CN111333578B - 含1-甲基-3-(4-氟苯基)-4-氯吡唑单元的氰基丙烯酸酯的制备和应用 - Google Patents
含1-甲基-3-(4-氟苯基)-4-氯吡唑单元的氰基丙烯酸酯的制备和应用 Download PDFInfo
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Abstract
本发明涉及含1‑甲基‑3‑(4‑氟苯基)‑4‑氯吡唑单元的氰基丙烯酸酯(I)的制备和应用。通过1‑甲基‑3‑(4‑氟苯基)‑4‑氯吡唑‑5‑甲基胺与取代丙烯酸酯缩合得到。所述含1‑甲基‑3‑(4‑氟苯基)‑4‑氯吡唑单元的氰基丙烯酸酯对肿瘤细胞HepG2呈现出良好的抑制作用,该化合物可用于制备抗肿瘤细胞药物。
Description
技术领域
本发明涉及医药领域,具体涉及含1-甲基-3-(4-氟苯基)-4-氯吡唑单元的氰基丙烯酸酯的制备和应用。
背景技术
恶性肿瘤是威胁人类健康的三大疾病之一,近年来癌症的发病率逐步上升。所以,寻找与发现有效的抗癌药物与治疗方法是目前医学界重要研究热点之一。
吡唑化合物是一类重要的含氮杂环,许多吡唑杂环化合物对肿瘤细胞显示出优异的抑制效果,一些含有吡唑环的药物如塞来昔布等已被用于治疗许多疾病。
氰基丙烯酸酯也是一类重要化合物,一些氰基丙烯酸酯化合物对肿瘤细胞也显示出良好的抑制活性,如Zhang等制备的化合物A对人***癌细胞PC3表现出较好的抑制作用,在10μg/mL浓度下,化合物A对人***癌细胞PC3的抑制活性达80.1%(J.Heterocyclic Chem.,2005,42,1211-1214)。
因此,为了继续从氰基丙烯酸酯化合物中寻找与发现具有良好抗肿瘤活性的药物,合理地将取代吡唑单元与氰基丙烯酸酯骨架衔接在一起。本发明公开了一类具有药用价值的含1-甲基-3-(4-氟苯基)-4-氯吡唑单元的氰基丙烯酸酯。
发明内容
本发明的目的是提供对HepG2肿瘤细胞具有良好抑制作用的一类含1-甲基-3-(4-氟苯基)-4-氯吡唑单元的氰基丙烯酸酯。
本发明的另一目的是提供上述化合物的制备方法。
本发明的又一个目的是提供上述化合物在制备抗肿瘤细胞药物方面的用途。
为解决上述技术问题,本发明提供含1-甲基-3-(4-氟苯基)-4-氯吡唑单元的氰基丙烯酸酯,其具有通式I结构,
优选地,含1-甲基-3-(4-氟苯基)-4-氯吡唑单元的氰基丙烯酸酯,具有如下结构:
本发明提供上述含1-甲基-3-(4-氟苯基)-4-氯吡唑单元的氰基丙烯酸酯的制备方法,其特征在于包括如下步骤:
将中间体Ⅱ溶于有机溶剂中,再加入中间体Ⅲ,反应一段时间后,停止反应,除去溶剂后所得粗品通过硅胶柱层析纯化得目标化合物,
优选地,含1-甲基-3-(4-氟苯基)-4-氯吡唑单元的氰基丙烯酸酯的制备方法,包括如下步骤:
其中,中间体II可参照文献(Chin.J.Org.Chem.2015,35,2399)方法制备得到,中间体III可参照文献(J.Agric.Food Chem.2003,51,5030)方法制备得到。
通式I化合物对肿瘤细胞显示出良好抑制作用,所述的肿瘤细胞有HepG2。
本发明公开的含1-甲基-3-(4-氟苯基)-4-氯吡唑单元的氰基丙烯酸酯对肿瘤细胞HepG2展现出良好的抑制活性,因此可以用来制备抗肿瘤细胞药物。
具体实施方式
为了便于对本发明的进一步了解,下面提供的实施例对其做了更详细的说明。这些实施例仅供叙述而并非用来限定本发明的范围或实施原则。
实施例1:
将20mmol中间体Ⅱ溶于50mL二甲基亚砜(DMSO),室温下加入中间体Ⅲa 20mmol,加好后,加热至80℃反应15小时。除去溶剂后,所得粗品通过硅胶柱层析纯化得目标物Ia;1H NMR(400MHz,CDCl3):δ10.23(s,1H,NH),7.83~7.86(m,2H,Ar-H),7.10~7.15(m,2H,Ar-H),4.86(d,J=5.6Hz,2H,CH2),4.30(t,J=4.8Hz,2H,CH2),3.92(s,3H,CH3),3.65(t,J=4.8Hz,2H,CH2),3.39(s,3H,OCH3),2.73(s,3H,CH3).
实施例2:
将10mmol中间体Ⅱ溶于30mL1,4-二氧六环,室温下向其中加入中间体Ⅲb 8mmol,加好后,加热回流反应18小时。除去溶剂以后,所得粗品通过硅胶柱层析纯化得目标物Ib;1H NMR(400MHz,CDCl3):δ10.24(s,1H,NH),7.83~7.86(m,2H,Ar-H),7.10~7.14(m,2H,Ar-H),4.86(d,J=5.6Hz,2H,CH2),4.29(t,J=5.0Hz,2H,CH2),3.92(s,3H,CH3),3.68(t,J=5.0Hz,2H,CH2),3.56(q,J=6.9Hz,2H,CH2),2.73(s,3H,CH3),1.19(t,J=7.0Hz,3H,CH3).
实施例3:
将6mmol中间体Ⅱ溶于35mL N,N-二甲基甲酰胺(DMF),室温搅拌下向其中加入中间体Ⅲc 6mmol,加好后,继续室温搅拌12小时。除去溶剂后,所得粗品通过硅胶柱层析纯化得目标物Ic;1H NMR(400MHz,CDCl3):δ10.22(s,1H,NH),7.83~7.87(m,2H,Ar-H),7.10~7.14(m,2H,Ar-H),6.95~7.01(m,1H,Ar-H),6.75~6.82(m,2H,Ar-H),4.87(d,J=5.6Hz,2H,CH2),4.52(t,J=4.8Hz,2H,CH2),4.31(t,J=5.0Hz,2H,CH2),3.93(s,3H,CH3),2.74(s,3H,CH3).
实施例4:
样品对肿瘤细胞的活性筛选
采用四甲基氮唑蓝比色法(MTT)测定了目标物的体外抗肿瘤活性。供试对象为人肝癌细胞株HepG2。选择5-氟尿嘧啶(5-FU)作为阳性对照药。取处于指数生长期的人癌细胞HepG2制成1×104个细胞/mL的细胞悬液,接种于96孔板中,在37℃、5%CO2培养箱中培养24小时。接着将待测化合物的供试液(10μL)加入测试孔中,每个浓度设5个平行孔,并使用等量的DMSO作空白对照,在5%CO2培养箱中培养72小时后,弃上清液,每孔加MTT(2mg/mL inPBS)20μL,继续培养4小时后,吸弃培养基,每孔加入150μL DMSO,在振动器振荡10分钟溶解形成的蓝紫色沉淀,接着用酶标仪在490nm波长测定OD值,计算细胞抑制率。细胞抑制率=(阴性对照组OD值-受试物组OD值)/阴性对照组OD值×100%。以简化概率单位法计算出IC50值。
表1.Ia-Ic的细胞毒性数据(IC50,μM)
化合物 | HepG2 |
Ia | 27.99 |
Ib | 21.05 |
Ic | 34.66 |
5-FU | 37.80 |
由试验结果(表1)可以看出,所合成的化合物Ia-Ic对人肝癌细胞株HepG2都显示出较好的抑制效果,其化合物Ia-Ic对人肝癌细胞株HepG2的抗肿瘤活性要高于阳性对照药5-氟尿嘧啶(5-FU)。实验结果表明,在氰基丙烯酸酯活性单元中引入1-甲基-3-(4-氟苯基)-4-氯吡唑基团,形成的化合物对人肝癌细胞株HepG2展现出较好的抗肿瘤作用。
以上显示和描述了本发明的基本原理、主要特征和本发明的优点。本行业的技术人员应该了解,本发明不受上述实例的限制,上述实例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等同物界定。
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