CN105541805A - 一类吲哚乙酰基吡唑衍生物的制备方法与应用 - Google Patents
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Abstract
本发明公开了一类吲哚乙酰基吡唑衍生物的制备方法与应用,所述合成的化合物的结构如式所示,
Description
技术领域
本发明属于药物化学领域,尤其涉及一类吲哚乙酰基吡唑衍生物的制备方法与应用。
背景技术
微管蛋白(Tubulin),是广泛分布的一类球状蛋白质,是细胞内微管的基本结构单位,在细胞的运动和分裂中都发挥着重要作用。作为亚基可以形成细胞骨架结构元件——微管。大多数微观蛋白有α和β两条链,两者可以组成一种稳定的存在形式。此外,还有γ、δ和ε微管蛋白。癌细胞通过有丝分裂而无限制地增殖.由微管蛋白所形成的微管在有丝分裂过程中促使姐妹染色单体分离,从而形成两个子细胞并获得质与量都相同的遗传信息。在抗癌药中,发现有一类药的作用机制是与微管蛋白相结合从而干扰了染色体的分离,导致癌细胞停滞于有丝分裂的早期或前中期而死亡。微管蛋白为当前研究热点,它的封锁已被临床验证成为肿瘤治疗的一个有效的方法。
吲哚类化合物是一类重要的杂环衍生物生物碱,该类化合物的癌症治疗作用得到了普遍的关注,比如长春碱、吲哚美辛具有良好的抗肿瘤作用。吡唑环是很多天然化合物和合成药物中的核心结构单元。作为杂环化合物中的一个重要分支,吡唑类杂环化合物因其具有广泛的生物活性而倍受关注,研究表明吡唑类化合物具有抗高血糖、消炎、止痛、退热、抑菌、杀菌、抗癌、抗凝血剂等药理活性。近年来,研究合成一系列不同基团修饰的吡唑衍生物进而筛选具有高效抗肿瘤生物活性的药物,是广大科研人员热衷的研究热点之一。本发明的一类吲哚乙酰基吡唑衍生物可能有希望成为开发新的,有效的和安全的导向化合物。
发明内容
本发明的目的在于提供一类作为微管蛋白抑制剂的吲哚乙酰基吡唑衍生物、其制备方法及其在抗癌药物中的应用。
技术方案:一类吲哚乙酰基吡唑衍生物,其结构如式所示,
一种制备吲哚乙酰基吡唑衍生物的方法,所述吲哚乙酰基吡唑衍生物的结构如式所示,
制备方法见具体实施方式。
一类吲哚乙酰基吡唑衍生物在制备抗癌药物中的应用,其结构如式所示
一种抗癌药物,包括结构如式所示的化合物及医学上可接受的载体,
本发明对人肝癌细胞(HepG2),人乳腺癌细胞(MCF-7)以及人肺腺癌细胞(A549)有明显的抑制作用,因此本发明的一类吲哚乙酰基吡唑衍生物可以应用于制备抗肿瘤药物。
具体实施方式
在某个具体的实施例中,本发明的制备过程和相关产物的结构式如下所述:
实施例一:1-(5-(1-甲基-1H-吲哚-3-基)-3-苯基-4,5-二氢-1H-吡唑-1-基)乙酮(6a)的制备
冰浴条件下,向反应容器中依次加入POCl3(20mL)与DMF(40mL),1a(35mmol),反应2h,倒入冰水中用NaOH调节PH至9.0,用乙酸乙酯萃取干燥得2a。在冰浴下向反应容器中加入2a(25mmol),THF(15mL),NaH(62.5mmol),搅拌15min,再加入CH3I(33mmol)室温反应24h。TLC跟踪,充分反应后用乙酸乙酯萃取干燥得3a。向反应容器中加入3a(2mmol)与乙酰苯(2mmol),无水乙醇(20mL)以及KOH(6mmol,336mg),室温反应24h,过滤后乙醇与二氯甲烷重结晶得4a。依次向反应容器中加入无水乙醇溶液(5mL),4a(1mmol),水合肼(2mmol),回流2h,冷却转移至-20℃过夜,固体过滤用石油醚洗净得5a。向反应容器中加入乙酸(2mmol),EDC·HCl(3mmol),HOBt(1.2mmol)以及二氯甲烷(5mL),在氮气保护下加入5a(1mmol),反应24h后,过滤并用乙醇与水洗净,粗产物在乙醇与二氯甲烷中重结晶得6a。Yield:30.2%.m.p.171~172℃.1HNMR(DMSO-d6,400MHz)δ:7.93-7.76(m,2H),7.57-7.43(m,3H),7.40(d,J=8.2Hz,1H),7.33(d,J=7.9Hz,1H),7.25(s,1H),7.13(t,J=7.4Hz,1H),6.97(t,J=7.3Hz,1H),5.81(dd,J=11.8,4.4Hz,1H),3.84(dd,J=18.0,11.9Hz,1H),3.72(s,3H),3.25(dd,J=18.0,4.4Hz,1H),2.26(s,3H).MS(ESI)m/z:318.15(C20H19N3O,[M+H]+).Anal.CalcdforC20H19N3O:C,75.69;H,6.03;N,13.24.Found:C,75.81;H,6.04;N,13.22.
实施例二:1-(3-(4-甲氧基苯基)-5-(1-甲基-1H-吲哚-3-基)-4,5-二氢-1H-吡唑-1-基)乙酮(6b)的制备
制备方法参考实施例一。Yield:34.5%.m.p.156~158℃.1HNMR(DMSO-d6,400MHz)δ:7.77(d,J=8.8Hz,2H),7.39(d,J=8.2Hz,1H),7.33(d,J=7.9Hz,1H),7.23(s,1H),7.13(t,J=7.4Hz,1H),7.03(d,J=8.8Hz,2H),6.96(t,J=7.4Hz,1H),5.77(dd,J=11.8,4.2Hz,1H),3.87-3.75(m,4H),3.72(s,3H),3.22(dd,J=17.9,4.3Hz,1H),2.23(s,3H).MS(ESI)m/z:348.16(C21H21N3O2,[M+H]+).Anal.CalcdforC21H21N3O2:C,72.60;H,6.09;N,12.10.Found:C,72.54;H,6.09;N,12.11.
实施例三:1-(3-(3,4-二甲氧基苯基)-5-(1-甲基-1H-吲哚-3-基)-4,5-二氢-1H-吡唑-1-基)乙酮(6c)的制备
制备方法参考实施例一。Yield:14.3%.m.p.169~171℃.1HNMR(DMSO-d6,400MHz)δ:7.39(d,J=8.4Hz,2H),7.36-7.29(m,2H),7.23(s,1H),7.13(t,J=7.6Hz,1H),7.02(d,J=8.4Hz,1H),6.97(t,J=7.5Hz,1H),5.78(dd,J=11.7,4.2Hz,1H),3.88-3.75(m,7H),3.72(s,3H),3.25(dd,J=17.8,4.3Hz,1H),2.25(s,3H).MS(ESI)m/z:378.17(C22H23N3O3,[M+H]+).Anal.CalcdforC22H23N3O3:C,70.01;H,6.14;N,11.13.Found:C,69.90;H,6.15;N,11.15.
实施例四:1-(5-(1-甲基-1H-吲哚-3-基)-3-(3,4,5-三甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)乙酮(6d)的制备
制备方法参考实施例一。Yield:43.1%.m.p.224~226℃.1HNMR(DMSO-d6,400MHz)δ:7.38(t,J=8.7Hz,2H),7.22(s,1H),7.14(t,J=7.6Hz,1H),7.09(s,2H),6.99(t,J=7.4Hz,1H),5.81(dd,J=11.7,4.2Hz,1H),3.87-3.76(m,7H),3.72(d,J=5.5Hz,6H),3.32(dd,J=17.9,4.4Hz,1H),2.27(s,3H).MS(ESI)m/z:408.18(C23H25N3O4,[M+H]+).Anal.CalcdforC23H25N3O4:C,67.80;H,6.18;N,10.31.Found:C,67.95;H,6.17;N,10.33.
实施例五:1-(3-(4-氯苯基)-5-(1-甲基-1H-吲哚-3-基)-4,5-二氢-1H-吡唑-1-基)乙酮(6e)的制备
制备方法参考实施例一。Yield:11.1%.m.p.182~183℃.1HNMR(DMSO-d6,400MHz)δ:7.84(d,J=8.6Hz,2H),7.55(d,J=8.6Hz,2H),7.40(d,J=8.2Hz,1H),7.32(d,J=7.9Hz,1H),7.25(s,1H),7.13(t,J=7.6Hz,1H),6.97(t,J=7.5Hz,1H),5.81(dd,J=11.8,4.4Hz,1H),3.83(dd,J=18.0,11.9Hz,1H),3.72(s,3H),3.25(dd,J=18.0,4.5Hz,1H),2.25(s,3H).MS(ESI)m/z:352.11(C20H18ClN3O,[M+H]+).Anal.CalcdforC20H18ClN3O:C,68.28;H,5.16;N,11.94.Found:C,68.21;H,5.15;N,11.96.
实施例六:1-(3-(4-溴苯基)-5-(1-甲基-1H-吲哚-3-基)-4,5-二氢-1H-吡唑-1-基)乙酮(6f)的制备
制备方法参考实施例一。Yield:17.7%.m.p.183~185℃.1HNMR(DMSO-d6,400MHz)δ:7.77(d,J=8.6Hz,2H),7.68(d,J=8.6Hz,2H),7.39(d,J=8.2Hz,1H),7.32(d,J=7.9Hz,1H),7.25(s,1H),7.13(t,J=7.4Hz,1H),6.97(t,J=7.4Hz,1H),5.81(dd,J=11.9,4.4Hz,1H),3.83(dd,J=18.0,11.9Hz,1H),3.72(s,3H),3.25(dd,J=18.0,4.5Hz,1H),2.25(s,3H).MS(ESI)m/z:396.06(C20H18BrN3O,[M+H]+).Anal.CalcdforC20H18BrN3O:C,60.62;H,4.58;N,10.60.Found:C,60.67;H,4.59;N,10.58.
实施例七:1-(5-(1-甲基-1H-吲哚-3-基)-3-(4-(三氟甲基)苯基)-4,5-二氢-1H-吡唑-1-基)乙酮(6g)的制备
制备方法参考实施例一。Yield:61.6%.m.p.218~220℃.1HNMR(DMSO-d6,400MHz)δ:8.04(d,J=8.1Hz,2H),7.84(d,J=8.3Hz,2H),7.40(d,J=8.2Hz,1H),7.33(d,J=7.9Hz,1H),7.28(s,1H),7.14(t,J=7.5Hz,1H),6.98(t,J=7.4Hz,1H),5.85(dd,J=11.9,4.5Hz,1H),3.89(dd,J=18.1,12.0Hz,1H),3.73(s,3H),3.33-3.22(m,1H),2.28(s,3H).MS(ESI)m/z:386.14(C21H18F3N3O,[M+H]+).Anal.CalcdforC21H18F3N3O:C,65.45;H,4.71;N,10.90.Found:C,65.31;H,4.70;N,10.87.
实施例八:1-(5-(5-甲氧基-1-甲基-1H-吲哚-3-基)-3-苯基-4,5-二氢-1H-吡唑-1-基)乙酮(6h)的制备
制备方法参考实施例一。Yield:45.0%.m.p.175~176℃.1HNMR(DMSO-d6,400MHz)δ:7.93-7.79(m,2H),7.56-7.42(m,3H),7.29(d,J=8.8Hz,1H),7.20(s,1H),6.80(s,1H),6.77(d,J=8.8Hz,1H),5.78(dd,J=11.7,3.8Hz,1H),3.82(dd,J=17.9,11.7Hz,1H),3.68(s,3H),3.54(s,3H),3.25(dd,J=17.9,3.9Hz,1H),2.26(s,3H).MS(ESI)m/z:348.16(C21H21N3O2,[M+H]+).Anal.CalcdforC21H21N3O2:C,72.60;H,6.09;N,12.10.Found:C,72.71;H,6.10;N,12.12.
实施例九:1-(5-(5-甲氧基-1-甲基-1H-吲哚-3-基)-3-(4-甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)乙酮(6i)的制备
制备方法参考实施例一。Yield:46.7%.m.p.158~160℃.1HNMR(DMSO-d6,400MHz)δ:7.78(d,J=8.8Hz,2H),7.28(d,J=8.8Hz,1H),7.18(s,1H),7.03(d,J=8.9Hz,2H),6.81(s,1H),6.77(d,J=8.8Hz,1H),5.75(dd,J=11.6,3.8Hz,1H),3.84-3.69(m,4H),3.68(s,3H),3.56(s,3H),3.21(dd,J=17.8,3.9Hz,1H),2.23(s,3H).MS(ESI)m/z:378.17(C22H23N3O3,[M+H]+).Anal.CalcdforC22H23N3O3:C,70.01;H,6.14;N,11.13.Found:C,69.91;H,6.16;N,11.13.
实施例十:1-(3-(3,4-二甲氧基苯基)-5-(5-甲氧基-1-甲基-1H-吲哚-3-基)-4,5-二氢-1H-吡唑-1-基)乙酮(6j)的制备
制备方法参考实施例一。Yield:10.2%.m.p.186~187℃.1HNMR(DMSO-d6,400MHz)δ:7.42(s,1H),7.34(d,J=8.3Hz,1H),7.29(d,J=8.8Hz,1H),7.17(s,1H),7.03(d,J=8.4Hz,1H),6.83(s,1H),6.78(d,J=8.8Hz,1H),5.76(dd,J=11.5,3.4Hz,1H),3.86-3.72(m,7H),3.68(s,3H),3.58(s,3H),3.24(dd,J=17.7,3.6Hz,1H),2.25(s,3H).MS(ESI)m/z:408.18(C23H25N3O4,[M+H]+).Anal.CalcdforC23H25N3O4:C,67.80;H,6.18;N,10.31.Found:C,67.93;H,6.17;N,10.32.
实施例十一:1-(3-(4-氟苯基)-5-(5-甲氧基-1-甲基-1H-吲哚-3-基)-4,5-二氢-1H-吡唑-1-基)乙酮(6k)的制备
制备方法参考实施例一。Yield:29.8%.m.p.178~180℃.1HNMR(DMSO-d6,400MHz)δ:7.90(dd,J=8.7,5.5Hz,2H),7.31(dd,J=18.0,8.9Hz,3H),7.19(s,1H),6.85-6.73(m,2H),5.78(dd,J=11.7,3.8Hz,1H),3.82(dd,J=17.9,11.8Hz,1H),3.68(s,3H),3.57(s,3H),3.25(dd,J=17.9,3.9Hz,1H),2.25(s,3H).MS(ESI)m/z:366.15(C21H20FN3O2,[M+H]+).Anal.CalcdforC21H20FN3O2:C,69.03;H,5.52;N,11.50.Found:C,69.31;H,5.51;N,11.48.
实施例十二:1-(3-(4-氯苯基)-5-(5-甲氧基-1-甲基-1H-吲哚-3-基)-4,5-二氢-1H-吡唑-1-基)乙酮(6l)的制备
制备方法参考实施例一。Yield:36.7%.m.p.169~170℃.1HNMR(DMSO-d6,400MHz)δ:7.86(d,J=8.6Hz,2H),7.55(d,J=8.6Hz,2H),7.29(d,J=8.6Hz,1H),7.20(s,1H),6.78(d,J=8.7Hz,2H),5.79(dd,J=11.7,3.9Hz,1H),3.81(dd,J=18.0,11.8Hz,1H),3.68(s,3H),3.57(s,3H),3.24(dd,J=17.9,4.0Hz,1H),2.25(s,3H).MS(ESI)m/z:382.12(C21H20ClN3O2,[M+H]+).Anal.CalcdforC21H20ClN3O2:C,66.05;H,5.28;N,11.00.Found:C,65.98;H,5.27;N,10.98.
实施例十三:1-(3-(4-溴苯基)-5-(5-甲氧基-1-甲基-1H-吲哚-3-基)-4,5-二氢-1H-吡唑-1-基)乙酮(6m)的制备
制备方法参考实施例一。Yield:38.6%.m.p.172~173℃.1HNMR(DMSO-d6,400MHz)δ:7.78(d,J=8.5Hz,2H),7.68(d,J=8.4Hz,2H),7.29(d,J=8.5Hz,1H),7.19(s,1H),6.78(d,J=8.6Hz,2H),5.79(dd,J=11.7,3.9Hz,1H),3.81(dd,J=18.0,11.9Hz,1H),3.68(s,3H),3.58(s,3H),3.24(dd,J=18.0,4.0Hz,1H),2.25(s,3H).MS(ESI)m/z:426.07(C21H20BrN3O2,[M+H]+).Anal.CalcdforC21H20BrN3O2:C,59.17;H,4.73;N,9.86.Found:C,59.33;H,4.71;N,9.85.
实施例十四:1-(5-(5-溴-1-甲基-1H-吲哚-3-基)-3-苯基-4,5-二氢-1H-吡唑-1-基)乙酮(6n)的制备
制备方法参考实施例一。Yield:59.0%.m.p.173~174℃.1HNMR(DMSO-d6,400MHz)δ:7.94-7.74(m,2H),7.61(s,1H),7.57-7.41(m,3H),7.39(d,J=8.7Hz,1H),7.29(s,1H),7.25(d,J=8.7Hz,1H),5.81(dd,J=11.7,4.2Hz,1H),3.84(dd,J=18.0,11.8Hz,1H),3.72(s,3H),3.25(dd,J=18.0,4.3Hz,1H),2.27(s,3H).MS(ESI)m/z:396.06(C20H18BrN3O,[M+H]+).Anal.CalcdforC20H18BrN3O:C,60.62;H,4.58;N,10.60.Found:C,60.79;H,4.57;N,10.63.
实施例十五:1-(5-(5-溴-1-甲基-1H-吲哚-3-基)-3-(2-甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)乙酮(6o)的制备
制备方法参考实施例一。Yield:58.5%.m.p.180~181℃.1HNMR(DMSO-d6,400MHz)δ:7.85(d,J=6.1Hz,1H),7.63(s,1H),7.46(t,J=7.0Hz,1H),7.39(d,J=8.7Hz,1H),7.30(s,1H),7.25(d,J=6.9Hz,1H),7.14(d,J=8.3Hz,1H),7.06(t,J=7.9Hz,1H),5.74(dd,J=11.8,4.2Hz,1H),3.88(dd,J=18.5,11.8Hz,1H),3.81(s,3H),3.73(s,3H),3.28(dd,J=18.5,4.2Hz,1H),2.23(s,3H).MS(ESI)m/z:426.07(C21H20BrN3O2,[M+H]+).Anal.CalcdforC21H20BrN3O2:C,59.17;H,4.73;N,9.86.Found:C,59.31;H,4.74;N,9.84.
实施例十六:1-(5-(5-溴-1-甲基-1H-吲哚-3-基)-3-(3-甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)乙酮(6p)的制备
制备方法参考实施例一。Yield:59.9%.m.p.184~185℃.1HNMR(DMSO-d6,400MHz)δ:7.60(s,1H),7.44-7.36(m,3H),7.34(s,1H),7.29(s,1H),7.26(d,J=6.9Hz,1H),7.11-7.02(m,1H),5.80(dd,J=11.7,4.3Hz,1H),3.89-3.78(m,4H),3.72(s,3H),3.26(dd,J=18.0,4.3Hz,1H),2.27(s,3H).MS(ESI)m/z:426.07(C21H20BrN3O2,[M+H]+).Anal.CalcdforC21H20BrN3O2:C,59.17;H,4.73;N,9.86.Found:C,59.24;H,4.72;N,9.87.
实施例十七:1-(5-(5-溴-1-甲基-1H-吲哚-3-基)-3-(4-甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)乙酮(6q)的制备
制备方法参考实施例一。Yield:75.8%.m.p.208~209℃.1HNMR(DMSO-d6,400MHz)δ:7.77(d,J=8.8Hz,2H),7.59(s,1H),7.39(d,J=8.7Hz,1H),7.28(s,1H),7.25(d,J=7.0Hz,1H),7.03(d,J=8.8Hz,2H),5.77(dd,J=11.6,4.1Hz,1H),3.91-3.75(m,4H),3.72(s,3H),3.21(dd,J=17.9,4.2Hz,1H),2.25(s,3H).MS(ESI)m/z:426.07(C21H20BrN3O2,[M+H]+).Anal.CalcdforC21H20BrN3O2:C,59.17;H,4.73;N,9.86.Found:C,59.19;H,4.72;N,9.85.
实施例十八:1-(5-(5-溴-1-甲基-1H-吲哚-3-基)-3-(3,4-二甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)乙酮(6r)的制备
制备方法参考实施例一。Yield:64.8%.m.p.229~231℃.1HNMR(DMSO-d6,400MHz)δ:7.61(s,1H),7.43-7.36(m,2H),7.33(d,J=8.3Hz,1H),7.26(d,J=9.1Hz,2H),7.03(d,J=8.4Hz,1H),5.78(dd,J=11.6,4.0Hz,1H),3.85-3.75(m,7H),3.72(s,3H),3.24(dd,J=17.9,4.1Hz,1H),2.27(s,3H).MS(ESI)m/z:456.08(C22H22BrN3O3,[M+H]+).Anal.CalcdforC22H22BrN3O3:C,57.90;H,4.86;N,9.21.Found:C,57.98;H,4.87;N,9.22.
实施例十九:1-(5-(5-溴-1-甲基-1H-吲哚-3-基)-3-(3,4,5-三甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)乙酮(6s)的制备
制备方法参考实施例一。Yield:40.6%.m.p.228~229℃.1HNMR(DMSO-d6,400MHz)δ:7.65(s,1H),7.39(d,J=8.7Hz,1H),7.26(t,J=5.1Hz,2H),7.09(s,2H),5.82(dd,J=11.6,4.1Hz,1H),3.87-3.76(m,7H),3.72(s,6H),3.30-3.28(m,1H),2.29(s,3H).MS(ESI)m/z:486.10(C23H24BrN3O4,[M+H]+).Anal.CalcdforC23H24BrN3O4:C,56.80;H,4.97;N,8.64.Found:C,56.81;H,4.97;N,8.62.
实施例二十:1-(5-(5-溴-1-甲基-1H-吲哚-3-基)-3-(4-氟苯基)-4,5-二氢-1H-吡唑-1-基)乙酮(6t)的制备
制备方法参考实施例一。Yield:38.6%.m.p.199~200℃.1HNMR(DMSO-d6,400MHz)δ:7.89(dd,J=8.7,5.5Hz,2H),7.60(s,1H),7.39(d,J=8.7Hz,1H),7.33(t,J=8.9Hz,2H),7.30(s,1H),7.25(d,J=6.9Hz,1H),5.81(dd,J=11.7,4.2Hz,1H),3.83(dd,J=18.0,11.7Hz,1H),3.72(s,3H),3.26(dd,J=18.0,4.3Hz,1H),2.26(s,3H).MS(ESI)m/z:414.05(C20H17BrFN3O,[M+H]+).Anal.CalcdforC20H17BrFN3O:C,57.99;H,4.14;N,10.14.Found:C,57.88;H,4.14;N,10.16.
实施例二十一:1-(5-(5-溴-1-甲基-1H-吲哚-3-基)-3-(4-氯苯基)-4,5-二氢-1H-吡唑-1-基)乙酮(6u)的制备
制备方法参考实施例一。Yield:48.5%.m.p.200~201℃.1HNMR(DMSO-d6,400MHz)δ:7.84(d,J=8.5Hz,2H),7.60(s,1H),7.54(d,J=8.5Hz,2H),7.38(d,J=8.7Hz,1H),7.29(s,1H),7.25(d,J=8.7Hz,1H),5.81(dd,J=11.7,4.1Hz,1H),3.82(dd,J=18.0,11.8Hz,1H),3.71(s,3H),3.25(dd,J=18.0,4.3Hz,1H),2.27(s,3H).MS(ESI)m/z:430.02(C20H17BrClN3O,[M+H]+).Anal.CalcdforC20H17BrClN3O:C,55.77;H,3.98;N,9.76.Found:C,55.91;H,3.97;N,9.78.
实施例二十二:1-(5-(5-溴-1-甲基-1H-吲哚-3-基)-3-(4-溴苯基)-4,5-二氢-1H-吡唑-1-基)乙酮(6v)的制备
制备方法参考实施例一。Yield:37.0%.m.p.206~207℃.1HNMR(DMSO-d6,400MHz)δ:7.77(d,J=8.5Hz,2H),7.68(d,J=8.6Hz,2H),7.59(s,1H),7.39(d,J=8.7Hz,1H),7.30(s,1H),7.25(d,J=7.0Hz,1H),5.81(dd,J=11.7,4.3Hz,1H),3.82(dd,J=18.0,11.8Hz,1H),3.72(s,3H),3.25(dd,J=18.0,4.4Hz,1H),2.27(s,3H).MS(ESI)m/z:473.97(C20H17Br2N3O,[M+H]+).Anal.CalcdforC20H17Br2N3O:C,50.55;H,3.61;N,8.84.Found:C,50.42;H,3.61;N,8.86.
实施例二十三:一类吲哚乙酰基吡唑衍生物的体外抗癌活性研究进展
采用MTT[3-(4,5)-双甲基-2-噻唑-(2,5)-苯基溴化四氮唑蓝]法来测定含甲硝唑骨架的吡唑硝基咪唑衍生物对人肝癌细胞(HEPG2),人乳腺癌细胞(MCF-7)以及人肺腺癌细胞(A549)的抑制率达到50%时的药物浓度(halfmaximalinhibitoryconcentration,IC50)。以及对人肾上皮细胞(293T)的细胞毒性,每个化合物的毒性用抑制293T细胞存活率到50%时的浓度来表示。
(1)培养液的配制:DMEM(基础培养基)89%,胎牛血清10%,青霉素链霉素溶液(10000IU/mL,10000μg/mL)1%。
(2)四种贴壁癌细胞的培养:利用上述培养液(培养液体积约为培养瓶容量的1/10),在37℃,5%CO2培养箱中培养,根据癌细胞的生长状态判断传代时间。
(3)不同浓度药物的配制:利用三蒸水(少量DMSO助溶)配制储备液,加药后的每孔细胞悬液中DMSO的终浓度一般不超过0.05%-0.1%;用三蒸水把储备液稀释至六个浓度梯度(10μg/mL,2μg/mL,0.4μg/mL,0.08μg/mL,0.016μg/mL,0.003μg/mL);保存于-20℃冰箱中备用。
(4)细胞孵育:取对数生长期肿瘤细胞,调细胞悬液浓度为1-1.5×105/mL,混匀后加入96孔培养板中(100μL/孔),在37℃,5%CO2培养箱中培养24h。
(5)加药:将稀释好的不同浓度梯度的药物分别加入到96孔培养板中,每个浓度梯度设3个平孔,继续培养48h。实验分为实验组(培养液、细胞、药物)、对照组(培养液和细胞)和空白组(只有培养液)。
(6)存活细胞检测:在培养了48h后的96孔板中,加MTT(5mg/mL)10μL/孔;在37℃放置4h后,移除上清液,加DMSO150μL/孔,振荡至formazan结晶全部溶解;利用自动酶标仪在570nm波长处检测各孔的光密度(OD值)。
抑制率的计算:
生长抑制率=(1-存活率)×100%=[1-(OD实验-OD空白)/(OD对照-OD空白)]×100%(OD实验表示实验组的平均光密度,OD对照表示对照组的平均光密度,OD空白表示空白组的平均光密度)。
根据药物浓度-细胞生长抑制率的标准曲线,求其IC50。
本发明所列一类吲哚乙酰基吡唑衍生物对肿瘤细胞,正常细胞以及微管蛋白聚合的抑制IC50值(μmol/mL)见下表
从上述实验可知:本发明对人肝癌细胞(HEPG2),人乳腺癌细胞(MCF-7)以及人肺腺癌细胞(A549)有明显的抑制作用,与对照组相比,活性明显提高。本发明对人肾上皮细胞(293T)表现出了相当或者优于阳性对照药物的细胞毒性,可以用于制取抗肿瘤药物。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种等同变换,这些等同变换均属于本发明的保护范围。另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合。为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。此外,本发明的各种不同的实施方式之间也可以进行任意组合,只要其不违背本发明的思想,其同样应当视为本发明所公开的内容。
Claims (4)
1.一类吲哚乙酰基吡唑衍生物,其结构如式所示,
2.一种制备吲哚乙酰基吡唑衍生物的方法,其特征在于,所述一类吲哚乙酰基吡唑衍生物的结构如式所示,
制备方法步骤如下:
步骤1.冰浴条件下,向反应容器中依次加入结构如式A所示的化合物,POCl3于DMF中反应,充分反应后,得到结构如式B所示的化合物。
步骤2.依次向反应容器中加入THF,NaH以及结构如式B所示的化合物,冰浴反应,再加入CH3I室温反应,TLC跟踪,充分反应后,得到结构如式C所示的化合物。
步骤3.室温下,依次向反应容器中加入无水乙醇溶液,结构如式C所示的化合物,不同取代的乙酰苯,KOH,充分反应,得到结构如式D所示的化合物。
步骤4.依次向反应容器中加入无水乙醇溶液,结构如式D所示的化合物,水合肼,回流2h,冷却转移至-20℃过夜,充分反应后得到结构如式E所示的化合物。
步骤5.依次向反应容器中加入乙酸,EDC·HCl,HOBt以及二氯甲烷溶液,随后在N2保护下加入结构如式E所示的化合物,充分反应后得到结构如式F所示的化合物。
其中,R1,R2选自下列:
3.一类吲哚乙酰基吡唑衍生物在制备抗癌药物中的应用,其特征在于,其结构如式所示
4.一种抗癌药物,其特征在于,包括结构如式所示的化合物及医学上可接受的载体,
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