CN113549038B - 多取代异苯并呋喃化合物及其用途 - Google Patents
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- DVMFMSYWBGARIJ-UHFFFAOYSA-N trimethylsilylformamide Chemical compound C[Si](C)(C)C(N)=O DVMFMSYWBGARIJ-UHFFFAOYSA-N 0.000 claims abstract description 5
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- WIHMBLDNRMIGDW-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile;hydron;bromide Chemical compound [Br-].O1CC2=CC(C#N)=CC=C2C1(CCC[NH+](C)C)C1=CC=C(F)C=C1 WIHMBLDNRMIGDW-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明属于药物化学技术领域，具体涉及一种多取代异苯并呋喃化合物及其用途。以2‑芳基甲酰基芳醛为原料，通过与三甲基硅烷甲酰胺试剂反应，现场获得醛基甲酰胺化中间产物，再在酸性条件下分子内关环缩合获得多取代异苯并呋喃化合物。用MTT法测定了多取代异苯并呋喃部分化合物对人肾癌细胞增殖的抑制作用，结果显示了多取代异苯并呋喃化合物的潜在抗肿瘤活性。
Description
技术领域
本发明属于药物化学技术领域，具体涉及一种多取代异苯并呋喃化合物及其用途。
背景技术
异苯并呋喃类化合物是一类重要的杂环化合物，作为高活性、多功能的合成中间体，广泛用于化学化工和材料领域。同时，很多异苯并呋喃衍生物具有很好的生物活性，已有不少被开发成药物上市。如可用于治疗便秘的酚酞片包含异苯并呋喃酮结构，又如具有独特抗抑郁作用的氢溴酸西酞普兰则含有二氢异苯并呋喃结构。但是到目前为止，尚未见异苯并呋喃骨架本身出现在活性化合物中，各种取代的异苯并呋喃更多的是作为基础原料或医药中间体被报道。
发明内容
本发明要解决的技术问题是：基于多取代异苯并呋喃结构的重要性及生物活性的空白，本发明提供一种多取代异苯并呋喃类化合物，该类化合物可以有效抑制肾癌细胞的生长。
本发明解决其技术问题所采用的技术方案是：提供一种具有化学结构式(I)所示的多取代异苯并呋喃类化合物:
化学结构式(I)中，R1选自氢、甲基、乙基、氟、氯；R2选自氢、甲基、乙基、氟、氯；R3选自氢、氟、氯；R4选自甲基、乙基、丙基、异丙基、叔丁基；R5选自甲基、乙基、丙基、异丙基、叔丁基。
本发明具体的合成路线如方程式(1)所示：
其中，R1、R2、R3、R4、R5的定义同前。
方程式(1)中，酰氯化合物1为直接商业购买或从购买的相应羧酸制备而来，化合物3为直接商业购买，三甲基硅烷甲酰胺试剂6为直接商业购买或参照已知文献(CunicoR.F.,Chen J.,Synthetic Communications,2003,33(11),1963-1968)制备。化合物5的制备方法参考已知文献：Jacq J.,Einhorn C.,Einhorn J.,Organic Leters,2008,10(17),3757-3760。
化学结构式(I)的合成方法如下：氮气保护下，向封管反应器中依次加入2-芳基甲酰基芳醛(化合物5)、无水四氢呋喃和三甲基硅烷甲酰胺试剂6，密封后置于油浴中，搅拌下加热至回流反应。12小时后，冷却至室温，加入浓度4M的盐酸水溶液，接着室温下搅拌反应2小时。加入饱和碳酸氢钠溶液中和，得到的反应液用乙酸乙酯萃取，有机相干燥后浓缩，得到的残留物以乙酸乙酯和石油醚为洗脱液，硅胶柱色谱分离纯化，得到化学结构式(I)的多取代异苯并呋喃类产物。
其中，2-芳基甲酰基芳醛、三甲基硅烷甲酰胺和4M盐酸水溶液的摩尔比为1：1.1～1.5：2.0～5.0。
选取上述多取代异苯并呋喃类产物中部分化合物，运用MTT法测定化合物对癌细胞增殖的抑制作用。本发明采用MTT法测定目标化合物对人癌细胞增殖的抑制作用。选取OSRC-2型肾癌细胞为测试细胞株，运用MTT法对上述合成的目标化合物进行体外抗肿瘤活性评价，并以空白为对照。取对数生长期的肿瘤细胞，离心后用RPMI1640培养液稀释成5×104个/mL，接种于96孔板中。37℃培养过夜后加入不同浓度的样品，再孵育72h，加入10uL/孔的MTT溶液(5mg/mL)，于37℃孵化4h后每孔加入100uL DMSO。10min后，震荡，将孔板置于自动微孔板分光光度计上，在570nm和630nm处测定吸收度值，并用Bliss法计算半数有效抑制浓度(IC50)。每组样品进行3次平行测试。
采用上述MTT法测试后得知：当R1、R2、R3均为氯，R4、R5均为甲基时，该化合物对癌细胞增殖有明显的抑制作用；当R1、R2、R3均为氢，R4、R5均为甲基，或者R1、R2为氢，R3为氯，R4、R5均为甲基，又或者R1为氯，R2为氢，R3为氟，R4、R5均为甲基时，对癌细胞有抗癌活性；其它结构的化合物具有潜在的抗癌活性，可应用在抗肿瘤药物中。
本发明的有益效果是：本发明提供了一种结构新颖的多取代异苯并呋喃类化合物；MTT法活性测试表明该类化合物具有潜在的生物活性，可用于制备抗癌药物。
具体实施方式
现在结合具体实施例对本发明作进一步说明，以下实施例旨在说明本发明而不是对本发明的进一步限定。
本发明所用的试剂是参考相关文献制备，溶剂经过纯化和精制。
实施例1
取10mL封管，称取5a 105mg，加入1mL四氢呋喃和290mg N,N,1,1,1-五甲基硅烷甲酰胺试剂6a，抽真空换氮气，油浴70℃反应12小时。停止反应，冷却后加入0.5mL 4M盐酸水溶液，室温下搅拌2小时。加入饱和碳酸氢钠溶液中和，得到的反应液用乙酸乙酯萃取，有机相干燥后浓缩，得到的残留物以乙酸乙酯和石油醚为洗脱液，硅胶柱色谱分离纯化，得到浅黄色固体A，产率为68％。1H NMR(300MHz,CDCl3)δ8.16–8.13(m,1H),7.92–7.82(m,3H),7.54–7.45(m,2H),7.39–7.33(m,1H),7.19–7.06(m,2H),3.36(br,6H).13C NMR(75MHz,CDCl3)δ160.70,145.89,137.04,130.86,130.32,129.06,128.15,127.26,125.83,125.48,121.63,121.10,119.54,29.65.HRMS(ESI)m/z理论值C17H16NO2 +[M+H]+266.1176,实测值266.1162.
实施例2
取10mL封管，称取5b 112mg，加入1mL四氢呋喃和290mg N,N,1,1,1-五甲基硅烷甲酰胺试剂6a，抽真空换氮气，油浴70℃反应12小时。停止反应，冷却后加入0.5mL 4M盐酸水溶液，室温下搅拌2小时。加入饱和碳酸氢钠溶液中和，得到的反应液用乙酸乙酯萃取，有机相干燥后浓缩，得到的残留物以乙酸乙酯和石油醚为洗脱液，硅胶柱色谱分离纯化，得到浅黄色固体B，产率为60％。1H NMR(300MHz,CDCl3)δ8.13(dt,J＝8.9,0.9Hz,1H),7.61–7.50(m,2H),7.39–7.28(m,3H),7.16(ddd,J＝8.9,6.4,0.8Hz,1H),7.03(ddd,J＝8.8,6.4,0.9Hz,1H),3.30(br,6H),2.45(s,3H).13C NMR(75MHz,CDCl3)δ160.58,147.35,136.64,131.16,129.77,129.59,129.27,128.84,127.18,125.84,125.19,125.08,122.22,121.09,119.52,29.48,20.38.HRMS(ESI)m/z理论值C18H18NO2 +[M+H]+280.1332,实测值280.1337.
实施例3
取10mL封管，称取5c 122mg，加入1mL四氢呋喃和290mg N,N,1,1,1-五甲基硅烷甲酰胺试剂6a，抽真空换氮气，油浴70℃反应12小时。停止反应，冷却后加入0.5mL 4M盐酸水溶液，室温下搅拌2小时。加入饱和碳酸氢钠溶液中和，得到的反应液用乙酸乙酯萃取，有机相干燥后浓缩，得到的残留物以乙酸乙酯和石油醚为洗脱液，硅胶柱色谱分离纯化，得到浅黄色固体C，产率为64％。1H NMR(400MHz,CDCl3)δ8.16(d,J＝8.9Hz,1H),7.64–7.60(m,1H),7.54–7.51(m,2H),7.39–7.33(m,2H),7.14(dd,J＝8.7,6.4Hz,1H),7.04(dd,J＝8.5,6.7Hz,1H),3.32(br,6H).13C NMR(100MHz,CDCl3)δ160.53,143.73,138.24,132.63,131.36,130.83,129.94,129.48,129.11,127.15,126.88,125.57,122.96,121.39,119.43,29.59.HRMS(ESI)m/z理论值C17H15ClNO2 +[M+H]+300.0786,实测值300.0798.
实施例4
取10mL封管，称取5d 157mg，加入1mL四氢呋喃和290mg N,N,1,1,1-五甲基硅烷甲酰胺试剂6a，抽真空换氮气，油浴70℃反应12小时。停止反应，冷却后加入0.5mL 4M盐酸水溶液，室温下搅拌2小时。加入饱和碳酸氢钠溶液中和，得到的反应液用乙酸乙酯萃取，有机相干燥后浓缩，得到的残留物以乙酸乙酯和石油醚为洗脱液，硅胶柱色谱分离纯化，得到浅黄色固体D，产率为55％。1H NMR(400MHz,CDCl3)δ8.18(s,1H),7.46–7.44(m,2H),7.37–7.34(m,1H),7.20(dd,J＝8.0,0.5Hz,1H),7.04(dd,J＝8.2,1.7Hz,1H),3.28(br,6H).13C NMR(100MHz,CDCl3)δ160.24,141.21,138.40,136.92,133.41,131.66,129.11,128.59,127.92,127.53,122.42,120.84,120.09,29.72.HRMS(ESI)m/z理论值C17H13Cl3NO2 +[M+H]+368.0006,实测值368.0007.
实施例5
取10mL封管，称取5e 114mg，加入1mL四氢呋喃和290mg N,N,1,1,1-五甲基硅烷甲酰胺试剂6a，抽真空换氮气，油浴70℃反应12小时。停止反应，冷却后加入0.5mL 4M盐酸水溶液，室温下搅拌2小时。加入饱和碳酸氢钠溶液中和，得到的反应液用乙酸乙酯萃取，有机相干燥后浓缩，得到的残留物以乙酸乙酯和石油醚为洗脱液，硅胶柱色谱分离纯化，得到浅黄色固体E，产率为70％。1H NMR(300MHz,CDCl3)δ7.84–7.81(m,1H),7.79–7.76(m,1H),7.65–7.61(m,1H),7.50–7.43(m,2H),7.37–7.32(m,1H),7.25–7.21(m,1H),3.32(br,6H).13C NMR(75MHz,CDCl3)δ163.82(d,J＝252.8Hz),159.79,146.63(d,J＝1.5Hz),138.38(d,J＝27.8Hz),131.64(d,J＝8.2Hz),130.45(d,J＝25.5Hz),130.42,129.92,128.62,128.47,121.63,122.25(d,J＝10.5Hz),103.58(d,J＝24.8Hz),29.62.HRMS(ESI)m/z理论值C17H15FNO2 +[M+H]+284.1081,实测值284.1083.
实施例6
取10mL封管，称取5f 131mg，加入1mL四氢呋喃和290mg N,N,1,1,1-五甲基硅烷甲酰胺试剂6a，抽真空换氮气，油浴70℃反应12小时。停止反应，冷却后加入0.5mL 4M盐酸水溶液，室温下搅拌2小时。加入饱和碳酸氢钠溶液中和，得到的反应液用乙酸乙酯萃取，有机相干燥后浓缩，得到的残留物以乙酸乙酯和石油醚为洗脱液，硅胶柱色谱分离纯化，得到浅黄色固体F，产率为75％。1H NMR(400MHz,CDCl3)δ7.73–7.69(m,1H),7.57–7.49(m,3H),7.39–7.36(m,2H),6.86–6.82(m,1H),3.30(br,6H).13C NMR(100MHz,CDCl3)δ161.52(d,J＝235.0Hz),160.21,141.52,138.19,136.79,132.77,131.38,130.93,130.37,129.73,127.02,122.31(d,J＝10.5Hz),120.82,118.56(d,J＝30.1Hz),117.68,103.38(d,J＝25.2Hz),29.62.HRMS(ESI)m/z理论值C17H14ClFNO2 +[M+H]+318.0692,实测值318.0695.
实验测试
按照前述MTT方法，对化合物A、B、C、D、E和F进行了抗癌活性测试，结果列于下述表一中。结果表明化合物D对人肾癌细胞的生长有明显的抑制作用，化合物A、E和F对人肾癌细胞有抗癌活性，化合物B和C对人肾癌细胞有潜在的抗癌活性。
表一多取代异苯并呋喃类化合物对人肾癌细胞的活性测试
以上述依据本发明的理想实施例为启示，通过上述的说明内容，相关工作人员完全可以在不偏离本项发明技术思想的范围内，进行多样的变更以及修改。本项发明的技术性范围并不局限于说明书上的内容，必须要根据权利要求范围来确定其技术性范围。
Claims (6)
1.一种多取代异苯并呋喃化合物，其特征在于：所述多取代异苯并呋喃化合物的结构通式为：
其中，R1选自氢、甲基、乙基、氟、氯；R2选自氢、甲基、乙基、氟、氯；R3选自氢、氟、氯；R4选自甲基、乙基、丙基、异丙基、叔丁基；R5选自甲基、乙基、丙基、异丙基、叔丁基。
2.一种如权利要求1所述的多取代异苯并呋喃化合物的制备方法，其特征在于：所述制备方法为：氮气保护下，向封管反应器中依次加入2-芳基甲酰基芳醛、无水四氢呋喃和三甲基硅烷甲酰胺试剂，密封后置于油浴中，搅拌下加热至回流反应，12小时后冷却至室温，加入浓度4M的盐酸水溶液，接着室温下搅拌反应2小时，加入饱和碳酸氢钠溶液中和，得到的反应液用乙酸乙酯萃取，有机相干燥后浓缩，得到的残留物以乙酸乙酯和石油醚为洗脱液，硅胶柱色谱分离纯化，得到多取代异苯并呋喃类产物。
3.如权利要求2所述的多取代异苯并呋喃化合物的制备方法，其特征在于，所述2-芳基甲酰基芳醛的结构式为：
4.如权利要求2所述的多取代异苯并呋喃化合物的制备方法，其特征在于，所述三甲基硅烷甲酰胺的结构式为：
5.如权利要求2所述的多取代异苯并呋喃化合物的制备方法，其特征在于，所述2-芳基甲酰基芳醛、三甲基硅烷甲酰胺和4M盐酸水溶液的摩尔比为1:1.1～1.5:2.0～5.0。
6.如权利要求1所述的多取代异苯并呋喃化合物的用途，其特征在于：所述的多取代异苯并呋喃化合物应用在制备抗肿瘤药物中。
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| CN103154018A (zh) * | 2010-08-03 | 2013-06-12 | 葛雷菲尼迪制药有限公司 | 用于通过亲和色谱法的抗体和Fc-融合蛋白纯化的配体 |
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