CN101265266A - 青藤碱衍生物及其制备方法和应用 - Google Patents
青藤碱衍生物及其制备方法和应用 Download PDFInfo
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- CN101265266A CN101265266A CNA2008100240512A CN200810024051A CN101265266A CN 101265266 A CN101265266 A CN 101265266A CN A2008100240512 A CNA2008100240512 A CN A2008100240512A CN 200810024051 A CN200810024051 A CN 200810024051A CN 101265266 A CN101265266 A CN 101265266A
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Abstract
本发明针对青藤碱分子结构对酸碱热不稳定的性质,提出创新性的结构改造思路,通过化学合成制备了新的青藤碱A环、C环和D环青藤碱衍生物,包括青藤碱1位氨基化及其酰基化,1位C-C或者C-O方式连接,3,4位双羰基化及六元氮杂环化,4位羟基和1位氨基连接的两分子青藤碱加合,6位氨基化及其酰基化,6,7位同时氨基化及六元N杂环化,D环开环及其末端氨基修饰,方法新颖,具有独特性;采用滑膜肿瘤细胞(SW982)评价其抗炎活性,生物活性良好,可应用于抗类风湿性关节炎(RA)药物和保健品中。
Description
技术领域
本发明属于高分子化合物技术领域,涉及青藤碱的衍生物,具体为青藤碱衍生物及其制备方法和应用。
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,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,对青藤碱的结构改造主要集中在C、D环,新的青藤碱衍生物还有待研究发现。
发明内容
本发明要解决的问题是:通过对青藤碱的结构进行改造,得到结构新颖的、抗炎活性更高效的青藤碱衍生物。
本发明的技术方案是:青藤碱衍生物,青藤碱结构式如下:
在青藤碱A环、C环和D环通过化学合成后得到青藤碱衍生物,包括:
1)通过硝化还原在1位得到氨基连接取代基的青藤碱衍生物S1-S5:
2)或通过4位羟基或1位氨基形成的两分子青藤碱加合物S6-S8:
3)或在3,4位连接有吡嗪环的青藤碱衍生物S9-S14:
4)或在6位通过氨基/羟基连接取代基的青藤碱衍生物S15-S22:
R1=H,R2=SO2R3其中R3=CH3;Ph;2-OH-3,5-Cl2C6H2;2,4-Cl2-5-COOHC6H2等。
或者
R1=H,R2=COR3其中R3=Ph;4-Cl-C6H4;3,4-Cl2-C6H3;4-CH3-C6H4;4-OCH3-C6H4等。
或者
R1=H,R2=-COC(R3)NHR4其中R3=CH3,PhCH2,(CH3)2CHCH2;CH3SCH2CH2等,R4=H;SO2Ph;CONHC6H5等。
5)或在6,7位通过氨基形成吡嗪环的双青藤碱分子衍生物S23-S24:
6)或对青藤碱D环开环后末端氨基进行改造的衍生物S25-S26:
R1=H或CH3,R2=SO2R3其中R3=CH3;Ph;2-OH-3,5-Cl2C6H2;2,4-Cl2-5-COOHC6H2等。
或者
R1=H或CH3,R2=COR3其中R3=Ph;4-Cl-C6H4;3,4-Cl2-C6H3;4-CH3-C6H4;4-OCH3-C6H4等。或者
R1=H或CH3,R2=-COC(R3)NHR4其中R3=CH3,PhCH2,(CH3)2CHCH2;CH3SCH2CH2等,R4=H;SO2Ph;CONHC6H5等。
7)或在青藤碱A环1位以C-C或者C-O方式连接形成的青藤碱衍生物S32-S34:
R1=Cl,Br,OMe,CO2Me,CHO,CH2CO2CH4,CH2CN,NHCOCF3,CH3,COPh,NH2,CN,CF3,CH(OH)COOH等;
R2=R3=OH,NH2,NO2,或者R2=OH,R3=OCH3,NO2,Cl,Br,CH3等,R4=R5=H;
R3=R5=NO2,R2=R4=H。
本发明青藤碱衍生物的制备方法如下:
通过1位氨基化及其酰基化制备青藤碱衍生物S1-S5,化学式:
R1=H,R2=SO2R3其中R3=CH3;Ph;2-OH-3,5-Cl2C6H2;2,4-Cl2-5-COOHC6H2等。
或者
R1=H,R2=COR3其中R3=Ph;4-Cl-C6H4;3,4-Cl2-C6H3;4-CH3-C6H4;4-OCH3-C6H4等。
或者
R1=H,R2=-COC(R3)NHR4其中R3=CH3,PhCH2,(CH3)2CHCH2;CH3SCH2CH2等,R4=H;SO2Ph;CONHC6H5等。
通过4位羟基或1位氨基连接两分子青藤碱加合制备青藤碱衍生物S6-S8,化学式:
通过3,4位双羰基化及六元氮杂环化制备青藤碱衍生物S9-S14,化学式:
R3,R4,R5,R6=H,C1-14的饱和及不饱和烷基,F,Cl,Br,I,OH,NH2,OCH3,OC2H5,NO2,CN,CF3,COOCH3,COPh,COOH,Ph为苯基。
通过6位氨基化及其酰基化制备青藤碱衍生物S15-S22,通过6,7位同时氨基化及六元氮杂环化制备青藤碱衍生物S23-S24,化学式:
R1=H,R2=SO2R3其中R3=CH3;Ph;2-OH-3,5-Cl2C6H2;2,4-Cl2-5-COOHC6H2等。
或者
R1=H,R2=COR3其中R3=Ph;4-Cl-C6H4;3,4-Cl2-C6H3;4-CH3-C6H4;4-OCH3-C6H4等。
或者
R1=H,R2=-COC(R3)NHR4其中R3=CH3,PhCH2,(CH3)2CHCH2;CH3SCH2CH2等,R4=H;SO2Ph;CONHC6H5等。
制备青藤碱衍生物S25-S26的化学式如下,S27-S31为中间化合产物:
R1=H或CH3,R2=SO2R3其中R3=CH3;Ph;2-OH-3,5-Cl2C6H2;2,4-Cl2-5-COOHC6H2等。
或者
R1=H或CH3,R2=COR3其中R3=Ph;4-Cl-C6H4;3,4-Cl2-C6H3;4-CH3-C6H4;4-OCH3-C6H4等。
或者
R1=H或CH3,R2=-COC(R3)NHR4其中R3=CH3,PhCH2,(CH3)2CHCH2;CH3SCH2CH2等,R4=H;SO2Ph;CONHC6H5等。
制备青藤碱衍生物S32-S34的方法包括:(1):微生物/酶催化多底物交叉偶联,(2):Suzuki芳基交叉偶联;
通过微生物/酶催化多底物交叉偶联制备,其制备步骤如下:
1)菌株分离:野外采取特定生境,稀释涂布分离,选择性筛选,菌种斜面0℃保藏;转化粗酶来自上述菌株,粗酶的分离采用蛋白质盐析分离方法,其余使用的酶购自Sigma;
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;
通过Suzuki芳基交叉偶联反应制备,其制备步骤如下:
将1-溴代青藤碱(0.5mmol)、芳基硼酸(0.7mmol)、Pd(OAc)2(3mol%)、DABCO(6mol%)和K2CO3(1.5mmol)组成的混合物,悬浮于3ml的DMF中,80℃下搅拌反应,TLC检测反应完毕后,过滤,萃取,干燥,柱分离得产物。
通过微生物/酶催化多底物交叉偶联的制备步骤1)中的生物转化菌株或者酶包括: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、脂肪酶、漆酶、水解酶、纤维素酶、淀粉酶、蛋白酶。
本发明针对青藤碱分子结构对酸碱热不稳定的性质,提出创新性的结构改造思路,通过化学合成制备了新的青藤碱A环、C环和D环青藤碱衍生物,方法新颖,具有独特性;采用滑膜肿瘤细胞(SW982)评价其抗炎活性,生物活性良好,可应用于抗类风湿性关节炎(RA)药物和保健品中。
附图说明
图1为本发明青藤碱衍生物采用滑膜肿瘤细胞(SW982)评价其抗炎活性的测试结果图。
具体实施方式
下面结合具体实施例来说明本发明。
实施例1
1,10位氮硫六元杂环的合成
如上述化学式,称取化合物1:1-氨基青藤碱550mg(1.6mmol),加入4.0ml KSCN(632mg,2.4mmol)的冰醋酸溶液中,搅拌溶解后缓慢滴加Br2(96mg,0.6mmol)的冰醋酸溶液1.5ml。室温搅拌24h,冰浴下滴加10%NaOH进行淬灭,调节pH值至8.0,用CHCl3萃取,得到的有机层用饱和食盐水水洗,再由无水NaSO4干燥,减压浓缩,硅胶柱分离(CH3Cl∶CH3OH=9∶1),得相应化合物2,产率59%。
化合物2:
1H NMR(300MHz,CDCl3)δppm 8.45(s,1H),7.35(s,1H),6.30(s,1H),5.85(s,1H,OH),5.50(s,1H),4.24(d,1H,J=15.9Hz),3.82(s,3H),3.29(m,4H),3.08(s,1H),2.56(m,1H),2.44(s,3H),2.40(s,1H),2.07-1.90(m,4H).
13C NMR(300MHz,CDCl3)δ192.50,178.92,151.72,146.90,141.90,128.05,120.68,114.55,111.58,95.68,59.90,56.18,54.99,49.09,46.64,45.48,44.69,42.77,40.90,35.80.
实施例2
1位氨基磺酰化反应
如上述化学式,称取化合物1:1-氨基青藤碱550mg(1.6mmol),溶于3ml CH2Cl2,滴加Et3N 0.34ml(2.5mmol),冰浴下加入对甲基苯磺酰氯381mg(2.0mmol),冰浴下搅拌5h。倒入30ml CH2Cl2中萃取,有机层用用饱和食盐水水洗,再用无水NaSO4干燥,减压浓缩,硅胶柱分离(CH3Cl∶CH3OH=9∶1),得相应化合物3,产率52%。
化合物3:
1H NMR(300MHz,CDCl3)δppm 7.58(d,2H,J=6.6Hz),7.25(d,2H,J=6.6Hz),6.39(s,1H),5.85(s,1H,OH),5.39(s,1H),4.30(d,1H,J=15.9Hz),3.85(s,1H),3.62(s,3H),3.47(s,3H),3.20(brd,1H),3.01(brd,1H),2.78(m,1H),2.59-2.44(brd,1H),2.40(s,3H),2.36(s,1H),2.19(brd,3H),2.03-1.82(m,4H).
13C NMR(300MHz,CDCl3)δ193.50,152.66,144.80,143.81,129.80,129.71,127.41,126.98,126.90,123.93,114.09,108.15,63.20,60.93,56.18,55.89,54.89,48.92,46.71,42.22,40.46,35.43.
实施例3
1位氨基酰化反应
如上述化学式,称取化合物1:1-氨基青藤碱550mg(1.6mmol),溶于3ml CH2Cl2,滴加Et3N 0.34ml(2.5mmol),冰浴下加入苯甲酰氯313mg(2.0mmol),冰浴下搅拌5h。倒入30ml CH2Cl2中萃取,有机层用饱和食盐水水洗,再用无水NaSO4干燥,减压浓缩,硅胶柱分离(CH3Cl∶CH3OH=9∶1),得相应化合物4,产率73%。
化合物4:
1H NMR(300MHz,CDCl3)δppm 7.95(d,2H,J=7.2Hz),7.54(d,1H,J=9.3Hz),7.53(dd,2H,J=7.2,9.3Hz),6.93(s,1H),5.49(s,1H),4.39(s,1H,J=15.9Hz),3.82(s,3H),3.61(brd,1H),3.51(s,3H),3.40(brd,1H),3.10-2.90(m,4H),2.65(s,3H),2.55-2.48(m,2H),2.21-2.05(m,2H).
13C NMR(300MHz,CDCl3)δ193.63,152.68,145.79,143.77,134.17,132.14,128.80,127.45,126.03,123.55,121.34,113.03,108.84,57.38,56.20,55.07,49.97,49.70,49.41,49.13,48.01,47.56,43.15,41.54,39.69,33.83.
实施例4
通过4-OH形成两分子青藤碱加合物
称取青藤碱(sinomenine)329mg(1mmol),溶于25ml CH2Cl2,滴加Et3N 1.1ml(8mmol),冰浴下加入戊二酰氯169mg(1mmol),冰浴下搅拌5h。倒入30ml CH2Cl2中萃取,有机层用饱和食盐水水洗,无水NaSO4干燥,减压浓缩,硅胶柱分离(CH3Cl∶CH3OH=15∶1),得相应化合物5,产率72%。
化合物5:
1H NMR(300MHz,CDCl3)δppm 6.91(d,1H,J=9Hz),6.76(d,1H,J=9Hz),5.44(s,1H),5.28(s,1H,OH),3.82(d,1H,J=15Hz),3.74(s,3H),3.46(s,3H),3.27(s,1H),3.10-3.01(m,2H),2.89-2.70(m,3H),2.6(d,1H,J=12Hz),2.54(s,1H),2.47(s,3H),2.18(td,1H,J=6,12Hz),2.24-2.13(m,1H),1.95(td,1H,J=6,12Hz),1.6(d,1H,J=12Hz).
13C NMR(300MHz,CDCl3)δ192.18,172.14,152.56,149.98,139.59,129.73,129.03,125.59,114.34,110.98,56.73,56.02,54.97,49.92,46.88,45.36,42.53,40.46,36.80,33.29,24.35,20.18.
实施例5
6位氨基磺酰化反应
如上述化学式,称取化合物6:6-氨基-7,8二氢青藤碱260mg(0.78mmol),溶于20ml CH2Cl2,滴加Et3N 0.16ml(1.17mmol),冰浴下加入对甲苯磺酰氯179mg(0.94mmol),冰浴下搅拌6h。倒入30ml CH2Cl2中萃取,有机层用饱和食盐水水洗,无水NaSO4干燥,减压浓缩,硅胶柱分离(CH3Cl∶CH3OH=9∶1),得相应化合物7,产率98%。
化合物7:
1H NMR(300MHz,CDCl3)δppm 7.62(d,2H,J=6.0Hz),7.23(d,2H,J=6.0Hz),6.71(d,1H,J=9.0Hz),6.60(d,1H,J=9.0Hz),4.11(d,1H,J=9.0Hz),3.86(brd,1H),3.84(s,3H),3.77(dd,1H,J=3.0,15.0Hz),3.27(s,1H),3.20(dd,1H,J=3.0,12.0Hz),2.92(s,3H),2.86(s,1H),2.77-2.67(m,1H),2.48-2.39(m,1H),2.36(s,3H),2.34(s,3H),1.97(dt,1H,J=6.0,12.0Hz),1.81(dt,1H,J=6.0,12.0Hz),1.59-1.47(m,2H),1.37(d,1H,J=12.0Hz),1.28(d,1H,J=12.0Hz).
13C NMR(300MHz,CDCl3)δ145.21,144.63,142.60,138.86,129.52,129.16,127.03,126.96,124.13,119.34,109.91,79.13,57.41,56.52,55.85,51.03,47.28,44.12,42.29,37.50,37.32,35.20,32.50,28.79,23.86,21.52.
实施例6
6位氨基酰化反应
如上述化学式,称取化合物6:6-氨基-7,8二氢青藤碱150mg(0.45mmol),溶于10ml CH2Cl2,滴加Et3N 0.1ml(0.68mmol),冰浴下加入苯甲酰氯62μL(0.54mmol),冰浴下搅拌6h。倒入30ml CH2Cl2中萃取,有机层用饱和食盐水水洗,无水NaSO4干燥,减压浓缩,硅胶柱分离(CH3Cl∶CH3OH=9∶1),得相应化合物8,产率90%。
化合物8:
1H NMR(300MHz,CDCl3)δppm 7.62-7.24(m,5H),6.76(d,1H,J=9.0Hz),6.67(d,1H,J=9.0Hz),5.92(d,1H,J=9.0Hz),4.94-4.90(m,1H),4.03(dd,1H,J=3.0,15.0Hz),3.59-3.53(m,1H),3.51(s,1H),3.38(s,1H),3.07-2.85(m,3H),2.58-2.53(m,1H),2.45(s,3H),2.10-1.95(m,3H),1.98(d,1H,J=12.0Hz),1.67-1.58(m,2H),1.43(dd,1H,J=15.0,3.0Hz),1.31(t,1H,J=6.0Hz).
13C NMR(300MHz,CDCl3)δ166.51,144.90,144.87,134.47,130.98,130.31,127.99(2C),126.89(2C),125.07,119.26,108.66,78.86,57.50,56.12,55.57,47.44,46.13,44.50,42.56,37.88,36.82,35.60,29.75,24.05.
实施例7
6位羟基还原
称取青藤碱(sinomenine)3.6g溶于30ml甲醇,冰浴下缓慢分批加入10g NaBH4,反应24h,冰浴下滴加丙酮终止反应,减压浓缩成固体,加入稀HCl溶解,浓氨水调节pH值至9.0,用CH2Cl2(50ml)进行3次萃取,有机层用用饱和食盐水水洗,无水NaSO4干燥,减压浓缩,硅胶柱分离(CH3Cl∶CH3OH=15∶1),得化合物9,产率55%,以及化合物10,产率30%。
化合物9:
1H NMR(300MHz,CDCl3)δppm 6.65(s,1H,J=9.0Hz),6.57(s,1H,J=9.0Hz),5.29(s,1H,OH),4.49(s,1H),4.17(d,1H,J=6.0Hz),3.80(s,3H),3.68(d,1H,J=15.0Hz),3.48(s,3H),3.03(s,1H),2.90(d,1H,J=18.0Hz),2.75(dd,1H,J=6.0,18.0Hz),2.50(brd,2H),2.40(s,3H),2.01(td,1H,J=3.0,12.0Hz),1.89(d,1H,J=12.0Hz),1.72(dd,1H,J=3.0,15.0Hz),1.63(dd,1H,J=6.0,15.0Hz).
13C NMR(300MHz,CDCl3)δ156.68,144.87,144.44,131.32,125.28,119.04,108.90,97.23,66.95,57.94,56.19,54.47,48.10,45.36,42.78,40.07,36.68,34.40,24.61.
化合物10:
1H NMR(300MHz,CDCl3)δppm 6.62(d,1H,J=9.0Hz),6.53(d,1H,J=9.0Hz),4.39(s,1H),4.20-4.26(m,1H),3.83(s,3H),3.66(dd,1H,J=6.0,12.0Hz),3.44(s,3H),3.01(s,1H),2.89(d,1H,J=12.0Hz),2.75-2.67(m,2H),2.53(d,1H,J=3.0Hz),2.41(s,3H),2.06(td,1H,J=3.0,12.0Hz),1.82-1.74(m,2H),1.59(t,1H,J=12.0Hz).
13C NMR(300MHz,CDCl3)δ156.53,144.63(2C),131.47,124.52,118.21,108.21,96.62,66.95,57.46,56.21,54.48,47.86,45.36,42.84,41.13,37.42,36.05,24.13.
实施例8
青藤碱A环1位以C-C或者C-O方式连接形成青藤碱衍生物:
采用普通微生物分离方法从特定生境中分离得到青藤碱(sinomenine)转化菌株霉菌Antrodiella semisupina。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愈创木酚,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值到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,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。分离得化合物11,产率13%,以及化合物12,产率5%。
化合物11:
1H NMR(300MHz,CDCl3)δppm 6.94(d,1H,J=8.4Hz),6.68(brs,1H),6.67(dd,1H,J=8.4,1.8Hz),6.56(s,1H),5.46(d,1H,J=1.9Hz),4.42(d,1H,J=15.6Hz),3.89(s,1H),3.80(s,3H),3.52(s,3H),3.12(brt,J=4.0Hz),3.01(dd,1H,J=4.0,1.9Hz),2.75(brd,1H,J=18.6Hz),2.75(dd,1H,J=18.6,4.0Hz),2.57(ddd,1H,J=12.2,4.4,1.5Hz),2.49(d,1H,J=15.6Hz),2.31(s,3H),2.10(td,J=12.2,3.2Hz),2.02(dt,1H,J=12.4,3.2Hz),1.89(td,1H,J=12.4,4.4Hz).
13C NMR(300MHz,CDCl3)δ194.2,152.3,143.8,146.3,144.6,144.5,134.3,131.8,127.7,122.5,121.9,115.2,114.3,111.7,111.0,56.6,56.0,55.9,54.9,49.1,47.4,45.6,43.8,40.8,35.8,23.4.
化合物12:
1H NMR(300MHz,CDCl3)δppm 7.00-6.96(overlapped,2H),6.75(m,1H),6.44(s,1H),6.36(dd,1H,J=8.5,1.1Hz),5.39(d,1H,J=1.8Hz),4.37(d,1H,J=15.7Hz),3.95(s,3H),3.73(s,3H),3.49(s,3H),3.19(brt,1H,J=5.8Hz),3.03(brd,1H,J=5.8Hz),3.00(d,1H,J=18.5Hz),2.58(ddd,1H,J=12.0,4.4,1.8Hz),2.47(d,1H,J=15.7Hz),2.36(s,3H),2.36(dd,1H,J=18.5,5.8Hz),2.14(td,1H,J=12.0,3.4Hz),2.00(dt,1H,J=12.4,3.4Hz),1.93(td,1H,J=12.4,4.4Hz).
13C NMR(300MHz,CDCl3)δ193.7,152.4,149.1,147.5(2C),141.7,144.1,122.3,120.7,114.8,114.6,123.4,122.5,112.2,103.1,56.1,56.0,55.8,54.8,49.0,47.0,45.6,42.7,40.4,35.6,18.5.
实施例9
青藤碱A环1位以C-C方式连接形成的青藤碱衍生物:
采用普通微生物分离方法从特定生境中分离得到青藤碱(sinomenine)转化菌株霉菌Coriolus unicolor。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邻苯二酚,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值至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,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。分离得化合物13,产率15%。
化合物13:
1H NMR(300MHz,CDCl3)δppm 6.81(d,1H,J=9.0Hz),6.61(s,1H),6.52(s,1H),6.48(d,1H,J=9.0Hz),5.43(s,1H),4.37(d,1H,J=15.0Hz),3.74(s,3H),3.47(s,3H),3.38(brd,1H),2.75-2.53(m,3H),2.45(d,1H,J=15.0Hz),2.34(s,3H),2.21-2.13(m,1H,),2.02-1.89(m,3H).
13C NMR(300MHz,CDCl3)δ194.53,152.41,144.97,144.28,143.76,143.58,133.97,132.26,126.06,121.53,120.83,116.11,115.09,114.58,111.53,56.96,56.00,54.96,47.52,44.24,42.05,40.40,34.64,29.72,23.81.
实施例10
通过4位羟基形成两分子青藤碱加合物:
称取青藤碱(sinomenine)1.5g(4.56mmol),溶于20ml EtOH,加入K2CO33.15g(22.8mmol),滴加1,3-二溴丙烷232μL(2.28mmol),回流5h。反应完全后,用稀HCl调节pH值至3,搅拌10min,再用浓NH4OH调节pH值至8~9,二氯甲烷多次萃取,合并二氯甲烷萃取液,无水NaSO4干燥,旋转蒸干溶剂,硅胶柱分离(CH3Cl∶CH3OH=9∶1),得相应化合物14,产率53%。
化合物14:
1H NMR(300MHz,CDCl3)δppm 6.99-6.66(m,2H),5.46(s,1H),4.35-4.14(m,3H),3.78(s,3H),3.47(s,3H),3.16-3.14(m,1H),2.95-2.76(m,2H),2.72(dd,1H,J=6.0,12.0Hz),2.53-2.45(m,3H),2.41(s,3H),2.07-1.87(m,4H).
13C NMR(300MHz,CDCl3)δ193.71,152.57,151.53,148.26,130.02,129.98,122.54,115.28,111.54,69.69,56.68,55.90,54.89,50.01,47.26,46.18,42.83,40.91,37.46,31.55,24.65.
实施例11
对青藤碱D环开环后末端氨基进行改造:
称取青藤碱(sinomenine)1.5g(4.56mmol),溶于200ml 15%NaOH溶液中,煮沸8min,流水冷却,用浓HCl调节pH值至4,再进行过滤,滤液用浓NH4OH,使pH值调节至8,用二氯甲烷多次萃取,合并二氯甲烷萃取液,用无水NaSO4干燥,旋转蒸干溶剂,硅胶柱分离(CH3Cl∶CH3OH=9∶1),得相应化合物15,产率33%。
化合物15:
1H NMR(300MHz,CDCl3)δppm 6.73(d,1H,J=9.0Hz),6.66(d,1H,J=9.0Hz),6.0(s,1H),5.76(s,1H),4.23(dd,1H,J=18.0Hz),3.86(s,3H),3.70(s,3H),3.17-3.11(m,2H),2.97(s,1H),2.84(dd,1H,J=6.0,18.0Hz),2.66(d,1H,J=18.0Hz),2.42(dd,1H,J=3.0,12.0Hz),2.36(s,3H),2.19(dt,1H,J=12.0,12.0,3.0Hz),2.06(dt,1H,J=12.0,12.0,3.0Hz),1.56(dd,1H,J=12.0Hz)
13C NMR(300MHz,CDCl3)δ194.84,151.21,144.79,143.85,130.67,127.08,119.80,118.77,109.07,58.10,56.29,54.97,48.37,47.26,43.30,42.09,38.28,28.25,27.59.
实施例12
通过Suzuki芳基交叉偶联反应,制备在青藤碱A环1位以C-C或者C-O方式连接形成的青藤碱衍生物S32-S34:
R1=Cl,Br,OMe,CO2Me,CHO,CH2CO2CH4,CH2CN,NHCOCF3,CH3,COPh,NH2,CN,CF3,CH(OH)COOH等;
R2=R3=OH,NH2,NO2,或者R2=OH,R3=OCH3,NO2,Cl,Br,CH3等,R4=R5=H;
R3=R5=NO2,R2=R4=H
其制备步骤如下:
1-溴代青藤碱(0.5mmol)、芳基硼酸(0.7mmol)、Pd(OAc)2(3mol%)、DABCO(6mol%)和K2CO3(1.5mmol)组成的混合物,悬浮于3ml的二甲基甲酰胺DMF中,80℃下搅拌反应,TLC检测反应完毕后,过滤,萃取,干燥,柱分离得产物。
实施例13
青藤碱衍生物的抗炎作用:取滑膜肿瘤细胞SW982于24孔盘培养,培养密度1×104/孔,24h后用L-15的完全培养基CGM(终浓度为10%胎牛血清,100U/ml的青霉素和链霉素,2mM的L-谷胺酰胺,pH=7.40)置换培养液,CGM中以0.2%牛血清白蛋白(BSA)替换胎牛血清(FBS),再24h后,以1ng/ml 1L-1β的培养基置换培养液,培养基含0.2%的BSA和终浓度分别为200μmol/L,100μmol/L,50μmol/L的测试药物,即本发明的青藤碱衍生物;继续培养48h后,取细胞上清液,用Human IL-6试剂盒检测,结果见图1。
从图1可以看出,化合物13,14在三种浓度下均对细胞炎症因子IL-6表现出强的抑制作用,化合物11在三种浓度下显示了一定的抑制作用,化合物5,7,8在高浓度下(200μM)对IL-6有一定的抑制作用,而化合3在低浓度下(50μM)有一定抑制作用,化合物15则在中等浓度下(100μM)对IL-6有抑制作用。其他化合物,如4,6对IL-6有强的促进作用,化合物10,12也有一定的促进作用。化合物9抑制作用基本上与青藤碱持平。
本发明实施例中使用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。
Claims (9)
1、青藤碱衍生物,青藤碱结构式如下:
其特征是在青藤碱A环、C环和D环通过化学合成后得到青藤碱衍生物,包括:
1)通过硝化还原在1位得到氨基连接取代基的青藤碱衍生物S1-S5:
2)或通过4位羟基或1位氨基形成的两分子青藤碱加合物S6-S8:
3)或在3,4位连接有吡嗪环的青藤碱衍生物S9-S14:
4)或在6位通过氨基/羟基连接取代基的青藤碱衍生物S15-S22:
R1=H,R2=SO2R3其中R3=CH3;Ph;2-OH-3,5-Cl2C6H2;2,4-Cl2-5-COOHC6H2等。
或者
R1=H,R2=COR3其中R3=Ph;4-Cl-C6H4;3,4-Cl2-C6H3;4-CH3-C6H4;4-OCH3-C6H4等。
或者
R1=H,R2=-COC(R3)NHR4其中R3=CH3,PhCH2,(CH3)2CHCH2;CH3SCH2CH2等,R4=H;SO2Ph;CONHC6H5等
5)或在6,7位通过氨基形成吡嗪环的双青藤碱分子衍生物S23-S24:
6)或对青藤碱D环开环后末端氨基进行改造的衍生物S25-S26:
R1=H或CH3,R2=SO2R3其中R3=CH3;Ph;2-OH-3,5-Cl2C6H2;2,4-Cl2-5-COOHC6H2等。
或者
R1=H或CH3,R2=COR3其中R3=Ph;4-Cl-C6H4;3,4-Cl2-C6H3;4-CH3-C6H4;4-OCH3-C6H4等。
或者
R1=H或CH3,R2=-COC(R3)NHR4其中R3=CH3,PhCH2,(CH3)2CHCH2;CH3SCH2CH2等,R4=H;SO2Ph;CONHC6H5等。
7)或在青藤碱A环1位以C-C或者C-O方式连接形成的青藤碱衍生物S32-S34:
R1=Cl,Br,OMe,CO2Me,CHO,CH2CO2CH4,CH2CN,NHCOCF3,CH3,COPh,NH2,CN,CF3,CH(OH)COOH等;
R2=R3=OH,NH2,NO2,或者R2=OH,R3=OCH3,NO2,Cl,Br,CH3等,R4=R5=H;
R3=R5=NO2,R2=R4=H。
2、、根据权利要求1所述的青藤碱衍生物的制备方法,其特征是通过1位氨基化及其酰基化制备青藤碱衍生物S1-S5,化学式如下:
R1=H,R2=SO2R3其中R3=CH3;Ph;2-OH-3,5-Cl2C6H2;2,4-Cl2-5-COOHC6H2等。
或者
R1=H,R2=COR3其中R3=Ph;4-Cl-C6H4;3,4-Cl2-C6H3;4-CH3-C6H4;4-OCH3-C6H4等。
或者
R1=H,R2=-COC(R3)NHR4其中R3=CH3,PhCH2,(CH3)2CHCH2;CH3SCH2CH2等,R4=H;SO2Ph;CONHC6H5等。
5、根据权利要求1所述的青藤碱衍生物的制备方法,其特征是通过6位氨基化及其酰基化制备青藤碱衍生物S15-S22,通过6,7位同时氨基化及六元氮杂环化制备青藤碱衍生物S23-S24,化学式如下:
R1=H,R2=SO2R3其中R3=CH3;Ph;2-OH-3,5-Cl2C6H2;2,4-Cl2-5-COOHC6H2等。
或者
R1=H,R2=COR3其中R3=Ph;4-Cl-C6H4;3,4-Cl2-C6H3;4-CH3-C6H4;4-OCH3-C6H4等。
或者
R1=H,R2=-COC(R3)NHR4其中R3=CH3,PhCH2,(CH3)2CHCH2;CH3SCH2CH2等,R4=H;SO2Ph;CONHC6H5等。
7、根据权利要求1所述的青藤碱衍生物的制备方法,其特征是制备青藤碱衍生物S32-S34的方法包括:(1)微生物/酶催化多底物交叉偶联,(2)Suzuki芳基交叉偶联;
通过微生物/酶催化多底物交叉偶联制备,其制备步骤如下:
1)菌株分离:野外采取特定生境,稀释涂布分离,选择性筛选,菌种斜面0℃保藏;
转化粗酶来自上述菌株,粗酶的分离采用蛋白质盐析分离方法,其余使用的酶购自Sigma;
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;
通过Suzuki芳基交叉偶联反应制备,其制备步骤如下:
1-溴代青藤碱(0.5mmol)、芳基硼酸(0.7mmol)、Pd(OAc)2(3mol%)、DABCO(6mol%)和K2CO3(1.5mmol)组成的混合物,悬浮于3ml的二甲基甲酰胺DMF中,80℃下搅拌反应,TLC检测反应完毕后,过滤,萃取,干燥,柱分离得产物。
8、根据权利要求7所述的青藤碱衍生物的制备方法,其特征是通过微生物/酶催化多底物交叉偶联的制备步骤1)中的生物转化菌株或者酶包括:霉菌菌株Antrodiellasemisupina及其同属菌株、单色云芝Coriolus unicolor及其同属菌株、过氧化物酶、脂肪酶、漆酶、水解酶、纤维素酶、淀粉酶、蛋白酶。
9、权利要求1所述的青藤碱衍生物在制备类风湿性关节炎的抗炎药物和保健品中的应用。
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