CN107722035B - 一类青蒿素-哌嗪衍生物及其制法和在制备抗肝癌药物中的应用 - Google Patents
一类青蒿素-哌嗪衍生物及其制法和在制备抗肝癌药物中的应用 Download PDFInfo
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Abstract
本发明公开了一类青蒿素‑哌嗪衍生物及其制备方法和这类衍生物在制备抗肝癌药物中的应用。该方法以三乙胺为缚酸剂,通过“一锅法”制备青蒿素‑哌嗪衍生物,反应条件温和,操作简便,收率较好。此外,所制衍生物对人肝癌SMMC‑7721细胞具有明显的体外抑制作用,与一线抗肝癌临床化疗药物长春新碱的抑制效果相当。本发明为青蒿素‑哌嗪衍生物在制备抗肝癌药物中的应用提供了可行性策略。
Description
技术领域
本发明涉及一类青蒿素-哌嗪衍生物及其制法和在制备抗肝癌药物中的应用。
背景技术
青蒿素具有良好的抗疟活性,但是其抗肿瘤活性研究较少。青蒿素及其衍生物虽然在临床上应用多年,但仍存在油溶性和水溶性不佳,热稳定性差,易受湿、热和还原性物质的影响而分解,临床复发率高等缺点使其应用受到限制。因此,通过化学改造的方法,设计和制备一系列新型青蒿素衍生物,并考察其抗肿瘤活性,是一项有意义的工作。
哌嗪可以通过形成多个氢键或离子键的方式,提高药物的生物活性,还可以调节药物的溶解性和酸碱平衡,促进药物的药代动力学,在抗肿瘤方面有明显的效果。因此,常作为一类增效基团引入到药物分子中。
氨基二硫代甲酸酯类化合物是一类具有独特结构和性质的重要含硫化合物,在合成药物中占有重要的位置。其具有广泛的生物活性,如抗菌、抗病毒、抗氧化以及治疗慢性酒精中毒和重金属中毒等。近年来,越来越多的研究发现,氨基二硫代甲酸酯类化合物具有较好的肿瘤预防和抗肿瘤活性,引起了国内外学者的研究兴趣。
本发明通过“一锅煮”的方法,以哌嗪为连接物,在温和的条件下,将氨基二硫代甲酸酯结构引入青蒿素分子中,制备的青蒿素-哌嗪衍生物,对人肝癌细胞(SMMC-7721)生长有明显的抑制作用,因此青蒿素-哌嗪衍生物作为很有潜力的抗肝癌药物的前景十分值得关注。
发明内容
鉴于上述,本发明的目的在于提供一类青蒿素-哌嗪衍生物。该类衍生物制备方法简易,抗肝癌活性高。
本发明的另一目的在于提供一类青蒿素-哌嗪衍生物的制备方法。
本发明还有一个目的在于提供一类青蒿素-哌嗪衍生物在抗肝癌方面的应用。
本发明的目的是通过以下技术方案实现:
(一).一类青蒿素-哌嗪衍生物,其特征是它有如下通式:
式中R为:
(二).青蒿素-哌嗪衍生物的制备方法:
将青蒿素-哌嗪和用量为青蒿素-哌嗪四倍量的二硫化碳溶于乙腈,然后加入用量为青蒿素-哌嗪十倍量的三乙胺,室温搅拌10min后,加入用量为青蒿素-哌嗪两倍量的卤代物乙腈溶液,逐渐升至60℃,反应4~12h,TLC跟踪,磷钼酸显色,反应结束后,蒸除溶剂,硅胶柱层析分离纯化(PE:EA=16:1~6:1),得到青蒿素-哌嗪衍生物。
青蒿素-哌嗪衍生物反应用化学式表示如下:
本发明的优点和产生的有益效果是:
1.本发明以三乙胺作为缚酸剂,在“一锅煮”条件下,通过多组分的串联反应,高效率制备该类青蒿素-哌嗪,该反应条件温和,实验操作简便可行,不必在苛刻的无水无氧条件下进行,无金属试剂,对环境友好,原子利用率高。
2.本发明的青蒿素-哌嗪衍生物对人肝癌SMMC-7721细胞生长有明显的抑制作用,因此本发明的青蒿素-哌嗪衍生物可以应用于制备抗肝癌药物。
具体实施方式
通过以下实施例进一步详细说明本发明,但本发明的范围并不受这些实施例的任何限制。
实施例一:青蒿素-哌嗪-氨基二硫代甲酸苄基酯(化合物1)的制备
室温下,向圆底烧瓶中依次加入(1.2mmol,0.42g)青蒿素哌嗪、(4.8mmol,0.36g)二硫化碳、20mL乙腈以及(12mmol,1mL)三乙胺,搅拌10分钟后,加入5mL溶有(2.5mmol,0.43g)溴苄的乙腈溶液,逐渐加热至60℃,反应12h,TLC跟踪反应结束后,蒸除溶剂,经硅胶柱层析[洗脱剂:V(石油醚):V(乙酸乙酯)=16:1]纯化得目标化合物。白色固体,产率72.6%,m.p.130.4-130.8℃, 1H NMR(400MHz,CDCl3)δ:7.37(t,J=12.6Hz,2H),7.32–7.26(m,3H),5.29(d,J=10.7Hz,1H),4.56(s,2H),4.35(s,2H),4.07(d,J=9.8Hz,1H),3.89(s,2H),3.07(s,2H),2.79(s,2H),2.58(s,1H),2.34(td,J=13.8,3.5Hz,1H),2.00(d,J=14.4Hz,1H),1.94–1.81(m,1H),1.78–1.65(m,2H),1.55(d,J=12.8Hz,2H),1.49–1.15(m,5H),1.03(dd,J=18.0,7.7Hz,2H),0.95(d,J=6.1Hz,3H),0.83(d,J=6.5Hz,3H);13C NMR(101MHz,CDCl3)δ:196.01,135.90,129.36,128.54,127.44,103.98,91.54,90.35,80.19,77.20,51.63,46.92,45.70,42.07,37.35,36.25,34.20,28.50,25.97,24.70,21.57,20.25,13.46;IR(KBr)ν/cm-1:2981,2941,2866,1600,1491,1447,1378,1310,1217,1161,1101,1039,999,955,926,880,842,743,712,611,550,486;HRMS m/z:calcd for C27H38N2NaO4S2 541.2168,found 541.2170[M+Na]+.
实施例二:青蒿素-哌嗪-氨基二硫代甲酸-(2-甲基)苄基酯(化合物2)的制备
制备方法同实施例一,以邻甲基溴苄替代溴苄,得目标化合物,淡黄色固体,产率55.6%,m.p.87.4-88.4℃, 1H NMR(400MHz,CDCl3)δ:7.34(d,J=7.1Hz,1H),7.16(tt,J=6.2,3.7Hz,3H),5.27(s,1H),4.51(s,2H),4.35(s,2H),4.06(d,J=10.2Hz,1H),3.89(s,2H),3.06(s,2H),2.78(s,2H),2.57(dqd,J=11.2,7.3,4.7Hz,1H),2.44–2.27(m,4H),1.99(ddd,J=14.6,5.0,2.9Hz,1H),1.86(ddt,J=13.6,6.7,3.4Hz,1H),1.70(dp,J=10.6,3.4Hz,2H),1.60–1.38(m,5H),1.38–1.16(m,4H),1.08–0.91(m,3H),0.82(d,J=7.1Hz,3H);13C NMR(101MHz,CDCl3)δ:196.11,137.36,133.17,130.40,130.38,127.85,126.13,103.92,91.49,90.29,80.14,51.58,50.16,46.87,45.65,40.67,37.29,36.20,34.15,28.45,25.93,24.65,21.52,20.22,19.28,13.42;IR(KBr)ν/cm-1:2924,2870,1462,1422,1376,1310,1275,1230,1209,1130,1101,1040,1020,982,879,734,550,510;HRMS m/z:calcd for C28H41N2O4S2 533.2429,found 533.2514[M+H]+.
实施例三:青蒿素-哌嗪-氨基二硫代甲酸-(4-甲基)苄基酯(化合物3)的制备
制备方法同实施例一,以4-甲基溴苄替代溴苄,得目标化合物。白色固体,产率50.3%,m.p.135.9-136.9℃, 1H NMR(400MHz,CDCl3)δ:7.27(d,J=7.5Hz,2H),7.12(d,J=7.8Hz,2H),5.27(s,1H),4.52(s,2H),4.35(s,2H),4.06(d,J=10.3Hz,1H),3.91(s,2H),3.05(s,2H),2.78(s,2H),2.57(ddd,J=10.9,7.2,4.3Hz,1H),2.35–2.29(m,4H),2.00(ddd,J=14.4,4.9,3.0Hz,1H),1.86(ddt,J=13.6,6.8,3.6Hz,1H),1.70(ddd,J=13.0,7.3,3.5Hz,2H),1.59(s,2H),1.55(dt,J=13.8,4.4Hz,1H),1.49–1.40(m,1H),1.38(s,2H),1.32(td,J=13.4,3.6Hz,1H),1.22(td,J=11.3,6.5Hz,1H),1.00(dd,J=12.1,3.7Hz,1H),0.94(d,J=6.2Hz,3H),0.82(d,J=7.1Hz,3H);13C NMR(101MHz,CDCl3)δ:196.19,137.20,132.67,129.28,129.26,104.00,91.55,90.36,80.20,77.20,51.65,46.93,45.72,41.91,37.36,36.26,34.21,28.52,25.97,24.71,21.59,21.13,20.26,13.46;IR(KBr)ν/cm-1:2924,2869,2846,1512,1456,1416,1376,1278,1230,1135,1055,980,879,825,741,487;HRMS m/z:calcd forC28H40NaN2O4S2555.2429,found 555.2338[M+Na]+.
实施例四:青蒿素-哌嗪-氨基二硫代甲酸-(2-氯)苄基酯(化合物4)的制备
制备方法同实施例一,以邻氯氯苄替代溴苄,加热反应4h,得目标化合物,粉色固体,产率50.6%,m.p.90.3-91℃, 1H NMR(400MHz,CDCl3)δ:7.56(dd,J=5.8,3.6Hz,1H),7.37(dd,J=5.7,3.6Hz,1H),7.21(dd,J=5.9,3.5Hz,2H),5.27(s,1H),4.72(s,2H),4.35(s,2H),4.06(d,J=10.2Hz,1H),3.91(s,2H),3.50(s,1H),3.06(s,2H),2.78(s,2H),2.57(ddd,J=10.9,7.2,4.4Hz,1H),2.34(td,J=13.9,3.9Hz,1H),2.03–1.96(m,1H),1.91–1.82(m,1H),1.71(ddd,J=12.4,7.3,3.5Hz,2H),1.56(s,2H),1.48–1.41(m,1H),1.38(s,3H),0.94(d,J=6.2Hz,3H),0.82(d,J=7.1Hz,3H);13C NMR(101MHz,CDCl3)δ:195.76,134.45,134.18,131.48,129.46,128.89,126.87,104.01,91.52,90.32,80.21,77.20,51.58,50.55,45.66,39.42,37.30,36.19,34.13,28.48,25.86,24.63,21.53,20.18,13.40;IR(KBr)ν/cm-1:3096,3023,1885,1472,1404,1275,1231,1208,1185,1130,1053,983,926,879,826,743,550;HRMS m/z:calcd for C27H37ClNaN2O4S2575.1776,found 575.1778[M+Na]+.
实施例五:青蒿素-哌嗪-氨基二硫代甲酸-(4-氯)苄基酯(化合物5)的制备
制备方法同实施例一,以对氯溴苄替代溴苄,得目标化合物,白色固体,产率71.5%,m.p.111.3-112.2℃, 1H NMR(400MHz,CDCl3)δ:7.35–7.30(m,2H),7.28(d,J=2.3Hz,2H),5.27(s,1H),4.54(s,2H),4.34(s,2H),4.07(d,J=10.2Hz,1H),3.97–3.83(m,2H),3.49(d,J=5.0Hz,1H),3.06(s,2H),2.78(s,2H),2.57(ddd,J=11.0,7.1,4.3Hz,1H),2.34(td,J=13.9,3.9Hz,1H),2.00(dt,J=14.6,3.8Hz,1H),1.90–1.82(m,1H),1.71(ddd,J=12.5,7.4,3.5Hz,2H),1.58–1.42(m,3H),1.38(s,4H),1.04–0.97(m,1H),0.95(d,J=6.2Hz,3H),0.82(d,J=7.1Hz,3H);13C NMR(101MHz,CDCl3)δ:195.48,134.85,133.20,130.67,128.64,104.00,91.56,90.35,80.20,77.20,51.63,50.90,45.70,41.02,37.36,36.25,34.19,28.51,25.98,24.69,21.58,20.26,13.46;IR(KBr)ν/cm-1:2926,2865,1738,1488,1424,1378,1305,1276,1159,1104,1052,978,926,879;HRMS m/z:calcd for C27H37ClNaN2O4S2 575.1780,found 575.1782[M+Na]+.
实施例六:青蒿素-哌嗪-氨基二硫代甲酸-(4-溴)苄基酯(化合物6)的制备
制备方法同实施例一,以对溴氯苄替代溴苄,得目标化合物,白色固体,产率55.7%,m.p.136.9-138℃, 1H NMR(400MHz,CDCl3)δ:7.45–7.40(m,2H),7.30–7.24(m,4H),5.27(s,1H),4.53(s,2H),4.34(s,2H),4.06(d,J=10.3Hz,1H),3.90(d,J=27.5Hz,2H),3.06(s,2H),2.78(s,2H),2.57(ddd,J=10.7,7.2,4.3Hz,1H),2.38–2.29(m,1H),2.00(ddd,J=14.5,4.9,2.9Hz,1H),1.86(ddt,J=10.1,7.0,3.4Hz,1H),1.75–1.66(m,1H),1.59–1.46(m,2H),1.38(s,3H),1.30(dd,J=13.7,3.7Hz,1H),1.22(td,J=11.2,6.5Hz,1H),1.07–0.98(m,1H),0.95(d,J=6.2Hz,3H),0.82(d,J=7.2Hz,3H);13C NMR(101MHz,CDCl3)δ:195.44,135.42,131.59,131.01,121.32,104.00,91.56,90.35,80.20,77.20,51.64,46.94,45.71,41.04,37.36,36.25,34.20,28.51,25.98,24.70,21.58,20.25,13.46;IR(KBr)ν/cm-1:2925,2865,1476,1425,1378,1305,1276,1229,1158,1042,1020,979,931,879,826,609;HRMS m/z:calcd forC27H38BrN2O4S2597.1378,found 597.1465[M+H]+.
实施例七:青蒿素-哌嗪-氨基二硫代甲酸-(4-氰基)苄基酯(化合物7)的制备
制备方法同实施例一,对氰基溴苄替代溴苄,加热反应4h,经硅胶柱层析[洗脱剂:V(石油醚):V(乙酸乙酯)=12:1]纯化得到淡黄色固体,产率65.8%,m.p.146.7-147.3℃, 1H NMR(400MHz,CDCl3)δ:7.62–7.57(m,2H),7.52–7.48(m,2H),5.27(s,1H),4.65(s,2H),4.34(s,2H),4.07(d,J=10.3Hz,1H),3.91(d,J=29.7Hz,2H),3.07(s,2H),2.79(s,2H),2.57(ddd,J=10.9,7.3,4.4Hz,1H),2.34(ddd,J=14.5,13.3,4.0Hz,1H),2.05–1.96(m,1H),1.86(ddt,J=13.6,6.7,3.6Hz,1H),1.75–1.67(m,2H),1.57(d,J=1.9Hz,1H),1.55–1.46(m,1H),1.38(s,4H),1.34–1.27(m,1H),1.27–1.19(m,1H),1.02(td,J=13.1,12.2,4.0Hz,1H),0.95(d,J=6.2Hz,3H),0.82(d,J=7.2Hz,3H);13C NMR(101MHz,CDCl3)δ:194.67,142.62,132.19,129.98,118.78,111.03,104.01,91.56,90.34,80.20,77.20,51.62,50.87,45.69,40.78,37.35,36.23,34.18,28.50,25.97,24.68,21.57,20.24,13.45;IR(KBr)ν/cm-1:3140,2937,2864,2229,1736,1606,1477,1378,1305,1276,1158,1051,980,926,880,543cm-1;HRMS m/z:calcd forC28H37NaN3O4S2 566.2116,found 566.2118[M+Na]+.
实施例八:青蒿素-哌嗪-氨基二硫代甲酸-(4-硝基)苄基酯(化合物8)的制备
制备方法同实施例一,以4-硝基溴苄替代溴苄,得目标化合物,黄色固体,产率67.6%,m.p.82.2-82.9℃, 1H NMR(400MHz,CDCl3)δ:8.19–8.13(m,2H),7.59–7.54(m,2H),5.27(s,1H),4.69(s,2H),4.34(s,2H),4.07(d,J=10.3Hz,1H),3.92(d,J=31.3Hz,2H),3.07(s,2H),2.80(s,2H),2.57(ddd,J=10.9,7.2,4.3Hz,1H),2.39–2.29(m,1H),2.00(dt,J=14.4,4.1Hz,1H),1.90–1.82(m,1H),1.71(ddd,J=12.7,7.6,3.6Hz,2H),1.59–1.46(m,2H),1.42(s,1H),1.38(s,3H),1.34–1.18(m,2H),1.07–0.92(m,4H),0.90–0.78(m,3H);13C NMR(101MHz,CDCl3)δ:196.96,194.68,142.62,132.20,129.98,111.04,104.02,103.98,91.56,90.34,80.21,77.20,51.63,50.88,45.69,40.79,37.35,37.16,36.26,34.20,31.16,28.51,28.32,25.97,24.69,22.28,21.58,20.25,13.96,13.46;IR(KBr)ν/cm-1:3316,3047,2924,2870,2011,1754,1599,1453,1345,1275,1159,1041,983,879,724cm-1;HRMS m/z:calcd for C27H37N3NaO6S2 586.2016,found586.2018[M+Na]+.
实施例九:青蒿素-哌嗪-氨基二硫代甲酸-2-萘甲基酯(化合物9)的制备
制备方法同实施例一,以2-溴甲基萘代替溴苄,经硅胶柱层析[洗脱剂:V(石油醚):V(乙酸乙酯)=12:1]纯化得到白色固体,产率60.3%,m.p.143.8-144.0℃, 1H NMR(400MHz,CDCl3)δ:7.86–7.77(m,5H),7.51–7.42(m,3H),5.27(s,1H),4.74(s,2H),4.37(s,2H),4.07(d,J=10.2Hz,1H),3.93(s,2H),3.07(s,2H),2.79(s,2H),2.57(tt,J=11.2,6.9Hz,1H),2.38–2.29(m,1H),1.99(dd,J=14.4,4.2Hz,1H),1.86(ddd,J=13.6,6.6,3.4Hz,1H),1.71(ddd,J=12.7,7.6,3.6Hz,2H),1.58(s,3H),1.40(d,J=16.5Hz,4H),1.34–1.18(m,1H),1.07–0.90(m,3H),0.90–0.78(m,3H);13C NMR(101MHz,CDCl3)δ:195.88,133.41,133.26,132.64,128.27,128.11,127.70,127.59,127.27,126.11,125.87,103.96,91.52,90.33,80.17,77.20,51.61,46.91,45.68,42.28,40.07,37.32,36.23,34.17,28.49,26.85,25.95,24.67,21.55,20.23,13.44;IR(KBr)ν/cm-1:2924,2870,1599,1508,1422,1376,1309,1275,1231,1159,1130,1020,982,879,755,474;HRMS m/z:calcd for C31H40NaN2O4S2 591.2429,found 591.2342[M+Na]+.
实施例十:青蒿素-哌嗪-氨基二硫代甲酸戊基酯(化合物10)的制备
制备方法同实施例一,以氯戊烷替代溴苄,加热反应10h,得目标化合物,淡黄色固体,产率58.0%,m.p.135.8-136.2℃. 1H NMR(400MHz,CDCl3)δ:5.25(s,1H),4.32(s,2H),4.05(d,J=10.2Hz,1H),4.00–3.82(m,2H),3.27(t,J=7.4Hz,2H),3.04(dt,J=11.8,5.2Hz,2H),2.76(p,J=4.9Hz,2H),2.56(ddt,J=10.1,7.1,3.6Hz,1H),2.32(td,J=13.9,3.9Hz,1H),1.98(ddd,J=14.5,5.0,3.0Hz,1H),1.84(ddt,J=13.6,6.8,3.5Hz,2H),1.69(ddt,J=14.8,10.2,5.4Hz,5H),1.53(dt,J=13.6,4.3Hz,1H),1.47–1.26(m,8H),1.21(td,J=11.2,6.4Hz,1H),1.07–0.96(m,1H),0.96–0.85(m,6H),0.81(d,J=7.1Hz,3H);13C NMR(101MHz,CDCl3)δ:196.89,103.92,91.51,90.29,80.16,51.60,50.11,46.87,45.68,37.31,37.11,36.22,34.17,31.12,28.48,28.28,25.93,24.66,22.24,21.55,20.23,13.93,13.44;IR(KBr)ν/cm-1:3232,3079,2937,1755,1423,1388,1277,1233,1160,1131,1022,999,932,881cm-1;HRMS m/z:calcd for C25H42N2NaO4S2521.2477,found 521.2479[M+Na]+.
实施例十一:青蒿素-哌嗪-氨基二硫代甲酸十八烷基酯(化合物11)的制备
制备方法同实施例一,以1-氯十八烷替代溴苄,得目标化合物,黄色蜡状固体,产率49.3%, 1H NMR(400MHz,CDCl3)δ:5.25(s,1H),4.32(s,2H),4.05(d,J=10.2Hz,1H),3.27(t,J=7.5Hz,2H),3.04(dt,J=11.0,4.9Hz,2H),2.76(dt,J=11.3,4.8Hz,2H),2.56(ddd,J=11.2,7.2,4.2Hz,1H),2.32(td,J=13.9,3.9Hz,1H),1.98(ddd,J=14.5,4.9,2.9Hz,1H),1.84(ddt,J=13.5,6.7,3.5Hz,1H),1.74–1.63(m,4H),1.53(dt,J=13.9,4.4Hz,1H),1.30(d,J=49.8Hz,39H),1.01(td,J=13.1,12.3,4.0Hz,1H),0.93(d,J=6.2Hz,3H),0.89–0.77(m,6H);13C NMR(101MHz,CDCl3)δ:196.84,103.87,91.47,90.27,80.12,51.58,46.87,45.66,37.28,37.12,36.20,34.16,31.84,29.62,29.60,29.58,29.53,29.44,29.29,29.15,28.97,28.56,28.45,25.90,24.64,22.61,21.52,20.20,14.07,13.41;IR(KBr)ν/cm-1:2923,2852,1466,1421,1376,1310,1275,1231,1130,1055,983,880,834,721,551;HRMS m/z:calcd for C38H69N2O4S2681.4621,found681.4713[M+H]+.
实施例十二:青蒿素-哌嗪-氨基二硫代甲酸-(苄氧酰基)甲酯(化合物12)的制备
制备方法同实施例一,以溴乙酸苄酯替代溴苄,经硅胶柱层析[洗脱剂:V(石油醚):V(乙酸乙酯)=6:1]纯化得到橙黄色固体,产率35%,m.p.82.3-83.3℃, 1H NMR(400MHz,CDCl3)δ:7.40–7.36(m,4H),7.33(dddd,J=11.4,4.9,2.9,1.8Hz,1H),5.28(s,1H),5.19(s,2H),4.31(s,2H),4.21(s,2H),4.07(d,J=10.2Hz,1H),3.95(d,J=32.2Hz,2H),3.08(dt,J=11.3,5.0Hz,2H),2.80(dt,J=11.5,5.2Hz,2H),2.63–2.53(m,1H),2.34(ddd,J=14.5,13.3,3.9Hz,1H),2.05–1.96(m,1H),1.87(ddd,J=13.6,6.6,3.4Hz,1H),1.71(ddt,J=11.2,6.5,3.5Hz,2H),1.60(s,1H),1.55(dt,J=13.6,4.3Hz,1H),1.49–1.41(m,1H),1.38(s,3H),1.35–1.18(m,2H),1.07–0.98(m,1H),0.95(d,J=6.2Hz,3H),0.83(d,J=7.1Hz,3H);13C NMR(101MHz,CDCl3)δ:194.32,168.57,135.47,128.52,128.30,128.29,104.01,91.54,90.36,80.20,67.46,51.64,46.91,45.71,38.91,37.36,36.26,34.21,28.53,26.88,25.97,24.71,21.59,20.26,13.46;IR(KBr)ν/cm-1:2925,2871,1738,1425,1376,1275,1235,1040,980,925,878,741,697,550;HRMS m/z:calcd for C29H40NaN2O6S2 599.2328,found 599.2246[M+Na]+.
实施例十三:青蒿素-哌嗪衍生物体外抗人肝癌SMMC-7721细胞活性研究
采用MTT(四甲基偶氮唑盐比色法),选取青蒿素-哌嗪衍生物(化合物1~12),测定其对人肝癌SMMC-7721细胞的抑制率,计算IC50值(μM)。具体操作步骤如下:
1、细胞复苏
细胞培养基:1640+10%FBS+1%(Penicillin-Streptomycin Solution)
(1)将SMMC7721细胞分别从液氮中取出,快速放入37℃水浴锅中,轻摇冻存管使冻存液溶解;
(2)溶解后把细胞分别转移到含有5mL培养基的离心管中,离心收集细胞,室温1000rpm离心5min,弃上清;
(3)用含10%胎牛血清的完全培养基悬浮细胞,接种到培养皿中,轻轻吹打混匀,37℃、5%CO2、饱和湿度条件下培养。
2、细胞传代
细胞的密度达到80%时,对细胞进行传代:
(1)弃去培养基,用PBS洗一遍;
(2)加1-2mL 0.25%胰蛋白酶消化细胞,显微镜下观察,消化30-60s,可看到细胞相互分离变圆,即消化完成;
(3)快速弃去胰酶,加入完全培养基,吹打细胞,制成单细胞悬液,按1:3的比例传代,37℃、5%CO2、饱和湿度条件下扩大培养。
3、细胞处理及MTT检测
(1)取处于对数生长期,生长状态良好的SMMC7721细胞,用1640培养基调整细胞密度到1×104个/mL,接入96孔板,每孔100μL细胞悬液,同时设空白组,37℃培养过夜(在细胞孔周围孔内加入100μL无菌PBS);
(2)待细胞贴壁生长良好24h后,吸收旧的培养液,向各个培养孔中加入不同浓度化合物1~12的供试液。每浓度设5个平行重复孔,同时设等体积二甲基亚砜(DMSO)溶剂的和不含药物培养基的空白对照孔,于37℃,5%CO2的培养箱内继续培养。
分别培养24h、48h、72h后,弃去上清液,每孔加10μL(2mg/mL in PBS)MTT,继续培养4h后,吸出孔内培养上清液,每孔加入150μL二甲基亚砜,振荡10min使蓝紫色结晶物溶解充分后,于波长568nm处用酶标仪测定每孔样品的吸光度值(OD值),去除最高值与最低值,取剩余值的平均值。
抑制率的计算:细胞生长的抑制率按照下列公式计算:
抑制率(%)=[1-(测试样品OD值-空白OD值)/(阴性对照OD值-空白OD值)]×100%
表1青蒿素-哌嗪衍生物1~12对人肝癌SMMC-7721细胞的抑制率
表2青蒿素-哌嗪衍生物1~12对人肝癌SMMC-7721细胞的抑制IC50值(μM)
[a]赵晨阳,邱嵘,郑荣梁.兰州大学学报(自科版),2000,36(4),66-68.(长春新碱:IC50=63.2±1.8μg/mL=0.074±0.002μM);[b]J.J.Lu,L.H.Meng,Y.J.Cai,etal.Cancer.Biol.Ther.2008,7,1017-1023.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1328563A (zh) * | 1998-11-25 | 2001-12-26 | 朱马制药有限公司 | 有机磷化合物及其应用 |
CN102153564A (zh) * | 2011-01-31 | 2011-08-17 | 中国科学院上海药物研究所 | 含氮原子的青蒿素二聚体、其制备方法及用途 |
CN102718773A (zh) * | 2012-06-05 | 2012-10-10 | 上海交通大学 | 一种由青蒿酸制备青蒿素的方法 |
CN106928249A (zh) * | 2017-03-14 | 2017-07-07 | 宁夏大学 | 一种简便、高效的青蒿砜—氨基二硫代甲酸酯类化合物的制备方法 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1328563A (zh) * | 1998-11-25 | 2001-12-26 | 朱马制药有限公司 | 有机磷化合物及其应用 |
CN102153564A (zh) * | 2011-01-31 | 2011-08-17 | 中国科学院上海药物研究所 | 含氮原子的青蒿素二聚体、其制备方法及用途 |
CN102718773A (zh) * | 2012-06-05 | 2012-10-10 | 上海交通大学 | 一种由青蒿酸制备青蒿素的方法 |
CN106928249A (zh) * | 2017-03-14 | 2017-07-07 | 宁夏大学 | 一种简便、高效的青蒿砜—氨基二硫代甲酸酯类化合物的制备方法 |
Non-Patent Citations (1)
Title |
---|
"Synthesis and evaluation of cytotoxic activities of artemisinin derivatives";Qian Sun等;《Chem Biol Drug Des.》;20170510;第90卷;第1019-1028页 * |
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