.41(1H,d,J=15.6Hz,5-H),3.51(3H,s,7-OCH3),5.43(1H,d,J=2.4Hz,8-H),3.08(brt,J=4.0Hz,9-H),2.42(1H,dd,J=18.6,5.3Hz,10-H),2.32(1H,brd,J=18.6Hz,10-H),2.99(1H,brs,14-H),2.02(1H,dt,J=12.2,3.4Hz,15-H),1.91(1H,td,J=12.2,3.4Hz,15-H),2.57(1H,ddd,J=12.0,4.3,2.1Hz,16-H),2.16(td,J=12.0,3.4Hz,16-H),2.35(3H,s,17-N-CH3)。另外的一半从1′到17′与1到17相同。
碳谱(溶剂为Chloroform-d):130.7(C-1),110.7(C-2),144.8(C-3),56.0(C-3-OCH3),143.8(C-4),49.3(C-5),193.8(C-6),152.5(C-7),54.8(C-7-OCH3),115.0(C-8),56.4(C-9),23.9(C-10),127.8(C-11),123.3(C-12),40.9(C-13),45.8(C-14),35.9(C-15),47.2(C-16),43.0(C-17-NCH3)。另外的一半从1′到17′与1到17相同。
实施例2:
碳碳连接双去氮甲基青藤碱的立体选择性生物合成,其合成路线是:
其方法同实施例1,但是底物为N-去甲青藤碱,得到去氮甲基双青藤碱100mg,产率20%。
去甲双青藤碱A(3):正离子ESI-MS m/z 609[M+H]+。
氢谱(溶剂为Chloroform-d):6.30(1H,s,2-H),3.75(3H,s,3-OCH3),2.51(1H,d,J=15.6Hz,5-H),4.37(1H,d,J=15.6Hz,5-H),3.49(3H,s,7-OCH3),5.38(1H,d,J=2.4Hz,8-H),3.36(brt,J=4.0Hz,9-H),2.75(1H,dd,J=18.4,5.6Hz,10-H),2.19(1H,brd,J=18.4Hz,10-H),2.90(1H,brs,14-H),2.02(1H,brd,J=12.2Hz,15-H),1.72(1H,td,J=13.0,3.9Hz,15-H),2.85(1H,dd,J=13.0,3.9Hz,16-H),2.60(1H,td,J=13.0,3.9Hz,16-H)。另外的一半从1′到17′与1到17相同。
碳谱(溶剂为Chloroform-d):131.0(C-1),110.4(C-2),145.1(C-3),56.0(C-3-OCH3),143.8(C-4),49.7(C-5),193.8(C-6),152.3(C-7),54.8(C-7-OCH3),114.5(C-8),49.4(C-9),32.4(C-10),127.6(C-11),122.9(C-12),41.6(C-13),46.3(C-14),36.3(C-15),39.4(C-16)。另外的一半从1′到17′与1到17相同。
双青藤碱A(1)数据见实施例1。
实施例3:
碳碳连接双青藤碱的化学合成,其合成路线是:
方法A:于反应瓶中加入青藤碱200mg(0.61mmol),溶于20ml甲醇中,加入二氧化锰1g(11.5mmol),室温搅拌反应48h。离心分离,取上清液减压浓缩,得棕色油状物。经硅胶柱色谱(氯仿-甲醇15∶1V/V)分离得白色化合物1(约60%)和6(约40%)。
方法B:于反应瓶中加入青藤碱盐酸盐200mg(0.61mmol),溶于20ml水中,加入50mM高锰酸钾溶液10ml,室温搅拌,TLC检测反应进程。反应终止时,加入氨水调节pH值为8.0-9.0,用100ml二氯甲烷萃取,有机相用无水硫酸钠干燥,减压干燥,得黄色油状物。经硅胶柱色谱(氯仿-甲醇15∶1V/V)分离得白色化合物1(约60%)和6(约40%)。
方法C:分别配制0.1-10mg/mL的青藤碱盐酸盐和高锰酸钾溶液溶液,按图1(毛细管微反应器)所示,利用毛细管微反应器,反应流出液加入氨水调节pH值为8.0-9.0,用二氯甲烷萃取,有机相用无水硫酸钠干燥,减压干燥,得黄色油状物。经硅胶柱色谱以氯仿-甲醇15∶1 V/V分离得产物。利用微反应器可以提高反应的产率。
上述化学反应在pH值为5.5-7.0之间可以提高活性化合物1的收率(1约92%和6约8%)。
双青藤碱B(6):EI-MS m/z:656[25.1%,M+]。
氢谱(溶剂为Chloroform-d):6.45(1H,s,2-H),3.81(3H,s,3-OCH3),2.51(1H,d,J=15.7Hz,5-H),4.43(1H,d,J=15.7Hz,5-H),3.51(3H,s,7-OCH3),5.27(1H,d,J=1.3Hz,8-H),3.03-3.15(overlapped,9-H),1.83(1H,dd,J=18.7,5.1Hz,10-H),2.53(1H,brd,J=18.7Hz,10-H),3.03-3.15(overlapped,14-H),2.03(1H,m,15-H),1.97(1H,td,J=12.7,4.0Hz,15-H),2.66(1H,brd,J=11.2Hz,16-H),2.13(td,J=11.2,2.6Hz,16-H),2.36(3H,s,17-NCH3)。另外的一半从1′到17′与1到17相同。
碳谱(溶剂为Chloroform-d):130.8(C-1),109.5(C-2),145.2(C-3),56.1(C-3-OCH3),144.0(C-4),48.9(C-5),193.6(C-6),152.5(C-7),54.5(C-7-OCH3),114.0(C-8),56.5(C-9),22.6(C-10),127.5(C-11),122.9(C-12),40.4(C-13),45.0(C-14),35.3(C-15),47.4(C-16),42.8(C-17-NCH3)。另外的一半从1′到17′与1到17相同。
青藤碱衍生物的抗炎作用(见附表1):
附表1青藤碱衍生物的抗炎作用
化合物 | 细胞液中Hu IL-6检测水(pg/ml) |
空白 | 107.8 |
Sinomenine | 98.7 |
1 | 80.9 |
3 | 71.6 |
6 | 115.8 |
取滑膜细胞SW982于24孔盘培养,培养密度5×104/孔,24h后用CGM(其中以0.2%BSA替换FBS)置换培养液,再24h后,加测试药物(终浓度为10-5mol/L),24h后,以10ng/ml 1L-1β的L-15(含0.2%的BSA和10-5mol/L的测试药物)置换培养液,继续培养48h后取培养液用Human IL-6试剂盒检测。结果见表1,表明生物转化产物具有较强的细胞炎症因子抑制作用。
青藤碱衍生物的抗肿瘤作用(见附表2):
附表2青藤碱衍生物的抗肿瘤作用
化合物 | 对肺肿瘤细胞BGC的抑制率(%) | 对肝肿瘤细胞7721的抑制率(%) |
空白 | 0 | 0 |
Sinomenine | 0.5 | 3.5 |
1 | 12.7 | 7.6 |
3 | 4.0 | 3.2 |
6 | 11.3 | 10.3 |
取肺肿瘤细胞BGC和肝肿瘤细胞7721于96孔培养盘(培养液含10%胎小牛血清),培养密度1×104/孔,加入测试药物(终浓度为10-5mol/L),培养48h后,每孔加10μl MTT的PBS溶液(5mg/ml),继续孵育4小时,终止培养,小心吸弃孔内培养上清液。每孔加150ul DMSO,振荡10分钟,结晶物充分融解。选择570nm波长,在酶联免疫监测仪上测定各孔光吸收值,记录结果,计算肿瘤抑制率。如表2,表明化合物1、2、6和9相比青藤碱而言,对肿瘤细胞有较强的抑制作用。
Claims (6)
1.一种碳碳方式连接的双青藤碱衍生物,通式为:
式中:
R4=H或OH(α和β);
R2,R3=
R1=乙基,丙基,丁基,异丙基,烯丙基等直链烃基;或是环戊基,环己基,环庚基等环状烃基;或是β-氟乙基,环丙基甲基,环丁基甲基,苯甲基,吡啶甲基,呋喃甲基,β-苯基乙基,α-甲基苄基,烷氧基甲基,吡唑甲基等取代基。或者是R1=R5S(OO)-其中R5=甲基,乙基,丙基,三氟甲基的烃基及取代烃基,苯基及取代基;
或:R2,R3=
R1=CH3,H,R5为羰基或者羟基;
或:R2,R3=
R5,R6=
R7,R8,R9,R10=H,C1-14的饱和及不饱和烷烃基,F,Cl,Br,I,-OH,-NH2,-OCH3,-OC2H5,-NO2,-CN,-CF3,COOCH3,COPh,COOH,Ph为苯基;
或:R2,R3=
R1=CH3,R6,R7=C1-14的烷烃及不饱和烷烃基,R5=H,O,S,C1-10的烷基,带有1-3个取代基或者不带取代基的五元或者六元的芳环,含氮杂环,含氧杂环和含硫杂环,所述的取代基是C1-10的烃基,卤素,C1-14的烷基或含氟烷基,硝基,腈基,甲氧基或烃基,代表双键或者单键;
或:R2,R3=
R3=H,CH3,酰胺,磺酰胺,杂环等;R5=C1-20的饱和或不饱和烃基)或:R2,R3=
R3=H,CH3,酰胺,磺酰胺,杂环等;R5=O,-OH,-NH2,NHCONH2,NHCOPh,C1-20芳烃或者脂肪烃基,R6=C1-20的饱和或不饱和烃基;
或:R2,R3=
R3=H,CH3,酰胺,磺酰胺,杂环;R5=C1-20的饱和或不饱和烃基。
2.权利要求1所述碳碳方式连接双青藤碱衍生物的生物制备方法,其特征在于制备步骤如下:
1)菌株分离:野外采样,稀释涂布分离,选择性筛选,菌种斜面0℃保藏。
2)生物转化产物的制备:活化7天的斜面菌种,转接到发酵培养基中,在25℃,150r/min的摇床上培养4天,加入青藤碱盐酸盐,终浓度≤400μg/ml,同样条件下继续培养1天后加入第二种底物,终浓度≤400μg/ml,相同条件下继续培养4天,停止培养;将发酵液过滤,滤液用NH4OH调节pH值8~9,用二氯甲烷多次萃取,合并二氯甲烷萃取液,无水NaSO4干燥,过滤,旋转蒸干溶剂,得转化产物;
3)生物转化产物的分离:采用填充的层析柱为硅胶柱,层析液为100∶0~50∶50V/V氯仿-甲醇混合液,。
3.根据权利要求2所述的碳碳方式连接双青藤碱衍生物的生物制备方法,其特征在于步骤1)中的生物转化菌株包括:霉菌菌株Antrodiella semisupina及其同属菌株、单色云芝Coriolus unicolor及其同属菌株、过氧化物酶Peroxidase或漆酶Laccase。
4.权利要求1所述碳碳方式连接双青藤碱衍生物的化学制备方法,其特征在于在反应瓶中加入青藤碱,溶于甲醇中,加入过量二氧化锰,室温搅拌反应,离心分离,取上清液减压浓缩,得棕色油状物,经硅胶柱色谱以氯仿-甲醇15∶1V/V分离得到产物;
或者:在反应瓶中加入青藤碱盐酸盐,溶于水中,加入过量高锰酸钾溶液,室温搅拌,TLC检测反应进程,反应终止时,加入氨水调节pH值为8.0-9.0,用二氯甲烷萃取,有机相用无水硫酸钠干燥,减压干燥,得黄色油状物。经硅胶柱色谱以氯仿-甲醇15∶1V/V分离得产物。
或者:分别配制0.1-10mg/mL的青藤碱盐酸盐和高锰酸钾溶液溶液,通过毛细管微反应器,反应流出液加入氨水调节pH值为8.0-9.0,用二氯甲烷萃取,有机相用无水硫酸钠干燥,减压干燥,得黄色油状物。经硅胶柱色谱以氯仿-甲醇15∶1V/V分离得产物。利用微反应器可以提高反应的产率。
上述化学反应在pH值为5.5-7.0之间可以提高活性化合物1的收率。
5.权利要求1所述碳碳方式连接双青藤碱类衍生物在制备治疗炎症药物中的应用。
6.权利要求1所述碳碳方式连接双青藤碱类衍生物在制备抗肿瘤药物中的应用。
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WO2011098035A1 (zh) | 2010-02-10 | 2011-08-18 | 中国科学院上海有机化学研究所 | 一种青藤碱衍生物、合成方法及其用途 |
CN106539797A (zh) * | 2016-10-14 | 2017-03-29 | 上海交通大学医学院 | 青藤碱衍生物在制备治疗多发性骨髓瘤药物中的应用 |
CN112274514A (zh) * | 2019-07-24 | 2021-01-29 | 中国医学科学院药物研究所 | 青藤碱类化合物在制备预防或治疗神经胶质瘤药物中的应用 |
CN114387856A (zh) * | 2020-10-05 | 2022-04-22 | 蒙家英 | 一种微量药物化学实验化验一体化的教学方法 |
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CN1298718C (zh) * | 2005-03-18 | 2007-02-07 | 中国科学院上海有机化学研究所 | C环连接有吡嗪环的青藤碱衍生物、合成方法及其用途 |
CN1298720C (zh) * | 2005-03-18 | 2007-02-07 | 中国科学院上海有机化学研究所 | C环连接有五元杂环的青藤碱衍生物和合成方法 |
CN1785976A (zh) * | 2005-12-15 | 2006-06-14 | 南京大学 | 一类n-烃基青藤碱及其制备方法 |
CN1785977A (zh) * | 2005-12-15 | 2006-06-14 | 南京大学 | 一类17-磺酰基青藤碱及其制备方法 |
CN100480241C (zh) * | 2006-01-09 | 2009-04-22 | 四川大学 | 青藤碱c环结构修饰的衍生物及合成方法 |
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Cited By (6)
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WO2011098035A1 (zh) | 2010-02-10 | 2011-08-18 | 中国科学院上海有机化学研究所 | 一种青藤碱衍生物、合成方法及其用途 |
CN106539797A (zh) * | 2016-10-14 | 2017-03-29 | 上海交通大学医学院 | 青藤碱衍生物在制备治疗多发性骨髓瘤药物中的应用 |
CN106539797B (zh) * | 2016-10-14 | 2019-05-21 | 上海交通大学医学院 | 青藤碱衍生物在制备治疗多发性骨髓瘤药物中的应用 |
CN112274514A (zh) * | 2019-07-24 | 2021-01-29 | 中国医学科学院药物研究所 | 青藤碱类化合物在制备预防或治疗神经胶质瘤药物中的应用 |
CN112274514B (zh) * | 2019-07-24 | 2023-01-06 | 中国医学科学院药物研究所 | 青藤碱类化合物在制备预防或治疗神经胶质瘤药物中的应用 |
CN114387856A (zh) * | 2020-10-05 | 2022-04-22 | 蒙家英 | 一种微量药物化学实验化验一体化的教学方法 |
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