CN117843572A - 一类青藤碱衍生物及其制备方法和应用 - Google Patents
一类青藤碱衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及天然药物及药物化学技术领域，涉及一类青藤碱衍生物及其制备方法和应用。本发明以青藤碱为先导化合物，设计并合成了一系列青藤碱硫化氢供体衍生物，均为新的化合物，并测试了合成青藤碱衍生物在抗肿瘤方面的生物活性，药理试验证明本发明制备的目标衍生物具有抗肿瘤细胞增殖作用且对正常细胞具有良好的选择性，可以用于进一步制备抗肿瘤药物。
Description
技术领域
本发明涉及天然药物及药物化学技术领域，涉及一类青藤碱衍生物及其制备方法和应用，具体涉及一系列具有抗肿瘤活性的青藤碱衍生物、制备方法及其在抗肿瘤方面的用途。
背景技术
青藤碱作为中药清风藤的主要成分，其结构为吗啡烷型异喹啉类生物碱，在体外和/或体内有具各种重要生物学作用，包括镇痛、抗血管生成、抗惊厥、抗炎、免疫抑制和抗癌活性。青藤碱的抗癌潜力被不断发掘，对多种不同癌症表现抑制作用，如肺癌、肝癌、乳腺癌、骨肉瘤、结直肠癌和胃癌。青藤碱可以通过诱导细胞凋亡抑制多种肿瘤细胞株的生长，这使其成为药物开发的热点先导化合物之一。青藤碱衍生物应用于抗肿瘤药物的相关研究较少，对青藤碱的结构修饰、衍生物合成的研究越来越受到重视，以期得到更多具有抗多种肿瘤细胞增殖活性的衍生物应用于临床药物。
发明内容
为解决现有技术中的技术问题，本发明的目的在于提供一系列具有抗肿瘤活性的青藤碱衍生物、制备方法及其在抗肿瘤方面的用途。
为解决上述技术问题，本发明提供如下技术方案：
一类青藤碱硫化氢供体衍生物，其结构通式如式3所示：
其中，R为卤素、甲基、甲氧基或氢原子，含有4-12个碳原子的芳香环或卤代芳香环、芳杂环或卤代芳杂环，所述的芳杂环中包含1-3个N、O、或S的杂原子；n为1-10的整数。
基于上述技术方案，进一步地，R为卤素或氢原子，含有4-12个碳原子的芳香环或卤代芳香环、芳杂环或卤代芳杂环，所述的芳杂环中包含1-3个N、O、或S的杂原子；n为1-8的整数。
基于上述技术方案，进一步地，R为溴、氯或氢原子；n为2-6的整数。
基于上述技术方案，进一步地，所述的青藤碱硫化氢供体衍生物的结构式如下所示：
本发明的青藤碱衍生物可用下列方法制备得到：
a：NXS,X＝Cl或Br；二氯甲烷；室温；
b：二溴类试剂，碳酸钾，丙酮回流；
c：2a-e，碳酸钾，丙酮回流。
将青藤碱溶于氯仿，与NCS室温反应得到化合物1a。然后用同样的方法加入NBS合成得到1b。将硫化氢供体2溶于丙酮，加入无水碳酸钾和对应二溴代烷得到2a-e；2a-e加入到无水丙酮中，加入无水碳酸钾，加入青藤碱1或衍生物1a-b回流得到衍生物3a-o。
本发明相对于现有技术具有的有益效果如下：
本发明以青藤碱为先导化合物，设计并合成了一系列青藤碱衍生物，并测试了合成衍生物在抗肿瘤方面的生物活性，药理试验证明，本发明制备的部分目标衍生物具有极好的抗人乳腺癌细胞、人肺癌细胞、人胰腺癌细胞、人慢性髓原白血病细胞、人宫颈癌细胞和人肝癌细胞增殖活性且对正常细胞具有良好的选择性，可以用于进一步制备抗肿瘤药物。
具体实施方式
实施例1
青藤碱衍生物3a的制备方法，主要包括以下步骤：
(1)将化合物2硫化氢供体(1g，6.54mmol)加入到100mL无水丙酮中，随后加入无水碳酸钾(2.7g，19.5mmol)，1,2-二溴乙烷(6.54mmol，563mL)，加热回流反应6h，TLC监测，反应完全，将反应液冷却到室温，浓缩，加入二氯甲烷，用水洗3次，无水硫酸钠干燥，过滤，浓缩，粗产物经过硅胶柱色谱分离(二氯甲烷：甲醇＝100：1)，得化合物2a 1.2g。
(2)将39mg化合物2a(0.15mmol)用5mL无水丙酮溶解，加入62.2mg无水碳酸钾(0.45mmol)搅拌15min，然后加入49.4mg化合物青藤碱1(0.15mmol)，回流12h，TLC监测，反应完全，然后加入10mL蒸馏水和1mL 0.6M的盐酸溶液，二氯甲烷萃取3次，饱和食盐水洗1次，无水硫酸钠干燥，过滤，浓缩，得粗产物80mg，硅胶柱色谱分离(二氯甲烷：甲醇＝100：1)，得到目标化合物3a，黄色粉末，产率53％。
化合物3a表征数据如下：
1H NMR(600MHz,CDCl3)δ:7.58(d,J＝8.9Hz,2H,Ar-H),6.98(d,J＝8.8Hz,2H,Ar-H),6.74(d,J＝8.4Hz,1H,Ar-H),6.70(d,J＝8.4Hz,1H,Ar-H),5.49(d,J＝2.0Hz,1H,CH),4.14(m,4H,2CH2),3.75(s,3H,CH3),3.49(s,3H,CH3),3.19(t,J＝4.4Hz,1H,CH),3.03–2.97(m,2H,CH2),2.76(dd,J＝18.3,5.3Hz,1H,CH),2.56–2.50(m,1H,CH),2.49(d,J＝16.0Hz,1H,CH),2.44(s,3H,CH3),2.06–1.96(m,3H,CH3),1.91(td,J＝12.3,4.4Hz,1H,CH)；13C NMR(151MHz,CDCl3)δ:193.73,162.49,152.55,151.44,147.73,133.98(×2),129.96,122.74,115.31(×2),115.27,111.27,103.63,71.31,68.18,56.56,55.64,54.83,49.95,47.07,45.94,42.65,40.80,37.25,26.71,25.69,24.63；HR-ESIMS m/z calcd for C28H32N2O5SNa[M+Na]+531.1930,found 531.1924.
实施例2
青藤碱衍生物3b的制备方法，实验步骤参照实施例1的合成方法，区别仅在于，步骤(1)中的1,2-二溴乙烷替换为1,3-二溴丙烷，硅胶柱色谱分离获得黄色粉末化合物3b，产率为35％。
化合物3b表征数据如下：
1H NMR(600MHz,CDCl3)δ:7.62–7.56(m,2H,Ar-H),7.04–6.97(m,2H,Ar-H),6.79–6.70(m,2H,Ar-H),5.45(d,J＝2.1Hz,1H),5.30(s,1H,CH),4.35–4.22(m,4H,2CH2),4.07(d,J＝15.9Hz,1H,CH),3.70(s,3H,CH3),3.50(s,3H,CH3),3.42(s,1H,CH),3.30(s,1H,CH),3.02(d,J＝18.4Hz,1H,CH),2.97–2.88(m,1H,CH),2.57(s,3H,CH3),2.51(d,J＝15.8Hz,1H,CH),2.33(p,J＝6.2Hz,2H,CH2),2.25–2.15(m,1H,CH),2.12(d,J＝13.7Hz,1H,CH),1.92–1.86(m,1H,CH)；13CNMR(151MHz,CDCl3)δ:193.01,162.36,152.79,151.77,147.57,134.03(×2),129.19,123.02,119.33,115.30(×2),113.58,111.62,103.81,68.27,65.03,57.25,55.60,54.95,49.35,47.44,44.58,42.09,40.27,36.25,29.99,29.71,24.80；HR-ESIMS m/z calcd for C29H35N2O5S[M+H]+523.2267,found 523.2263.
实施例3
青藤碱衍生物3c的制备方法，实验步骤参照实施例1的合成方法，区别仅在于，步骤(1)中的1,2-二溴乙烷替换为1,4-二溴丁烷，硅胶柱色谱分离获得黄色粉末化合物3c，产率为52％。
化合物3c表征数据如下：
1H NMR(600MHz,CDCl3)δ:7.60–7.54(m,2H,Ar-H),7.01–6.96(m,2H,Ar-H),6.76–6.68(m,2H,Ar-H),5.49(d,J＝2.1Hz,1H,CH),4.18–4.12(m,4H,2CH2),3.75(s,3H,CH3),3.50(s,3H,CH3),3.19(t,J＝4.4Hz,1H,CH),3.03–2.96(m,2H,CH2),2.76(dd,J＝18.1,5.3Hz,1H,CH),2.58–2.45(m,2H,CH2),2.44(s,3H,CH3),2.10–1.95(m,4H,2CH2),1.96–1.85(m,2H,CH2)；13C NMR(151MHz,CDCl3)δ:193.70,162.48,152.57,151.46,147.74,133.98(×2),129.88,122.75,119.39,115.27,115.24(×2),111.29,103.63,71.31,68.18,56.60,55.64(×2),54.83,49.93,47.09,45.91,42.64,40.78,37.22,26.71,25.69,24.64；HR-ESIMS m/z calcd for C30H36N2O5SNa[M+Na]+559.2243,found 559.2238.
实施例4
青藤碱衍生物3d的制备方法，实验步骤参照实施例1的合成方法，区别仅在于，步骤(1)中的1,2-二溴乙烷替换为1,5-二溴戊烷，硅胶柱色谱分离获得白色粉末化合物3d，产率为48％。
化合物3d表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.61–7.54(m,2H,Ar-H),7.00–6.90(m,2H,Ar-H),6.78–6.69(m,2H,Ar-H),5.49(d,J＝2.2Hz,1H,CH),4.18–4.09(m,2H,2CH2),4.11–4.06(m,1H,CH),4.06(dd,J＝6.5,2.4Hz,1H,CH),3.76(s,3H,CH3),3.50(s,3H,CH3),3.27(t,J＝4.5Hz,1H,CH),3.10(s,1H,CH),3.01(d,J＝18.2Hz,1H,CH),2.82(dd,J＝18.2,5.3Hz,1H,CH),2.64–2.58(m,1H,CH),2.50(d,J＝16.0Hz,1H,CH),2.48(s,3H,CH3),2.12–1.98(m,1H,CH),2.01(s,1H,CH),2.00–1.86(m,6H,3CH2),1.68(q,J＝7.5Hz,2H,CH2)；13C NMR(100MHz,CDCl3)δ:193.55,152.62,151.60,147.87,133.96(×2),129.61,129.35,122.71,119.37,115.24(×2),114.79,111.43,103.60,71.82,68.30,56.81,55.68,54.86,49.70,47.23,45.49,45.02,42.46,40.59,36.89,29.87,28.79,24.70,22.40；HR-ESIMS m/z calcd forC31H39N2O5S[M+H]+551.2580,found 551.2589.
实施例5
青藤碱衍生物3e的制备方法，实验步骤参照实施例1的合成方法，区别仅在于，步骤(1)中的1,2-二溴乙烷替换为1,6二溴己烷，硅胶柱色谱分离获得白色粉末化合物3d，产率为81％。
化合物3e表征数据如下：
1H NMR(600MHz,CDCl3)δ:7.60–7.54(m,2H,Ar-H),6.97–6.90(m,2H,Ar-H),6.72(q,J＝8.5Hz,2H,Ar-H),5.47(d,J＝2.1Hz,1H,CH),4.15(d,J＝16.0Hz,1H,CH),4.14–3.97(m,4H,2CH2),3.77(s,3H,CH3),3.50(s,3H,CH3),3.27(s,1H,CH),3.11(s,1H,CH),3.00(d,J＝18.2Hz,1H,CH),2.82(d,J＝18.2Hz,1H,CH),2.61(s,1H,CH),2.51(s,1H,CH),2.48(s,3H,CH3),2.06(s,1H,CH),1.95–1.78(m,6H,3CH2),1.60–1.53(m,2H,CH2),1.49(td,J＝7.6,4.3Hz,1H,CH),1.27(s,2H,CH2),1.26(d,J＝7.8Hz,1H,CH)；13C NMR(151MHz,CDCl3)δ:193.51,162.48,152.64,151.68,147.99,133.97(×2),129.61,122.66,119.38,115.22(×2),114.69,111.48,103.62,72.03,68.37,56.83,55.72,54.86,49.63,47.24,45.42,42.42,40.56,36.83,30.14,29.71,28.97,25.81,25.62,24.73；HR-ESIMS m/z calcd forC32H40N2O5SNa[M+Na]+587.2556,found 587.2563.
实施例6
青藤碱衍生物3f的制备方法，主要包括以下步骤：
(1)将1g化合物1青藤碱(3.03mmol)用50mL氯仿溶解，在室温条件下加入480mgNCS(10.08mmol)，然后室温搅拌，过夜反应，TLC监测，反应完全，然后依次加入水、2N的NaOH溶液，室温搅拌2h后，抽滤，滤饼用二氯甲烷洗，将滤液浓缩得到化合物1a 800mg。将化合物2硫化氢供体(1g，6.54mmol)加入到100mL无水丙酮中，随后加入无水碳酸钾(2.7g，19.5mmol)，1,2-二溴乙烷(6.54mmol，563mL)，加热回流反应6h，TLC监测，反应完全，将反应液冷却到室温，浓缩，加入二氯甲烷，用水洗3次，无水硫酸钠干燥，过滤，浓缩，粗产物经过硅胶柱色谱分离(二氯甲烷：甲醇＝100：1)，得化合物2a 1.2g。
(2)将39mg化合物2a(0.15mmol)用5mL无水丙酮溶解，加入62.2mg无水碳酸钾(0.45mmol)搅拌15min，然后加入54.6mg化合物1a(0.15mmol)，回流12h，TLC监测，反应完全，然后加入10mL蒸馏水和1mL 0.6M的盐酸溶液，二氯甲烷萃取3次，饱和食盐水洗1次，无水硫酸钠干燥，过滤，浓缩，得粗产物80mg，硅胶柱色谱分离(二氯甲烷：甲醇＝100：1)，得到目标化合物3f，白色粉末，产率56％。
化合物3f表征数据如下：
1H NMR(600MHz,DMSO-d6)δ:7.62–7.55(m,2H,Ar-H),7.04–6.98(m,2H,Ar-H),6.82(s,1H,Ar-H),5.45(d,J＝2.1Hz,1H,CH),4.34–4.20(m,4H,2CH2),4.04(d,J＝15.8Hz,1H,CH),3.69(s,3H,CH3),3.50(s,3H,CH3),3.37(dd,J＝5.9,3.5Hz,1H,CH),3.16(s,1H,CH),3.05(dt,J＝18.9,1.5Hz,1H,CH),2.66(d,J＝10.8Hz,1H,CH),CH,2.61(dd,J＝19.0,5.7Hz,1H,CH),2.50(s,3H,CH3),2.49(d,J＝15.8Hz,1H,CH),2.31(p,J＝6.1Hz,2H,CH2),2.03(dtd,J＝36.0,12.5,3.6Hz,2H,CH2),1.89(t,J＝2.1Hz,1H,CH)；13C NMR(151MHz,DMSO-d6)δ:192.96,162.31,152.70,151.80,146.35,134.03(×2),131.34,127.67,126.51,115.28(×2),114.15,112.46,68.34,64.92,56.23,55.74(×2),54.97,49.54,46.96,45.08,42.44,40.91,36.59,29.93,23.29；HR-ESIMS m/z calcd for C28H32ClN2O5S[M+H]+543.1720,found 543.1713.
实施例7
青藤碱衍生物3g的制备方法，实验步骤参照实施例6的合成方法，区别仅在于，步骤(2)中的1,2-二溴乙烷替换为1,3-二溴丙烷，硅胶柱色谱分离得到白色粉末化合物3g，产率为68％。
化合物3g表征数据如下：
1H NMR(600MHz,CDCl3)δ:7.57–7.51(m,2H,Ar-H),6.98–6.93(m,2H,Ar-H),6.76(s,1H,Ar-H),5.40(d,J＝2.0Hz,1H,CH),4.43–4.28(m,4H,2CH2),4.08(d,J＝15.9Hz,1H),3.70(s,3H,CH3),3.43(s,3H,CH3),3.20(t,J＝4.5Hz,1H,CH),3.00–2.93(m,2H,CH2),2.44(d,J＝6.4Hz,1H,CH),2.37(s,3H,CH3),1.96–1.80(m,3H,3CH),1.22–1.17(m,2H,CH2)；13CNMR(151MHz,CDCl3)δ:192.54,161.04,151.59,150.48,133.01(×2),130.69,126.87,126.45,118.19,114.37(×2),113.86,111.38,103.17,68.72,66.89,54.90,54.85(×2),53.90(×2),48.69,45.80,44.81,41.67,40.33,35.62,22.22；HR-ESIMS m/z calcd forC29H34ClN2O5S[M+H]+557.1877,found 557.1868.
实施例8
青藤碱衍生物3h的制备方法，实验步骤参照实施例6的合成方法，区别仅在于，步骤(2)中的1,2-二溴乙烷替换为1,4-二溴丁烷，硅胶柱色谱分离得到白色粉末化合物3h，产率为79％。
化合物3h表征数据如下：
1H NMR(600MHz,CDCl3)δ:7.61–7.55(m,2H,Ar-H),7.01–6.94(m,2H,Ar-H),6.77(s,1H,Ar-H),5.44(d,J＝2.1Hz,1H,CH),4.22(dt,J＝7.5,3.8Hz,1H,CH),4.17–4.09(m,4H,2CH2),3.77(s,3H,CH3),3.66(s,1H,CH),3.58(dt,J＝5.5,2.7Hz,1H,CH),3.51(s,3H,CH3),3.13(d,J＝19.3Hz,1H,CH),3.07–2.98(m,2H,CH2),2.69(s,3H,CH3),2.61(d,J＝15.8Hz,1H,CH),2.33(d,J＝8.1Hz,2H,CH2),2.07–1.96(m,6H,3CH2)；13C NMR(151MHz,CDCl3)δ:192.52,162.41,152.97,152.19,147.81,134.00,128.41,123.00,119.34,115.25(×2),112.21,112.00,103.74,71.54,68.05,57.88,55.69,55.06,48.77,47.87,46.51,43.39,41.59,39.79,35.25,29.71,26.73,25.62,24.98；HR-ESIMS m/z calcd forC30H36ClN2O5S[M+H]+571.2033,found 571.2036.
实施例9
青藤碱衍生物3i的制备方法，实验步骤参照实施例6的合成方法，区别仅在于，步骤(2)中的1,2-二溴乙烷替换为1,5二溴戊烷，硅胶柱色谱分离得到白色粉末化合物3i，产率为41％。
化合物3i表征数据如下：
1H NMR(600MHz,CDCl3)δ:7.60–7.55(m,2H,Ar-H),6.95(d,J＝8.8Hz,2H,Ar-H),6.81(s,1H,Ar-H),5.46(d,J＝2.2Hz,1H,CH),5.30(s,1H,CH),4.15–4.02(m,6H,3CH2),3.76(s,3H,CH3),3.50(s,3H,CH3),3.30(t,J＝4.5Hz,1H,CH),3.09–3.00(m,2H,CH2),2.63–2.52(m,2H,CH2),2.51(d,J＝16.0Hz,1H,CH),2.46(s,3H,CH3),2.04–1.84(m,6H,3CH2),1.68(q,J＝7.6Hz,2H,CH2)；13CNMR(151MHz,CDCl3)δ:193.26,162.44,152.64,151.82,133.97(×2),131.46,127.36,126.99,115.22(×2),114.68,112.40,103.67,71.95,68.25,56.08,55.82,54.92(×2),49.65,46.92,45.49,42.60,41.04,36.81,29.83,29.69,28.79,23.27,22.38；HR-ESIMS m/z calcd for C31H38ClN2O5S[M+H]+585.2190,found585.2186.
实施例10
青藤碱衍生物3j的制备方法，实验步骤参照实施例6的合成方法，区别仅在于，步骤(2)中的1,2-二溴乙烷替换为1,6-二溴己烷，硅胶柱色谱分离得到白色粉末化合物3j，产率为36％。
化合物3j表征数据如下：
1H NMR(600MHz,CDCl3)δ:7.57(d,J＝8.8Hz,2H,Ar-H),6.97–6.92(m,2H,Ar-H),6.80(s,1H,Ar-H),5.47(d,J＝2.0Hz,1H,CH),5.30(s,1H,CH),4.16–3.97(m,6H,3CH2),3.76(s,3H,CH3),3.50(s,3H,CH3),3.26(dd,J＝6.5,3.2Hz,1H,CH),3.03(dd,J＝18.2,1.8Hz,2H,CH2),2.56–2.46(m,4H,2CH2),2.43(s,3H,CH3),2.02–1.90(m,2H CH2),1.92–1.77(m,4H,2CH2),1.61–1.53(m,3H,3CH)；13C NMR(151MHz,CDCl3)δ:193.34,162.45,152.57,151.76,146.76,133.94,131.60,127.29,127.25,119.34,115.22,115.19,114.98,112.35,103.60,72.11,68.33,55.94,55.81,54.88,53.48,49.72,46.84,45.72,42.70,41.12,36.98,30.08,28.94,25.78,25.58,23.23；HR-ESIMS m/z calcd forC32H39ClN2O5SNa[M+Na]+621.2166,found 621.2164.
实施例11
青藤碱衍生物3k的制备方法，主要包括以下步骤：
(1)将化合物2(1g，6.54mmol)加入到100mL无水丙酮中，随后加入无水碳酸钾(2.7g，19.5mmol)，1,2-二溴乙烷(6.54mmol，563mL)，加热回流反应6h，TLC监测，反应完全，将反应液冷却到室温，浓缩，加入二氯甲烷，用水洗3次，无水硫酸钠干燥，过滤，浓缩，粗产物经过硅胶柱色谱分离(二氯甲烷：甲醇＝100：1)，得化合物2a 1.2g。
(2)将39mg化合物2b(0.15mmol)用5mL无水丙酮溶解，加入62.2mg无水碳酸钾(0.45mmol)搅拌15min，然后加入61.2mg化合物1a(0.15mmol)，回流12h，TLC监测，反应完全，然后加入10mL蒸馏水和1mL 0.6M的盐酸溶液，二氯甲烷萃取3次，饱和食盐水洗1次，无水硫酸钠干燥，过滤，浓缩，得粗产物80mg，硅胶柱色谱分离(二氯甲烷：甲醇＝100：1)，得到目标化合物3k，白色粉末，产率77％。
化合物3k表征数据如下：
1H NMR(600MHz,CDCl3)δ:7.66–7.57(m,2H,Ar-H),7.05–6.97(m,3H,Ar-H),5.46(d,J＝2.2Hz,1H,CH),4.55(ddd,J＝10.8,5.4,2.6Hz,1H,CH2),4.50–4.29(m,3H,CH2),4.21–4.10(m,1H,CH),3.77(s,3H,CH3),3.50(s,3H,CH3),3.26(s,1H,CH),3.10–2.98(m,1H,CH),2.53(s,2H,CH2),2.52(d,J＝16.0Hz,1H,CH),2.44(s,3H,CH3),1.97(s,1H,CH),1.92(d,J＝18.8Hz,2H,CH2),1.47–1.37(m,1H,CH)；13C NMR(151MHz,CDCl3)δ:193.55,162.05,152.62,146.49,134.22,132.47,130.89,128.81,119.21,118.36,115.56,104.23,69.74,68.16,67.89,56.29,55.91,54.94,46.84,42.71,41.54,38.74,30.37,29.71,29.33,28.94,26.41,23.75,22.71；HR-ESIMS m/z calcd for C28H31BrN2O5SNa[M+Na]+609.1035,found609.1033.
实施例12
青藤碱衍生物3l的制备方法，实验步骤参照实施例11的合成方法，区别仅在于，步骤(2)中的1,2-二溴乙烷替换为1,3-二溴丙烷，硅胶柱色谱分离得到白色粉末化合物3l，产率分别为51％。
化合物3l表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.63–7.53(m,2H,Ar-H),7.01(s,1H,Ar-H),7.00(d,J＝5.8Hz,2H,Ar-H),5.44(d,J＝2.3Hz,1H,CH),4.34–4.18(m,4H,2CH2),4.04(d,J＝15.9Hz,1H,CH),3.69(s,3H,CH3),3.50(s,3H,CH3),3.29(s,1H,CH),3.00(d,J＝18.9Hz,1H,CH),2.46(s,3H,CH3),2.31(p,J＝6.1Hz,2H,CH2),1.86(d,J＝11.8Hz,1H,CH)；13C NMR(150MHz,CDCl3)δ:193.08,162.30,152.66,134.09,134.02,119.29,118.07,115.53,115.27(×2),115.17,115.07,103.85,68.26,64.91,56.44,55.75,54.94,49.63,46.88,42.52,41.20,31.93,29.92,29.70,26.40,23.25,22.69；HR-ESIMS m/z calcd for C29H34BrN2O5S[M+H]+601.1372,found 601.1381.
实施例13
青藤碱衍生物3m的制备方法，实验步骤参照实施例11的合成方法，区别仅在于，步骤(2)中的1,2-二溴乙烷替换为1,4-二溴丁烷，硅胶柱色谱分离得到白色粉末化合物3m，产率分别为52％。
化合物3m表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.61–7.55(m,2H,Ar-H),7.00(s,1H,Ar-H),6.99–6.96(m,2H,Ar-H),5.44(d,J＝2.3Hz,1H,CH),4.15(dd,J＝6.0,3.2Hz,2H,CH2),4.14–4.11(m,3H,CH,CH2),4.10(s,1H,CH),4.08(s,1H,CH),3.76(s,3H,CH3),3.50(s,3H,CH3),3.35(s,1H,CH),3.11(s,1H,CH),3.00(d,J＝19.0Hz,1H,CH),2.56–2.50(m,1H,CH),2.47(s,3H,CH3)；13C NMR(150MHz,CDCl3)δ:193.10,162.41,152.68,151.95,147.16,134.00,119.34,117.91,115.63,115.24,112.48,103.75,71.52,68.07,60.40,56.31,55.83,54.96,49.51,46.83,42.27,41.09,36.50,31.94,29.71,26.70,26.46,25.67,23.32,22.70；HR-ESIMS m/z calcd for C30H35BrN2O5SNa[M+Na]+637.1348,found 637.1356.
实施例14
青藤碱衍生物3n的制备方法，实验步骤参照实施例11的合成方法，区别仅在于，步骤(2)中的1,2-二溴乙烷替换为1,5-二溴戊烷，硅胶柱色谱分离得到白色粉末化合物3n，产率分别为51％。
化合物3n表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.57(m,2H,Ar-H),7.02(s,1H,Ar-H),6.98–6.91(m,2H,Ar-H),5.42(d,J＝2.1Hz,1H,CH),4.17–4.08(m,3H,CH,CH2),4.10–3.98(m,3H,CH,CH2),3.77(s,3H,CH3),3.50(s,3H,CH3),3.03(d,J＝19.2Hz,1H,CH),2.81(s,1H,CH),2.70(d,J＝19.5Hz,1H,CH),2.55(s,3H,CH3),2.12(s,2H,CH2),2.07(s,2H,CH2)；13C NMR(100MHz,CDCl3)δ:192.75,174.80,162.42,152.81,152.23,147.32,133.99,119.33,117.81,115.89,115.21,115.17,103.73,72.03,68.22,68.10,55.89,55.01,49.05,47.01,41.79,40.68,31.94,30.02,29.82,29.71,28.79,26.54,22.70,22.39,21.20；HR-ESIMS m/zcalcd for C31H38BrN2O5S[M+H]+629.1685,found 629.1682.
实施例15
青藤碱衍生物3o的制备方法，实验步骤参照实施例11的合成方法，区别仅在于，步骤(2)中的1,2-二溴乙烷替换为1,6-二溴己烷，硅胶柱色谱分离得到白色粉末化合物3o，产率分别为46％。
化合物3o表征数据如下：
1H NMR(400MHz,CDCl3)δ:7.58–7.56(m,2H,Ar-H),6.99(s,1H,Ar-H),6.95–6.93(m,2H,Ar-H),5.45(t,J＝2.3Hz,1H,CH),4.12(d,J＝16.1Hz,2H,CH2),4.08(td,J＝7.0,4.7Hz,3H,CH,CH2),4.03(t,J＝6.6Hz,3H,CH,CH2),3.83(d,J＝15.5Hz,2H,CH2),3.77(s,3H,CH3),3.49(s,3H,CH3),3.30(s,2H,CH2),3.10–2.96(m,4H,2CH2),2.56–2.43(m,4H,2CH2),1.91(d,J＝8.5Hz,1H,CH)；13C NMR(100MHz,CDCl3)δ:193.20,162.45,152.66,151.98,147.37,133.97,119.35,117.75,115.21,114.52,103.65,72.17,68.33,56.50,55.84,55.03,54.94,50.87,49.53,46.98,42.55,41.16,33.70,31.93,30.12,30.08,29.74,29.37,28.96,26.43,25.80,25.60,23.28,22.70；HR-ESIMS m/z calcd forC32H39BrN2O5SNa[M+Na]+665.1665,found 665.1663.
实施例16
本实施例是对实施例1-15制备的化合物的药理活性进行评价。
实验设备与试剂
表1本实施例实验过程使用的仪器、试剂和细胞株
实验方法
细胞生长抑制活性实验方法
通过CCK-8法检测目标化合物在六种癌细胞(人肺癌细胞系A549，人慢性骨髓性白血病细胞系K562，人乳腺肿瘤细胞系MCF-7，人胰腺癌细胞系PANC-1，人肝癌细胞系HepG2和人三阴性乳腺癌细胞系MDA-MB-231)和一种正常细胞系(外周血单个核细胞PMBC)中的抗增殖活性。所有细胞系均来自中国南京KeyGEN Biotech公司，所有细胞培养均采用标准DMEM或RPMI 1640培养基。然后在5％CO2的湿润环境中于37℃下孵育24h后，将对数生长的细胞种植到96孔板中，在37℃和5％ CO2下孵育24h。然后，将目标化合物或阳性对照(taxol)添加到预定浓度的不同细胞系中，培养48h。给药后，小心吸弃培养液，于每个孔中加入含10％CCK-8的无血清培养基孵育1h，然后在酶标仪上测量每个孔的OD值，波长为450nm，计算目标化合物的IC50值。
实验结果
表2目标化合物对不同细胞系的抗增殖作用
aIC50：通过CCK-8测定法测量的半数抑制浓度，上述数值均为三个独立实验的平均值±标准偏差。
药理试验证明，本发明制备的目标衍生物在抗人乳腺癌细胞、人肺癌细胞、人胰腺癌细胞、人慢性骨髓性白血病细胞、和人肝癌细胞具有增殖活性，部分目标衍生物具有极好的抗人乳腺癌细胞、人肺癌细胞、人白血病细胞和人肝癌细胞增殖活性且对正常细胞具有良好的选择性，可以用于进一步制备抗肿瘤药物。
最后应说明的是：以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (10)
1.通式3所示的一类青藤碱硫化氢供体衍生物：
其中，R为卤素、甲基、甲氧基或氢原子，含有4-12个碳原子的芳香环或卤代芳香环、芳杂环或卤代芳杂环，所述的芳杂环中包含1-3个N、O、或S的杂原子；n为1-10的整数。
2.根据权利要求1所述的青藤碱硫化氢供体衍生物，其特征在于，R为卤素或氢原子，含有4-12个碳原子的芳香环或卤代芳香环、芳杂环或卤代芳杂环，所述的芳杂环中包含1-3个N、O、或S的杂原子；n为1-8的整数。
3.根据权利要求1-2所述的青藤碱硫化氢供体衍生物，其特征在于，R为溴、氯或氢原子；n为2-6的整数。
4.权利要求1-3任何一项所述的青藤碱硫化氢供体衍生物，其特征在于，所述青藤碱硫化氢供体衍生物结构式如下：
5.权利要求1所述的青藤碱硫化氢供体衍生物的制备方法，其特征在于：所述制备方法的制备路线如下所示：
a：NXS,X＝Cl或Br；二氯甲烷；室温；
b：二溴类试剂，碳酸钾，丙酮回流；
c：2a-e，碳酸钾，丙酮回流。
6.权利要求5所述的青藤碱硫化氢供体衍生物的制备方法，其特征在于：包括以下步骤：
将青藤碱溶于氯仿，与NCS室温反应得到化合物1a；以同样的方法加入NBS合成得到1b；
将硫化氢供体2溶于无水丙酮中，加入无水碳酸钾和对应二溴代烷得到2a-e；
2a-e加入到无水丙酮中，加入无水碳酸钾，加入青藤碱1或衍生物1a-b回流得到衍生物3a-o。
7.一种药物组合物，其特征在于，其包含权利要求1-4任一项所述的青藤碱硫化氢供体衍生物中的一种或两种以上。
8.根据权利要求7所述的药物组合物，其特征在于，所述药物组合物含有治疗有效量的所述青藤碱硫化氢供体衍生物和药学上可接受的载体。
9.权利要求1-4任一项所述的青藤碱硫化氢供体衍生物、权利要求7-8任一项所述药物组合物在制备治疗肿瘤疾病的药物中的应用。
10.根据权利要求9所述的应用，其特征在于，所述的肿瘤包括乳腺癌肿瘤、肺癌肿瘤、白血病、胰腺癌肿瘤或肝癌肿瘤。
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