CN111499568B - 一种含吡啶联4-巯基芳基单元的氰基丙烯酸酯衍生物的制备和应用 - Google Patents
一种含吡啶联4-巯基芳基单元的氰基丙烯酸酯衍生物的制备和应用 Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
本发明涉及一种含吡啶联4‑巯基芳基单元的氰基丙烯酸酯衍生物(I)的制备和应用。通过吡啶联4‑巯基芳基甲基胺化合物与取代丙烯酸酯缩合得到。所述吡啶联4‑巯基芳基对肿瘤细胞HepG2显示出较好的抑制效果,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,具体涉及一种含吡啶联4-巯基芳基单元的氰基丙烯酸酯衍生物的制备和应用。
背景技术
恶性肿瘤近年来严重威胁人类健康,恶性肿瘤的防治是医药科学研究的重要领域,但随着抗肿瘤药物广泛的使用,传统抗肿瘤药的抗性问题日益增加,同时加上新的肿瘤疾病逐年增加,使得新型抗肿瘤药物的继续研究与开发成为必然选择。
近年来,吡啶杂环化合物作为重要的含氮单元而备受广大科研工作者关注,许多吡啶基化合物由于对肿瘤细胞表现出优良的抑制作用,在医疗保健领域具有重要的应用。
氰基丙烯酸酯类化合物亦为重要的一类化合物,某些氰基丙烯酸酯衍生物对肿瘤细胞体现出良好的抑制效果。
因此,为了继续从氰基丙烯酸酯中探索具有较好抗肿瘤作用的药物,我们采用活性亚结构拼接方法将吡啶联4-巯基芳基片段与氰基丙烯酸酯活性单元结合在一起。本发明公开了一类具有药用价值的一种含吡啶联4-巯基芳基单元的氰基丙烯酸酯衍生物。
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种含吡啶联4-巯基芳基单元的氰基丙烯酸酯衍生物。
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,本发明提供一种含吡啶联4-巯基芳基单元的氰基丙烯酸酯衍生物,其具有通式I结构,
优选地,一种含吡啶联4-巯基芳基单元的氰基丙烯酸酯衍生物,具有如下结构:
本发明提供上述一种含吡啶联4-巯基芳基单元的氰基丙烯酸酯衍生物的制备方法,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,减压除去溶剂,所得粗品经过纯化得目标物,
优选地,一种含吡啶联4-巯基芳基单元的氰基丙烯酸酯衍生物的制备方法,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化合物对肿瘤细胞如HepG2等呈现优良的治疗效果。
本发明公开的一种含吡啶联4-巯基芳基单元的氰基丙烯酸酯衍生物对肿瘤细胞HepG2显示出优良的治疗效果,因此可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16mmol中间体Ⅱ溶于50mL四氯化碳,室温下加入中间体Ⅲa 12mmol,加好后,继续室温搅拌18小时。旋蒸除去溶剂后,所得粗品通过硅胶柱层析分离得到化合物Ia;1H NMR(400MHz,CDCl3):δ10.29(s,1H,NH),8.18(d,J=2.0Hz,1H,Py-H),7.56~7.58(m,1H,Py-H),7.14~7.29(m,5H,Ar-H and Py-H),7.03~7.10(m,1H,Ar-H),6.72~6.77(m,1H,Ar-H),6.62~6.65(m,1H,Ar-H),4.74(d,J=6.0Hz,2H,CH2),4.48(t,J=5.2Hz,2H,CH2),4.18(t,J=5.2Hz,2H,CH2),4.04(s,2H,CH2),2.67(s,3H,CH3).
实施例2:
将10mmol中间体Ⅱ溶于35mL乙醇,室温下向其中加入中间体Ⅲb 10mmol,加好后,加热回流反应15小时。旋蒸除去溶剂后,所得粗品经过硅胶柱层析分离得化合物Ib;1H NMR(400MHz,CDCl3):δ10.29(s,1H,NH),8.18(d,J=1.6Hz,1H,Py-H),7.56~7.59(m,1H,Py-H),7.14~7.29(m,5H,Ar-H and Py-H),6.41~6.45(m,3H,Ar-H),4.74(d,J=5.6Hz,2H,CH2),4.49(t,J=5.2Hz,2H,CH2),4.19(t,J=5.2Hz,2H,CH2),4.04(s,2H,CH2),2.67(s,3H,CH3).
实施例3:
将20mmol中间体Ⅱ溶于30mL乙腈,室温搅拌下向其中加入中间体Ⅲc18 mmol,加好后,加热回流反应10小时。旋蒸除去溶剂后,所得粗品经过硅胶柱层析分离得化合物Ic;1H NMR(400MHz,CDCl3):δ10.29(s,1H,NH),8.18(d,J=2.4Hz,1H,Py-H),7.55~7.58(m,1H,Py-H),7.14~7.29(m,5H,Ar-H and Py-H),6.93~7.02(m,1H,Ar-H),6.71~6.84(m,2H,Ar-H),4.74(d,J=2.0Hz,2H,CH2),4.53(t,J=5.2Hz,2H,CH2),4.32(t,J=5.2Hz,2H,CH2),4.04(s,2H,CH2),2.66(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)测试了化合物对人肝癌细胞株HepG2的体外抗肿瘤活性。选以5-氟尿嘧啶(5-FU)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的培养箱中培养24h。然后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72h,然后弃上清液,每孔加MTT(2mg/mL in PBS)20μL,继续培养4h后,吸弃培养基,每孔加入150μL DMSO,在振动器振荡10min溶解形成的蓝紫色沉淀,最后用酶标仪在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化合物的IC50值。
表1.化合物Ia-Ic的抗肿瘤活性数据(IC50,μmol/L)
化合物 | HepG2 |
Ia | 21.30 |
Ib | 23.75 |
Ic | 35.20 |
5-FU | 37.80 |
通过表1的抗肿瘤活性数据可看出,化合物Ia-Ic对人肝癌细胞株HepG2均呈现出较好的抑制效果,化合物Ia-Ic对人肝癌细胞株HepG2的抑制活性都高于阳性对照药5-氟尿嘧啶(5-FU)的药效。以上试验数据也表明,在氰基丙烯酸酯分子结构中引入吡啶联4-巯基芳基片段,得到的化合物对人肝癌细胞株HepG2显示出较好的防治效果。
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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CN1603307A (zh) * | 2004-07-30 | 2005-04-06 | 贵州大学 | 氰基丙烯酸酯衍生物及制备方法和生物活性 |
CN101817799A (zh) * | 2009-02-26 | 2010-09-01 | 南开大学 | 氰基丙烯酸酯类化合物及在农药和医药上的应用 |
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CN101817799A (zh) * | 2009-02-26 | 2010-09-01 | 南开大学 | 氰基丙烯酸酯类化合物及在农药和医药上的应用 |
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新型含1,3,4-噁二唑环结构的氰基丙烯酸酯类化合物的合成及生物活性研究;石玉军,等;《有机化学》;20161231;第36卷;2472-2478 * |
新型含5-芳基异噁唑结构的氰基丙烯酸酯类化合物的合成及生物活性;石玉军,等;《高等学校化学学报》;20170331;第38卷;421-428 * |
新型含氟甲基吡唑结构的氰基丙烯酸酯类化合物的合成及其生物活性;石玉军,等;《有机化学》;20161231;第36卷;1431-1437 * |
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