CN113956256B - 苦参碱d环结构改造的衍生物及其在制备抗肿瘤药物中的应用 - Google Patents
苦参碱d环结构改造的衍生物及其在制备抗肿瘤药物中的应用 Download PDFInfo
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Abstract
本发明属于药物化学领域,具体公开了苦参碱D环结构改造的衍生物及其在制备抗肿瘤药物中的应用。苦参碱是一种药用植物,其自身具有一定药理作用,如抗癌、抗病毒、止痛、抗心律不齐和杀虫活性等。本发明以苦参碱为起始原料,碱性条件下水解开环,经酯化、16‑N Boc保护、水解、酰胺偶联、脱保护、还原氨基化反应,得到一系列苦参碱D环结构改造化合物。本发明用MTT比色法对合成的一系列衍生物进行抗癌活性测试,新衍生物抗癌活性得到大大提高。
Description
技术领域
本发明属于药物化学领域,特别涉及一系列苦参碱D环结构改造,并对所合成一系列化合物进行抗癌活性测试。
背景技术
中医药是中华民族的瑰宝,也是世界传统医学的重要组成部分。其历史悠久,更是为了以后的医药行业添砖加瓦。从《本草纲目》到《中国药典》以及许多上市药物中,都表明天然产物具有广泛的生物活性及较小的毒性,因此从天然资源中寻找新型抗肿瘤活性物质几乎成为近几年的抗癌药物的研究热点。
苦参生物碱是由豆科植物苦参的干燥根、植株、果实经乙醇等有机溶剂提取的一种生物碱,主要成分包括苦参碱、槐果碱、氧化槐果碱、槐定碱等多种生物碱,以苦参碱、氧化生物碱含量最高。
苦参碱结构为:
根据文献报道,苦参碱药理用途十分广泛,具有广谱性,同时对多种癌症都具有预防作用,如胃癌、肝癌、白血病K-562,肺癌、宫颈癌等。研究进一步表明,苦参碱具有促进细胞凋亡,诱导肿瘤细胞分化和抑制肿瘤细胞增殖和转移等作用。此外,苦参碱作为肿瘤MDR逆转剂药物也越来越受到重视。
2020年本课题组对苦参碱D环开环水解,接着在11位右侧引入酰胺键,酰胺键连接苯环上,设计相同位置连有不同取代基。采用MTT法测其化合物对A549、HepG2、MCF-7三种癌细胞的抑制效果。结果发现苦参碱侧链开环后引入间溴苯胺得到化合物10,抗癌活性会大大提高。因此,我们侧链引入间溴苯胺,向16-N上引取代苄、苄基、萘环等基团。通过以上方式,期望筛选出抗癌活性更好的苦参碱开环衍生物。
发明内容
本发明以苦参碱为起始原料,经水解开环、酯化反应、16-N进行Boc保护,水解、酰胺偶联、脱保护、还原氨基化一系列反应,合成苦参碱D环结构改造产物,并对这些化合物进行抗癌活性测试,所合成的化合物对苦参碱均有抗癌活性。
苦参碱D环结构改造的结构式为:
苦参碱D环结构改造衍生物合成路线如下:
一、5-氨基-2-(2-(二甲氨基)乙基)-1H-苯并[de]异喹啉-1,3(2H)-二酮(8)的合成具体合成步骤如下:
(1)将5-硝基-1H,3H-苯并[de]异戊烯-1,3-二酮(化合物6)和N,N-二甲基乙胺溶于DMF中,于60℃加热搅拌。TLC进行监测,用乙醇重结晶,得到2-(2-(二甲氨基)乙基)-5-硝基-1H-苯并[de]异喹啉-1,3(2H)-二酮7。其中,溶剂为DMF。化合物6:N,N-二甲基乙胺摩尔比为:1:1.1;加热搅拌时间为3h。
(2)N2保护下,三颈瓶中依次加入乙醇、化合物7、5%钯碳、三乙胺。10min内加入甲酸以控制反应放热,回流1-2h后,TLC进行监测反应。硅藻土抽滤,正己烷洗涤,正己烷稀释混合滤液,冷却至0-5℃,过滤得固体。干燥1h得到5-氨基-2-(2-(二甲氨基)乙基)-1H-苯并[de]异喹啉-1,3(2H)-二酮8。其中,溶剂为乙醇;碱为三乙胺;酸为甲酸;催化剂为5%钯碳。
化合物7:5%钯碳:三乙胺:甲酸的摩尔比为1:0.2:4.4:4.2。
二、苦参碱D环结构改造衍生物合成路线具体合成方法步骤如下:
(1)在碱的作用下,以苦参碱为起始原料,加入4mol/L NaOH,于90-100℃
加热回流反应,后处理得到化合物2。
苦参碱与4mol/L NaOH的摩尔比为1:3.5;加热时间为12h。
(2)冰浴下,将氯化亚砜缓慢滴加到甲醇中,低温搅拌1h。将化合物2用甲醇溶解,在加入含氯化亚砜的甲醇溶液中,冰浴搅拌2h。加热回流3-5h,后处理,得到化合物3。其中,溶剂为甲醇。
化合物2与氯化亚砜的摩尔比1:8.3。
(3)将化合物3用二氯甲烷中溶解,加入4-DMAP,在室温下搅拌反应,然后加入二碳酸二叔丁酯,室温搅拌16-20h。得到化合物4。其中,溶剂为二氯甲烷,碱为4-DMAP,保护基试剂为二碳酸二叔丁酯。
化合物3:4-DMAP:二碳酸二叔丁酯的摩尔比为1:0.1:1.5。
(4)在碱性条件下,将化合物4加入4mol/L氢氧化钠,室温反应2-6h。得到化合物5。4mol/L氢氧化钠与甲醇体积比为1:3。
(5)将化合物5溶于DMF中,加入酰胺偶联试剂HATU,冰浴下加入DIEA,冰浴搅拌30-45min。加入间溴苯胺或化合物8,室温反应16-18h。TLC监测反应得到酰胺化合物9或A1。其中,溶剂为DMF;酰胺偶联试剂为HATU;碱为DIEA;胺为间溴苯胺或化合物8。
化合物5:HATU:DIEA:胺的摩尔比为1:1.2:2.5:1.5。
(6)将化合物9或A1溶于二氯甲烷中,缓缓通入氯化氢气体,可快速脱去Boc保护基,得到化合物10或B1,该步反应迅速,但要设有尾气处理装置。
(7)将化合物10或B1溶于1,2-二氯乙烷中,加入碱,然后加入醛类化合物,加热回流,再将还原剂缓慢分批加入反应液中,继续回流,冷却至室温,浓缩萃取,柱层析纯化,得到化合物Ci。
所述溶剂为1,2-二氯乙烷,碱为三乙胺,还原剂为三乙酰氧基硼氢化钠。
化合物10或B1:三乙胺:三乙酰氧基硼氢化钠:醛的摩尔比为1:1.3:1.5:1.5。
本发明的有益效果为:
本方法的优点是:制备了一些列全新的苦参碱D环结构改造衍生物,并对其进行抗癌活性测试,结果表明,新衍生物抗癌活性明显优于苦参碱。
具体实施方式
现在结合实例对本发明做进一步的说明。
一、苦参碱D环衍生物的合成
实施例1
4-(十氢-1H,4H-吡啶并[1,6]萘啶-1-基)丁酸(2)的制备将苦参碱(20g,80.5mmol)溶于水(456mL)中,加入氢氧化钠(9.1g,228mmol)溶解,在90℃下,加热回流12h。反应完毕,用2N盐酸溶液调pH至5-7,将溶剂浓缩,再加入460mL乙醇,室温搅拌30min,抽滤得白色固体(21g,产率99%)。1H NMR(300MHz,D2O):δ1.58–1.98(m,13H),2.11-2.16(m,1H),2.25(t,J=5.1Hz,3H),2.65(s,1H),2.71(s,1H),2.85–2.92(m,2H),3.10(dd,J1=10.2Hz,J2=4.5Hz,1H),3.23(t,J=10.0Hz,1H),3.34-3.40(m,1H).13CNMR(75MHz,D2O):δ22.00,22.26,23.16,27.27,28.33,32.52,35.32,39.68,40.25,46.18,58.64,58.70,64.32.HRMS(ESI):m/z[M-H]-calcd for C15H25N2O2:265.1922;found:265.1924.
实施例2
4-(十氢-1H,4H-吡啶并[1,6]萘啶-1-基)丁酸甲酯(3)的制备
0℃下,将SOCl2(29.5mL,40.7mmol)溶于MeOH(336mL)中,搅拌1h。接着将溶于MeOH(168mL)的化合物2(13g,48.8mmol)的混合物加入其中,冰浴反应2h,撤走冰浴后回流3h。反应结束,冷却至室温,加入356mL CHCl3,50g NaHCO3,室温搅拌0.5h,抽滤,滤液浓缩,得到白色固体(9g,产率66%)。1H NMR(300MHz,CD3OD):δ1.44–1.69(m,10H),1.71-1.80(m,3H),1.93(d,1H,J=13.0Hz),1.99–2.08(m,3H),2.26(s,1H),2.37–2.41(m,2H),2.80-2.86(m,2H),2.96(dd,J1=12.0Hz,J2=4.0Hz,1H),3.43(t,J=12.8Hz,1H),3.54-3.60(m,1H),3.64(d,J=5.4Hz,3H).HRMS(ESI):m/z
[M+Na]+calcd.for C16H28O2Na:303.2043;found:303.2039.
实施例3
叔丁基(1R,3aS,3aS,10aR)-1-(4-甲氧基-4-氧代丁基)八氢-1H,4H-吡啶并[1,6]二氮杂萘-2(3H)-甲酸乙酯(4)的制备
将化合物3(6.5g,23.2mmol)和4-二甲氨基吡啶(650mg,5.32mmol)溶于二氯甲烷(116mL)中,接着将二碳酸二叔丁酯(7.6g,34.8mmol)的二氯甲烷(23mL)溶液溶入其中,室温搅拌反应16h。TLC监测反应,浓缩。柱层析[洗脱剂:V(二氯甲烷):V(甲醇)=50:1],得到黄色粘稠状液体(7.3g,产率83%)。1H NMR(300MHz,CDCl3):δ1.17-1.40(m,3H),1.44(s,11H),1.50–1.58(m,2H),1.83–1.63(m,9H),1.96(t,J=3.1Hz,1H),2.31–2.38(m,2H),2.68(t,J=6.8Hz,2H),3.30(dd,J1=13.6Hz,J2=7.4Hz,1H),3.54(dd,J1=13.6Hz,J2=8.3Hz,1H),3.65(s,3H),3.78-3.86(m,1H).HRMS(ESI):m/z[M+H]+calcd for C21H37N2O4:381.2748;found:381.2749.
实施例4
4-((3aS,3aS,10aR)-2-(叔丁氧基羰基)十氢-1H,4H-吡啶并[1,6]萘啶-1-基)丁酸(5)的制备
将化合物4(5g,13.1mmol)溶于甲醇(59mL)中,加入4mol/L氢氧化钠溶液(13.2mL),室温搅拌反应4h。TLC监测,浓缩。柱层析[洗脱剂:V(二氯甲烷):V(甲醇)=10:1],得到白色固体(4g,产率85%,m.p.135-137℃)。1H NMR(400MHz,CDCl3):δ1.32–1.35(m,1H),1.40(s,10H),1.46–1.64(m,6H),1.76–1.78(d,J=7.2Hz,2H),1.86–1.89(m,3H),2.02(s,1H),2.16(t,J=11.7Hz,2H),2.27–2.33(m,1H),2.39–2.45(m,1H),2.59(s,1H),3.27(dd,J1=20.3Hz,J2=11.2Hz,2H),3.38–3.45(m,1H),3.64(dd,J1=13.7Hz,J2=5.1Hz,1H),3.77–3.84(m,1H).HRMS(ESI):m/z[M+H]+calcd for C20H35N2O4:367.2591;found:367.2593.
实施例5
叔丁基(1R,3aS,3aS,10aR)-1-(4-((2-甲基苯基)氨基)-4-氧代丁基)八氢-1H,4H-吡啶并[1,6]萘啶-2(3H)-羧酸叔丁酯(9)的制备
将化合物5(4g,10.9mmol)和HATU(4.98g,13.1mmol)溶于N,N-二甲基甲酰胺中,25℃条件下搅拌30min。然后将反应瓶转移至冰水浴中,缓慢加入DIEA(4.75mL,27.25mmol),滴加完毕,撤去冰水浴,25℃条件下搅拌1h,接着加入间溴苯胺(1.76mL,16.35mmol),室温搅拌17h。TLC监测反应结束。将反应液浓缩,柱层析[洗脱剂:V(二氯甲烷):V(甲醇)=50:1-40:1]。得到白色固体9,产率85%,m.p.62-68℃。1H NMR(300MHz,CD3OD):δ1.49(s,9H),1.56–1.87(m,12H),1.95(s,2H),2.23(s,1H),2.42–2.47(m,2H),2.78–2.86(m,2H),3.22(s,2H),3.26(s,1H),3.65(d,J=8.7Hz,2H,),3.81-3.88(m,1H),7.22–7.24(m,2H),7.45–7.49(m,1H),7.95–7.99(m,1H).HRMS(ESI):m/z[M+H]+calcd for C26H39BrN3O3:520.2169;found:520.2164.
实施例6
叔丁基(1R,3aS,3a1S,10aR)-1-(4-((2-(二甲氨基)乙基-1,3-二氧基-2,3-二氢-1H-苯并[de]异喹啉-5-基)氨基)-4-氧丁基)八氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-2(3H)-羧酸盐(A1)的制备
使用合成化合物9同样的方法,将间溴苯胺换为化合物8,得到黄色固体A1,产率85%。1H NMR(300MHz,CDCl3)δ9.31(s,1H),8.70(s,1H),8.40–8.32(m,2H),7.98–7.87(m,1H),7.59(t,J1=8.0Hz,J2=8.0Hz,1H),4.28(t,J1=6.3Hz,J2=6.3Hz,2H),4.13–4.06(m,1H),3.88–3.82(m,1H),3.47(t,J 1=7.7Hz,J 2=7.7Hz,2H),2.78–2.72(m,4H),2.65–2.60(m,1H),2.53–2.47(m,1H),2.41(s,6H),2.10(s,1H),2.02(s,1H),1.90(d,J=9.6Hz,3H),1.73(d,J=11.6Hz,4H),1.63(s,3H),1.54(s,1H),1.45(s,9H),1.34(s,1H),1.23(t,J=7.2,7.2Hz,2H).13C NMR(75MHz,CDCl3)δ172.68,171.26,164.39,163.80,156.07,137.48,133.78,132.38,129.57,127.25,124.74,124.52,122.77,122.11,79.63,77.58,77.16,76.73,63.84,60.49,57.41,56.99,56.85,54.75,46.06,45.82,40.37,37.93,36.96,35.60,30.78,28.63,27.69,22.21,21.13,21.07,14.27.HRESIMS:m/z[M+H]+calcd forC36H49N5O5:632.3807;found:632.3804.
实施例7
4-((1R,3aS,3aS,10aR)-十氢-1H,4H-吡啶并[1,6]萘啶-1-基)-N-(2-甲基苯基)丁酰胺(10)的制备
0℃下,将化合物9(1g,2.73mmol)溶于二氯甲烷(10mL)中,通入氯化氢气体,直至反应结束,加入10%碳酸钠溶液调节至pH至7-8,将反应液过滤浓缩,爬大板得到淡黄色粘稠液体10,产率95%。1H NMR(400MHz,CD3OD):δ1.29–1.66(m,9H),1.76–2.11(m,9H),2.25(s,3H),2.53(t,2H,J=6.5Hz),2.85(t,2H,J=12.2Hz),2.96(dd,1H,J1=12.4Hz,J2=4.3Hz),3.43(t,1H,J=12.8Hz),3.60–3.63(m,1H),7.13–7.19(m,2H),7.20–7.25(m,1H),7.31–7.33(m,1H).13C NMR(75MHz,CD3OD):δ18.13,20.99,21.24,21.51,26.74,27.67,30.81,34.55,36.20,39.43,45.08,54.22,57.79,57.88,63.13,127.12,127.31,127.57,131.61,134.43,136.72,174.26.HRESIMS:m/z[M+H]+calcd for C22H34N3O:356.2696;found:356.2694.
实施例8
4-((1R,3aS,3a1S,10aR)-十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)-N-(2-(二甲氨基)乙基)-1,3-二氧基-2,3-二氢-1H-苯并[de]异喹啉-5-基)丁胺(B1)的制备
使用合成化合物10同样的方法,将化合物9换为A1,得到黄色固体B1,产率87%。1HNMR(500MHz,CDCl3)δ10.15(s,1H),8.66(s,1H),8.21(d,J=7.3Hz,2H),7.86(d,J=8Hz,1H),7.49(t,J1=7.7Hz,J2=7.7Hz,1H),4.23(t,J1=6.3Hz,J2=6.3Hz,2H),3.95(s,3H),2.88–2.74(m,3H),2.65–2.60(m,3H),2.50–2.48(m,1H),2.36(s,6H),2.13(s,1H),2.01–1.89(m,6H),1.65–1.54(m,5H),1.93(d,J=15.4Hz,3H),1.39(d,J=11Hz,1H),1.24(s,1H).13C NMR(126MHz,CDCl3)δ172.96,164.12,164.02,137.67,133.73,132.26,129.45,127.16,124.39,124.10,122.47,121.86,121.70,77.41,77.16,76.90,63.55,57.40,57.29,57.18,51.95,45.90,45.47,40.71,38.22,37.42,35.77,31.70,31.23,27.72,26.69,22.76,21.64,21.18,20.90,14.24.HRESIMS:m/z[M+H]+calcd for C31H41N5O3:532.3282;found:532.3288.
实施例9
4-((3aS,3aS,10aR)-2-苄基十氢-1H,4H-吡啶并[1,6]萘啶-1-基)-N-(3-溴苯胺)丁酰胺(C1)的制备
将化合物10(300mg,0.71mmol)和三乙胺(108μL)溶于1,2-二氯乙烷(4mL)中,逐滴加入苯甲醛(109μL),反应液回流2h后,再将三乙酰氧基硼氢化钠(225mg)缓慢分批加入反应液中,继续回流6h。冷却至室温,浓缩萃取。用10mL的乙酸乙酯萃取3次,再用8mL的水洗涤3次,8mL的饱和食盐水洗涤3次,将有机相倒入干净的锥形瓶中,加入适量的无水硫酸钠干燥半小时。柱层析纯化[洗脱剂:V(二氯甲烷):V(甲醇)=40:1-30:1]。得到白色固体C1,产率82%。1H NMR(300MHz,CDCl3)δ10.18(s,1H),8.18(s,1H),7.74(d,J=7.4Hz,1H),7.47–7.26(m,5H),7.09–7.06(m,2H),4.07–3.87(m,1H),3.69–3.60(m,1H),3.35(d,J=54.1Hz,2H),3.03(t,J1=7.4,J2=7.4Hz,1H),2.78(d,J=15.3Hz,1H),2.56–2.51(m,2H),2.28(s,2H),2.04–1.84(m,6H),1.54–1.37(m,8H),1.20(dd,J1=12.7Hz,J2=5.5Hz,2H).13C NMR(75MHz,CDCl3)δ172.51,140.60,129.93,128.61,126.27 122.56,122.18,118.34,77.58,77.16,76.73,60.40,56.56,56.30,53.79,53.50,35.07,33.79,29.67,27.90,25.84,25.25,20.30,19.25,14.17.HRESIMS:m/z[M+H]+calcd for C28H36BrN3O:510.2115;found:510.1212.
实施例10
N-(3-溴苯基)-4-((1R,3aS,3a1S,10aR)-2-(4-甲基苄基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)丁酰胺(C2)的制备
使用合成化合物C1同样的方法,将苯甲醛换为对甲基苯甲醛,得到白色固体C2,产率85%。1H NMR(400MHz,CDCl3)δ10.26(s,1H),8.30(s,1H),7.88(d,J=7.8Hz,1H),7.47(d,J=7.2Hz,2H),7.31(dd,J=12.9,7.8Hz,4H),3.90–3.98(m,2H),3.54(t,J1=13.2Hz,J2=13.2Hz,1H),3.34(s,2H),2.92–2.72(m,4H),2.52(s,6H),2.34–2.32(m,1H),2.24–2.20(m,1H),2.01(dd,J1=59.0Hz,J2=14.3Hz,6H),1.76–1.60(m,6H).13C NMR(75MHz,CD3OD):δ172.36,140.47,138.12,133.30,131.17,130.00,129.54,127.26,126.40,122.65,122.26,118.42,77.58,77.16,77.31,64.43,56.39,49.12,35.65,34.98,29.54,26.51,26.11,25.63,21.21,20.53,19.59,19.17.HRESIMS:m/z[M+H]+calcd for C29H38BrN3O:524.2271;found:524.2275.
实施例11
N-(3-溴苯基)-4-((1R,3aS,3a1S,10aR)-2-(4-甲氧基苄基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)丁酰胺(C3)的制备
使用合成化合物C1同样的方法,将苯甲醛换为对甲氧基苯甲醛,得到白色固体C3,产率87%。1H NMR(500MHz,CD3OD)δ7.97(d,J=2.2Hz,1H),7.50(d,J=6.9Hz,1H),7.39(d,J=8.0Hz,2H),7.20(d,J=7.0Hz,2H),6.94(d,J=8.5Hz,2H),5.51(s,1H),3.82(s,5H),2.98–3.08(m,3H),2.73(d,J=12.3Hz,1H),2.50–2.51(m,2H),2.35–2.32(m,2H),1.98–2.14(m,4H),1.85–1.78(m,4H),11.72–1.46(m,10H).13C NMR(126MHz,CD3OD)δ173.93,164.46,141.50,132.78,131.39,129.80,127.76,123.68,123.28,121.16,119.40,115.26,64.94,57.81,57.77,57.26,55.80,54.42,49.51,49.34,49.17,49.00,48.83,48.66,48.49,43.89,42.31,36.90,36.27,33.34,28.41,27.98,27.43,27.00,26.43,21.45,21.00,19.50.HRESIMS:m/z[M+H]+calcd for C29H38BrN3O:540.2220;found:540.2238.
实施例12
N-(3-溴苯基)-4-((1R,3aS,3a1S,10aR)-2-(4-硝基苄基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)丁酰胺(C4)的制备
使用合成化合物C1同样的方法,将苯甲醛换为对硝基苯甲醛,得到白色固体C4,产率88%。1H NMR(300MHz,CDCl3)δ9.84(s,1H),8.10-8.08(m,3H),7.65(d,J=7.2Hz,1H),7.46(d,J=8.5Hz,2H),7.26–7.04(m,2H),3.83–3.78(m,3H),3.34(t,J=18.8Hz,2H),2.99(s,1H),2.67(d,J=10.8Hz,1H),2.5–2.33(m,3H),2.16(d,J=13.3Hz,2H),1.87(d,J=13.1Hz,3H),1.64–1.43(m,6H),1.21(d,J=2.8Hz,2H).13C NMR(75MHz,CDCl3)δ173.12,172.42,147.60,147.00,140.36,130.04,128.69,126.50,123.71,122.57,122.26,118.29,77.58,77.16,76.73,66.03,56.46,53.52,49.29,35.03,31.57,29.68,26.22,25.96,25.39,22.64,20.01,19.36,18.76,14.13.HRESIMS:m/z[M+H]+calcd for C28H35BrN4O3:555.1966;found:555.1974.
实施例13
4-((1R,3aS,3a1S,10aR)-2-(4-溴苯基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)-N-(3-溴苯基)丁酰胺(C5)的制备
使用合成化合物C1同样的方法,将苯甲醛换为对溴苯甲醛,得到白色固体C5,产率82%。1H NMR(400MHz,CDCl3)δ9.63(s,1H),8.09(s,1H),7.65(d,J=6.9Hz,1H),7.41(d,J=7.92Hz,2H),7.09–7.26(m,4H),3.71(s,2H),3.50(d,J=6.9Hz,1H),3.52–3.48(m,3H),2.86(s,1H),2.67(d,J=9.1Hz,1H),2.44(d,J=1.8Hz,3H),2.18(s,1H),2.02–1.78(m,6H),1.43–1.41(m,4H),1.56–1.54(m,4H),1.24(s,2H).13C NMR(75MHz,CDCl3)δ172.49,140.33,137.47,131.70,130.24,130.11,128.83,126.62,122.71,122.37,121.03,118.40,77.58,77.36,77.16,76.73 65.87,56.57,49.07,35.38,34.68,29.78,29.34,26.24,25.69,20.14,19.62,19.04.HRESIMS:m/z[M+H]+calcd for C28H35Br2N3O:590.1190;found:590.1212.
实施例14
N-(3-溴苯基)-4-((1R,3aS,3a1S,10aR)-2-(4-氯苄基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)丁酰胺(C6)的制备
使用合成化合物C1同样的方法,将苯甲醛换为对氯苯甲醛,得到白色固体C6,产率85%。1H NMR(500MHz,CD3OD)δ7.92(s,1H),7.46–7.45(m,1H),7.38–7.30(m,4H),7.21–7.16(m,2H),4.16(dd,J1=16.0Hz,J2=8.2Hz,1H),3.41–3.35(m,1H),3.21–3.06(m,3H),2.78–2.69(m,2H),2.55–2.41(m,3H),2.12(d,J=7.15Hz,1H),2.03–1.98(m,2H),1.84–1.79(m,5H),1.74–1.58(m,5H),1.46(d,J=13.7Hz,1H),1.28(s,2H).13C NMR(126MHz,CD3OD)δ174.25,141.47,134.15,131.82,131.34,129.60,127.73,,123.68,123.25,121.19,119.41,65.50,57.15,57.09,51.27,49.51,49.34,49.17,49.00,48.83,48.66,48.49,37.86,37.23,33.24,30.73,28.66,27.12,26.51,20.93,20.76,20.62.HRESIMS:m/z[M+H]+calcd for C28H35BrClN3O:544.1725;found:544.1749.
实施例15
N-(3-溴苯基)-4-((1R,3aS,3a1S,10aR)-2-(3-氯苄基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)丁酰胺(C7)的制备
使用合成化合物C1同样的方法,将苯甲醛换为间氯苯甲醛,得到白色固体C7,产率75%。1H NMR(400MHz,CDCl3)δ9.72(s,1H),7.7(d,J=7.4Hz,2H),7.26–7.17(m,5H),6.96(t,J1=7.2Hz,J2=6.8Hz,1H),3.87(s,1H),3.61–3.32(m,4H),2.99(s,1H),2.73–2.71(m,1H),2.46–2.43(m,4H),2.17(s,2H),1.90–1.82(m,5H),1.55–1.32(m,7H),1.2(s,2H).13CNMR(75MHz,CDCl3)δ172.34,139.15,134.42,129.88,128.70,128.23,127.37,126.45,123.59,119.90,77.58,77.36,77.16,76.74,66.28,56.43,56.34,53.54,48.63,34.92,34.08,29.74,28.50,25.86,25.30,20.14,19.19,18.48.HRESIMS:m/z[M+H]+calcd forC28H35BrClN3O:544.1725;found:544.1751.
实施例16
N-(3-溴苯基)-4-((1R,3aS,3a1S,10aR)-2-(2-氯苄基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)丁酰胺(C8)的制备
使用合成化合物C1同样的方法,将苯甲醛换为邻氯苯甲醛,得到白色固体C8,产率83%。1H NMR(500MHz,CDCl3)7.86(d,J=7.3Hz,2H),7.65(d,J=7.6Hz,1H),7.31(dd,J1=23.0Hz,J2=8.1Hz,3H),7.19(t,J1=7.7Hz,J2=7.7Hz,1H),7.04(t,J1=7.5Hz,J2=7.5Hz,1H),3.99–3.89(m,2H),3.64–3.58(m,2H),3.39–3.36(m,2H),3.04(t,J1=7.6Hz,J2=7.6Hz,1H),2.82–2.79(m,1H),2.54–2.43(m,3H),2.34–2.17(m,2H),2.00–1.90(m,4H),1.76(s,1H),1.63–1.27(m,8H).13C NMR(75MHz,CDCl3)δ172.44,139.20,136.49,133.60,129.56,129.26,128.68,128.00,127.24,123.54,119.88,77.58,77.16,76.74,66.47,56.54,56.37,53.13,49.06,45.56,34.83,34.36,29.74,28.63,25.96,25.47,20.42,19.35,18.57.HRESIMS:m/z[M+H]+calcd for C28H35BrClN3O:544.1725;found:544.1751.
实施例17
N-(3-溴苯基)-4-((1R,3aS,3a1S,10aR)-2-(4-氟苄基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)丁酰胺(C9)的制备
使用合成化合物C1同样的方法,将苯甲醛换为对氟苯甲醛,得到白色固体C9,产率76%。1H NMR(400MHz,CDCl3)δ8.10(s,1H),7.66(d,J=6.3Hz,1H),7.25(dd,J=12.54Hz,2H),7.11-7.04(m,2H),6.95(t,J=8.5,8.5Hz,2H),3.73(s,2H),3.53(d,J=13.6Hz,1H),3.34–3.22(m,3H),2.70–2.68(m,1H),2.45–2.40(m,4H),2.19-2.16(m,1H),1.96–1.82(m,6H),1.53–1.40(m,4H),1.40–1.37(m,3H),1.21(s,1H).13C NMR(75MHz,CDCl3)δ172.50,163.77,160.51,140.46,130.06,126.52,122.68,122.35,118.38,115.60,115.31,77.58,77.16,76.74,56.64,48.88,34.30,34.42,29.77,26.25,25.67,20.23,19.60,18.94.HRESIMS:m/z[M+H]+calcd for C28H35BrFN3O:528.2021;found:528.2024.
实施例18
N-(3-溴苯基)-4-((1R,3aS,3a1S,10aR)-2-(3-氟苄基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)丁酰胺(C10)的制备
使用合成化合物C1同样的方法,将苯甲醛换为间氟苯甲醛,得到白色固体C10,产率78%。1H NMR(500MHz,CDCl3)δ7.76(d,J=8.2Hz,1H),7.26(t,J1=8.5Hz,J2=8.5Hz,3H),7.13–7.04(m,3H),6.93(t,J1=8.4Hz,J2=8.4Hz,1H),3.78(t,J=13.1Hz,2H),3.55(d,J=14.0Hz,1H),3.30(d,J=41.4Hz,2H),2.88–2.70(m,2H),2.50–2.37(m,4H),2.18–1.85(m,7H),1.68–1.53(m,4H),1.46–1.39(m,3H),1.26(s,1H).13C NMR(126MHz,CDCl3)δ172.20,164.13,162.17,138.96,129.99,129.93,128.75,123.92,123.70,119.93,115.16,114.99,114.03,113.86,77.41,77.16,76.90,65.95,63.81,57.30,57.22,56.69,53.25,43.24,41.52,35.54,35.37,32.88,27.75,27.19,26.43,20.12.HRESIMS:m/z[M+H]+calcdfor C28H35BrFN3O:528.2021;found:528.2024.
实施例19
N-(3-溴苯基)-4-((1R,3aS,3a1S,10aR)-2-(2-氟苄基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)丁酰胺(C11)的制备
使用合成化合物C1同样的方法,将苯甲醛换为邻氟苯甲醛,得到白色固体C11,产率75%。1H NMR(300MHz,CDCl3)δ10.08(s,1H),8.16(s,1H),7.70(d,J=7.3Hz,1H),7.45(t,J1=6.6Hz,J2=6.6Hz,1H),7.21–7.12(m,1H),7.09–6.98(m,3H),6.98–6.90(m,1H),4.06–3.78(m,2H),3.57–3.31(m,4H),3.00(s,1H),2.79–2.73(m,1H),2.50–2.10(m,5H),1.97–1.76(m,5H),1.62–1.16(m,8H).13C NMR(75MHz,CDCl3)δ171.63,161.92,158.67,139.55,128.90,125.30,123.45,123.40,121.57,121.21,117.27,114.17,113.87,76.49,76.07,75.64,65.38,55.44,55.26,52.46,47.52,33.68,32.60,27.04,24.81,24.57,24.28,19.17,18.17,17.37.HRESIMS:m/z[M+H]+calcd for C28H35BrFN3O:528.2021;found:528.2024.
实施例20
N-(3-溴苯基)-4-((1R,3aS,3a1S,10aR)-2-乙基十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)丁酰胺(C12)的制备
使用合成化合物C1同样的方法,将苯甲醛换为乙醛,得到白色固体C12,产率85%。1HNMR(400MHz,CDCl3)δ9.89(s,1H),7.98(s,1H),7.60(s,1H),7.10(s,2H),3.53–2.74(m,6H),2.46(d,J=37.9Hz,3H),2.07–1.75(m,8H),1.53–1.22(m,12H).13C NMR(126MHz,CDCl3)δ171.72,140.35,130.09,126.47,122.63,122.28,118.49,77.41,77.16,76.90,61.63,58.89,56.69,56.52,50.68,36.55,31.99,29.73,26.82,26.38,26.03,20.51,20.32,19.62,14.17.HRESIMS:m/z[M+H]+calcd for C23H34BrN3O:448.1958;found:448.1961.
实施例21
N-(3-溴苯基)-4-((1R,3aS,3a1S,10aR)-2-(萘-1-基甲基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)丁酰胺(C13)的制备
使用合成化合物C1同样的方法,将苯甲醛换为1-萘甲醛,得到白色固体C13,产率87%。1H NMR(400MHz,CDCl3)δ10.08(s,1H),8.22(s,1H),8.09–8.06(m,1H),7.86–7.84(m,1H),7.73(dt,J1=14.8Hz,J2=7.6Hz,J3=7.6Hz,3H),7.48–7.41(m,3H),7.15–7.07(m,2H),4.24(d,J=11.2Hz,1H),4.01(d,J=14.8Hz,2H),3.63(s,1H),3.36(s,2H),3.07(s,1H),2.85(s,1H),2.60–2.44(m,4H),2.18(dd,J1=63.4Hz,J2=10.7Hz,4H),1.89(dd,J=16.4,8.4Hz,4H),1.57–1.24(m,8H).13C NMR(75MHz,CDCl3)δ172.71,140.60,133.75,131.86,130.01,128.90,127.50,126.42,126.02,125.87,125.66,122.96,122.68,122.29,118.40,77.58,77.16,76.74,66.51,56.46,56.33,49.15,34.91,34.28,29.75,26.14,25.83,25.42,20.68,19.20,18.57.HRESIMS:m/z[M+H]+calcd for C32H38BrN3O:560.2271;found:560.2275.
实施例22
N-(3-溴苯基)-4-((R,3aS,3a1S,10aR)-2-(萘-2-基甲基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)丁酰胺(C14)
使用合成化合物C1同样的方法,将苯甲醛换为2-萘甲醛,得到白色固体C14,产率88%。1H NMR(300MHz,CDCl3)δ8.82(s,1H),7.95(s,1H),7.83–7.79(m,4H),7.49–7.46(m,4H),7.11(dt,J1=15.8Hz,J2=8.0Hz,J3=8.0Hz,2H),4.2(s,1H),3.76(d,J=13.3Hz,1H),3.39(s,1H),3.16–2.97(m,3H),2.77–2.38(m,5H),2.19(s,1H),2.04–1.78(m,7H),1.52(t,J1=14.0Hz,J2=14.0Hz,4H),1.39–1.33(m,1H),1.26(d,J=8.0Hz,2H).13C NMR(75MHz,CDCl3)δ172.19,139.84,133.37,133.12,130.26,128.81,128.47,127.98,127.83,126.95,126.81,126.57,126.41,122.89,122.45,118.59,77.58,77.36,77.16,76.74,56.18,56.12,49.26,40.79,36.01,35.83,30.54,29.79,27.10,26.18,25.99,19.93,19.50,19.38.HRESIMS:m/z[M+H]+calcd for C32H38BrN3O:560.2271;found:560.2275.
实施例23
N-(3-溴苯基)-4-((1R,3aS,3a1S,10aR)-2-(噻吩-3-基甲基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)丁酰胺(C15)的制备
使用合成化合物C1同样的方法,将苯甲醛换为3-噻吩甲醛,得到白色固体C15,产率89%。1H NMR(400MHz,CDCl3)δ9.95(s,1H),8.11(s,1H),7.69(d,J=7.6Hz,1H),7.13–7.05(m,5H),3.99(s,1H),3.74(s,2H),3.36(s,1H),3.12(s,2H),2.70–2.63(m,2H),2.52–2.47(m,1H),2.29(d,J=9.5Hz,3H),2.04–1.83(m,5H),1.68–1.39(m,8H),1.23(s,1H).13CNMR(75MHz,CDCl3)δ172.38,140.47,130.04,128.34,126.46,122.66,122.30,118.43,77.58,77.36,77.16,76.73,56.51,49.54,35.56,34.69,29.75,26.28,25.75,20.33,19.71,19.28,13.73.HRESIMS:m/z[M+H]+calcd for C26H34BrN3OS:516.1679;found:516.1682.
实施例24
N-(3-溴苯基)-4-((1R,3aS,3a1S,10aR)-2-(吡啶-3-基甲基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)丁酰胺(C16)的制备
使用合成化合物C1同样的方法,将苯甲醛换为3-吡啶甲醛,得到白色固体C16,产率68%。1H NMR(500MHz,CDCl3)δ8.57(s,1H),8.48(d,J=16.0Hz,2H),8.18(s,1H),7.71(t,J1=7.2Hz,J2=7.2Hz,2H),7.28–7.26(m,2H),7.11(dt,J1=15.9Hz,J2=8.2Hz,J3=8.2Hz,1H),3.75–3.31(m,3H),2.77(s,1H),2.44(dd,J1=14.3Hz,J2=4.5Hz,3H),2.25(s,2H),1.90(dd,J1=44.1Hz,J2=30.0Hz,4H),1.60(d,J=13.1Hz,2H),1.45–1.42(t,J1=14.0Hz,J2=14.0Hz,3H),1.27–1.24(m,4H),0.86–0.82(m,3H).13C NMR(75MHz,CDCl3)δ172.46,149.68,148.75,140.45,135.02,130.06,128.74,126.55,122.68,122.37,119.92,118.35,77.58,77.16,76.74,62.49,56.66,41.52,34.86,29.78,27.21,26.17,25.63,22.78,20.23,20.09,19.51,14.22.HRESIMS:m/z[M+H]+calcd for C27H35BrN4OS:511.2067;found:511.2065.
实施例25
N-(3-溴苯基)-4-((1R,3aS,3a1S,10aR)-2-(吡啶-2-基甲基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)丁酰胺(C17)的制备
使用合成化合物C1同样的方法,将苯甲醛换为2-吡啶苯甲醛,得到白色固体C17,产率73%。1H NMR(300MHz,CDCl3)δ10.17(s,1H),8.45(d,J=54.4Hz,1H),8.18(s,1H),7.74–7.62(m,2H),7.49(d,J=7.8Hz,1H),7.16–7.04(m,3H),3.79(s,2H),3.53(s,1H),3.31(s,2H),2.78(s,1H),2.53–2.33(m,5H),2.11(s,1H),1.94–1.81(m,5H),1.59–1.38(m,7H),1.21(s,2H).13C NMR(75MHz,CDCl3)δ172.66,148.98,140.64,137.15,129.97,126.35,122.62,122.34,122.24,118.34,77.58,77.36,77.16,76.73,66.89,56.41,56.26,53.53,34.91,31.90,31.61,29.72,25.95,25.58,22.84,22.72,20.36,19.21,18.61,14.17.HRESIMS:m/z[M+H]+calcd for C27H35BrN4OS:511.2067;found:511.2065.
实施例26
4-((1R,3aS,3a1S,10aR)-2-苄基十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)-N-(2-(二甲氨基)乙基)-1,3-二氧基-2,3-二氢-1H-苯并[de]异喹啉-5-基)丁酰胺(C18)的制备
使用合成化合物C1同样的方法,将化合物10换为B1,得到黄色固体C18,产率75%。1HNMR(300MHz,CD3OD)δ8.58(s,1H),8.38(s,1H),8.27(d,J=7.2Hz,1H),8.03(d,J=8.3Hz,1H),7.71–7.61(m,2H),7.55(d,J=6.8Hz,1H),7.41(d,J=6.9Hz,1H),7.33–7.21(m,2H),4.75(s,2H),4.65(t,J1=6.9Hz,J2=7.3Hz,2H),4.28(d,J=13.0Hz,1H),3.72–3.67(m,2H),3.45(d,J=13.1Hz,1H),3.24(s,5H),3.15–3.06(m,2H),2.87–2.40(m,6H),2.07–1.25(m,15H).13CNMR(75MHz,CD3OD)δ174.58,164.91,164.68,139.03,138.18,135.22,134.38,134.30,133.39,132.06,130.52,130.60,130.41,129.55,128.75,128.63,128.56,125.43,125.17,123.10,122.83,122.46,69.23,65.34,61.78,58.91,57.62,54.84,51.76,50.78,49.85,49.56,49.28,49.00,48.71,48.43,48.15,38.42,37.64,35.01,33.68,30.75,29.21,27.79,27.16,21.30.HRESIMS:m/z[M+H]+calcd for C38H47N5O3:622.3752;found:622.3756.
实施例27
4-((1R,3aS,3a1S,10aR)-2-(4-氯苄基)十氢-1H,4H-吡啶[3,2,1-ij][1,6]萘啶-1-基)-N-(2-(二甲氨基)乙基)-1,3-二氧基-2,3-二氢-1H-苯并[de]异喹啉-5-基)丁酰胺(C19)的制备
使用合成化合物C1同样的方法,将化合物10换为B1,苯甲醛换成对氯苯甲醛,得到黄色固体C19,产率83%。1H NMR(400MHz,CD3OD)δ8.60(s,1H),8.35–8.25(m,2H),7.88(s,1H),7.71(d,J=7.1Hz,1H),7.65–7.56(m,3H),7.39–7.25(m,4H),5.08(s,1H),4.75–4.70(m,2H),4.22(d,J=5.5Hz,1H),3.68(d,J=6.0Hz,1H),3.33–3.26(m,5H),2.88(s,2H),2.63(s,1H),2.21(s,2H),2.21–1.96(m,2H),1.76–1.68(m,6H),1.43–1.30(m,9H),0.98–0.88(m,3H).13CNMR(75MHz,CD3OD)δ169.30,165.02,164.66,138.33,137.03,135.91,134.50,133.91,133.55,133.17,132.41,132.19,131.27,130.57,129.85,129.77,129.71,129.23,127.30,123.38,69.08,68.25,64.87,61.60,56.82,50.85,49.85,49.57,49.28,49.00,48.71,48.43,48.15,40.13,37.71,35.03,33.05,31.59,30.73,30.11,28.77,26.59,25.68,24.92,24.01,23.72,20.36,14.42,11.41.HRESIMS:m/z[M+H]+calcd forC38H46ClN5O3:678.3187;found:678.3120.
二、5-氨基-2-(2-(二甲氨基)乙基)-1H-苯并[de]异喹啉-1,3(2H)-二酮(8)的合成
实施例28
2-(2-(二甲氨基)乙基)-5-硝基-1H-苯并[de]异喹啉-1,3(2H)-二酮(7)的制备
将5-硝基-1H,3H-苯并[de]异戊烯-1,3-二酮6(5g,20mmol)溶于DMF(16mL)中,加入N,N-二甲基乙二胺(2.5mL,22mmol),加热至60℃,搅拌3h。TLC监测,得到黄色固体化合物7(4.2g,67%)。1H NMR(300MHz,CDCl3):δ9.25(d,J=2.2Hz,2H),9.09(d,J=2.3Hz,2H),8.74(dd,J=7.3,1.2Hz,2H),8.40(dd,J=8.3,1.2Hz,2H),7.92(dd,J1=8.3Hz,J2=7.4Hz,2H),4.32(t,J1=6.8Hz,J2=6.8Hz,4H),2.65(t,J1=6.8Hz,J2=6.8Hz,4H),2.32(s,13H).13CNMR(126MHz,CDCl3):δ163.20,162.60,146.36,135.63,134.53,131.03,130.25,129.16,128.99,124.70,124.25,123.22,77.41,77.16,76.90,56.97,45.83,38.60.HRESIMS:m/z[M+H]+calcd for C16H15N3O4:314.1136;found:314.1143.
实施例29
5-氨基-2-(2-(二甲氨基)乙基)-1H-苯并[de]异喹啉-1,3(2H)-二酮(8)的制备
N2保护下,三颈瓶中依次加入乙醇(20mL)、化合物7(4g,12.8mmol)、5%钯碳(2.7g,1.3mmol)、三乙胺(8.0mL,56.3mmol)。10min内加入甲酸(2.0mL,53.8mmol)以控制反应放热,回流1-2h后,TLC进行监测反应。硅藻土抽滤,正己烷洗涤,正己烷稀释混合滤液,冷却至0-5℃,过滤得固体。干燥1h得到黄色固体化合物8(2.6g,73%)。1H NMR(300MHz,DMSO-d6):δ7.92–8.02(m,3H),7.55(dd,J1=8.3Hz,J2=7.2Hz,1H),7.24(d,J=2.3Hz,1H),5.97(s,2H),4.08(t,J1=6.9Hz,J2=6.9Hz,2H),2.43–2.51(m,2H),2.17(s,6H).13CNMR(75MHz,DMSO-d6):δ163.66,163.50,147.83,133.47,131.40,126.83,125.37,122.45,121.71,121.65,120.53,111.71,56.50,45.40,40.35,40.07,39.79,39.52,39.24,38.96,38.68,37.47.HRESIMS:m/z[M+H]+calcd for C16H17N3O2:284.1394;found:284.1401.
抗癌活性的应用
将待测化合物用二甲基亚砜溶解后,稀释成浓度,取对数生长期的A549、HepG2、MCF-7,按每孔10000个细胞(100μL培养基)接种于无菌96孔板;同时设置空白组、对照组、给药组,每组设3个平行孔,置于37℃培养箱中孵育16-18h,移除旧培养基,加入50μM待测化合物继续孵育72h。72h后弃旧培养基,每孔加入5mg/mL MTT培养液50μL孵育4h。弃MTT液体,每孔加入DMSO 100μL,振摇10min,用赛默飞酶标仪在570nm处测定吸光值(OD),并计算细胞增值抑制率(细胞抑制率=(空白组OD值-给药组OD值)/空白组OD值*100%)。实验结果至少重复两次以上独立实验所得的平均值。筛选出细胞增值率较高的化合物进行测IC50。结果见表1。
表1化合物的抑制率(50μM)
根据50μM初筛的结果,把抑制率超过65%的化合物分别设置6个浓度梯度,由于每个化合物测得结果不同,因此需要对各个化合物的浓度进行调整,至少重复两次实验,利用软件GraphPad Prism 7对化合物浓度和抑制率作图计算IC50,结果可见表2。
表2化合物的IC50(μM)
由表2可知,上述化合物中,只有C10对A549、MCF-7两种种癌细胞株IC50均大于50μM,活性较差,其余苦参碱衍生物与苦参碱本身相比,抗癌活性均提高百倍以上。C13和C14对三种癌细胞的IC50值更小,活性更好。化合物C4对HepG2、MCF-7的IC50分别为16.02μM、21.13μM,而对于A549的IC50为9.67μM;化合物C10对A549、MCF-7IC50均大于50μM,对HepG2IC50为36.56μM。这说明C4、C10对抗肿瘤活性具有选择性。
通过MTT实验与分析化合物结构可知,Ci类化合物16-N位连接不同位置取代位置的苄基时,对三种癌细胞的抑制效果非常明显;当苄基上是4位取代时,活性最好。与无取代的苄基相比,取代基为4位时对癌细胞的抑制效果基本都有所改善。当16-N连接不同杂环如吡啶时,抑制效果并没有改善,连接3-噻吩时活性较好。在上述化合物中,对MCF-7抑制效果最好的C13、C14的IC50值分别为6.13±0.41μM、6.03±0.95μM。这说明对16-N进行化学修饰产生了意想不到的结果,值得进一步研究,也为苦参碱衍生物的构效关系研究提供了新的启发。
Claims (5)
2.根据权利要求1所述苦参碱D环结构改造衍生物在制备抗肿瘤药物中的应用。
3.根据权利要求2所述苦参碱D环结构改造衍生物在制备抗肿瘤药物中的应用,其特征在于:所述抗肿瘤药物为抗肺癌、肝癌、乳腺癌中的一种或几种。
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