CN103588769A - 一类新颖的二氢吡唑-噻唑啉酮类衍生物的合成及在抗癌药物中的应用 - Google Patents
一类新颖的二氢吡唑-噻唑啉酮类衍生物的合成及在抗癌药物中的应用 Download PDFInfo
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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Abstract
Description
发明内容
本发明涉及含一类新颖的二氢吡唑-噻唑啉酮类衍生物的制备方法及其用途。
背景技术
二氢吡唑是一类重要的杂环化合物,广泛分布在自然界中。自从发现吡唑环有镇痛消炎及退热作用以来,该类化合物因其具有高效、低毒,以及其环上取代基的多方位变换而在药物领域中得到广泛应用。研究发现吡唑类化合物具有消炎、止痛、抑菌、杀菌、抗高血糖、抗癌、抗凝血剂等药理活性。近年来,许多新型吡唑类医药相继商品化,对吡唑类化合物的深入研究已成为当今药物设计合成研究的热点之一。
此外,许多噻唑啉酮衍生物显示出强大生物活性和低毒性,但很少有报告报导设计和合成同时含有二氢吡唑和噻唑啉酮的化合物,两者结合的二氢吡唑环子结构,可能会表现出协同抗癌作用。
基于此,本发明将噻唑啉酮引入到二氢吡唑衍生物中,设计合成了一系列结构新颖的二氢吡唑-噻唑啉酮衍生物,期望具有更好的生物活性、更高的选择性、更低的毒性、更长或更短的残效期等。
发明内容
本发明的技术方案如下:
1.一类二氢吡唑-噻唑啉酮类衍生物的合成及制备,其特征是它有如下通式:
R2:H;Cl;Br;F;CH3;OCH3
一种上述的二氢吡唑-噻唑啉酮类衍生物的合成,它由下列步骤组成:
步骤1.在反应容器中加入适量的水,在所需低温下,加入NAOH使得溶剂成碱性,在所需的低温下,慢慢加入1号化合物。待其搅拌均匀后,缓慢加入苯乙酮相关衍生物,并严格控制其温度不高于0℃。继续搅拌反应(TLC跟踪反应,直至至少一种原料很少甚至没有),反应结束后,有大量固体形成。将其倒入冷水中,得到目标化合物2固体产物。
步骤2.在反应容器中加入适量化合物2的衍生物和适量的有机溶剂,在一定温度下搅拌使之溶解,按适量比例加入氨基硫脲,再滴加少量的碱,回流反应一段时间(TLC跟踪反应,直至至少一种原料很少甚至没有),反应结束后,将其倒入冷水中,用酸调其溶液到一定pH值时,会有大量固体析出,采用某种方法得到目标化合物3固体产物。
步骤3.在反应容器中加入适量化合物3的衍生物和适量的有机溶剂,在一定温度下搅拌使之溶解,按适量比例加入溴乙酸乙酯,再滴加少量的乙酸钠,回流反应一段时间(TLC跟踪反应,直至至少一种原料很少甚至没有)。将其放入大量的冰水中,经某种方法得到粗品,粗品经柱层析或采用适当的有机溶剂重结晶提纯得目标化合物4固体产物。
具体实施方式
实施例一:2-(5-苯基-3-(2-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
在150mL的圆底烧瓶中加入冰水50mL,加入NAOH(10mmol)使得溶剂成碱性,在0℃下慢慢加入二吡啶甲醛(20mmol),待其搅拌均匀后,缓慢加入苯乙酮(20mmol),并严格控制其温度不高于0℃。搅拌反应2h(TLC监测反应,展开剂:V石油醚:V乙酸乙酯=4:1)。此时已有大量固体形成,将其倒入冷水中抽滤、烘干,得到目标化合物2的固体产物。
在150mL圆底烧瓶中加入化合物2(10mmol),加入75mL无水乙醇作为溶剂,搅拌使之溶解,按适量比例加入氨基硫脲(10mmol),KOH(10mmol),在80℃温度搅拌,回流反应12h(TLC监测反应;展开剂:V石油醚:V乙酸乙酯=5:1),反应结束后,将其倒入冷水中,用盐酸调pH值至中性,会有大量固体析出,抽滤,重结晶,烘干后得到目标化合物3固体产物。
在150mL圆底烧瓶中加入化合物3(10mmol),加入75mL乙醇作为溶剂,搅拌使之溶解,然后加入溴乙酸乙酯(10mmol),滴加乙酸钠(10mmol),在80℃下回流反应8h(TLC监测反应;展开剂:V石油醚:V乙酸乙酯=5:1),将其放入大量的冰水中。用盐酸调pH值到中性时,会有大量固体析出。抽滤,重结晶。烘干后得绿色固体2.04g,产率63%,m.p.189~191℃;1H NMR(CDCl3,300MHz);δ:8.55(d,J=3.2Hz,2H,Ar);7.81(d,J=6.5Hz,2H,Ar);7.70(t,J=6.9Hz,1H,Ar);7.48(d,J=7.1Hz,4H,Ar);5.91(q,J=9.1Hz,1H,CH);3.95(q,J=8.3Hz,1H,CH);3.87(s,2H,CH2);3.79(q,J=9.2Hz,1H,CH).ESI-MS:323.27(C17H14N4OS[M+H]+).Anal.Calcd for C17H14N4OS:C,63.33;H,4.38;N,17.38.Found:C,63.54;H,4.61;N,17.19.
实施例二:2-(5-(4-氯苯基)-3-(2-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以对氯苯乙酮代替苯乙酮,得到黄色目标化合物。产率57%,m.p.142-144℃;1H NMR(CDCl3,300MHz);δ:8.54(d,J=6.2Hz,2H,Ar);7.78(d,J=7.3Hz,2H,Ar);7.73(t,J=8.1Hz,1H,Ar);7.36(d,J=6.4Hz,3H,Ar);5.86(q,J=6.7Hz,1H,CH);3.99(q,J=5.3Hz,1H,CH);3.92(s,2H,CH2);3.84(q,J=8.2Hz,1H,CH).ESI-MS:357.95(C17H13ClN4OS[M+H]+).Anal.Calcd for C17H13ClN4OS:C,57.22;H,3.67;N,15.70.Found:C,57.41;H,3.79;N,15.67.
实施例三:2-(5-(4-溴苯基)-3-(2-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以对溴苯乙酮代替苯乙酮,得到黄色目标化合物。产率51%,m.p.183~186℃;1H NMR(CDCl3,300MHz);δ:8.48(d,J=3.3Hz,2H,Ar);7.73(d,J=7.6Hz,2H,Ar);7.68(t,J=4.3Hz,1H,Ar);7.34(d,J=5.4Hz,3H,Ar);5.88(q,J=5.1Hz,1H,CH);3.89(q,J=9.8Hz,1H,CH);3.68(s,2H,CH2);3.48(q,J=5.1Hz,1H,CH).ESI-MS:401.15(C17H13BrN4OS[M+H]+).Anal.Calcd for C17H13BrN4OS:C,50.88;H,3.27;N,13.96.Found:C,50.65;H,3.35;N,13.74.
实施例四:2-(5-(4-氟苯基)-3-(2-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以对氟苯乙酮代替苯乙酮,得到黄色目标化合物。产率67%,m.p.162~164℃;1H NMR(CDCl3,300MHz);δ:8.67(d,J=4.5Hz,2H,Ar);7.85(d,J=3.2Hz,2H,Ar);7.69(t,J=7.9Hz,1H,Ar);7.28(d,J=3.4Hz,3H,Ar);5.89(q,J=4.7Hz,1H,CH);3.93(q,J=4.8Hz,1H,CH);3.88(s,2H,CH2);3.80(q,J=5.1Hz,1H,CH).ESI-MS:341.21(C17H13FN4OS[M+H]+).Anal.Calcd for C17H13FN4OS:C,59.99;H,3.85;N,16.46.Found:C,60.12;H,3.99;N,16.51.
实施例五:2-(5-(4-甲苯基)-3-(2-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以对甲基苯乙酮代替苯乙酮,得到黄色目标化合物。产率53%,m.p.147~149℃;1H NMR(CDCl3,300MHz);δ:8.56(d,J=5.3Hz,2H,Ar);7.71(d,J=6.8Hz,2H,Ar);7.47(t,J=2.0Hz,1H,Ar);7.26(d,J=9.1Hz,3H,Ar);5.91(q,J=6.2Hz,1H,CH);3.87(q,J=8.2Hz,1H,CH);3.74(s,2H,CH2);3.61(q,J=5.1Hz,1H,CH);2.42(s,3H,CH3).ESI-MS:337.21(C18H16N4OS[M+H]+).Anal.Calcd for C18H16N4OS:C,64.26;H,4.79;N,16.65.Found:C,64.42;H,4.82;N,16.81.
实施例六:2-(5-(4-甲氧基苯基)-3-(2-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以对甲氧基苯乙酮代替苯乙酮,得到黄色目标化合物。产率62%,m.p.154~156℃;1H NMR(CDCl3,300MHz);δ:8.60(d,J=6.3Hz,2H,Ar);7.78(d,J=9.9Hz,2H,Ar);7.56(t,J=2.9Hz,1H,Ar);6.92(d,J=5.1Hz,3H,Ar);5.83(q,J=4.1Hz,1H,CH);3.93(q,J=5.3Hz,1H,CH);3.88(d,J=4.1Hz,3H,OCH3);3.86(s,2H,CH2);3.79(q,J=6.2Hz,1H,CH).ESI-MS:353.07(C18H16N4O2S[M+H]+).Anal.Calcd for C18H16N4O2S:C,61.35;H,4.58;N,15.90.Found:C,61.21;H,4.71;N,15.71
实施例七:2-(5-苯基-3-(3-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以3-吡啶甲醛代替2-吡啶甲醛,得到橘黄色目标化合物。产率59%,m.p.134~135℃;1H NMR(CDCl3,300MHz);δ:8.59(d,J=4.7Hz,2H,Ar);7.92(d,J=5.4Hz,2H,Ar);7.81(t,J=8.9Hz,1H,Ar);7.51(d,J=5.1Hz,4H,Ar);5.81(q,J=3.1Hz,1H,CH);3.89(q,J=7.3Hz,1H,CH);3.84(s,2H,CH2);3.76(q,J=7.2Hz,1H,CH).ESI-MS:323.31(C17H14N4OS[M+H]+).Anal.Calcd for C17H14N4OS:C,63.33;H,4.38;N,17.38.Found:C,63.42;H,4.41;N,17.42.
实施例八:2-(5-(4-氯苯基)-3-(3-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以3-吡啶甲醛代替2-吡啶甲醛,以对氯苯乙酮取代苯乙酮。得到黄色目标化合物.产率73%,m.p.187-189℃;1H NMR(CDCl3,300MHz);δ:8.57(d,J=5.4Hz,2H,Ar);7.74(d,J=8.5Hz,2H,Ar);7.58(d,J=7.6Hz,2H,Ar);7.48(d,J=8.4Hz,3H,Ar);5.86(q,J=3.8Hz,1H,CH);4.02(q,J=11.5Hz,1H,CH);3.89(s,2H,CH2);3.41(q,J=4.0Hz,1H,CH).ESI-MS:357.92(C17H13ClN4OS[M+H]+).Anal.Calcd for C17H13ClN4OS:C,57.22;H,3.67;N,15.70.Found:C,57.32;H,3.69;N,15.77.
实施例九:2-(5-(4-溴苯基)-3-(3-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以3-吡啶甲醛代替2-吡啶甲醛,以对溴苯乙酮取代苯乙酮,得到橘黄色目标化合物。产率67%,m.p.157~159℃;1H NMR(CDCl3,300MHz);δ:8.56(d,J=5.0Hz,2H,Ar);7.66(d,J=7.2Hz,2H,Ar);7.57(t,J=11.0Hz,2H,Ar);7.27(d,J=4.9Hz,2H,Ar);5.86(q,J=3.9Hz,1H,CH);3.99(q,J=11.4Hz,1H,CH);3.88(s,2H,CH2);3.42(q,J=4.2Hz,1H,CH).ESI-MS:401.35(C17H13BrN4OS[M+H]+).Anal.Calcd for C17H13BrN4OS:C,50.88;H,3.27;N,13.96.Found:C,50.95;H,3.31;N,13.99.
实施例十:2-(5-(4-氟苯基)-3-(3-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以3-吡啶甲醛代替2-吡啶甲醛,以对氟苯乙酮取代苯乙酮,得到黄色目标化合物。产率52%,m.p.154~155℃;1H NMR(CDCl3,300MHz);δ:8.69(d,J=6.1Hz,2H,Ar);7.91(d,J=8.2Hz,2H,Ar);7.72(t,J=6.3Hz,1H,Ar);7.39(d,J=5.4Hz,3H,Ar);5.85(q,J=6.2Hz,1H,CH);3.98(q,J=5.7Hz,1H,CH);3.87(s,2H,CH2);3.81(q,J=7.1Hz,1H,CH).ESI-MS:341.21(C17H13FN4OS[M+H]+).Anal.Calcd for C17H13FN4OS:C,59.99;H,3.85;N,16.46.Found:C,60.21;H,3.95;N,16.59.
实施例十一:2-(5-(4-甲苯基)-3-(3-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以3-吡啶甲醛代替2-吡啶甲醛,以对甲基苯乙酮取代苯乙酮,得到黄色目标化合物。产率71%,m.p.147~149℃;1H NMR(CDCl3,300MHz);δ:8.57(d,J=2.6Hz,2H,Ar);7.69(d,J=8.2Hz,2H,Ar);7.59(t,J=2.0Hz,1H,Ar);7.27(d,J=9.1Hz,3H,Ar);5.82(q,J=4.1Hz,1H,CH);3.99(q,J=11.3Hz,1H,CH);3.89(s,2H,CH2);3.41(q,J=4.2Hz,1H,CH);2.44(s,3H,CH3).ESI-MS:337.12(C18H16N4OS[M+H]+).Anal.Calcd for C18H16N4OS:C,64.26;H,4.79;N,16.65.Found:C,64.31;H,4.92;N,16.72.
实施例十二:2-(5-(4-甲氧基苯基)-3-(3-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以3-吡啶甲醛代替2-吡啶甲醛,以对甲氧基苯乙酮取代苯乙酮,得到黄色目标化合物。产率54%,m.p.143~144℃;1H NMR(CDCl3,300MHz);δ:8.57(d,J=3.3Hz,2H,Ar);7.81(d,J=7.9Hz,2H,Ar);7.36(t,J=4.9Hz,1H,Ar);6.72(d,J=8.1Hz,3H,Ar);5.81(q,J=3.1Hz,1H,CH);3.89(q,J=8.3Hz,1H,CH);3.86(d,J=3.1Hz,3H,OCH3);3.82(s,2H,CH2);3.74(q,J=8.2Hz,1H,CH).ESI-MS:353.27(C18H16N4O2S[M+H]+).Anal.Calcd for C18H16N4O2S:C,61.35;H,4.58;N,15.90.Found:C,61.51;H,4.61;N,15.81.
实施例十三:2-(5-苯基-3-(4-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以4-吡啶甲醛代替2-吡啶甲醛,得到白色目标化合物。产率63%,m.p.189~191℃;1H NMR(CDCl3,300MHz);δ:8.55(d,J=3.2Hz,2H,Ar);7.81(d,J=6.5Hz,2H,Ar);7.70(t,J=6.9Hz,1H,Ar);7.48(d,J=7.1Hz,4H,Ar);5.91(q,J=9.1Hz,1H,CH);3.95(q,J=8.3Hz,1H,CH);3.87(s,2H,CH2);3.79(q,J=9.2Hz,1H,CH).ESI-MS:323.27(C17H14N4OS[M+H]+).Anal.Calcd for C17H14N4OS:C,63.33;H,4.38;N,17.38.Found:C,63.54;H,4.61;N,17.19.
实施例十四:2-(5-(4-氯苯基)-3-(4-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以4-吡啶甲醛代替2-吡啶甲醛,以对氯苯乙酮取代苯乙酮,得到橘黄色目标化合物。产率56%,m.p.165~166℃;1H NMR(CDCl3,300MHz);δ:8.63(d,J=6.1Hz,2H,Ar);7.81(d,J=7.5Hz,2H,Ar);7.63(d,J=6.7Hz,2H,Ar);7.51(d,J=10.4Hz,3H,Ar);5.83(q,J=4.1Hz,1H,CH);4.04(q,J=9.3Hz,1H,CH);3.92(s,2H,CH2);3.35(q,J=4.3Hz,1H,CH).ESI-MS:357.71(C17H13ClN4OS[M+H]+).Anal.Calcd for C17H13ClN4OS:C,57.22;H,3.67;N,15.70.Found:C,57.38;H,3.59;N,15.81.
实施例十五:2-(5-(4-溴苯基)-3-(4-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以4-吡啶甲醛代替2-吡啶甲醛,以对溴苯乙酮取代苯乙酮,得到红色目标化合物。产率55%,m.p.166~168℃;1H NMR(CDCl3,300MHz);δ:8.51(d,J=5.3Hz,2H,Ar);7.64(d,J=6.9Hz,2H,Ar);7.53(t,J=9.1Hz,2H,Ar);7.41(d,J=8.4Hz,2H,Ar);5.81(q,J=6.1Hz,1H,CH);3.94(q,J=3.7Hz,1H,CH);3.89(s,2H,CH2);3.49(q,J=7.6Hz,1H,CH).ESI-MS:401.42(C17H13BrN4OS[M+H]+).Anal.Calcd for C17H13BrN4OS:C,50.88;H,3.27;N,13.96.Found:C,50.81;H,3.39;N,14.01.
实施例十六:2-(5-(4-氟苯基)-3-(4-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以4-吡啶甲醛代替2-吡啶甲醛,以对氟苯乙酮取代苯乙酮,得到橘黄色目标化合物。产率47%,m.p.172~174℃;1HNMR(CDCl3,300MHz);δ:8.64(d,J=5.4Hz,2H,Ar);7.87(d,J=5.1Hz,2H,Ar);7.79(t,J=6.2Hz,1H,Ar);7.34(d,J=6.2Hz,3H,Ar);5.81(q,J=7.8Hz,1H,CH);3.98(q,J=5.2Hz,1H,CH);3.86(s,2H,CH2);3.77(q,J=3.4Hz,1H,CH).ESI-MS:341.43(C17H13FN4OS[M+H]+).Anal.Calcd for C17H13FN4OS:C,59.99;H,3.85;N,16.46.Found:C,60.21;H,3.96;N,16.59.
实施例十七:2-(5-(4-甲苯基)-3-(4-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以4-吡啶甲醛代替2-吡啶甲醛,以对甲基苯乙酮取代苯乙酮,得到黄色目标化合物。产率66%,m.p.176~178℃;1H NMR(CDCl3,300MHz);δ:8.62(d,J=8.3Hz,2H,Ar);7.73(d,J=6.8Hz,2H,Ar);7.64(t,J=8.1Hz,1H,Ar);7.47(d,J=5.1Hz,3H,Ar);5.79(q,J=4.6Hz,1H,CH);4.02(q,J=7.3Hz,1H,CH);3.91(s,2H,CH2);3.50(q,J=6.1Hz,1H,CH);2.49(s,3H,CH3).ESI-MS:337.24(C18H16N4OS[M+H]+).Anal.Calcd for C18H16N4OS:C,64.26;H,4.79;N,16.65.Found:C,64.39;H,4.87;N,16.81.
实施例十八:2-(5-(4-甲氧基苯基)-3-(4-吡啶基)-4,5-二氢吡唑基)噻唑-4-酮的制备
制备方法同实施例一。以4-吡啶甲醛代替2-吡啶甲醛,以对甲氧基苯乙酮取代苯乙酮,得到黄色目标化合物。产率62%,m.p.145~147℃;1H NMR(CDCl3,300MHz);δ:8.59(d,J=3.9Hz,2H,Ar);7.75(d,J=8.6Hz,2H,Ar);7.29(t,J=3.8Hz,1H,Ar);6.99(d,J=4.1Hz,3H,Ar);5.79(q,J=3.1Hz,1H,CH);3.99(q,J=11.3Hz,1H,CH);3.87(d,J=5.1Hz,3H,OCH3);3.85(s,2H,CH2);3.79(q,J=4.2Hz,1H,CH).ESI-MS:353.17(C18H16N4O2S[M+H]+).Anal.Calcd for C18H16N4O2S:C,61.35;H,4.58;N,15.90.Found:C,61.47;H,4.71;N,15.99.
实施例十九:二氢吡唑-噻唑啉酮类衍生物体外抗肿瘤活性研究
采用MTT[3-(4,5)-双甲基-2-噻唑-(2,5)-苯基溴化四氮唑蓝]法来测定二氢吡唑-噻唑啉酮类衍生物对人乳腺癌细胞株(MCF-7)、增殖表皮癌细胞(Hela)、小鼠黑色素瘤细胞(B16-F10)的半数抑制浓度(IC50)。
(1)培养液(每升)的配制:①悬浮细胞:RPMI-1640培养粉各一袋(10.4g),新生牛血清各100ml,青霉素溶液(20万U/ml)0.5ml,链霉素溶液(20万U/ml)0.5ml,加三蒸水溶解后,用5.6%的NaHCO3溶液调PH值至7.2-7.4,最后定容至1000ml。过滤灭菌。②贴壁细胞:同上,再加入NaHCO32.00g,HEPES2.38g。
(2)D-Hanks缓冲液(每升)的配制:NaCl8.00g,KCl0.40g,Na2HPO4·12H2O0.06g,KH2PO40.06g,NaHCO30.35g。高压灭菌。
(3)胰蛋白酶液的配制:利用D-Hanks缓冲液配成浓度为0.5%胰蛋白酶液。过滤除菌。
(4)实验药液的配制:将测试样品用少量的三蒸水溶解配成储备液,一般按实验最高浓度的10倍配制储备液。根据化合物溶解性不同,可用三蒸水直接溶解,或用少量DMSO助溶,再加三蒸水溶解。DMSO在培养液中的浓度不宜过大,加药后的每孔细胞悬液中DMSO的终浓度一般不超过0.05%-0.1%。储备 液保存于-20℃冰箱中备用。
(5)人乳腺癌细胞株(MCF-7)、增殖表皮癌细胞(Hela)、小鼠黑色素瘤细胞(B16-F10)的培养:为悬浮生长细胞,常规培养于RPMI-1640培养液内(含10%小牛血清、100U/ml链霉素),置于37℃、5%CO2培养箱中培养,每隔3-4天传代一次。传代时将原瓶中培养液转移至离心管中,1000rpm离心5min,弃去原培养液,加入等量新鲜培养液,吹打均匀,移取适量至新鲜培养瓶中,再补充新鲜培养液至原体积(培养液体积约为培养瓶容量的1/10)。
(6)细胞孵育:取对数生长期的肿瘤细胞,调细胞悬液浓度为1-1.5×105个ml-1。在96孔培养板中每孔加细胞悬液100μl,置37℃,5%CO2培养箱中培养24h。培养24h后,分别按设计加入药液。
(8)加药:将测试药液按照最终浓度的浓度梯度分别加入到各个孔中,每个浓度设6个平行孔。实验分为药物试验组(分别加入不同浓度的测试药)、对照组(只加培养液和细胞,不加测试药)和空白组(只加培养液,不加细胞和测试药)。将加药后的96孔板置于37℃,5%CO2培养箱中培养48h。阳性对照药物的活性按照测试样品的方法测定。
(9)存活细胞的测定:在培养了48h后的96孔板中,每孔加MTT40μl(用D-Hanks缓冲液配成4mg/ml)。在37℃放置4h后,移去上清液。每孔加150μl DMSO,振荡5min,使formazan结晶溶解。最后,利用自动酶标仪在570nm波长处检测各孔的光密度(OD值)。
抑制率的计算:细胞生长的抑制率按照下列公式计算:
生长抑制率=(1-存活率)×100%=[1-(OD实验-OD空白)/(OD对照-OD空白)]×100%(OD实验表示测试药物组的平均光密度,OD对照表示对照组的平均光密度,OD空白表示对照组的平均光密度)。
半数抑制浓度(IC50)定义为当50%的肿瘤细胞存活时的药物浓度。根据测定的光密度(OD值),制作细胞生长抑制率的标准曲线,在标准曲线上求得其对应的药物浓度。
测得的IC50见表1,表2所示。
表1本发明所列二氢吡唑-噻唑啉酮类衍生物编号
表2本发明所列二氢吡唑-噻唑啉酮类衍生物对肿瘤细胞的抑制IC50值(μM)
埃罗替尼:阳性对照 。
Claims (3)
2.一种上述的二氢吡唑-噻唑啉酮类衍生物的合成,它由下列步骤组成:
步骤1.在反应容器中加入适量的水,在所需低温下,加入NAOH使得溶剂成碱性,在所需的低温下,慢慢加入1号化合物。待其搅拌均匀后,缓慢加入苯乙酮相关衍生物,并严格控制其温度不高于0℃。继续搅拌反应(TLC跟踪反应,直至至少一种原料很少甚至没有),反应结束后,有大量固体形成。将其倒入冷水中,得到目标化合物2固体产物。
步骤2.在反应容器中加入适量化合物2的衍生物和适量的有机溶剂,在一定温度下搅拌使之溶解,按适量比例加入氨基硫脲,再滴加少量的碱,回流反应一段时间(TLC跟踪反应,直至至少一种原料很少甚至没有),反应结束后,将其倒入冷水中,用酸调其溶液到一定pH值时,会有大量固体析出,采用某种方法得到目标化合物3固体产物。
步骤3.在反应容器中加入适量化合物3的衍生物和适量的有机溶剂,在一定温度下搅拌使之溶解,按适量比例加入溴乙酸乙酯,再滴加少量的乙酸钠,回流反应一段时间(TLC跟踪反应,直至至少一种原料很少甚至没有)。将其放入大量的冰水中,经某种方法得到粗品,粗品经柱层析或采用适当的有机溶剂重结晶提纯得目标化合物4固体产物。
3.根据权利要求所述的二氢吡唑-噻唑啉酮类衍生物的合成以及抗肿瘤药物中的应用。
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