CN101914095B - 2-氯吡啶衍生物及其制法与在制备抗肝癌药物中的应用 - Google Patents
2-氯吡啶衍生物及其制法与在制备抗肝癌药物中的应用 Download PDFInfo
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- CN101914095B CN101914095B CN2010102448692A CN201010244869A CN101914095B CN 101914095 B CN101914095 B CN 101914095B CN 2010102448692 A CN2010102448692 A CN 2010102448692A CN 201010244869 A CN201010244869 A CN 201010244869A CN 101914095 B CN101914095 B CN 101914095B
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Abstract
Description
技术领域
本发明涉及2-氯吡啶衍生物及其制备方法与在制备抗肝癌药物中的应用。
背景技术。
肝癌(hepatocellular carcinoma,HCC)是指肝细胞或肝内胆管细胞发生的癌,是恶性程度及转移率很高的肿瘤之一,并且是是当今世界上最具威胁的疾病之一。目前有几种治疗肝癌的药物,但它们都有严重的副作用,因此限制了其临床应用。由于缺乏治疗肝癌的有效药物,发现有效的具有抗肝癌细胞增殖活性的新化合物是一个很迫切的任务。
2-氯-5-氯甲基吡啶(2-chloro-5-chloromethylpyridine,简称CCMP),纯品为浅黄色晶体,熔点33-35℃,沸点75-85℃/133.322Pa,通过它的烷基化反应、与杂环的缩合反应以及氨化后的进一步反应,可以制备一系列新的具有好的生物活性的先导化合物,是合成农药和医药的重要中间体。
1,3,4-噁二唑杂环化合物具有抗炎、抗菌、抗惊厥、抗肿瘤等生物活性。据文献报道,在具有杂环化合物的分子中引入硫原子供电原子可以显著增加受体与配体形成复合物的亲和力,有利于提高生物活性。
噁二唑硫醇环外有-SH,它可以作为活泼的亲核试剂和各种亲电试剂发生反应生成硫醚,硫醚可进一步转化为非常有用的另一种噁二唑硫酮衍生物,由于其硫酮结构的存在,3-位活泼的NH还可以和醛、仲胺或伯胺的盐酸盐缩合,生成更具广谱生物活性的杂环Mannich碱。因此,含各种取代基的噁二唑硫醚的合成,迄今仍方兴未艾。
本发明将2-氯吡啶分子中引入1,3,4-噁二唑杂环,制备的2-氯吡啶衍生物,对人肝癌细胞(Hep-G2)生长有明显的抑制作用,因此2-氯吡啶衍生物作为很有潜力的抗肝癌药物的前景十分值得关注。随着对2-氯吡啶类药物研究的不断深入,在对其抗肿瘤作用机制不断了解的基础上进行有效的结构改造与修饰和分子设计,将会有越来越多的高效、低毒的2-氯吡啶类抗肝癌药物用于临床,造福人类。
发明内容
本发明的目的在于提供一类2-氯吡啶衍生物以及它们的制备方法与用途。
本发明的技术方案如下:
一类2-氯吡啶衍生物,其特征是它有如下通式:
式中R为:
一种制备上述的2-氯吡啶衍生物的方法,其特征是它由下列步骤组成:
步骤1.将按通法制备的2mmol 5-取代-2-巯基-1,3,4-噁二唑,2mmolNaOH,适量乙腈加入到100ml圆底烧瓶中,加热搅拌溶解;
步骤2.用恒压滴液漏斗滴加5ml 2-氯-5-氯甲基吡啶的乙腈溶液(含2mmol,即0.324g 2-氯-5-氯甲基吡啶),回流8-24h,薄层色谱(TLC)跟踪反应;
步骤3.冷却至室温,减压蒸除溶剂,用EtOAC溶解,水洗,饱和食盐水洗;
步骤4.有机相用无水Na2SO4干燥,过滤,减压蒸除EtOAC,得粗产物;
步骤5.将步骤4得到的粗产物重结晶得到本发明的2-氯吡啶衍生物。
本发明的2-氯吡啶衍生物对人肝癌细胞(Hep-G2)生长有明显的抑制作用,因此本发明的2-氯吡啶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,但应注意本发明的范围并不受这些实施例的任何限制。
实施例一:2-氯-5-[5-(2-甲基苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物1)的制备
邻甲基苯甲酸在浓硫酸催化作用下进行酯化反应,得到邻甲基苯甲酸乙酯。得到的芳香酸酯溶于适量无水乙醇,加入稍过量的85%的水合肼,搅拌下回流8-12h。减压蒸除溶剂,然后加水,待固体析出后,过滤并用水洗,乙醇重结晶,得到取代的酰肼。将0.02mol酰肼,0.02mol KOH溶于适量95%乙醇后,再慢慢滴加稍过量的CS2搅拌回流至无H2S气体产生为止,反应终止后蒸除多余乙醇,倒入冷水中,用稀盐酸调pH值至5-6,产生大量沉淀,抽滤,水洗,晾干,用50%乙醇重结晶得到2-取代-5-巯基-1,3,4-噁二唑(本实施例得到2-(2-甲苯基)-5-巯基-1,3,4-噁二唑)。将2mmol 2-取代-5-巯基-1,3,4-噁二唑,2mmolNaOH,适量乙腈加入到100ml圆底烧瓶中,加热溶解,滴加5ml 2-氯-5-氯甲基吡啶的乙腈溶液(含2mmol,即0.324g 2-氯-5-氯甲基吡啶),回流8-24h,TLC跟踪反应。冷却至室温,减压蒸除溶剂,用EtOAC,先用水洗涤,然后用饱和食盐水洗。有机相用无水Na2SO4干燥,过滤,减压蒸除EtOAC,重结晶得目标化合物。白色固体,产率65.8%,m.p.80-81℃;1H NMR(300MHz,DMSO-d6)δ:2.55(s,3H),4.59(s,2H),7.38-7.43(m,2H),7.46-7.52(m,2H),7.81(d,J=7.9Hz,1H),7.98(d,J=8.2Hz,1H),8.51(s,1H).MS(ESI):318.8(C15H13ClN3OS,[M+H]+).Anal.Calcd for C15H12ClN3OS:C,56.69;H,3.81;N,13.22%;Found:C,56.66;H,3.78;N,13.26%.
实施例二:2-氯-5-[5-(4-甲基苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物2)的制备
制备方法同实施例一。以对甲基苯甲酸代替邻甲基苯甲酸,得目标化合物。淡黄色晶体,产率65.1%,m.p.148-149℃;1H NMR(500MHz,DMSO-d6)δ:2.40(s,3H),4.60(s,2H),7.41(d,J=8.0Hz,2H),7.53(d,J=9.0Hz,1H),7.84(d,J=8.0Hz,2H),8.00(d,J=8.5Hz,1H),8.52(s,1H).MS(ESI):318.8(C15H13ClN3OS,[M+H]+).Anal.Calcd for C15H12ClN3OS:C,56.69;H,3.81;N,13.22%;Found:C,56.76;H,3.75;N,13.28%.
实施例三:2-氯-5-[5-(2-甲氧基苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物3)的制备
制备方法同实施例一。以邻甲氧基苯甲酸代替邻甲基苯甲酸,得目标化合物。淡黄色晶体,产率52.7%,m.p.73-74℃;1H NMR(300MHz,DMSO-d6)δ:3.88(s,3H),4.57(s,2H),7.11(t,J=7.3Hz,1H),7.26(d,J=8.4Hz,1H),7.52(d,J=8.2Hz,1H),7.60(t,J=7.3Hz,1H),7.77(d,J=7.8Hz,1H),7.98(d,J=8.3Hz,1H),8.51(s,1H).MS(ESI):334.8(C15H13ClN3O2S,[M+H]+).Anal.Calcd forC15H12ClN3O2S:C,53.97;H,3.62;N,12.59%;Found:C,53.91;H,3.55;N,12.65%.
实施例四:2-氯-5-[5-(4-甲氧基苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物4)的制备
制备方法同实施例一。以对甲氧基苯甲酸代替邻甲基苯甲酸,得目标化合物。淡黄色粉末,产率53.9%,m.p.120-121℃;1H NMR(500MHz,DMSO-d6)δ:3.85(s,3H),4.58(s,2H),7.13(d,J=8.8Hz,2H),7.51(d,J=8.2Hz,1H),7.88(d,J=8.8Hz,2H),7.98(d,J=8.2Hz,1H),8.50(s,1H).MS(ESI):334.8(C15H13ClN3O2S,[M+H]+).Anal.Calcd for C15H12ClN3O2S:C,53.97;H,3.62;N,12.59%;Found:C,53.88;H,3.53;N,12.67%
实施例五:2-氯-5-[5-(4-羟基苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物5)的制备
制备方法同实施例一。以4-羟基苯甲酸代替邻甲基苯甲酸,得目标化合物。黄色晶体,产率67.5%,m.p.198-200℃;1H NMR(500MHz,DMSO-d6):4.58(s,2H),6.93(d,J=9.0Hz,2H),7.53(d,J=8.0Hz,1H),7.78(d,J=8.5Hz,2H),7.98(d,J=8.5Hz,1H),8.50(s,1H),10.35(s,1H).MS(ESI):320.8(C14H11ClN3O2S,[M+H]+).Anal.Calcd for C14H10ClN3O2S:C,52.59;H,3.15;N,13.14%;Found:C,52.66;H,3.18;N,13.17%.
实施例六:2-氯-5-[5-(2-氟苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物6)的制备
制备方法同实施例一。以2-氟苯甲酸代替邻甲基苯甲酸,得目标化合物。白色晶体,产率62.8%,m.p.109-110℃;1H NMR(300MHz,DMSO-d6)δ:4.60(s,2H),7.40-7.53(m,3H),7.65-7.73(m,1H),7.95-8.01(m,2H),8.52(s,1H).MS(ESI):322.8(C14H10ClFN3OS,[M+H]+).Anal.Calcd for C14H9ClFN3OS:C,52.26;H,2.82;N,13.06%;Found:C,52.21;H,2.73;N,13.12%
实施例七:2-氯-5-[5-(4-氟苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物7)的制备
制备方法同实施例一。以4-氟苯甲酸代替邻甲基苯甲酸,得目标化合物。淡黄色晶体,产率56.2%,m.p.132-133℃;1H NMR(500MHz,DMSO-d6)δ:4.61(s,2H),7.45(t,J=8.5Hz,2H),7.53(d,J=8.0Hz,1H),7.99-8.04(m,3H),8.53(s,1H).MS(ESI):322.8(C14H10ClFN3OS,[M+H]+).Anal.Calcd for C14H9ClFN3OS:C,52.26;H,2.82;N,13.06%;Found:C,52.33;H,2.77;N,13.01%.
实施例八:2-氯-5-[5-(2-氯苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物8)的制备
制备方法同实施例一。以2-氯苯甲酸代替邻甲基苯甲酸,得目标化合物。白色晶体,产率58.4%,m.p.79-80℃;1H NMR(300MHz,DMSO-d6)δ:4.61(s,2H),7.51-7.58(m,2H),7.61-7.72(m,2H),7.94(d,J=7.7Hz,1H),7.99(d,J=8.2Hz,1H),8.52(s,1H).MS(ESI):339.2(C14H10Cl2N3OS,[M+H]+).Anal.Calcd forC14H9Cl2N3OS:C,49.72;H,2.68;N,12.42%;Found:C,49.62;H,2.60;N,12.45%
实施例九:2-氯-5-[5-(4-氯苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物9)的制备
制备方法同实施例一。以4-氯苯甲酸代替邻甲基苯甲酸,得目标化合物。白色固体,产率61.3%,m.p.147-148℃;1H NMR(300MHz,DMSO-d6)δ:4.61(s,2H),7.52(d,J=8.2Hz,2H),7.67(d,J=8.4Hz,2H),7.95-8.00(m,3H),8.52(s,1H).MS(ESI):339.2(C14H10Cl2N3OS,[M+H]+).Anal.Calcd for C14H9Cl2N3OS:C,49.72;H,2.68;N,12.42%;Found:C,49.83;H,2.61;N,12.38%.
实施例十:2-氯-5-[5-(4-异丙基苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物10)的制备
制备方法同实施例一。以4-异丙基苯甲酸代替邻甲基苯甲酸,得目标化合物。黄色粉末,产率51.4%,m.p.195-197℃;1HNMR(500MHz,DMSO-d6)δ:1.24(d,J=7.0Hz,6H),2.97-3.00(m,1H),4.54(s,2H),4.60(s,2H),7.47(d,J=8.5Hz,2H),7.53(d,J=8.5Hz,1H),7.87(d,J=8.5Hz,2H),8.00(d,J=8.0Hz,1H),8.52(s,1H).MS(ESI):346.9(C17H17ClN3OS,[M+H]+).Anal.Calcd for C17H16ClN3OS:C,59.04;H,4.66;N,12.15%;Found:C,59.07;H,4.61;N,12.21%.
实施例十一:2-氯-5-[5-(4-氨基苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物11)的制备
制备方法同实施例一。以4-氨基苯甲酸代替邻甲基苯甲酸,得目标化合物。黄色粉末,产率58.9%,m.p.154-155℃;1H NMR(500MHz,DMSO-d6):4.54(s,2H),5.97(s,2H),6.66(d,J=9.0Hz,2H),7.52(d,J=8.5Hz,1H),7.58(d,J=8.5Hz,2H),7.96(d,J=8.0Hz,1H),8.49(s,1H).MS(ESI):319.8(C14H12ClN4OS,[M+H]+).Anal.Calcd for C14H11ClN4OS:C,52.75;H,3.48;N,17.58%;Found:C,52.71;H,3.50;N,17.55%.
实施例十二:2-氯-5-[5-(4-二甲氨基苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物12)的制备
制备方法同实施例一。以4-二甲氨基苯甲酸代替邻甲基苯甲酸,得目标化合物。黄色固体,产率61.3%,m.p.151-153℃;1H NMR(500MHz,DMSO-d6):3.02(s,6H),4.56(s,2H),6.82(d,J=9.0Hz,2H),7.53(d,J=8.0Hz,1H),7.72(d,J=8.5Hz,2H),7.98(d,J=8.0Hz,1H),8.50(s,1H).MS(ESI):347.8(C16H16ClN4OS,[M+H]+).Anal.Calcd for C16H15ClN4OS:C,55.41;H,4.36;N,16.15%;Found:C,55.48;H,4.31;N,16.18%.
实施例十三:2-氯-5-[5-(2-乙氧基苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物13)的制备
制备方法同实施例一。以2-乙氧基苯甲酸代替邻甲基苯甲酸,得目标化合物。棕色晶体,产率52.2%,m.p.87-88℃;1H NMR(500MHz,DMSO-d6)δ:1.33(t,J=6.5Hz,3H),4.17(q,J=7.0Hz,2H),4.58(s,2H),7.11(t,J=8.0Hz,1H),7.25(d,J=8.5Hz,1H),7.54(d,J=8.5Hz,1H),7.57-7.60(m,1H),7.78(d,J=7.5Hz,1H),7.98(d,J=8.5Hz,1H),8.50(s,1H).MS(ESI):348.8(C16H15ClN3O2S,[M+H]+).Anal.Calcd for C16H14ClN3O2S:C,55.25;H,4.06;N,12.08%;Found:C,55.33;H,4.01;N,12.11%.
实施例十四:2-氯-5-[5-(4-乙氧基苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物14)的制备
制备方法同实施例一。以4-乙氧基苯甲酸代替邻甲基苯甲酸,得目标化合物。白色粉末,产率57.1%,m.p.117-119℃;1H NMR(500MHz,DMSO-d6):1.36(t,J=7.0Hz,3H),4.13(q,J=6.5Hz,2H),4.59(s,2H),7.12(d,J=8.5Hz,2H),7.53(d,J=8.0Hz,1H),7.87(d,J=9.0Hz,2H),8.00(d,J=8.5Hz,1H),8.52(s,1H).MS(ESI):348.8(C16H15ClN3O2S,[M+H]+).Anal.Calcd for C16H14ClN3O2S:C,55.25;H,4.06;N,12.08%;Found:C,55.29;H,4.05;N,12.11%.
实施例十五:2-氯-5-[5-(3,4-二甲氧基苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物15)的制备
制备方法同实施例一。以3,4-二甲氧基苯甲酸代替邻甲基苯甲酸,得目标化合物。白色固体,产率58.1%,m.p.123-124℃;1H NMR(500MHz,DMSO-d6)δ:3.85(s,6H),4.59(s,2H),7.16(d,J=8.5Hz,1H),7.40(s,1H),7.53(d,J=9.0Hz,2H),7.99(d,J=8.0Hz,1H),8.52(s,1H).MS(ESI):364.8(C16H15ClN3O3S,[M+H]+).Anal.Calcd for C16H14ClN3O3S:C,52.82;H,3.88;N,11.55%;Found:C,52.76;H,3.91;N,11.51%.
实施例十六:2-氯-5-[5-(3,5-二甲氧基苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物16)的制备
制备方法同实施例一。以3,5-二甲氧基苯甲酸代替邻甲基苯甲酸,得目标化合物。白色粉末,产率58.4%,m.p.122-123℃;1H NMR(500MHz,DMSO-d6):3.88(s,6H),4.61(s,2H),6.76(s,1H),7.05(s,2H),7.54(d,J=8.0Hz,1H),8.00(d,J=8.5Hz,1H),8.53(s,1H).MS(ESI):364.8(C16H15ClN3O3S,[M+H]+).Anal.Calcd for C16H14ClN3O3S:C,52.82;H,3.88;N,11.55%;Found:C,52.91;H,3.92;N,11.48%.
实施例十七:2-氯-5-[5-(3,4,5-三甲氧基苯基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物17)的制备
制备方法同实施例一。以3,4,5-三甲氧基苯甲酸代替邻甲基苯甲酸,得目标化合物。黄色晶体,产率60.1%,m.p.119-120℃;1H NMR(500MHz,DMSO-d6)δ:3.75(s,3H),3.88(s,6H),4.60(s,2H),7.18(s,2H),7.54(d,J=8.5Hz,1H),8.00(d,J=8.0Hz,1H),8.54(s,1H).MS(ESI):394.8(C17H17ClN3O4S,[M+H]+).Anal.Calcd for C17H16ClN3O4S:C,51.84;H,4.09;N,10.67%;Found:C,51.75;H,4.08;N,10.70%.
实施例十八:2-氯-5-[5-(2-呋喃基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物18)的制备
制备方法同实施例一。以呋喃-2-羧酸代替邻甲基苯甲酸,得目标化合物。淡黄色晶体,产率59.3%,m.p.97-98℃;1H NMR(300MHz,DMSO-d6)δ:4.58(s,2H),6.80(s,1H),7.33(s,1H),7.53(d,J=8.0Hz,1H),7.98(d,J=8.5Hz,1H),8.06(s,1H),8.51(s,1H).MS(ESI):294.7(C12H9ClN3O2S,[M+H]+).Anal.Calcd forC12H8ClN3O2S:C,49.07;H,2.75;N,14.31%;Found:C,49.16;H,2.80;N,14.25%.
实施例十九:2-氯-5-[5-(2-噻吩基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物19)的制备
制备方法同实施例一。以噻吩-2-羧酸代替邻甲基苯甲酸,得目标化合物。白色粉末,产率58.3%,m.p.93-94℃;1H NMR(300MHz,DMSO-d6)δ:4.58(s,2H),7.27-7.30(m,1H),7.52(d,J=8.2Hz,1H),7.78-7.79(m,1H),7.94-7.95(m,1H),7.97-8.00(m,1H),8.51(s,1H).MS(ESI):310.8(C12H9ClN3OS2,[M+H]+).Anal.Calcd for C12H9ClN3OS2:C,46.52;H,2.60;N,13.56%;Found:C,46.48;H,2.53;N,13.62%.
实施例二十:2-氯-5-[5-(1-萘基)-1,3,4-噁二唑-2-硫代甲基]吡啶(化合物20)的制备
制备方法同实施例一。以1-萘甲酸代替邻甲基苯甲酸,得目标化合物。淡黄色晶体,产率61.4%,m.p.110-111℃;1H NMR(500MHz,DMSO-d6)δ:4.66(s,2H),7.55(d,J=8.5Hz,1H),7.66-7.76(m,3H),8.03(d,J=8.0Hz,1H),8.10(d,J=7.5Hz,1H),8.15(d,J=7.5Hz,1H),8.22(d,J=8.5Hz,1H),8.57(s,1H),8.99(d,J=9.0Hz,1H).MS(ESI):354.8(C18H13ClN3OS,[M+H]+).Anal.Calcd forC18H12ClN3OS:C,61.10;H,3.42;N,11.88%;Found:C,61.02;H,3.37;N,11.92%.
实施例二十一:2-氯吡啶衍生物体外抗人肝癌细胞(Hep-G2)活性研究
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2-氯吡啶衍生物对人肝癌细胞(Hep-G2)的抑制率,计算IC50值(μM)。
1.培养液等的配制
RPMI1640培养基一袋加水一升,补加2克碳酸氢钠,10万单位青霉素和100mg链霉素,调节pH值至7.4,用0.22μm除菌滤膜过滤除菌。90mL培养基加灭活新生牛血清10mL即为完全培养液。胰蛋白酶用D-hanks缓冲液配成0.25%溶液,过滤除菌后4℃保存备用。
2.药液配制
准确称取被测样品1.0mg,加到灭菌的1.5mL离心管中,加入DMSO 1mL,配成1mg/mL原液,-40℃冷冻保存。临用前融化后用适量D-hanks稀释成相应浓度应用。
3.细胞培养及传代
细胞均贴壁培养于含10mL完全培养液细胞培养瓶中,于37℃、5%CO2、饱和湿度下培养。细胞长满瓶底后用灭菌D-hanks液洗两次,加0.25%胰蛋白酶消化细胞2min,倒掉胰蛋白酶,待轻摇细胞能完全脱落后,加完全培养液30ml后,用移液管吹散细胞,分装于3个新的细胞培养瓶中,继续培养。
4.抗增殖活性测试
取刚刚长成完整单层的细胞一瓶,胰蛋白酶消化后收集细胞,用移液管吹打均匀,取两滴细胞悬液台盼蓝(Trypan Blue)染色,于显微镜下计数活细胞数目(死细胞数目不得超过5%),用完全培养液调整细胞数目至1×105个细胞/mL。于96孔细胞培养板中每孔加入100μL细胞悬液,将培养板置于CO2培养箱中培养12h,取出培养板后于每孔中加含不同浓度梯度的被测样品的溶液,每个浓度设3个平行孔,另设3孔细胞不加被测药作正常对照孔。加完药后培养板于微孔板振荡器上振荡混匀,置于CO2培养箱中继续培养48h。取出培养板,每孔加入25μL 4mg/mL的MTT液,振荡混匀,继续培养6h。加入每孔100μL SDS裂解液(90mL三蒸水+10g SDS+5mL异丙醇+2mL浓盐酸)后培养12h。于酶标仪测定各孔光吸收(OD值),测定波长570nm,参考波长630nm。根据各孔OD值计算药物对细胞增殖的抑制率:
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
半数抑制浓度(IC50)定义为当50%的肿瘤细胞存活时的药物浓度。根据测定的光密度(OD值),制作细胞生长抑制率的标准曲线,在标准曲线上求得其对应的药物浓度。
测得的IC50见表1所示
表1本发明所列2-氯吡啶衍生物的对人肝癌细胞(Hep-G2)的抑制IC50值(μM)
5-Fua),5-Fluorouracil,阳性对照。
Claims (3)
2.一种制备权利要求1所述的2-氯吡啶衍生物的方法,其特征是它由下列步骤组成:
步骤1.将按通法制备的2mmol 2-取代-5-巯基-1,3,4-噁二唑,2mmolNaOH,溶剂乙腈加入到100ml圆底烧瓶中,加热搅拌溶解;
步骤2.滴液漏斗滴加5ml含2mmol的2-氯-5-氯甲基吡啶的乙腈溶液,回流8-24h,薄层色谱跟踪反应;
步骤3.冷却至室温,减压蒸除溶剂,用EtOAC溶解,水洗,饱和食盐水洗;
步骤4.有机相用无水Na2SO4干燥,过滤,减压蒸除Et0AC,得粗产物;
步骤5.将步骤4得到的粗产物重结晶得到2-氯吡啶衍生物。
3.权利要求1所述的2-氯吡啶衍生物在制备抗肝癌药物中的应用。
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Non-Patent Citations (5)
Title |
---|
Cai-Jun Chen et al..Synthesis and antifungal activities of 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-thiadiazole and 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-oxadiazole derivatives.《Bioorganic & Medicinal Chemistry》.2007,第15卷(第12期),3981-3989. |
Cai-Jun Chen et al..Synthesis and antifungal activities of 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-thiadiazole and 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-oxadiazole derivatives.《Bioorganic & * |
Medicinal Chemistry》.2007,第15卷(第12期),3981-3989. * |
Qin WU 等.In(OTf)3-mediated Facile Preparation of 2-(3,4,5-Trimethoxyphenyl)-5-[(5-alkylthio-1,3,4-oxadiazol-2-yl)methylthio]-1,3,4-thiadiazole Derivatives in Aqueous Media.《Chinese Journal of Chemistry》.2008,第26卷(第7期),1327-1331. * |
张成仁 等.噁唑、苯并噁唑及1,3,4-噁二唑硫醚的合成及抗肿瘤活性研究.《有机化学》.2007,第27卷(第11期),1432-1437. * |
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