CN112194653B - 一种嘧啶苯并咪唑杂合物、制备方法及抗结肠癌用途 - Google Patents
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Abstract
本发明公开了一种嘧啶苯并咪唑杂合物、制备方法及抗结肠癌用途。本发明提供了一种新的嘧啶苯并咪唑杂合物及其制备方法，该嘧啶苯并咪唑杂合物对人结肠癌HCT‑116细胞具有极强的抑制活性，显著优于阳性药物吉非替尼，具有开发成抗人结肠癌的药物的前景。
Description
技术领域
本发明属于药物化学领域，涉及新化合物的合成和应用，具体涉及一种嘧啶苯并咪唑杂合物、制备方法及抗结肠癌用途。
背景技术
中国专利CN111004221A公开了一种嘧啶苯并咪唑杂合物，其结构通式为：
其中R选自如下基团：
活性研究表明，这些化合物对非小细胞肺癌细胞H1975、A549、HCC827有显著的增殖抑制作用，且抑制作用强于阳性药吉非替尼，但对人结肠癌细胞HCT116的增殖抑制能力较弱。其中，化合物1、2、8的抑制活性甚至可以忽略。
发明内容
本发明的目的在于提供一种改进的嘧啶苯并咪唑杂合物、制备方法及抗结肠癌用途。
本发明上述目的通过如下方案实现：
一种嘧啶苯并咪唑杂合物，具有如下的化学结构。
上述嘧啶苯并咪唑杂合物的制备方法，步骤如下：在圆底烧瓶中加入20ml的95％乙醇和0.02mol 1-(6-羟基-1H-苯并咪唑-2-乙基)-酮，搅拌15min使固体完全溶解，再加入8ml 10％的氢氧化钠水溶液，15min后，再加入2-环丙基苯甲醛0.02mol，TLC跟踪反应进程，反应10h后，向反应液中滴加3mol/LHCl溶液，析出灰色固体，抽滤，用HCl溶液中反复淋洗滤饼，干燥，得白色固体。重结晶后得到(E)-1-(6-羟基-1H-苯并咪唑-2-乙基)-3-(2-环丙基苯基丙基)-2-烯-1-酮。将(E)-1-(6-羟基-1H-苯并咪唑-2-乙基)-3-(2-环丙基苯基丙基)-2-烯-1-酮2mmol、碳酸钾3.5mmol、2,4,5-三氯嘧啶3.01mmol加到40mL DMF中，常温下反应，将反应液倒入冷水中有固体析出，过滤，干燥，称量，得到(E)-1-(6-((2,5-二氯嘧啶-4-乙基)氧基)-1H-苯并咪唑-2-乙基)-3-(2-环丙基苯基丙基)-2-烯-1-酮。将(E)-1-(6-((2,5-二氯嘧啶-4-乙基)氧基)-1H-苯并咪唑-2-乙基)-3-(2-环丙基苯基丙基)-2-烯-1-酮0.2mmol、2-甲氧基-4-(4-甲基哌啶-1-基)苯胺0.2mmol、TFA 100mmol加入25mL仲丁醇中，在105℃温度下反应6.5h，减压浓缩，柱层析即得。
上述嘧啶苯并咪唑杂合物在制备抗人结肠癌的药物中的应用。
有益效果：
本发明提供的嘧啶苯并咪唑杂合物对人结肠癌HCT-116细胞具有极强的抑制活性，显著优于阳性药物吉非替尼，具有开发成抗人结肠癌的药物的前景。
具体实施方式
下面结合实施例具体介绍本发明实质性内容，但并不以此限定本发明保护范围。
实施例1：嘧啶苯并咪唑杂合物的制备
在50ml圆底烧瓶中加入20ml的95％乙醇和3.52g(0.02mol)1-(6-羟基-1H-苯并咪唑-2-乙基)-酮，搅拌约15min使固体完全溶解，再加入8ml 10％的氢氧化钠水溶液，15min后，再加入2-环丙基苯甲醛2.93g(0.02mol)，TLC跟踪反应进程，反应10h后，向反应液中滴加3mol/LHCl溶液，析出灰色固体，抽滤，用HCl溶液中反复淋洗滤饼，干燥，得白色固体。重结晶后得到(E)-1-(6-羟基-1H-苯并咪唑-2-乙基)-3-(2-环丙基苯基丙基)-2-烯-1-酮。将(E)-1-(6-羟基-1H-苯并咪唑-2-乙基)-3-(2-环丙基苯基丙基)-2-烯-1-酮(2mmol)、碳酸钾(0.483g，3.5mmol)、2,4,5-三氯嘧啶(0.345mL，3.01mmol)加到40mLDMF中，常温下反应，将反应液倒入冷水中有固体析出，过滤，干燥，称量，得到(E)-1-(6-((2,5-二氯嘧啶-4-乙基)氧基)-1H-苯并咪唑-2-乙基)-3-(2-环丙基苯基丙基)-2-烯-1-酮。将(E)-1-(6-((2,5-二氯嘧啶-4-乙基)氧基)-1H-苯并咪唑-2-乙基)-3-(2-环丙基苯基丙基)-2-烯-1-酮(0.2mmol)、2-甲氧基-4-(4-甲基哌啶-1-基)苯胺(0.044g，0.2mmol)、TFA(6.5mL，100mmol)加入25mL仲丁醇中，在105℃温度下反应6.5h，减压浓缩，柱层析(二氯甲烷：甲醇＝20:1)得到黄色固体，总收率25.2％，纯度99.4％。根据高分辨质谱提供的分子量确定分子式为C35H34ClN7O3。1H-NMR(DMSO-d6,500MHz)δ:8.17(1H,s),6.99(1H,s),6.79(1H,d),7.41(1H,d),12.58(1H,s),6.55(1H,d),7.98(1H,d),7.18～7.35(4H,m),1.87(1H,m),1.26(2H,m),1.52(2H,m),8.91(1H,s),6.33(1H,s),6.44(1H,d),7.02(1H,d),3.88(3H,s),3.45(4H,t),2.35(4H,t),2.23(3H,s).
实施例2：抗肿瘤活性测试
一、实验材料
人结肠癌HCT-116细胞为实验室液氮冻存，复苏传代后使用。
嘧啶苯并咪唑杂合物按照实施例1方法制备。
FBS、DMEM高糖培养基购于美国Gibco公司。
二、实验方法
1、细胞培养
人结肠癌HCT-116细胞培养于含10％FBS及100U/ml青霉素、100μg/ml链霉素的DMEM高糖培养基于5％CO2、37℃培养箱中培养，每2～3d传代，取对数期细胞用于后续实验。
2、MTT测试
取对数生长期的人结肠癌HCT-116细胞，消化后用完全培养基重悬制成细胞悬液，接种于96孔培养板中，每孔100μL，每孔5000个细胞，于5％CO2、37℃培养箱中培养。24h后，每孔加入100μL含有不同浓度待测化合物(嘧啶苯并咪唑杂合物和阳性药物吉非替尼)的完全培养基，轻轻振荡混匀，每个浓度设置5个平行孔。同时设有不加化合物的溶剂对照组和无细胞的空白对照组。继续培养48h后，每孔加入20μL MTT溶液(5mg/mL)继续培养4h，吸弃上清液，每孔加入150μL DMSO，置摇床上低速振荡10min，使结晶物充分溶解，酶联免疫检测仪测定各孔在570nm波长处的吸收值，以溶剂对照组的细胞存活率为100％，计算不同浓度化合物孔的细胞存活率＝(化合物组吸收值-空白对照组吸收值)/(溶剂对照组吸收值-空白对照组吸收值)×100％，利用Graphpad Prism 5软件计算待测化合物对HCT-116细胞的IC50值。重复3次，计算平均值±SD。
三、实验结果
嘧啶苯并咪唑杂合物和阳性药物吉非替尼对HCT-116细胞的IC50值如表1所示。
表1待测化合物对HCT-116细胞的IC50值
| 嘧啶苯并咪唑杂合物 | 吉非替尼 | |
| IC<sub>50</sub>值(μM) | 1.64±0.49 | 11.95±0.73 |
本发明提供的嘧啶苯并咪唑杂合物对人结肠癌HCT-116细胞具有极强的抑制活性，显著优于阳性药物吉非替尼，具有开发成抗人结肠癌的药物的前景。
上述实施例的作用在于具体介绍本发明的实质性内容，但本领域技术人员应当知道，不应将本发明的保护范围局限于该具体实施例。
Claims (2)
1.一种嘧啶苯并咪唑杂合物，其特征在于，化学结构如下：
2.权利要求1所述嘧啶苯并咪唑杂合物在制备抗人结肠癌的药物中的应用。
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| KR101948805B1 (ko) * | 2016-07-05 | 2019-02-15 | 한국과학기술연구원 | 항종양 효과를 갖는 이미다조옥사졸 유도체 및 이를 포함하는 약학적 조성물 |
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