CN109206399B - 三级酰胺微管蛋白聚合抑制剂及其制备方法和应用 - Google Patents

三级酰胺微管蛋白聚合抑制剂及其制备方法和应用 Download PDF

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CN109206399B
CN109206399B CN201811267864.4A CN201811267864A CN109206399B CN 109206399 B CN109206399 B CN 109206399B CN 201811267864 A CN201811267864 A CN 201811267864A CN 109206399 B CN109206399 B CN 109206399B
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tubulin polymerization
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tertiary amide
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张雁冰
张赛扬
付冬君
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Zhengzhou University
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Abstract

本发明公开了一类新型三级酰胺微管蛋白聚合抑制剂、它们的制备方法及其在胃癌、***癌、乳腺癌等药物中的应用，属于抗肿瘤药物化学领域。本发明简单高效，绿色环保的合成了一类新型微管蛋白聚合抑制剂。其具有如下结构通式：

Description

三级酰胺微管蛋白聚合抑制剂及其制备方法和应用
技术领域
本发明涉及抗肿瘤药物化学领域，具体涉及一类新型三级酰胺微管蛋白聚合抑制剂、它们的制备方法及其作为一类新的抗肿瘤药物先导化合物的应用。
背景技术
微管是大多数真核生物细胞骨架的重要组分，与细胞内的物质运输、细胞运动、细胞的分化发育以及细胞***繁殖等生命活动密切相关。微管蛋白(Tubulin)的重要生理作用，使得其在肿瘤领域中成为重要的靶点。秋水仙碱作为微管蛋白聚合抑制剂可抑制细胞的有丝***，有抗肿瘤作用，但毒性大，现已少用。目前亟待开发新型抗肿瘤靶点药物。
发明内容
本发明目的在于提供一类抗肿瘤活性好的新型三级酰胺微管蛋白聚合抑制剂。
本发明的另一个目的在于提供一种简单高效，绿色环保的合成新型三级酰胺微管蛋白聚合抑制剂的方法。
为实现本发明目的，本发明所述一类新型三级酰胺微管蛋白聚合抑制剂类化合物具有如下通式：
Figure GDA0002602720480000011
R1为氢、不同位置单取代或多取代的氯、甲氧基、甲基；优选:R1为多取代的甲氧基。
Figure GDA0002602720480000012
为苯环，卤素、甲氧基、C1-5烷基单取代苯环或被氨基、甲氧基多取代的苯环、卤素单取代的苯并噻吩环、萘环、C1-3烷基单取代或多取代的吡啶环、喹唑啉环、苯并咪唑环。优选：
Figure GDA0002602720480000021
为苯环，卤素、甲氧基、甲基、异丁基单取代苯环或被氨基、甲氧基双取代的苯环、卤素单取代的苯并噻吩环、萘环、甲基基单取代的吡啶环。
R2为噻吩环、苯环、被甲氧基或卤素单取代的苯环。卤素优选：F。
本发明所述新型三级酰胺微管蛋白聚合抑制剂类化合物主要通过下列步骤制得：
Figure GDA0002602720480000022
(1)化合物(I)的制备方法：
溶剂中，将芳香基取代的亚甲基氯化合物，不同取代的苯胺在碱性条件下搅拌反应得化合物I。所用的碱性化合物是氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、磷酸钠、磷酸钾、碳酸氢钾、碳酸氢钠中的一种；所用的溶剂为乙醇、甲醇、丙酮、四氢呋喃、二氧六环、二氯甲烷中之一或其中任意两种的混合物；反应在60-120℃之间进行。
(2)化合物(II)的制备方法：
溶剂中，化合物(I)和取代的乙酰氯化合物在碱性条件下搅拌反应，得化合物II。所用的碱性化合物是氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、磷酸钠、十二水磷酸钠、磷酸钾、碳酸氢钾、碳酸氢钠中的一种；所用的溶剂为乙醇、甲醇、N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃、二氧六环、二氯甲烷中之一或其中任意两种的混合物；反应在0-70℃之间进行。
本发明优点：1、该类化合物体外抗癌活性试验表明其对多种肿瘤细胞PC3、MCF7、MGC803均具有一定的抑制作用，同时对微管蛋白的聚合有显著的抑制作用。化合物(IId、IIe、IIg、IIi、IIm、IIo、IIp、IIq、IIr)对三种癌细胞的活性优于抗肿瘤药物5-氟尿嘧啶。可作为进一步开发的候选或者先导化合物，应用于制备抗肿瘤药物。2、合成方法简单高效，绿色环保，收率高，达75％以上。
具体实施方式
为对本发明进行更好地说明，举实施例如下：
实施例1通式(II)的制备
(1)化合物(I)的制备方法：
乙醇溶剂中，60-120℃温度下，将芳香基取代的亚甲基氯化合物，不同取代的苯胺在氢氧化钠条下搅拌反应得化合物I。
(2)化合物(II)的制备方法：
将化合物(I)(5mmol)和不同取代的乙酰氯化合物(5mmol)加入15mL丙酮溶解，80摄氏度搅拌反应。TLC监测反应进程，待反应结束后，向体系中加入蒸馏水，然后用二氯乙烷萃取3次，再用饱和食盐水反萃二氯乙烷相2次，每次20mL，最后有机相用无水硫酸镁干燥，滤除硫酸镁，滤液减压蒸馏除去二氯乙烷。所得粗产品用硅胶柱柱层析分离纯化，石油醚/乙酸乙酯＝9:1洗脱，得不同的化合物(II)。
Figure GDA0002602720480000031
白色固体，1H NMR(400MHz,DMSO)δ7.4–7.1(m,6H),6.9(dd,1H),6.8(d,1H),6.4(s,2H),4.9(s,2H),3.7(s,2H),3.6(d,9H).，收率78％。
Figure GDA0002602720480000032
白色固体，1H NMR(400MHz,DMSO)δ7.4(d,1H),7.3(dd,2H),7.1(t,2H),7.0–6.9(m,1H),6.7(d,1H),6.4(s,2H),4.8(s,2H),3.7(s,2H),3.7(s,3H),3.6(s,6H).，收率82％。
Figure GDA0002602720480000041
白色固体，1H NMR(400MHz,DMSO)δ7.5–7.3(m,3H),7.2(d,2H),7.00–6.8(m,1H),6.7(d,1H),6.4(s,2H),4.8(s,2H),3.8(s,2H),3.7(d,9H).，收率76％。
Figure GDA0002602720480000042
白色固体，1H NMR(400MHz,DMSO)δ7.5(d,2H),7.4(d,1H),7.2(d,2H),7.0–6.8(m,1H),6.7(s,1H),6.4(s,2H),4.8(s,2H),3.7(s,2H),3.6(s,9H).，收率79％。
Figure GDA0002602720480000043
白色固体，1H NMR(400MHz,CDCl3)δ7.1–7.0(m,3H),6.8(dd,1H),6.7(d,2H),6.6(d,1H),6.0(s,2H),4.7(s,2H),3.8(s,3H),3.7(s,3H),3.6(s,2H),3.5(s,6H).，收率79％。
Figure GDA0002602720480000044
白色固体，1H NMR(400MHz,DMSO)δ7.4(dd,2H),7.1(t,3H),6.9(dd,1H),6.8(d,1H),6.5(s,2H),4.9(s,2H),3.8(s,2H),3.7(d,9H).，收率80％。
Figure GDA0002602720480000051
白色固体，1H NMR(400MHz,DMSO)δ7.4(d,1H),7.1(s,4H),6.9(dd,1H),6.7(d,1H),6.4(s,2H),4.8(s,2H),3.7(s,2H),3.6(d,9H),2.3(s,3H).，收率90％。
Figure GDA0002602720480000052
黄色固体，1H NMR(400MHz,DMSO)δ7.4–7.3(m,1H),7.3(d,2H),7.1(d,2H),7.0–6.9(m,1H),6.9(dd,1H),6.4(s,2H),4.8(s,2H),3.7(s,2H),3.6(s,3H),3.6(s,6H),1.2(s,9H).，收率86％。
Figure GDA0002602720480000053
黄色固体，1H NMR(400MHz,DMSO)δ7.4(dd,1H),6.9(dd,1H),6.7(d,1H),6.6(d,1H),6.5(s,1H),6.4(s,2H),6.3(dd,1H),4.7(s,2H),4.6(s,2H),3.7(s,3H),3.6(s,2H),3.6(s,3H),3.5(s,6H).，收率80％。
Figure GDA0002602720480000054
白色固体，1H NMR(400MHz,DMSO)δ7.5–7.2(m,4H),7.1(d,1H),6.9(dd,1H),6.7(d,1H),6.4(s,2H),4.9(s,2H),3.8(s,2H),3.6(s,9H).，收率82％。
Figure GDA0002602720480000061
黄色固体，1H NMR(400MHz,CDCl3)δ7.1(dd,2H),6.9(d,2H),6.9(d,1H),6.8(dd,1H),6.7(d,1H),6.0(s,2H),4.7(s,2H),3.8(s,3H),3.6(s,2H),3.5(s,6H),2.2(s,3H).，收率88％。
Figure GDA0002602720480000062
白黄色固体，1H NMR(400MHz,DMSO)δ8.0(d,1H),7.8(d,1H),7.6(s,1H),7.5–7.2(m,2H),7.0–6.8(m,1H),6.7(d,1H),6.3(s,2H),5.1(s,2H),3.7(s,2H),3.6(s,3H),3.5(s,6H).，收率76％。
Figure GDA0002602720480000063
黄色固体，1H NMR(400MHz,DMSO)δ8.0–7.8(m,3H),7.7(s,1H),7.5–7.4(m,4H),7.0–6.8(m,2H),6.5(s,2H),5.0(s,2H),3.8(s,2H),3.6(d,9H).，收率79％。
Figure GDA0002602720480000064
白色固体，1H NMR(400MHz,CDCl3)δ7.5(t,1H),7.1(dd,2H),7.0(d,1H),6.8(dd,1H),6.7(d,1H),6.3(s,2H),4.9(s,2H),3.8(s,3H),3.7(s,2H),3.6(s,6H),2.4(s,3H).，收率82％。
Figure GDA0002602720480000071
白色固体，1H NMR(400MHz,CDCl3)δ7.0(t,J＝8.2Hz,3H),6.7(t,J＝5.7Hz,2H),6.7(dd,J＝8.2,1.9Hz,1H),6.6–6.5(m,2H),5.9(s,2H),4.7(s,2H),3.8(s,3H),3.7(s,3H),3.6(s,3H),3.5(s,6H),3.4(s,2H).，收率88％。
Figure GDA0002602720480000072
黄色固体，yield:33％.1H NMR(400MHz,CDCl3)δ7.2–7.1(m,3H),7.0(d,2H),6.9(d,2H),6.7(d,2H),5.9(s,2H),4.7(s,2H),3.8(s,3H),3.7(s,3H),3.5(s,6H),3.4(s,2H).，收率86％。
Figure GDA0002602720480000073
白黄色固体，1H NMR(400MHz,CDCl3)δ7.1(d,2H),6.9(d,2H),6.8–6.6(m,4H),5.9(s,2H),4.7(s,2H),3.8(s,3H),3.7(d,6H),3.5(s,6H),3.3(s,2H).，收率80％。
Figure GDA0002602720480000074
白色固体，1H NMR(400MHz,CDCl3)δ7.1(d,2H),6.9(dd,2H),6.8(t,2H),6.7(d,2H),5.9(s,2H),4.7(s,2H),3.8(s,3H),3.7(s,3H),3.6(s,6H),3.4(s,2H).，收率76％。
实施例2上述化合物的抗肿瘤活性测定：
筛选所用化合物均是由本发明合成、纯化而得；样品储备液：称取1-2mg样品置于2mL EP管中，然后用DMSO配制成溶液，4℃保存放置，实验时根据所需浓度利用培养基稀释。取对数生长期的细胞，消化计数后，用培养基调整细胞密度，以4000-5000个cell/孔接种至96孔板中，每孔150μL，培养24h后，弃去培养基，加入用培养基稀释好的药物(50μg/mL、100μg/mL)，每个浓度设6个复孔，另设空白对照组及阴性对照组。药物作用72h后，每孔加入20μLMTT，继续培养4h后，吸去液体，加入150mL的DMSO，振荡均匀，酶标仪490nm处检测吸光度值，计算抑制率，计算公式如下：抑制率(％)＝(1-给药组吸光度值/空白组吸光度值)×100％，50μg/mL时抑制率大于50％的样品，重新设置浓度进行细筛。试验结果采用SPSS软件计算IC50值和相关系数。实验结果见表1。
表1化合物抑制瘤细胞株的IC50值
Figure GDA0002602720480000081
Figure GDA0002602720480000091
a每个数值用平均值±标准偏差(mean±SD)表示，方差分析：p<0.05.5-Fu：5-氟尿嘧啶.
结论：化合物(IId、IIe、IIg、IIi、IIm、IIo、IIp、IIq、IIr)对三种癌细胞的活性优于抗肿瘤药物抗肿瘤药物5-氟尿嘧啶。可作为进一步开发的候选或者先导化合物，应用于制备抗肿瘤药物。
实施例3化合物IId的Tubulin聚合抑制活性的测定：
提取的微管蛋白重悬于冰冷的G-PEM缓冲液中(80mM PIPES pH 5.9,5mM MgCl2,1mM EGTA,1mM ATP,5％(v/v)glycerol)，取100ul加至包含100ul化合物IId的96孔板内，微管蛋白终浓度为5.6g/L，药物浓度设置0uM，1uM，2uM，4uM四个梯度，样品充分混匀，分光光度计检测微管蛋白的聚合，间隔5min，总计60min，IC50值在30分钟使用GraphPad软件计算得到。结论：化合物IId对微管的酶活性小于3uM。

Claims (4)

1.一类三级酰胺微管蛋白聚合抑制剂，其特征在于，选自如下化合物：
Figure FDA0002625259730000011
Figure FDA0002625259730000021
2.如权利要求1所述的一类三级酰胺微管蛋白聚合抑制剂在制备药物中的应用，其特征在于，将其做为活性成分用于制备抗肿瘤药物或微管蛋白聚合抑制剂。
3.如权利要求2所述的一类三级酰胺微管蛋白聚合抑制剂在制备药物中的应用，其特征在于，所述的抗肿瘤药物为抗胃癌、***癌或乳腺癌的药物。
4.制备如权利要求1所述的一类三级酰胺微管蛋白聚合抑制剂的方法，其特征在于，包括以下步骤：
Figure FDA0002625259730000022
(1)化合物(I)的制备方法：
溶剂中，将芳香基取代的亚甲基氯化合物，不同取代的苯胺在碱性条件下搅拌反应得化合物I；所用的碱性化合物是氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、磷酸钠、磷酸钾、碳酸氢钾、碳酸氢钠中的一种；所用的溶剂为乙醇、甲醇、丙酮、四氢呋喃、二氧六环、二氯甲烷中之一或其中任意两种的混合物；反应在60-120℃之间进行；
(2)化合物(II)的制备方法：
溶剂中，化合物(I)和取代的乙酰氯化合物在碱性条件下搅拌反应，得化合物II；所用的碱性化合物是氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、磷酸钠、十二水磷酸钠、磷酸钾、碳酸氢钾、碳酸氢钠中的一种；所用的溶剂为乙醇、甲醇、N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃、二氧六环、二氯甲烷中之一或其中任意两种的混合物；反应在0-70℃之间进行；
Figure FDA0002625259730000031
为
Figure FDA0002625259730000032
R1为3,4,5位取代的甲氧基；
R2为
Figure FDA0002625259730000033
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