本发明涉及制药技术领域，具体涉及一类新的苦参碱吡咯、吲哚衍生物，以及制备方法和这些化合物在制备抗肿瘤药物中的应用。
背景技术：
研究发现作为苦参中的生物碱主要成分的苦参碱，具有广泛的药理活性。苦参碱在对中枢神经系统、心血管系统和消化系统都具有良好的疗效。其中以抗肿瘤、抗炎、抗病毒方面的研究较多。在抗肿瘤方面，苦参碱具有直接杀伤癌细胞的效果。随着研究的深入，吡咯，吲哚类药物的抗肿瘤活性也日益引起了人们的重视。未见兼具苦参碱的抗肿瘤活性和吡咯、吲哚类药物的抗肿瘤活性的相关药物。
技术实现要素：
本发明要解决的技术问题是提供一种用于制备抗肿瘤药物的苦参碱衍生物及其制备方法。
本发明所述的苦参碱吡咯、吲哚衍生物，其结构如下：
通式ⅰ：
通式ⅱ：
通式ⅲ：
通式ⅳ：
本发明还提供了上述化合物的制备方法，该方法采用如下反应路线：
本发明有益效果在于提供了一种有发展前景的抗肿瘤药物，给广大的癌症患者提供多一种治疗的可能。
附图说明
图1为目标化合物lz-06对cne2癌细胞凋亡的作用。
图2为目标化合物lz-06对smmc-7721癌细胞凋亡的作用。
图3为目标化合物lz-44对cne2癌细胞凋亡的作用。
图4为目标化合物lz-44对smmc-7721癌细胞凋亡的作用。
图5为目标化合物lz-06对cne2癌细胞周期阻滞作用。
图6为目标化合物lz-06对smmc-7721癌细胞周期阻滞作用。
图7为目标化合物lz-06对cne2癌细胞周期阻滞作用的细胞柱状分布图。
图8为目标化合物lz-06对smmc-7721癌细胞周期阻滞作用的细胞柱状分布图。
具体实施方式
下面通过实施例对本发明的技术方案作进一步阐述。
实施例1
(1)lz-01的制备：
具体制备lz-01的实验方法：
于100ml圆底烧瓶中分别加入100mmol(2.4g)氢化钠，50ml无水四氢呋喃，搅拌均匀，加入5mmol(1.24g)苦参碱，缓慢升温至80℃加入6mmol(0.654g)n-甲基-2-吡咯甲醛，反应24h至终点(tlc检测)。冷却，用3n的盐酸调节反应液至中性。二氯甲烷萃取(20mlx3)，合并有机相，无水na2so4干燥，减压抽滤、浓缩滤液后经硅胶柱层析(v己酸乙酯：v石油醚＝3：2)纯化，得0.543g黄色固体粉末苦参碱lz-01：14-(n-甲基-2-吡咯甲烯基)苦参碱：收率39％。
1hnmr(600mhz,chloroform-d)δ7.67(s,1h),6.73(dd,j＝2.6,1.6hz,1h),6.38(dd,j＝4.0,1.5hz,1h),6.23–6.17(m,1h),4.48(dd,j＝12.7,4.5hz,1h),4.02–3.93(m,1h),3.70(s,3h),3.22(t,j＝12.7hz,1h),2.90–2.77(m,3h),2.64–2.54(m,1h),2.33–2.18(m,1h),2.18–2.08(m,2h),2.05–1.85(m,3h),1.84–1.50(m,6h),1.50–1.39(m,3h).13cnmr(151mhz,cdcl3)δ165.17,129.55,125.61,124.69,122.45,112.36,108.39,63.85,57.32,57.28,52.67,43.20,41.85,35.81,34.39,27.83,26.55,24.84,23.31,21.24,20.85.esi-ms:[m+1]+,340
参考化合物lz-01的实验方法制备化合物lz-02～lz-23，化合物lz-02～lz-23结构鉴定数据如下：
化合物lz-02：14-(n-苄基-2-吡咯甲烯基)苦参碱：黄色固体粉末，收率53％；
1hnmr(600mhz,chloroform-d)δ7.67(s,1h),7.30–7.18(m,3h),7.11–7.02(m,2h),6.79(t,j＝2.1hz,1h),6.41(dd,j＝3.9,1.5hz,1h),6.26(t,j＝3.3hz,1h),5.17(s,2h),4.43(dd,j＝12.7,4.4hz,1h),3.96–3.90(m,1h),3.18(t,j＝12.6hz,1h),2.88–2.72(m,3h),2.63–2.49(m,1h),2.19–1.79(m,6h),1.79–1.71(m,2h),1.69–1.47(m,4h),1.46–1.34(m,3h).13cnmr(151mhz,cdcl3)δ164.92,137.70,129.22,128.74(2c),127.53,126.73(2c),126.20,124.18,122.53,112.73,109.01,63.79,57.31,57.27,52.64,50.68,43.15,41.86,35.78,27.83,26.55,24.85,23.42,21.25,20.86.esi-ms:[m+1]+,416
化合物lz-03：14-[n-(3-甲氧基苄基)-2-吡咯甲烯基]苦参碱：黄色固体粉末，收率41％；
1hnmr(600mhz,chloroform-d)δ7.67(s,1h),7.22(t,j＝7.9hz,1h),6.85–6.75(m,2h),6.68(d,j＝7.6hz,1h),6.60(t,j＝2.0hz,1h),6.42(d,j＝3.9,1.5hz,1h),6.28(t,j＝3.3hz,1h),5.18(s,2h),4.44(dd,j＝12.7,4.4hz,1h),4.01–3.91(m,1h),3.75(s,3h),3.20(t,j＝12.7hz,1h),2.90–2.79(m,3h),2.61–2.54(m,1h),2.24–2.06(m,2h),2.03–1.89(m,3h),1.81–1.74(m,2h),1.75–1.49(m,4h),1.48–1.42(m,3h),1.34–1.25(m,1h).13cnmr(151mhz,cdcl3)δ164.93,159.91,139.32,129.76,129.24,126.27,124.19,122.55,118.97,112.97,112.73,112.33,109.02,63.80,57.30,57.25,55.12,52.64,50.58,43.13,41.87,35.79,27.82,26.53,24.87,23.42,21.24,20.85.esi-ms:[m+1]+,446
化合物lz-04：14-[n-(4-甲氧基苄基)-2-吡咯甲烯基]苦参碱：黄色固体粉末，收率43％；
1hnmr(600mhz,chloroform-d)δ7.71(s,1h),7.09–7.04(m,2h),6.86–6.81(m,2h),6.80(dd,j＝2.7,1.6hz,1h),6.41(d,j＝3.9,1.5hz,1h),6.26(t,1h),5.13(s,2h),4.45(dd,j＝12.7,4.4hz,1h),4.01–3.91(m,1h),3.77(s,3h),3.21(t,j＝12.6hz,1h),2.89–2.76(m,3h),2.61–2.52(m,1h),2.17–2.07(m,3h),2.03–1.88(m,3h),1.82–1.49(m,5h),1.49–1.36(m,3h),1.29–1.26(m,1h).13cnmr(151mhz,cdcl3)δ165.04,159.02,129.70,129.16,128.24(2c),126.08,123.96,122.64,114.16(2c),112.68,108.83,63.84,57.33,57.28,55.24,52.68,50.26,43.17,41.90,35.80,27.83,26.56,24.88,23.41,21.25,20.87.esi-ms:[m+1]+,446
化合物lz-05：14-[n-(2-溴-3-甲氧基苄基)-2-吡咯甲烯基]苦参碱：黄色固体粉末，收率43％；
1hnmr(600mhz,chloroform-d)δ7.55(s,1h),7.44(d,j＝8.7hz,1h),6.82–6.76(m,1h),6.67(dd,j＝8.7,3.1hz,1h),6.45(dd,j＝3.8,1.5hz,1h),6.31(t,j＝3.3hz,1h),6.04(d,j＝3.0hz,1h),5.20(s,2h),4.44(dd,j＝12.8,4.4hz,1h),3.99–3.93(m,1h),3.64(s,3h),3.19(t,j＝12.7hz,1h),2.94–2.78(m,3h),2.65–2.56(m,1h),2.16–1.90(m,5h),1.81–1.73(m,1h),1.72–1.50(m,3h),1.50–1.38(m,3h),1.35–1.23(m,3h).13cnmr(151mhz,cdcl3)δ164.82,159.43,138.22,133.19,129.42,127.05,124.18,122.18,114.36,113.89,112.82,112.21,109.40,63.84,57.31,57.27,55.26,52.67,50.86,43.08,41.97,35.76,27.81,26.54,25.02,23.53,21.23,20.85.esi-ms:[m+1]+,524
化合物lz-06：14-[n-(3，5-二甲氧基苄基)-2-吡咯甲烯基]苦参碱：黄色固体粉末，收率32％；
1hnmr(600mhz,chloroform-d)δ7.65(s,1h),6.80(dd,j＝2.7,1.6hz,1h),6.41(dd,j＝3.9,1.5hz,1h),6.33(t,j＝2.3hz,1h),6.28–6.25(m,1h),6.21(d,j＝2.3hz,2h),5.13(s,2h),4.44(dd,j＝12.7,4.4hz,1h),4.00–3.91(m,1h),3.73(d,j＝1.1hz,6h),3.20(t,j＝12.6hz,1h),2.91–2.76(m,3h),2.62–2.52(m,1h),2.22–2.06(m,2h),2.04–1.89(m,3h),1.82–1.51(m,6h),1.49–1.38(m,3h),1.32–1.24(m,1h).13cnmr(151mhz,cdcl3)δ164.95,161.06(2c),140.12,129.30,126.43,124.18,122.55,112.68,108.99,104.71(2c),99.43,63.85,57.32,57.27,55.27(2c),52.66,50.65,43.12,41.89,35.79,27.82,26.54,24.91,23.43,21.24,20.85.esi-ms:[m+1]+,476
化合物lz-07：14-[n-(3，4，5-三甲氧基苄基)-2-吡咯甲烯基]苦参碱：黄色固体粉末，收率35％；
1hnmr(600mhz,chloroform-d)δ7.67(s,1h),6.80(dd,j＝2.7,1.6hz,1h),6.39(dd,j＝4.0,1.7hz,1h),6.28(d,j＝1.8hz,2h),6.25(dd,j＝3.8,2.7hz,1h),5.10(d,j＝2.3hz,2h),4.41(dd,j＝12.7,4.4hz,1h),3.97–3.90(m,1h),3.78(d,j＝19.0hz,9h),3.18(t,j＝12.7hz,1h),2.87–2.74(m,3h),2.60–2.51(m,1h),2.36–2.24(m,1h),2.13–2.04(m,2h),2.00–1.85(m,4h),1.77–1.52(m,5h),1.46–1.40(m,2h),1.29–1.23(m,1h).13cnmr(151mhz,cdcl3)δ164.91,153.41(2c),137.20,133.32,129.23,126.39,124.06,122.58,112.73,108.99,103.82(2c),63.77,60.77,57.28,57.24,56.01(2c),52.66,50.82,43.13,41.89,35.80,27.81,26.53,24.92,23.39,21.22,20.83.esi-ms:[m+1]+,506
化合物lz-08：14-[n-(2-甲基苄基)-2-吡咯甲烯基]苦参碱：白色固体粉末，收率44％；
1hnmr(600mhz,chloroform-d)δ7.64(s,1h),7.18(dd,j＝3.9,1.0hz,2h),7.13–7.08(m,1h),6.69–6.63(m,2h),6.45(dd,j＝4.0,1.5hz,1h),6.29–6.26(m,1h),5.16(s,2h),4.44(dd,j＝12.7,4.4hz,1h),4.04–3.91(m,1h),3.20(t,j＝12.6hz,1h),2.94–2.78(m,3h),2.65–2.54(m,1h),2.31(s,3h),2.24–2.08(m,3h),2.03–1.89(m,3h),1.81–1.74(m,2h),1.71–1.62(m,2h),1.60–1.51(m,1h),1.49–1.42(m,3h),1.33–1.26(m,1h).13cnmr(151mhz,cdcl3)δ164.99,135.62,135.37,130.28,129.47,127.62,126.99,126.37,123.94,122.42,112.57,108.92,63.84,57.33,57.29,52.69,48.67,43.14,41.93,35.80,27.84,26.57,24.95,23.49,21.26,20.88,18.99.esi-ms:[m+1]+,430
化合物lz-09：14-[n-(3-甲基苄基)-2-吡咯甲烯基]苦参碱：黄色固体粉末，收率47％；
1hnmr(600mhz,chloroform-d)δ7.68(s,1h),7.20(t,j＝7.6hz,1h),7.07(d,j＝7.6hz,1h),6.92(s,1h),6.89(d,j＝7.8hz,1h),6.81(dd,j＝2.7,1.6hz,1h),6.43(dd,j＝3.9,1.5hz,1h),6.28(t,j＝3.8,2.8hz,1h),5.17(s,2h),4.45(dd,j＝12.7,4.5hz,1h),4.00–3.93(m,1h),3.21(t,j＝12.6hz,1h),2.91–2.78(m,3h),2.62–2.53(m,1h),2.31(s,3h),2.18–2.08(m,2h),2.03–1.89(m,3h),1.85–1.74(m,4h),1.74–1.50(m,3h),1.51–1.38(m,2h),1.37–1.25(m,1h).13cnmr(151mhz,cdcl3)δ165.01,138.37,137.59,129.31,128.65,128.33,127.47,126.38,124.09,123.89,122.61,112.57,108.87,63.87,57.33,57.29,52.68,50.64,43.14,41.94,35.79,27.83,26.56,24.95,23.45,21.42,21.25,20.87.esi-ms:[m+1]+,430
化合物lz-10：14-[n-(4-甲基苄基)-2-吡咯甲烯基]苦参碱：黄色固体粉末，收率43％；
1hnmr(600mhz,chloroform-d)δ7.69(s,1h),7.12(d,j＝7.8hz,2h),7.01(d,j＝7.9hz,2h),6.81(dd,j＝2.7,1.5hz,1h),6.42(dd,j＝4.0,1.5hz,1h),6.27(t,j＝3.3hz,1h),5.17(s,2h),4.45(dd,j＝12.7,4.5hz,1h),4.02–3.92(m,1h),3.21(t,j＝12.6hz,1h),2.93–2.78(m,3h),2.63–2.54(m,1h),2.32(s,3h),2.16–2.07(m,2h),2.04–1.89(m,4h),1.82–1.51(m,5h),1.50–1.42(m,3h),1.38–1.25(m,1h).13cnmr(151mhz,cdcl3)δ165.02,137.20,134.61,129.43(2c),129.25,126.82(2c),126.17,124.07,122.63,112.63,108.84,63.86,57.33,57.29,52.68,50.54,43.15,41.91,35.79,27.83,26.56,24.90,23.42,21.25,21.09,20.87.esi-ms:[m+1]+,430
化合物lz-11：14-[n-(3,5-二甲基苄基)-2-吡咯甲烯基]苦参碱：黄色固体粉末，收率25％；
1hnmr(600mhz,chloroform-d)δ7.68(s,1h),6.89(s,1h),6.79(dd,j＝2.7,1.6hz,1h),6.71(s,2h),6.42(d,j＝3.9,1.5hz,1h),6.28(t,j＝3.8,2.7hz,1h),5.13(s,2h),4.46(dd,j＝12.7,4.4hz,1h),4.02–3.93(m,1h),3.21(t,j＝12.6hz,1h),2.93–2.75(m,3h),2.59(m,1h),2.27(s,6h),2.16–2.08(m,2h),2.03–1.90(m,3h),1.90–1.74(m,3h),1.74–1.53(m,3h),1.49–1.42(m,3h),1.30–1.20(m,1h).13cnmr(151mhz,cdcl3)δ165.03,138.27,137.51,129.30,129.23,126.42,124.61(2c),124.08,122.68,112.50,108.79,63.87,57.33,57.29,52.68,50.55,43.13,41.95,35.79,27.83,26.56,24.98,23.47,21.31(2c),21.25,20.87.esi-ms:[m+1]+,444
化合物lz-12：14-[n-(4-叔丁基苄基)-2-吡咯甲烯基]苦参碱：白色固体粉末，收率26％；
1hnmr(600mhz,chloroform-d)δ7.72(s,1h),7.33(d,2h),7.05(d,2h),6.82(t,j＝2.7,1.6hz,1h),6.43(dd,j＝4.0,1.5hz,1h),6.28(t,j＝3.8,2.7hz,1h),5.18(s,2h),4.46(dd,j＝12.7,4.4hz,1h),3.99–3.94(m,1h),3.22(t,j＝12.7hz,1h),2.92–2.78(m,3h),2.63–2.56(m,1h),2.17–2.08(m,2h),2.04–1.89(m,3h),1.83–1.52(m,6h),1.50–1.30(m,4h),1.30(s,9h).13cnmr(151mhz,cdcl3)δ165.03,150.40,134.64,129.26,126.55(2c),126.25,125.67(2c),124.08,122.64,112.60,108.89,63.86,57.34,57.30,52.69,50.36,43.16,41.92,35.80,34.49,31.34(3c),27.84,26.58,24.92,23.46,21.27,20.88.esi-ms:[m+1]+,472
化合物lz-13：14-[n-(3,5-二叔丁基苄基)-2-吡咯甲烯基]苦参碱：白色固体粉末，收率30％；
1hnmr(600mhz,chloroform-d)δ7.72(s,1h),7.31(t,j＝1.9hz,1h),6.89(d,j＝1.8hz,2h),6.78(dd,j＝2.7,1.6hz,1h),6.42–6.40(m,1h),6.27(t,1h),5.20(s,2h),4.46(dd,j＝12.7,4.4hz,1h),3.96(s,1h),3.21(t,j＝12.6hz,1h),2.95–2.79(m,3h),2.60(m,1h),2.20–2.06(m,2h),2.04–1.89(m,3h),1.83–1.73(m,3h),1.74–1.66(m,1h),1.62–1.54(m,2h),,1.49–1.44(m,3h),1.28(s,19h).13cnmr(151mhz,cdcl3)δ165.03,151.05(2c),136.71,129.37,126.47,123.95,122.87,121.41,121.18(2c),112.50,108.73,63.88,57.34,57.30,52.69,51.01,43.08,42.00,35.79,34.76(2c),31.40(6c),27.83,26.56,25.10,23.44,21.26,20.87.esi-ms:[m+1]+,528
化合物lz-14：14-[n-(2-氯苄基)-2-吡咯甲烯基]苦参碱：白色固体粉末，收率30％；
1hnmr(600mhz,chloroform-d)δ7.57(s,1h),7.38(dd,j＝7.9,1.3hz,1h),7.20(t,j＝7.7,1.7hz,1h),7.14(t,j＝7.6,1.3hz,1h),6.80(dd,j＝2.7,1.5hz,1h),6.56(d,j＝7.7,1.6hz,1h),6.46(d,j＝3.9,1.5hz,1h),6.32(t,j＝3.3hz,1h),5.29(s,2h),4.44(dd,j＝12.8,4.4hz,1h),4.00–3.92(m,1h),3.20(t,j＝12.6hz,1h),2.93–2.77(m,3h),2.65–2.56(m,1h),2.16–2.10(m,2h),2.04–1.87(m,4h),1.81–1.66(m,3h),1.64–1.52(m,2h),1.50–1.40(m,3h),1.34–1.26(m,1h).13cnmr(151mhz,cdcl3)δ164.75,135.55,132.07,129.37,129.30,128.72,127.71,127.22,126.83,124.22,122.09,112.78,109.35,63.74,57.27,57.23,52.61,48.28,43.06,41.91,35.74,27.80,26.51,24.94,23.50,21.21,20.83.esi-ms:[m+1]+,450
化合物lz-15：14-[n-(3-氯苄基)-2-吡咯甲烯基]苦参碱：黄色固体粉末，收率25％；
1hnmr(600mhz,chloroform-d)δ7.60(s,1h),7.25–7.19(m,2h),6.99(s,1h),6.98–6.94(m,1h),6.81(dd,j＝2.7,1.6hz,1h),6.43(dd,j＝3.9,1.5hz,1h),6.30(dd,j＝3.8,2.8hz,1h),5.18(d,j＝3.1hz,2h),4.43(dd,j＝12.7,4.4hz,1h),3.98–3.92(m,1h),3.20(t,j＝12.6hz,1h),2.89–2.77(m,3h),2.60–2.52(m,1h),2.15–2.06(m,3h),2.03–1.88(m,3h),1.82–1.74(m,2h),1.71–1.51(m,4h),1.49–1.37(m,2h),1.34–1.23(m,1h).13cnmr(151mhz,cdcl3)δ164.80,139.90,134.66,130.03,129.16,127.74,126.80,126.59,124.73,124.07,122.15,112.88,109.33,63.78,57.29,57.25,52.65,50.01,43.13,41.90,35.77,27.80,26.52,24.87,23.41,21.22,20.84.esi-ms:[m+1]+,450
化合物lz-16：14-[n-(4-氯苄基)-2-吡咯甲烯基]苦参碱：黄色固体粉末，收率32％；
1hnmr(600mhz,chloroform-d)δ7.61(s,1h),7.28–7.26(m,2h),7.04–6.99(m,2h),6.82(dd,j＝2.7,1.6hz,1h),6.43(dd,j＝4.0,1.5hz,1h),6.29(t,j＝3.8,2.7hz,1h),5.19–5.17(m,2h),4.43(dd,j＝12.7,4.4hz,1h),3.98–3.93(m,1h),3.20(t,j＝12.6hz,1h),2.89–2.78(m,3h),2.60–2.54(m,1h),2.16–2.07(m,2h),2.02–1.89(m,4h),1.81–1.74(m,2h),1.71–1.65(m,1h),1.66–1.49(m,2h),1.49–1.40(m,3h),1.36–1.23(m,1h).13cnmr(151mhz,cdcl3)δ164.75,136.33,133.25,129.06,128.85(2c),128.02(2c),126.34,124.10,122.20,112.91,109.24,63.71,57.26,57.22,52.59,50.01,43.13,41.84,35.77,27.80,26.51,24.77,23.37,21.22,20.82.esi-ms:[m+1]+,450
化合物lz-17：14-[n-(2-溴苄基)-2-吡咯甲烯基]苦参碱：白色固体粉末，收率35％；
1hnmr(600mhz,chloroform-d)δ7.59–7.53(m,2h),7.15(m,2h),6.79(dd,j＝2.7,1.6hz,1h),6.53–6.44(m,2h),6.32(t,j＝3.8,2.8hz,1h),5.25(s,2h),4.43(dd,j＝12.7,4.5hz,1h),4.01–3.90(m,1h),3.19(t,j＝12.7hz,1h),2.95–2.77(m,3h),2.65–2.54(m,1h),2.18–2.08(m,2h),2.04–1.89(m,4h),1.82–1.73(m,2h),1.71–1.61(m,2h),1.62–1.48(m,2h),1.48–1.41(m,2h),1.36–1.23(m,1h).13cnmr(151mhz,cdcl3)δ164.82,137.15,132.63,129.48,129.00,127.87,127.79,127.01,124.18,122.12,121.97,112.75,109.36,63.82,57.31,57.27,52.67,50.82,43.09,41.96,35.75,27.80,26.54,25.01,23.53,21.23,20.86.esi-ms:[m+1]+,494
化合物lz-18：14-[n-(3-溴苄基)-2-吡咯甲烯基]苦参碱：黄色固体粉末，收率40％；
1hnmr(600mhz,chloroform-d)δ7.59(s,1h),7.36(d,j＝8.1,1.9hz,1h),7.18–7.13(m,2h),6.99(d,j＝7.7hz,1h),6.82–6.77(m,1h),6.42(d,j＝3.9,1.5hz,1h),6.29(t,j＝3.3hz,1h),5.16(d,j＝3.6hz,2h),4.43(dd,j＝12.7,4.4hz,1h),3.98–3.92(m,1h),3.20(t,j＝12.6hz,1h),2.90–2.76(m,3h),2.60–2.52(m,1h),2.33–2.18(m,1h),2.14–2.07(m,2h),2.01–1.87(m,3h),1.80–1.73(m,2h),1.70–1.51(m,4h),1.48–1.40(m,3h).13cnmr(151mhz,cdcl3)δ164.84,140.13,130.71,130.33,129.54,129.19,126.89,125.23,124.05,122.90,122.18,112.88,109.35,63.80,57.31,57.27,52.67,49.97,43.15,41.93,35.78,27.82,26.54,24.91,23.42,21.24,20.86.esi-ms:[m+1]+,494
化合物lz-19：14-[n-(4-溴苄基)-2-吡咯甲烯基]苦参碱：黄色固体粉末，收率32％；
1hnmr(600mhz,chloroform-d)δ7.60(s,1h),7.43–7.38(m,2h),6.94(dd,j＝8.5,2.0hz,2h),6.82–6.79(m,1h),6.42(t,j＝3.9,1.6hz,1h),6.29–6.27(m,1h),5.14(s,2h),4.42(dd,j＝12.7,4.4hz,1h),3.98–3.91(m,1h),3.20(t,j＝12.6hz,1h),2.87–2.75(m,3h),2.59–2.51(m,1h),2.15–2.06(m,2h),2.02–1.87(m,3h),1.80–1.54(m,6h),1.46–1.41(m,3h),1.31–1.24(m,1h).13cnmr(151mhz,cdcl3)δ164.85,136.82,131.87(2c),129.16,128.36(2c),126.54,124.07,122.21,121.49,112.88,109.23,63.80,57.31,57.27,52.66,50.15,43.16,41.90,35.78,27.81,26.54,24.86,23.39,21.23,20.85.esi-ms:[m+1]+,494
化合物lz-20：14-[n-(4-氟苄基)-2-吡咯甲烯基]苦参碱：黄色固体粉末，收率15％；
1hnmr(600mhz,chloroform-d)δ7.64(s,1h),7.05(m,2h),6.97(m,2h),6.80(q,j＝2.0hz,1h),6.42(d,j＝3.8hz,1h),6.27(m,1h),5.15(d,j＝2.4hz,2h),4.43(dd,j＝12.8,4.5hz,1h),4.05–3.78(m,1h),3.20(t,j＝12.6hz,1h),2.90–2.76(m,3h),2.64–2.49(m,1h),2.17–2.05(m,2h),2.02–1.87(m,3h),1.80–1.48(m,6h),1.48–1.37(m,3h),1.32–1.23(m,1h).13cnmr(151mhz,cdcl3)δ164.88,c(162.97,161.34),133.50,129.13,128.43,128.38,126.39,124.01,122.32,115.71,115.57,112.83,109.13,63.80,57.30,57.26,52.65,50.05,43.15,41.89,35.78,27.80,26.53,24.85,23.39,21.22,20.84.esi-ms:[m+1]+,434
化合物lz-21：14-[n-(4-三氟甲氧基苄基)-2-吡咯甲烯基]苦参碱：白色固体粉末，收率35％；
1hnmr(600mhz,chloroform-d)δ7.62(s,1h),7.19–7.03(m,4h),6.89–6.76(m,1h),6.43(d,j＝3.6hz,1h),6.32–6.24(m,1h),4.43(dd,j＝12.7,4.4hz,1h),4.03–3.87(m,1h),3.20(t,j＝12.6hz,1h),2.91–2.75(m,3h),2.62–2.51(m,1h),2.36–2.16(m,1h),2.19–2.06(m,2h),2.03–1.87(m,4h),1.81–1.73(m,2h),1.71–1.50(m,4h),1.47–1.40(m,3h),1.36–1.24(m,1h).13cnmr(151mhz,cdcl3)δ164.84,148.54,136.52,129.17,128.01,126.69,124.02,122.13,121.26,c(122.96,121.23,119.55),117.85,112.86,109.30,63.79,57.30,57.26,52.67,49.93,43.16,41.92,35.78,27.80,26.53,24.86,23.40,21.23,20.84.esi-ms:[m+1]+,500
化合物lz-22：14-[n-(4-苄氧基苄基)-2-吡咯甲烯基]苦参碱：白色固体粉末，收率36％；
1hnmr(600mhz,chloroform-d)δ7.72(s,1h),7.43(d,j＝7.0hz,2h),7.40(t,j＝7.6hz,2h),7.36–7.32(m,1h),7.07(d,2h),6.92(d,2h),6.81(dd,j＝2.7,1.6hz,1h),6.43(dd,j＝3.9,1.5hz,1h),6.27(t,j＝3.3hz,1h),5.15(s,2h),5.04(s,2h),4.47(dd,j＝12.7,4.5hz,1h),4.00–3.94(m,1h),3.22(t,j＝12.6hz,1h),2.90–2.79(m,3h),2.62–2.55(m,1h),2.17–2.08(m,2h),2.04–1.86(m,5h),1.83–1.75(m,2h),1.71(m,1h),1.67–1.54(m,2h),1.51–1.42(m,3h).13cnmr(151mhz,cdcl3)δ165.04,158.28,136.95,130.01,129.18,128.58(2c),128.25(2c),127.95,127.48(2c),126.14,123.97,122.62,115.10(2c),112.67,108.85,70.04,63.86,57.34,57.30,52.69,50.25,43.18,41.90,35.80,27.84,26.57,24.89,23.42,21.26,20.88.esi-ms:[m+1]+,522
化合物lz-23：14-[n-(2-萘基亚甲基)-2-吡咯甲烯基]苦参碱：黄色固体粉末，收率21％；
1hnmr(600mhz,chloroform-d)δ7.82–7.70(m,4h),7.49(s,1h),7.46–7.41(m,2h),7.25–7.22(m,1h),6.89–6.78(m,1h),6.49–6.42(m,1h),6.34–6.28(m,1h),5.35(s,2h),4.43(dd,j＝12.7,4.4hz,1h),3.96–3.90(m,1h),3.18(t,j＝12.6hz,1h),2.88–2.72(m,3h),2.63–2.49(m,1h),2.19–1.79(m,6h),1.79–1.71(m,2h),1.69–1.47(m,4h),1.46–1.34(m,3h).13cnmr(151mhz,cdcl3)δ165.19,135.19,133.39,132.82,129.31,128.60,127.96,127.65,126.19,125.94,125.82,125.62,124.80,124.32,121.98,112.84,109.12,63.79,57.31,57.27,52.64,50.68,43.15,41.86,35.78,27.83,26.55,24.85,23.42,21.25,20.86.esi-ms:[m+1]+,466
(2)lz-24的制备：
具体制备lz-24的实验方法：
于100ml圆底烧瓶中分别加入100mmol(2.4g)氢化钠，50ml无水四氢呋喃，搅拌均匀，加入5mmol(1.24g)苦参碱，缓慢升温至80℃加入10mmol(2.35g)n-苄基-3-吲哚甲醛，反应24h至终点(tlc检测)。冷却，用3n的盐酸调节反应液至中性。二氯甲烷萃取(20mlx3)，合并有机相，无水na2so4干燥，减压抽滤、浓缩滤液后经硅胶柱层析(v己酸乙酯：v石油醚＝3：2)纯化，得1.041g黄色固体粉末苦参碱化合物lz-24：14-[n-(苄基)-3-吲哚甲烯基]苦参碱：黄色固体粉末，收率45％；
1hnmr(600mhz,chloroform-d)δ8.10(d,j＝1.9hz,1h),7.87(dd,j＝7.1,1.7hz,1h),7.36–7.27(m,5h),7.26–7.20(m,2h),7.14(d,2h),5.37(s,2h),4.55(dd,j＝12.7,4.5hz,1h),4.07–3.95(m,1h),3.25(t,j＝12.7hz,1h),2.96–2.78(m,3h),2.67–2.48(m,1h),2.19–2.12(m,2h),2.05–1.89(m,4h),1.86–1.53(m,5h),1.51–1.39(m,3h),1.37–1.24(m,1h).13cnmr(151mhz,cdcl3)δ165.32,136.92,136.14,128.87,128.72,128.48,127.81,126.70,125.94,125.88,122.73,120.43,119.65,112.58,109.77,63.92,57.36,57.33,52.70,50.36,43.11,41.97,35.81,27.87,26.60,25.14,24.20,21.30,20.91.[m+1]+,466
参考化合物lz-24的实验方法制备化合物lz-25～lz-52，化合物lz-25～lz-52结构鉴定数据如下：
化合物lz-25：14-[n-(3-甲氧基苄基)-3-吲哚甲烯基]苦参碱:白色固体粉末，收率32％；
1hnmr(600mhz,chloroform-d)δ8.09(s,1h),7.86(d,1h),7.29(t,j＝4.1hz,1h),7.26–7.19(m,4h),6.82(dd,j＝8.3,2.5hz,1h),6.71(d,1h),6.68(s,1h),5.33(s,2h),4.54(dd,j＝12.7,4.5hz,1h),4.04–3.96(m,1h),3.74(s,3h),3.25(t,j＝12.6hz,1h),2.94–2.78(m,3h),2.64–2.53(m,1h),2.19–2.11(m,2h),2.11–1.95(m,3h),1.92(d,j＝13.7hz,1h),1.87–1.71(m,3h),1.71–1.65(m,1h),1.64–1.52(m,2h),1.51–1.42(m,3h).13cnmr(151mhz,cdcl3)δ165.33,160.01,138.54,136.17,129.95,128.70,128.50,125.96,125.84,122.73,120.43,119.63,118.97,112.91,112.63,112.57,109.77,63.92,57.35,57.31,55.22,52.69,50.29,43.11,41.96,35.80,27.85,26.58,25.12,24.19,21.28,20.89.[m+1]+,496
化合物lz-26：14-[n-(4-甲氧基苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率35％；
1hnmr(600mhz,chloroform-d)δ8.09(s,1h),7.86(dd,j＝7.3,1.5hz,1h),7.31–7.26(m,1h),7.26(s,1h),7.24–7.18(m,2h),7.07(dd,j＝9.0,2.5hz,2h),6.86–6.82(m,2h),5.26(s,2h),4.54(dd,j＝12.7,4.5hz,1h),4.02–3.94(m,1h),3.76(s,3h),3.24(t,j＝12.6hz,1h),2.90–2.77(m,3h),2.59–2.53(m,1h),2.46–2.30(m,1h),2.18–2.09(m,2h),2.03–1.94(m,2h),1.91(d,j＝14.1hz,1h),1.83–1.62(m,4h),1.59–1.52(m,1h),1.50–1.38(m,3h),1.31–1.26(m,1h).13cnmr(151mhz,cdcl3)δ165.34,159.21,136.07,128.85,128.76,128.38,128.17,125.99,125.67,122.65,120.37,119.57,114.23,112.39,109.83,63.88,57.35,57.31,55.28,52.69,49.85,43.11,41.96,35.81,27.87,26.59,25.12,24.18,21.29,20.90.[m+1]+,496
化合物lz-27：14-[n-(3，5-二甲氧基苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率28％；
1hnmr(600mhz,chloroform-d)δ8.09(s,1h),7.85(d,1h),7.32–7.17(m,4h),6.38(t,j＝2.3hz,1h),6.28(d,j＝2.2hz,2h),5.28(s,2h),4.54(dd,j＝12.7,4.5hz,1h),4.04–3.96(m,1h),3.72(s,6h),3.24(t,j＝12.6hz,1h),2.93–2.79(m,3h),2.61–2.52(m,1h),2.21–2.12(m,2h),2.04–1.88(m,5h),1.87–1.64(m,4h),1.64–1.53(m,2h),1.51–1.41(m,2h).13cnmr(151mhz,cdcl3)δ165.33,161.22,139.35,136.21,128.69,128.49,125.97,125.86,122.74,120.43,119.63,112.58,109.74,104.87,99.30,63.92,57.35,57.32,55.33,52.70,50.39,43.11,41.96,35.81,27.86,26.59,25.12,24.20,21.28,20.90.[m+1]+,526
化合物lz-28：14-[n-(3，4，5-三甲氧基苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率27％；
1hnmr(600mhz,chloroform-d)δ8.08(s,1h),7.91–7.84(m,1h),7.33–7.30(m,1h),7.28–7.17(m,3h),6.35(s,2h),5.29(s,2h),4.54(dd,j＝12.8,4.5hz,1h),4.07–3.96(m,1h),3.84(s,3h),3.76(s,6h),3.25(t,j＝12.6hz,1h),2.94–2.77(m,3h),2.63–2.53(m,1h),2.20–2.09(m,2h),2.07–1.89(m,3h),1.88–1.72(m,4h),1.72–1.53(m,2h),1.52–1.40(m,3h).13cnmr(151mhz,cdcl3)δ165.30,153.63,137.54,136.25,132.49,128.67,128.34,126.02,125.94,122.76,120.50,119.70,112.61,109.70,103.84,63.90,60.87,57.33,57.30,56.15,52.69,50.48,43.06,42.02,35.78,27.84,26.58,25.18,24.21,21.26,20.87.[m+1]+,556
化合物lz-29：14-[n-(2-甲基苄基)-3-吲哚甲烯基]苦参碱:白色固体粉末，收率35％；
1hnmr(600mhz,chloroform-d)δ8.10(s,1h),7.90–7.87(m,1h),7.31–7.20(m,5h),7.18(s,1h),7.15–7.09(m,1h),6.76(d,j＝7.7hz,1h),5.33(s,2h),4.54(dd,j＝12.7,4.5hz,1h),4.05–3.95(m,1h),3.24(t,j＝12.6hz,1h),2.93–2.72(m,3h),2.58–2.49(m,1h),2.35(s,3h),2.18–2.10(m,2h),2.04–1.95(m,2h),1.94–1.86(m,2h),1.86–1.73(m,3h),1.71–1.54(m,3h),1.51–1.42(m,3h).13cnmr(151mhz,cdcl3)δ165.32,136.28,135.59,134.63,130.52,128.63,128.30,127.90,127.12,126.50,125.97,125.83,122.71,120.46,119.68,112.54,109.67,63.92,57.36,57.33,52.68,48.40,43.08,42.00,35.79,27.87,26.59,25.17,24.13,21.29,20.91,19.15.[m+1]+,480
化合物lz-30：14-[n-(3-甲基苄基)-3-吲哚甲烯基]苦参碱:白色固体粉末，收率38％；
1hnmr(600mhz,chloroform-d)δ8.11(s,1h),7.91–7.85(m,1h),7.32–7.27(m,1h),7.26–7.19(m,3h),7.11(d,j＝7.5hz,1h),6.98(d,j＝2.0hz,1h),6.93(d,j＝7.6hz,1h),5.32(s,2h),4.55(dd,j＝12.7,4.5hz,1h),4.03–3.97(m,1h),3.25(t,j＝12.7hz,1h),2.91–2.79(m,3h),2.59(m,1h),2.32(s,3h),2.16(td,j＝8.3,4.5hz,2h),2.06–1.91(m,4h),1.87–1.53(m,6h),1.52–1.43(m,2h),1.43–1.20(m,1h).13cnmr(151mhz,cdcl3)δ165.34,138.63,136.86,136.19,128.76,128.70,128.59,128.54,127.41,126.00,125.79,123.83,122.69,120.39,119.61,112.50,109.80,63.92,57.36,52.70,50.35,43.11,41.98,35.81,27.87,26.60,25.15,24.20,21.43,21.30,20.91.[m+1]+,480
化合物lz-31：14-[n-(4-甲基苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率34％；
1hnmr(600mhz,chloroform-d)δ8.11(s,1h),7.91–7.84(m,1h),7.28(s,2h),7.26–7.19(m,2h),7.12(d,j＝7.8hz,2h),7.04(d,2h),5.31(d,j＝2.8hz,2h),4.55(dd,j＝12.7,4.5hz,1h),3.99(td,j＝6.9,3.6hz,1h),3.25(t,j＝12.7hz,1h),2.91–2.79(m,3h),2.58(m,1h),2.33(s,3h),2.14(m,2h),2.05–1.89(m,4h),1.86–1.52(m,6h),1.50–1.42(m,3h),1.33–1.28(m,1h).13cnmr(151mhz,cdcl3)δ165.34,137.52,136.13,133.87,129.52,128.74,128.50,126.74,126.00,125.72,122.67,120.38,119.59,112.45,109.83,63.91,57.35,57.32,52.69,50.15,43.11,41.96,35.81,27.87,26.59,25.13,24.19,21.29,21.12,20.90.[m+1]+,480
化合物lz-32：14-[n-(4-叔丁基苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率31％；
1hnmr(600mhz,chloroform-d)δ8.11(d,j＝1.9hz,1h),7.91–7.85(m,1h),7.36–7.29(m,4h),7.27–7.19(m,2h),7.08(d,j＝8.2hz,2h),5.34(s,2h),4.56(dd,j＝12.7,4.5hz,1h),4.05–3.96(m,1h),3.26(t,j＝12.7hz,1h),2.91–2.79(m,3h),2.63–2.55(m,1h),2.21–2.12(m,2h),2.05–1.90(m,4h),1.87–1.65(m,4h),1.65–1.53(m,2h),1.51–1.43(m,3h),1.31(s,9h).13cnmr(151mhz,cdcl3)δ165.34,150.79,136.16,133.96,128.70,128.56,126.42,126.03,125.76,125.75,122.66,120.37,119.62,112.49,109.83,63.94,57.36,57.33,52.70,50.01,43.12,41.96,35.82,34.54,31.32,27.88,26.60,25.13,24.21,21.30,20.91.[m+1]+,522
化合物lz-33：14-[n-(2-氯苄基)-3-吲哚甲烯基]苦参碱:白色固体粉末，收率36％；
1hnmr(600mhz,chloroform-d)δ8.10(s,1h),7.89(dd,j＝6.7,2.0hz,1h),7.45(dd,j＝8.0,1.2hz,1h),7.31(s,1h),7.28–7.22(m,4h),7.12(d,j＝1.2hz,0h),6.64(d,j＝7.7,1.6hz,1h),5.47(s,2h),4.55(dd,j＝12.7,4.5hz,1h),4.07–3.96(m,1h),3.25(t,j＝12.6hz,1h),2.94–2.80(m,3h),2.64–2.55(m,1h),2.21–2.13(m,2h),2.06–1.90(m,3h),1.87–1.67(m,6h),1.65–1.55(m,1h),1.52–1.42(m,2h),1.39–1.24(m,1h).13cnmr(151mhz,cdcl3)δ165.26,136.11,134.53,132.40,129.59,129.01,128.65,128.56,127.91,127.33,126.18,125.81,122.92,120.60,119.74,112.88,109.67,63.92,57.35,57.32,52.70,47.96,43.11,41.99,35.80,27.86,26.59,25.15,24.19,21.28,20.90.[m+1]+,500
化合物lz-34：14-[n-(3-氯苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率36％；
1hnmr(600mhz,chloroform-d)δ8.09(s,1h),7.89–7.82(m,1h),7.27–7.19(m,6h),7.13(t,j＝1.7hz,1h),6.95(dd,j＝7.5,1.5hz,1h),5.29(s,2h),4.54(dd,j＝12.7,4.5hz,1h),4.04–3.90(m,1h),3.24(t,j＝12.7hz,1h),2.91–2.73(m,3h),2.62–2.51(m,1h),2.19–2.08(m,2h),2.03–1.94(m,2h),1.94–1.85(m,1h),1.85–1.60(m,5h),1.61–1.51(m,2h),1.51–1.41(m,3h),1.32–1.25(m,1h).13cnmr(151mhz,cdcl3)δ165.21,139.06,136.01,134.78,130.20,128.74,128.31,128.04,126.78,126.19,125.72,124.79,122.92,120.59,119.70,112.84,109.65,63.87,57.33,57.30,52.69,49.76,43.11,41.97,35.81,27.86,26.57,25.10,24.22,21.28,20.88.[m+1]+,500
化合物lz-35：14-[n-(4-氯苄基)-3-吲哚甲烯基]苦参碱:白色固体粉末，收率31％；
1hnmr(600mhz,chloroform-d)δ8.08(s,1h),7.86(dd,j＝7.1,1.8hz,1h),7.34–7.19(m,6h),7.06(d,j＝8.3hz,2h),5.33(d,j＝12.1hz,2h),4.54(dd,j＝12.7,4.5hz,1h),4.04–3.96(m,1h),3.25(t,j＝12.6hz,1h),2.94–2.78(m,3h),2.65–2.54(m,1h),2.20–2.09(m,1h),2.05–1.89(m,3h),1.87–1.52(m,8h),1.52–1.38(m,2h),1.38–1.22(m,1h).13cnmr(151mhz,cdcl3)δ165.25,135.99,135.42,133.67,129.06,128.73,128.21,128.02,126.16,125.79,122.88,120.58,119.77,112.83,109.63,63.91,57.34,57.31,52.69,49.73,43.10,41.99,35.79,27.84,26.58,25.15,24.20,21.26,20.88.[m+1]+,500
化合物lz-36：14-[n-(4-溴苄基)-3-吲哚甲烯基]苦参碱:白色固体粉末，收率35％；
1hnmr(600mhz,chloroform-d)δ8.08(s,1h),7.90–7.84(m,1h),7.43(d,j＝8.6,2.4hz,2h),7.27–7.19(m,4h),6.98(d,j＝8.7,2.3hz,2h),5.29(d,j＝3.3hz,2h),4.54(dd,j＝12.7,4.5hz,1h),4.04–3.95(m,1h),3.25(t,j＝12.6hz,1h),2.92–2.77(m,3h),2.61–2.52(m,1h),2.20–2.09(m,2h),2.05–1.89(m,3h),1.87–1.63(m,4h),1.64–1.53(m,1h),1.51–1.42(m,3h),1.30–1.25(m,2h).13cnmr(151mhz,cdcl3)δ165.24,135.98,131.99,128.74,128.35,128.25,126.14,125.76,122.88,121.71,120.58,119.72,112.81,109.65,63.89,57.33,57.29,52.68,49.75,43.10,41.98,35.79,27.84,26.57,25.13,24.21,21.26,20.87.[m+1]+,544
化合物lz-37：14-[n-(4-三氟甲氧基苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率42％；
1hnmr(600mhz,chloroform-d)δ8.09(s,1h),7.87(dd,j＝7.3,1.8hz,1h),7.28–7.21(m,4h),7.15(q,j＝8.6hz,4h),5.37(s,2h),4.54(dd,j＝12.7,4.5hz,1h),4.11–3.92(m,1h),3.25(t,j＝12.7hz,1h),2.92–2.78(m,3h),2.64–2.55(m,1h),2.19–2.12(m,2h),2.13–1.88(m,3h),1.86–1.66(m,4h),1.58(s,2h),1.51–1.42(m,3h),1.38–1.24(m,1h).13cnmr(151mhz,cdcl3)δ165.23,148.72,135.98,135.67,128.73,128.21,128.00,126.23,125.75,122.93,121.39,121.25,120.61,119.79,119.54,112.90,109.60,63.90,57.34,57.30,52.69,49.59,43.10,42.00,35.80,27.84,26.57,25.14,24.21,21.26,20.88.[m+1]+,550
化合物lz-38：14-[n-(4-苄氧基苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率34％；
1hnmr(600mhz,chloroform-d)δ8.10(s,1h),7.87(d,j＝7.6hz,1h),7.46–7.37(m,4h),7.37–7.19(m,5h),7.09(d,j＝8.4hz,2h),5.29(s,2h),5.05(s,2h),4.55(dd,j＝12.7,4.4hz,1h),4.05–3.96(m,1h),3.25(t,j＝12.6hz,1h),2.91–2.80(m,3h),2.61–2.55(m,1h),2.18–2.13(m,2h),2.08–1.97(m,3h),1.93(d,j＝13.6hz,1h),1.87–1.66(m,5h),1.64–1.55(m,1h),1.54–1.44(m,3h),1.37–1.29(m,1h).13cnmr(151mhz,cdcl3)δ165.36,158.43,136.80,136.08,129.17,128.75,128.61,128.36,128.17,128.03,127.45,126.01,125.74,122.67,120.40,119.64,115.20,112.46,109.80,70.07,63.93,57.37,57.33,52.70,49.87,43.11,41.98,35.81,27.87,26.61,25.15,24.19,21.30,20.91.[m+1]+,572
化合物lz-39：14-[n-(2-萘基亚甲基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率24％；
1hnmr(600mhz,chloroform-d)δ8.13(s,1h),7.91–7.88(m,1h),7.85–7.75(m,3h),7.60–7.57(m,1h),7.51–7.47(m,2h),7.35–7.32(m,2h),7.27(dd,j＝8.5,1.8hz,1h),7.25–7.22(m,2h),5.52(s,2h),4.55(dd,j＝12.7,4.5hz,1h),4.05–3.93(m,1h),3.25(t,j＝12.6hz,1h),2.94–2.76(m,3h),2.64–2.52(m,1h),2.18–2.12(m,2h),2.04–1.95(m,2h),1.94–1.87(m,2h),1.86–1.80(m,1h),1.81–1.71(m,1h),1.72–1.54(m,3h),1.50–1.41(m,3h),1.33–1.26(m,1h).13cnmr(151mhz,cdcl3)δ165.32,136.26,134.35,133.32,132.91,128.82(2c),128.78,128.48,127.85,127.73,126.46,126.17,125.93,125.57,124.61,122.79,120.50,119.68,112.70,109.80,63.92,57.35,57.32,52.70,50.58,43.12,41.97,35.82,27.87,26.59,25.12,24.21,21.29,20.89.[m+1]+,516
化合物lz-40：14-[5-溴-n-(3-氯苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率19％；
1hnmr(600mhz,chloroform-d)δ7.96(s,1h),7.94(s,1h),7.31–7.20(m,4h),7.11–7.06(m,2h),6.93(d,j＝7.4hz,1h),5.28(s,2h),4.52(dd,j＝12.7,4.5hz,1h),4.04–3.93(m,1h),3.24(t,j＝12.6hz,1h),2.92–2.75(m,3h),2.58–2.49(m,1h),2.21–2.08(m,2h),2.07–1.94(m,2h),1.94–1.88(m,1h),1.87–1.61(m,4h),1.62–1.52(m,2h),1.50–1.38(m,3h),1.35–1.24(m,1h).13cnmr(151mhz,cdcl3)δ164.94,138.55,134.91,134.64,130.33,130.28,129.14,128.23,127.05,126.71,125.77,124.90,124.67,122.45,114.02,112.38,111.17,63.83,57.31,57.28,52.68,49.97,43.08,42.03,35.77,27.82,26.55,25.12,24.19,21.24,20.86.[m+1]+,578
化合物lz-41：14-[5-溴-n-(2-萘基亚甲基)3-吲哚甲烯基]苦参碱:黄色固体粉末，收率20％；
1hnmr(600mhz,chloroform-d)δ8.01(d,j＝1.8hz,1h),7.99(s,1h),7.85–7.73(m,3h),7.53(s,1h),7.50–7.48(m,2h),7.31(s,1h),7.30–7.25(m,1h),7.24–7.19(m,1h),7.18–7.11(m,1h),5.47(s,2h),4.54(dd,j＝12.7,4.4hz,1h),4.03–3.93(m,1h),3.25(t,j＝12.6hz,1h),2.91–2.76(m,3h),2.58–2.51(m,1h),2.18–2.10(m,2h),2.05–1.95(m,2h),1.89(d,j＝13.3hz,1h),1.85–1.71(m,3h),1.70–1.51(m,3h),1.50–1.40(m,3h),1.35–1.25(m,1h).13cnmr(151mhz,cdcl3)δ165.05,134.87,133.85,133.27,132.93,130.39,129.38,128.94,127.84,127.76,126.74,126.58,126.30,125.64,125.55,125.11,124.41,122.39,113.93,112.19,111.38,63.85,57.31,57.28,52.67,50.77,43.09,42.00,35.78,27.82,26.54,25.11,24.18,21.24,20.85.[m+1]+,594
化合物lz-42：14-[5-溴-n-(4-三氟甲氧基苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率32％；
1hnmr(600mhz,chloroform-d)δ7.98(d,j＝1.9hz,1h),7.95(s,1h),7.31(dd,j＝8.7,1.9hz,1h),7.24(s,1h),7.17(d,j＝8.3hz,2h),7.13–7.09(m,3h),5.34(s,2h),4.52(dd,j＝12.7,4.5hz,1h),4.03–3.97(m,1h),3.25(t,j＝12.7hz,1h),2.90–2.78(m,3h),2.59–2.52(m,1h),2.20–2.12(m,2h),2.04–1.96(m,2h),1.95–1.88(m,2h),1.83–1.73(m,3h),1.71–1.64(m,1h),1.64–1.54(m,1h),1.49–1.43(m,2h),1.29–1.23(m,2h).13cnmr(151mhz,cdcl3)δ164.96,148.83,135.18,134.63,130.33,129.06,127.94,127.06,125.81,124.95,122.52,121.46,114.07,114.05,112.43,111.13,63.85,57.31,57.28,52.68,49.79,43.09,42.06,35.77,29.71,29.66,27.81,26.55,25.15,24.19.[m+1]+,628
化合物lz-43：14-[5-甲氧基-n-(2-氯苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率29％；
1hnmr(600mhz,chloroform-d)δ8.07(s,1h),7.46–7.41(m,1h),7.31(d,j＝2.4hz,1h),7.22(td,j＝7.7,1.6hz,1h),7.15–7.08(m,2h),6.89(dd,j＝8.8,2.4hz,1h),6.62(d,j＝7.7,1.6hz,1h),5.42(s,2h),4.54(dd,j＝12.7,4.5hz,1h),4.04–3.96(m,1h),3.88(s,3h),3.25(t,j＝12.6hz,1h),2.92–2.79(m,3h),2.63–2.51(m,1h),2.19–2.11(m,2h),2.05–1.88(m,4h),1.86–1.53(m,5h),1.51–1.28(m,5h).13cnmr(151mhz,cdcl3)δ165.38,154.96,134.60,132.34,131.12,129.56,129.25,128.99,128.95,127.86,127.32,125.87,125.50,113.60,112.46,110.61,100.80,63.91,57.34,57.31,55.84,52.68,48.15,43.17,41.93,35.84,27.87,26.59,25.07,24.12,21.28,20.89.[m+1]+,530
化合物lz-44：14-[5-甲氧基-n-(3-氯苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率21％；
1hnmr(600mhz,chloroform-d)δ8.05(s,1h),7.31–7.28(m,1h),7.26–7.20(m,3h),7.14–7.06(m,2h),6.96–6.91(m,1h),6.91–6.85(m,1h),5.27(s,2h),4.53(dd,j＝12.7,4.5hz,1h),4.04–3.97(m,1h),3.87(s,3h),3.24(t,j＝12.6hz,1h),2.90–2.77(m,3h),2.62–2.55(m,1h),2.18–2.10(m,3h),2.03–1.94(m,2h),1.91(d,j＝13.6hz,1h),1.88–1.77(m,2h),1.76–1.65(m,2h),1.63–1.54(m,2h),1.50–1.40(m,2h),1.34–1.24(m,1h).13cnmr(151mhz,cdcl3)δ165.34,154.94,139.08,134.80,131.03,130.19,129.35,128.65,128.04,126.71,125.79,125.57,124.70,113.59,112.46,110.55,100.83,63.89,57.34,57.30,55.84,52.68,50.00,43.16,41.93,35.84,27.87,26.59,25.05,24.15,22.66,21.28,20.88.[m+1]+,530
化合物lz-45：14-[5-甲氧基-n-(4-氯苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率27％；
1hnmr(600mhz,chloroform-d)δ8.05(d,j＝1.9hz,1h),7.32–7.25(m,3h),7.09(d,j＝8.9hz,1h),7.03(d,j＝8.3hz,2h),6.87(dd,j＝8.9,2.4hz,1h),5.27(s,2h),4.54(dd,j＝12.7,4.5hz,1h),4.00(ddd,j＝11.4,7.1,5.1hz,1h),3.87(s,3h),3.25(t,j＝12.6hz,1h),2.92–2.76(m,3h),2.62–2.52(m,1h),2.19–2.07(m,3h),2.03–1.96(m,2h),1.94–1.89(m,1h),1.85–1.77(m,2h),1.76–1.66(m,2h),1.62–1.54(m,2h),1.51–1.44(m,2h),1.29–1.23(m,2h).13cnmr(151mhz,cdcl3)δ165.34,154.92,135.48,133.63,131.01,129.36,129.03,128.61,127.96,125.80,125.50,113.55,112.39,110.58,100.81,63.89,57.34,57.31,55.84,52.67,49.93,43.15,41.94,35.83,27.87,26.60,25.07,24.15,21.28,20.89.[m+1]+,530
化合物lz-46：14-[5-甲氧基-n-(2-萘基亚甲基)-3-吲哚甲烯基]苦参碱：黄色固体粉末，收率23％；
1hnmr(600mhz,chloroform-d)δ8.09(d,j＝1.8hz,1h),7.86–7.74(m,3h),7.59–7.55(m,1h),7.50–7.47(m,2h),7.32(d,j＝2.9hz,2h),7.26(dd,j＝8.5,1.8hz,1h),7.19(d,j＝8.9hz,1h),6.87(dd,j＝8.9,2.4hz,1h),5.49(s,2h),4.55(dd,j＝12.7,4.5hz,1h),4.02–3.97(m,1h),3.89(s,3h),3.25(t,j＝12.6hz,1h),2.90–2.79(m,3h),2.64–2.56(m,1h),2.18–2.12(m,2h),2.03–1.96(m,2h),1.91(d,j＝13.6hz,1h),1.85–1.74(m,4h),1.72–1.65(m,1h),1.64–1.55(m,1h),1.51–1.42(m,2h),1.30–1.23(m,2h).13cnmr(151mhz,cdcl3)δ165.44,154.89,134.38,133.31,132.90,131.30,129.36,128.86,128.82,127.84,127.73,126.47,126.16,125.98,125.50,125.28,124.55,113.48,112.29,110.74,100.77,63.93,57.35,57.32,55.86,52.68,50.81,43.17,41.90,35.84,27.88,26.60,25.05,24.14,21.29,20.89.[m+1]+,546
化合物lz-47：14-[5-甲基-n-(3-氯苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率21％；
1hnmr(600mhz,chloroform-d)δ8.06(s,1h),7.67(s,1h),7.28–7.21(m,3h),7.17–7.11(m,2h),7.07(d,j＝8.4,1.5hz,1h),6.96(d,j＝7.4hz,1h),5.30(s,2h),4.54(dd,j＝12.7,4.5hz,1h),4.04–3.93(m,1h),3.25(t,j＝12.6hz,1h),2.91–2.78(m,3h),2.62–2.55(m,1h),2.48(s,3h),2.21–2.11(m,2h),2.09–1.96(m,2h),1.94–1.87(m,1h),1.86–1.52(m,5h),1.46(m,3h),1.36–1.22(m,2h).13cnmr(151mhz,cdcl3)δ165.31,139.17,134.80,134.38,130.18,130.03,129.03,128.29,128.01,126.75,125.91,125.82,124.71,124.51,119.48,112.40,109.29,63.93,57.35,57.32,52.69,49.85,43.13,41.94,35.81,27.86,26.60,25.09,24.18,21.50,21.28,20.90.[m+1]+,514
化合物lz-48：14-[5-甲基-n-(2-萘基亚甲基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率29％；
1hnmr(600mhz,chloroform-d)δ8.14(s,1h),7.84–7.80(m,1h),7.78(d,j＝8.5hz,1h),7.76–7.73(m,1h),7.72(s,1h),7.56(s,1h),7.49–7.45(m,2h),7.30(s,1h),7.24(dd,j＝8.5,1.7hz,1h),7.20(d,j＝8.3hz,1h),7.06(dd,j＝8.4,1.6hz,1h),5.45(s,2h),4.56(dd,j＝12.7,4.5hz,1h),4.02–3.94(m,1h),3.25(t,j＝12.6hz,1h),2.90–2.78(m,3h),2.61–2.55(m,1h),2.49(s,3h),2.14–2.09(m,2h),2.03–1.96(m,2h),1.89(d,j＝14.3hz,1h),1.85–1.73(m,3h),1.71–1.62(m,1h),1.61–1.52(m,2h),1.50–1.39(m,3h),1.37–1.26(m,1h).13cnmr(151mhz,cdcl3)δ165.39,134.64,134.51,133.32,132.88,129.88,129.10,128.78,128.58,127.85,127.73,126.44,126.13,126.07,125.51,125.49,124.62,124.39,119.38,112.18,109.54,63.91,57.36,57.32,52.68,50.59,43.15,41.89,35.84,27.89,26.59,25.05,24.19,21.55,21.31,20.90.[m+1]+,530
化合物lz-49：14-[6-氯-n-(3-氯苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率25％；
1hnmr(600mhz,chloroform-d)δ7.99(s,1h),7.74(d,j＝8.4hz,1h),7.33–7.20(m,4h),7.18(d,j＝8.5hz,1h),7.12(s,1h),6.95(d,j＝7.4hz,1h),5.28(s,2h),4.53(dd,j＝12.7,4.5hz,1h),4.04–3.93(m,1h),3.25(t,j＝12.6hz,1h),2.91–2.78(m,3h),2.62–2.55(m,1h),2.21–2.11(m,2h),2.09–1.96(m,2h),1.94–1.87(m,1h),1.86–1.52(m,5h),1.46(m,3h),1.36–1.22(m,2h).13cnmr(151mhz,cdcl3)δ165.02,138.49,136.42,134.95,130.32,128.98,128.71,128.27,127.24,126.97,126.69,125.11,124.67,121.32,120.71,113.03,109.62,63.86,57.29,57.26,52.67,49.81,43.09,42.00,35.77,27.79,26.52,.09,24.16,21.20,20.82.[m+1]+,534
化合物lz-50：14-[6-氯-n-(4-三氟甲氧基苄基)-3-吲哚甲烯基]苦参碱：黄色固体粉末，收率32％；
1hnmr(600mhz,chloroform-d)δ7.99(s,1h),7.75(d,j＝8.5hz,1h),7.24(d,j＝2.2hz,2h),7.19(dd,j＝8.5,1.9hz,3h),7.12(d,j＝8.7hz,2h),5.32(s,2h),4.52(dd,j＝12.7,4.5hz,1h),4.03–3.97(m,1h),3.25(t,j＝12.7hz,1h),2.90–2.78(m,3h),2.59–2.52(m,1h),2.20–2.12(m,2h),2.04–1.96(m,2h),1.95–1.88(m,2h),1.83–1.73(m,3h),1.71–1.64(m,1h),1.64–1.54(m,1h),1.49–1.43(m,2h),1.29–1.23(m,2h).13cnmr(151mhz,cdcl3)δ164.99,148.86,148.85,136.40,135.13,129.00,128.62,127.95,127.23,127.01,125.06,121.49,121.32,120.74,113.06,109.60,63.84,57.31,57.28,52.69,49.62,43.11,42.03,35.79,27.83,26.56,25.09,24.17,21.25,20.86.[m+1]+,584
化合物lz-51：14-[6-甲氧基-n-(4-氯苄基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率20％；
1hnmr(600mhz,chloroform-d)δ8.02(s,1h),7.72(d,j＝8.7,1.6hz,1h),7.30–7.25(m,2h),7.14(s,1h),7.04(d,j＝8.5,2.2hz,2h),6.89–6.84(m,1h),6.66(t,j＝2.0hz,1h),5.24(s,2h),4.52(dd,j＝12.8,4.4hz,1h),4.02–3.94(m,1h),3.80(d,j＝2.1hz,3h),3.23(t,j＝12.6hz,1h),2.89–2.76(m,3h),2.58–2.51(m,1h),2.38–2.09(m,3h),2.04–1.87(m,3h),1.85–1.70(m,3h),1.69–1.62(m,1h),1.62–1.37(m,4h),1.34–1.21(m,1h).13cnmr(151mhz,cdcl3)δ165.26,157.05,136.79,135.39,133.59,129.03,128.01,127.29,126.02,125.84,123.04,120.35,112.81,109.95,93.53,63.87,57.33,57.29,55.69,52.67,49.62,43.11,41.94,35.80,27.85,26.57,25.06,24.15,21.27,20.87.[m+1]+,530
化合物lz-52：14-[6-甲氧基-n-(2-萘基亚甲基)-3-吲哚甲烯基]苦参碱:黄色固体粉末，收率23％；
m,2h),7.57(s,1h),7.51–7.46(m,2h),7.29(s,1h),7.23(s,1h),6.90(dd,j＝8.7,2.2hz,1h),6.79(d,j＝2.2hz,1h),5.46(s,2h),4.54(dd,j＝12.7,4.5hz,1h),4.02–3.95(m,1h),3.80(s,3h),3.24(t,j＝12.6hz,1h),2.91–2.77(m,3h),2.62–2.51(m,1h),2.19–2.10(m,2h),2.04–1.95(m,2h),1.91(d,j＝13.7hz,1h),1.87–1.63(m,5h),1.61–1.53(m,1h),1.49–1.41(m,2h),1.35–1.26(m,2h).13cnmr(151mhz,cdcl3)δ165.34,157.02,137.05,134.30,133.33,132.89,128.82,127.85,127.73,127.53,126.46,126.16,126.01,125.85,125.51,124.61,123.08,120.34,112.74,109.94,93.63,63.93,57.35,57.32,55.70,52.68,50.48,43.13,41.92,35.81,27.86,26.58,25.05,24.15,21.28,20.89.[m+1]+,546
(3)lz-53的制备：
具体制备lz-53的实验方法：
于100ml圆底烧瓶中分别加入100mmol(2.4g)氢化钠，50ml无水四氢呋喃，搅拌均匀，加入5mmol(1.24g)苦参碱，缓慢升温至80℃加入10mmoln-(3-氯苄基)-4-吲哚甲醛，反应24h至终点(tlc检测)。冷却，用3n的盐酸调节反应液至中性。二氯甲烷萃取(20mlx3)，合并有机相，无水na2so4干燥，减压抽滤、浓缩滤液后经硅胶柱层析(v己酸乙酯：v石油醚＝3：2)纯化，得0.850g黄色固体粉末苦参碱化合物lz-53：14-[n-(3-氯苄基)-4-吲哚甲烯基]苦参碱:白色固体粉末，收率34％；
1hnmr(600mhz,chloroform-d)δ8.11(s,1h),7.28–7.10(m,6h),7.08(d,j＝6.8hz,1h),6.98(dd,j＝7.2,1.6hz,1h),6.67(d,j＝3.2hz,1h),5.29(s,2h),4.58(dd,j＝12.7,4.4hz,1h),4.04–3.95(m,1h),3.27(t,j＝12.7hz,1h),2.96–2.79(m,3h),2.57–2.48(m,1h),2.19–1.94(m,5h),1.93–1.73(m,3h),1.72–1.63(m,1h),1.62–1.41(m,5h),1.36–1.23(m,1h).13cnmr(151mhz,cdcl3)δ165.06,139.48,136.15,134.73,132.42,131.29,130.11,128.96,128.52,128.38,127.92,126.90,124.92,121.49,120.46,109.35,101.27,63.83,57.33,57.29,52.98,49.69,42.75,42.73,35.69,27.86,26.45,26.13,23.76,21.27,20.85.[m+1]+,500
参考化合物lz-53的实验方法制备化合物lz-54～lz-55，化合物lz-54～lz-55结构鉴定数据如下：
化合物lz-54：14-[n-(4-甲氧基苄基)-4-吲哚甲烯基]苦参碱：黄色固体粉末，收率32％；
1hnmr(600mhz,chloroform-d)δ8.12(s,1h),7.27(d,j＝8.2hz,1h),7.18(t,j＝7.7hz,1h),7.14(d,j＝3.2hz,1h),7.10–7.05(m,3h),6.87–6.82(m,2h),6.63(dd,j＝3.2,0.9hz,1h),5.24(s,2h),4.58(dd,j＝12.7,4.4hz,1h),4.02–3.95(m,1h),3.77–3.76(m,3h),3.27(t,j＝12.7hz,1h),2.95–2.80(m,3h),2.58–2.49(m,1h),2.19–2.08(m,2h),2.04–1.97(m,2h),1.92–1.73(m,3h),1.72–1.63(m,1h),1.60–1.55(m,2h),1.53–1.41(m,3h),1.36–1.26(m,2h).13cnmr(151mhz,cdcl3)δ165.10,159.13,136.20,132.60,131.11,129.31,128.78,128.52,128.33,128.30,121.19,120.23,114.16,109.57,100.70,63.83,57.33,57.29,55.27,52.97,49.74,42.74,42.71,35.70,27.87,26.45,26.13,23.77,21.28,20.86.[m+1]+,496
化合物lz-55：14-[n-(4-叔丁基苄基)-4-吲哚甲烯基]苦参碱:白色固体粉末，收率27％；
1hnmr(600mhz,chloroform-d)δ8.11(s,1h),7.37–7.33(m,2h),7.30(d,j＝8.2hz,1h),7.21–7.16(m,2h),7.08(dd,j＝14.5,7.8hz,3h),6.64(d,j＝3.1hz,1h),5.32(s,2h),4.58(dd,j＝12.7,4.4hz,1h),4.04–3.95(m,1h),3.27(t,j＝12.7hz,1h),2.96–2.81(m,3h),2.57–2.51(m,1h),2.19–2.08(m,2h),2.06–1.97(m,2h),1.93–1.75(m,3h),1.72–1.64(m,1h),1.62–1.57(m,1h),1.57–1.39(m,4h),1.39–1.21(m,11h).13cnmr(151mhz,cdcl3)h),1.49–1.41(m,2h),1.35–1.26(m,2h).13cnmr(151mhz,cdcl3)δ165.06,139.48,136.15,134.73,132.42,131.29,130.11,128.96,128.52,128.38,127.92,126.90,124.92,121.49,120.46,109.35,101.27,63.83,57.33,57.29,52.98,49.69,42.75,42.73,35.69,27.86,26.45,26.13,23.76,21.27,20.85.[m+1]+,522
(4)lz-56的制备：
具体制备lz-56的实验方法：
于100ml圆底烧瓶中分别加入100mmol(2.4g)氢化钠，50ml无水四氢呋喃，搅拌均匀，加入5mmol(1.24g)苦参碱，缓慢升温至80℃加入10mmoln-(3-氯苄基)-5-吲哚甲醛，反应24h至终点(tlc检测)。冷却，用3n的盐酸调节反应液至中性。二氯甲烷萃取(20mlx3)，合并有机相，无水na2so4干燥，减压抽滤、浓缩滤液后经硅胶柱层析(v己酸乙酯：v石油醚＝3：2)纯化，得1.047g黄色固体粉末苦参碱化合物lz-56：14-[n-(3-氯苄基)-5-吲哚甲烯基]苦参碱:白色固体粉末，收率42％；
1hnmr(600mhz,chloroform-d)δ7.89(s,1h),7.66(s,1h),7.27–7.19(m,4h),7.14(d,j＝3.0hz,2h),6.98(dd,j＝7.3,1.6hz,1h),6.59(d,j＝3.2hz,1h),5.28(s,2h),4.55(dd,j＝12.7,4.4hz,1h),4.01–3.95(m,1h),3.24(t,j＝12.7hz,1h),3.02–2.96(m,1h),2.91–2.81(m,2h),2.65–2.56(m,1h),2.18–2.05(m,3h),2.04–1.95(m,2h),1.94–1.88(m,1h),1.86–1.72(m,3h),1.72–1.61(m,1h),1.60–1.53(m,2h),1.50–1.42(m,2h),1.35–1.25(m,1h).13cnmr(151mhz,cdcl3)δ165.32,139.41,135.80,135.69,134.76,130.13,128.85,128.73,128.67,128.10,127.96,126.87,124.88,124.26,122.50,109.31,102.59,63.86,57.34,57.29,52.84,49.64,42.87,42.53,35.72,27.85,26.48,25.90,23.27,21.27,20.87.[m+1]+,500
参考化合物lz-56的实验方法制备化合物lz-56～lz-58，化合物lz-56～lz-58结构鉴定数据如下：
化合物lz-57：14-[n-(4-叔丁基苄基)-5-吲哚甲烯基]苦参碱:白色固体粉末，收率28％；
1hnmr(600mhz,chloroform-d)δ7.91(s,1h),7.69–7.64(m,1h),7.38–7.30(m,3h),7.22(dd,j＝8.6,1.6hz,1h),7.15(d,j＝3.2hz,1h),7.09(d,j＝8.3hz,2h),6.57(dd,j＝3.2,0.8hz,1h),5.30(s,2h),4.56(dd,j＝12.7,4.4hz,1h),4.06–3.94(m,1h),3.25(t,j＝12.7hz,1h),3.06–2.96(m,1h),2.86(dd,j＝28.9,11.2hz,2h),2.64–2.57(m,1h),2.20–2.06(m,3h),2.05–1.97(m,2h),1.94–1.89(m,1h),1.87–1.74(m,3h),1.73–1.64(m,1h),1.62–1.53(m,2h),1.52–1.42(m,2h),1.33–1.26(m,10h).13cnmr(151mhz,cdcl3)δ165.40,150.68,136.01,135.85,134.27,128.96,128.59,128.49,127.83,126.59,125.71,124.04,122.42,109.49,102.08,63.89,57.35,57.30,52.84,49.86,42.87,42.53,35.72,34.52,31.33,27.86,26.49,25.92,23.29,21.28,20.88.[m+1]+,522
化合物lz-58：14-[n-(2-萘基亚甲基)-5-吲哚甲烯基]苦参碱:白色固体粉末，收率39％；
1hnmr(600mhz,chloroform-d)δ7.91(s,1h),7.84–7.76(m,3h),7.69(s,1h),7.59(s,1h),7.50–7.46(m,2h),7.32(d,j＝8.5hz,1h),7.27(dd,j＝8.5,1.8hz,1h),7.22–7.19(m,2h),6.61(d,j＝3.1hz,1h),5.46(s,2h),4.56(dd,j＝12.7,4.4hz,1h),4.00–3.95(m,1h),3.25(t,j＝12.7hz,1h),3.03–2.96(m,1h),2.90–2.82(m,2h),2.64–2.56(m,1h),2.19–2.04(m,3h),2.04–1.96(m,2h),1.92–1.87(m,1h),1.86–1.73(m,3h),1.72–1.63(m,1h),1.61–1.54(m,2h),1.50–1.43(m,2h),1.34–1.28(m,1h).13cnmr(151mhz,cdcl3)δ165.37,135.95,135.92,134.71,133.33,132.88,129.05,128.75,128.70,128.59,127.97,127.84,127.73,126.41,126.11,125.67,124.80,124.13,122.50,109.52,102.30,63.87,57.35,57.30,52.84,50.45,42.88,42.52,35.72,27.86,26.48,25.90,23.29,21.28,20.88.[m+1]+,516
通过本发明制备的上述苦参碱吡咯、吲哚类衍生物，其构成纯度在百分99％以上。
以下表1给出了制备目标化合物的结构式：
实施例2以下通过实验进一步说明本发明的优异效果。
所述苦参碱衍生物在体外抗肿瘤活性研究，所述肿瘤为肝癌、肺癌、鼻咽癌。
药理实验体外抗肿瘤活性研究
实验准备
实验材料肿瘤细胞：人类肺癌细胞(a549)，人类肝癌细胞(smmc-7721)，人类鼻咽癌细胞(cne2)购自美国细胞保存中心(atcc)。
实验方法细胞毒性实验
所有细胞培养在含10％fbs和1％青霉素-链霉素的mccoy5a培养基中，并置于37℃，5％co2的细胞培养箱中。用mtt法进行测试，将苦参碱衍生物用dmso溶解后用完全培养基稀释成所需浓度。取5×105个对数生长期的以上细胞株，接种于96孔板中并设空白组、对照组以及给药组(100μl)，每组设3个平行孔。置于37℃，5％co2的细胞培养箱中，24h后加入不同浓度的药物，继续培养48h后，每个孔加入20μl5mg/mlmtt，培养箱孵育3h离心弃上清，加入150μldmso，振荡混匀，酶标仪测定其a490值。计算细胞生长抑制率，抑制率/％＝(a对照－a实验)/(a对照－a空白)×100％。上述实验重复3次，并用blies法计算出ic50值，组间进行比较采用的是t检验法，p<0.05为差异有显著性。
细胞周期和凋亡分析实验方法
对于细胞周期，首先通过血清剥夺饥饿法对smmc-7721和cne2细胞进行同步化处理，然后用含有不同lz-06和lz-44药物浓度的培养基继续培养24h。之后收集细胞并重悬于含70％乙醇的pbs中，-20℃过夜，通过流式细胞仪及细胞周期检测试剂盒检测各细胞周期所占百分比。而对于细胞凋亡，将smmc-7721和cne2细胞按3×105密度接种于6孔板中，待细胞完全贴壁后用含不同lz-06和lz-44药物浓度的培养基继续培养24h。通过流式细胞仪及细胞凋亡检测试剂盒检测细胞凋亡比例。细胞周期及细胞凋亡实验分别独立重复3次。
实验结果表2目标化合物对smmc-7721，a549和cne2细胞增殖的抑制
药理实验结果表明：合成的系列苦参碱衍生物均有良好的抗肿瘤活性，在以苦参碱为对照药，与合成的lz-1到lz-58系列化合物通式给药的情况下，初步的抗癌活性评估表明所有目标化合物都具有抗癌活性，所有的化合物的抗肿瘤活性均优于对照药苦参碱，58个苦参碱衍生物中几乎所有的化合物的ic50均小于50μm，其中lz-6，lz-30，lz-31，lz-32，lz-34，lz-37，lz-39，lz-43，lz-44，lz-45，lz-46，lz-48，lz-50和lz-53共14个新型化合物对三种肿瘤细胞的ic50均小于10μm，活性相比苦参碱有了极大的提高。并且化合物均显示对cne2人类鼻咽癌细胞系的抑制作用优于smmc-7721和a549细胞系。结果显示，目标化合物lz-06：14-[n-(3，5-二甲氧基苄基)-2-吡咯甲烯基]苦参碱和lz-44：14-[5-甲氧基-n-(3-氯苄基)-3-吲哚甲烯基]苦参碱对三种癌细胞显示出了最显著的抗癌活性，ic50的值在3.42-8.05μm，抗肿瘤活性远远超过了母体化合物(苦参碱)。
细胞凋亡调控和周期阻滞在细胞增殖过程中扮演了至关重要的角色。药物往往通过诱导肿瘤细胞凋亡和周期阻滞从而抑制肿瘤细胞的增殖。细胞周期阻滞以及检验点调控可以通过诱导细胞凋亡来清除损伤的细胞。阻断细胞周期进程可以引起凋亡，而凋亡也常伴有细胞生长阻滞，细胞增殖周期与凋亡密切相关。由于lz-06和lz-44具有良好的抗肿瘤活性，对其进行了进一步的细胞周期和细胞凋亡分析实验。通过实验，如说明书附图所示，lz-06和lz-44能够剂量依赖性的诱导smmc-7721和cne2细胞凋亡(分别如图1，图2，图3和图4)。如图1所示，在cne2中，凋亡细胞(右下象限，av+/pi和右上象限，av+/pi+)的百分比从4.93％(对照组)显著增加到11.96％(5μm)，34.04％(10μm)和50.50％(30μm)。在smmc-7721中，如图2所示凋亡细胞的百分比从2.60％(对照组)增加到19.93％(5μm)，53.58％(10μm)和61.0％(30μm)。如图3所示，在不同浓度的的lz-44药物处理24h后，cne2中细胞凋亡的百分比从5.29％(对照组)显著增加到17.52％(10μm)，38.60％(20μm)和74.20％(50μm)。而在smmc-7721细胞中，如图4所示凋亡细胞的百分比从2.60％(对照组)增加到39.00％(10μm)，58.80％(20μm)和95.00％(50μm)。另外lz-06还将smmc-7721和cne2癌细胞周期剂量性阻滞于g2/m期(分别如图5，图6)。如图5所示，cne2的g2/m阶段的细胞百分比从19.8％(对照组)逐渐增加到29.5％(5μm)，89.4％(10μm)和81.1％(30μm)。如图6所示，在smmc-7721细胞中的g2/m阶段的细胞百分比由18.4％(对照组)也逐渐增加到24.1％(5μm)，78.9％(10μm)和89％(30μm)。不同lz-06药物浓度处理的smmc-7721和cne2细胞的sub-g1,g1和g2/m期的分布柱状图分别如图7和图8。
本发明在于提供了一种有望成为新型的抗肿瘤药物，给广大癌症患者带来多一种选择的可能。