CN104230904A - 一类含萘环骨架的二氢吡唑磺胺衍生物的合成及在抗癌药物中的应用 - Google Patents
一类含萘环骨架的二氢吡唑磺胺衍生物的合成及在抗癌药物中的应用 Download PDFInfo
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Abstract
一类含萘环骨架的二氢吡唑磺胺衍生物的合成,其特征是有如下通式:
Description
发明内容
本发明的目的在于提供一类含萘环骨架的二氢吡唑磺胺衍生物的合成及在抗癌药物中的应用
背景技术
吡唑是一类重要的杂环化合物,广泛分布在自然界中。自从含吡唑环的安替吡啉被发现具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的性质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。
2H吡唑是极为重要的含氮的五元杂环化合物,它具有很多优异的生物活性,比如抗肿瘤、抗菌、抗病毒、抗真菌、抗结核、杀虫等活性。它是一个具有各种药理特性的结构性存在亚基,存在普遍药用生物活性的活性化合物先导。除此之外,由于2H吡唑多是手性的,可以导致环上的取代及分子的构象具有更大的多变性,因而,具有更好的生物活性潜质!2H吡唑类化合物在有机合成和其他领域中的应用越来越广泛,且手性2H吡唑类化合物具有诸多生物及药理性能,促进了药物的巨大发展,为以后的药物开发研究提供了很大的研究空间,发展前景非常广阔,因此构建具有2H吡唑结构的杂环体系具有重要的意义,是近几年被关注的热点。
磺胺类药物具有多种生物活性,一直是药物化学领域研究的热点,在抗菌、降血压、利尿等方面有广泛应用,但是,该类药物是抑菌剂,而无杀菌作用,易产生耐药性以及经常使用会产生许多不良反应,从而使其应用范围受到了极大的限制。但是由于其易产生抗药性,使用范围已逐渐减小。但是近年来的文献多次报道了其衍生物的具有除抗菌外其他方面的活性,其中最显著的是抗肿瘤活性。
萘环骨架在各类国际期刊上的报道非常之多,可以说是化合物结构修饰领域的一大热点。除了具有优秀的抗菌活性,而且也具有优秀的抗肿瘤活性。随着肿 瘤发生发展的机制逐渐被深入研究,萘环化合物逐渐更广泛地被应用于抗肿瘤先导化合物的开发中。
基于此,本发明将不同磺胺以及具有优秀生物活性的萘环骨架引入到二氢吡唑衍生物中,设计合成了一系列含萘环骨架的二氢吡唑磺胺衍生物,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:
一类含萘环骨架的二氢吡唑磺胺衍生物的合成,其特征是它有如下通式:
一种上述的含萘环骨架的二氢吡唑磺胺衍生物的合成,它由下列步骤组成:
步骤1.在室温搅拌下,依次向100mL的圆底烧瓶中加入不同取代基的苯 乙酮(10.0mmol)、40%KOH水溶液、不同取代基的萘甲醛(10.0mmol)、乙醇(50mL),继续搅拌反应4h后,将反应液倒入500mL烧杯中,1mol/L盐酸酸化(pH=7.0),过滤,固体依次用蒸馏水(3×100mL)、冷乙醇(3×50mL)、蒸馏水(3×100mL)洗涤,干燥得中间体2-16。
步骤2.依次将不同的查尔酮2-16(4mmol)、无水乙醇(25mL)、对肼基苯磺酰胺(4.5mmol)、乙酸(1.0mL)加入到50mL的圆底烧瓶中,室温搅拌反应1h后,仍有部分固体不溶;将反应烧瓶转移到油浴锅中,回流反应6h,TLC跟踪反应(展开剂VAcOEt∶VPE=1∶2),反应结束后,过滤,固体依次用1mol/L盐酸(3×100mL)、蒸馏水(3×150mL)、冷乙醇(3×50mL)、蒸馏水(3×100mL)洗涤,干燥,将得到的固体粗产物溶于无水乙醇重结晶得到晶体状目标化合物17-31。
本发明的含萘环骨架的二氢吡唑磺胺衍生物对人乳腺癌细胞(MCF-7)、***细胞(HeLa)、肺癌细胞(A549)、肝癌细胞(HepG2)及基质金属蛋白酶-2(MMP-2)有明显的抑制作用,同时对人肾上皮细胞(293T)表现出了相当或者优于阳性对照药物的细胞毒性。因此本发明的含萘环骨架的二氢吡唑磺胺衍生物可以应用于制备抗肿瘤药物。
具体实施方式
实施例一:4-(5-(α-萘基)-3-(p-甲氧基苯基)-4,5-二氢吡唑)苯磺酰胺(化合物17)的制备
在搅拌下依次将α-萘基的查尔酮(1.0g,3.87mmol)、乙醇(25mL)、对肼基苯磺酰胺(0.97g,5.03mmol)、乙酸(1.0mL)加入到50mL的圆底烧瓶中,仍有部分固体不溶;将烧瓶转移到油浴锅中,回流反应6h,TLC跟踪反应(展开剂VAcOEt∶V正已烷=1∶2),反应结束后,过滤,固体用蒸馏水洗涤,最后真空干燥,将得到的固体溶于无水乙醇重结晶提纯得到晶体状目标化合物。
得白色晶体,产率69.7%。m.p.194~196℃;1H NMR(DMSO-d6,300MHz)δ:8.33(s,1H,ArH),8.02(d,J=8.1Hz,1H,ArH),7.87(d,J=8.2Hz,1H,ArH),7.70~7.31(m,4H,ArH),7.42~7.31(m,4H,ArH),7.09~6.70(m,6H,ArH and NH2), 6.35(dd,J1=4.7,J2=4.8Hz,1H,5-H),4.21(dd,J1=12.1,J2=11.8Hz,1H,4-Hb),3.80(s,3H,OCH3),3.16(dd,J1=4.9,J2=4.7Hz,1H,4-Ha).ESI-MS:458.1[M+H]+.Anal.Calcd for C26H23N3O3S:C,H,N.
实施例二:4-(5-(α-萘基)-3-(m-甲基苯基)-4,5-二氢吡唑)苯磺酰胺(化合物18)的制备
制备方法同实施例一。得白色晶体,产率70.4%。m.p.229~230℃;1H NMR(DMSO-d6,300MHz)δ:8.33(s,1H,ArH),8.03(d,J=8.1Hz,1H,ArH),7.87(d,J=8.2Hz,1H,ArH),7.70~7.58(m,6H,ArH),7.42~7.21(m,3H,ArH),7.03(s,4H,ArH and NH2),6.36(dd,J1=5.4,J2=5.5Hz,1H,5-H),4.23(dd,J1=12.4,J2=12.2Hz,1H,4-Hb),3.16(dd,J1=3.8,J2=5.3Hz,1H,4-Ha),2.34(s,3H,CH3).ESI-MS:442.1[M+H]+.Anal.Calcd for C26H23N3O2S:C,H,N.
实施例三:4-(5-(α-萘基)-3-(o-甲基苯基)-4,5-二氢吡唑)苯磺酰胺(化合物19)的制备
制备方法同实施例一。得白色晶体,产率67.3%。n.p.232~235℃;1H NMR(DMSO-d6,300MHz)δ:7.92~7.84(m,4H,ArH),7.68(s,1H,ArH),7.59(t,J=6.8Hz,3H,ArH),7.53~7.48(m,2H,ArH),7.37~7.33(m,2H,ArH),7.14(d,J=8.9Hz,2H,ArH),7.00(s,2H,NH2),5.81(dd,J1=5.2,J2=5.2Hz,1H,5-H),4.05(dd,J1=12.3,J2=12.1Hz,1H,4-Hb),3.28(dd,J1=5.3,J2=5.2Hz,1H,4-Ha),2.37(s,3H,CH3).ESI-MS:442.1[M+H]+.Anal.Calcd for C26H23N3O2S:C,H,N.
实施例四:4-(5-(α-萘基)-3-(m-碘基苯基)-4,5-二氢吡唑)苯磺酰胺(化合物20)的制 备
制备方法同实施例一。得白色晶体,产率78.5%。m.p.218~220℃;1H NMR(DMSO-d6,300MHz)δ:8.31(s,1H,ArH),8.02(d,J=8.0Hz,1H,ArH),7.87(d,J=8.2Hz,1H,ArH),7.77(d,J=8.1Hz,2H,ArH),7.70~7.55(m,6H,ArH),7.39(d,J=6.9Hz,1H,ArH),7.08(s,2H,NH2),7.04(d,J=8.4Hz,3H,ArH),6.34(dd,J1=4.7,J2=4.8Hz,1H,5-H),4.21(dd,J1=12.8,J2=12.5Hz,1H,4-Hb),3.13(dd,J1=4.9,J2=4.7Hz,1H,4-Ha).ESI-MS:554.1[M+H]+.Anal.Calcd for C25H20IN3O2S:C,H,N.
实施例五:4-(5-(α-萘基)-3-(o-氯苯基)-4,5-二氢吡唑)苯磺酰胺(化合物21)的制备
制备方法同实施例一。得白色晶体,产率59.8.5%。m.p.190~191℃;1H NMR(DMSO-d6,300MHz)δ:8.33(s,1H,ArH),8.02(d,J=8.0Hz,1H,ArH),7.88~7.80(m,2H,ArH),7.77~7.61(m,5H,ArH),7.54~7.38(m,3H,ArH),7.01(s,2H,NH2),7.04(d,J=9.9Hz,1H,ArH),6.39(dd,J1=4.7,J2=4.8Hz,1H,5-H),4.39(dd,J1=12.7,J2=12.4Hz,1H,4-Hb),3.24(dd,J1=4.9,J2=4.7Hz,1H,4-Ha).ESI-MS:462.1[M+H]+.Anal.Calcd for C25H20C1N3O2S:C,H,N.
实施例六:4-(5-(α-萘基)-3-(2,4-二氟苯基)-4,5-二氢吡唑)苯磺酰胺(化合物22)的制备
制备方法同实施例一。得白色晶体,产率73.4%。m.p.250~252℃;1H NMR(DMSO-d6,300MHz)δ:8.03(q,J=8.7Hz,1H,ArH),7.93~7.85(m,4H,ArH),7.59(d,J=8.9Hz,2H,ArH),7.53~7.35(m,4H,ArH),7.24~7.20(m,1H,ArH),7.14(d,J=8.8Hz,2H,ArH),7.03(s,2H,NH2),5.80(dd,J1=5.5,J2=5.6Hz,1H,5-H),4.12(dd,J1=12.4,J2=12.4Hz,1H,4-Hb),3.29(dd,J1=4.4,J2=5.2Hz,1H,4-Ha).ESI-MS:464.1[M+H]+.Anal.Calcd for C25H19F2N3O2S:C,H,N.
实施例七:4-(5-(β-萘基)-3-(o-甲基苯基)-4,5-二氢吡唑)苯磺酰胺(化合物23)的制备
制备方法同实施例一。以β-萘基的查尔酮代替α-萘基的查尔酮得白色晶体,产率68.8%。m.p.228~229℃;1H NMR(DMSO-d6,300MHz)δ:7.92~7.87(m,4H,ArH),7.59(d,J=8.9Hz,2H,ArH),7.53~7.47(m,3H,ArH),7.38~7.25(m,4H,ArH),7.10(d,J=8.7Hz,2H,ArH),7.01(s,2H,NH2),5.75(dd,J1=5.3,J2=5.4Hz,1H,5-H),4.13(dd,J1=12.2,J2=12.1Hz,1H,4-Hb),3.34(dd,J1=4.4,J2=5.2Hz,1H,4-Ha),2.76(s,3H,CH3).ESI-MS:442.1[M+H]+.Anal.Calcd for C26H23N3O2S:C,H,N.
实施例八:4-(5-(β-萘基)-3-(m-甲氧基苯基)-4,5-二氢吡唑)苯磺酰胺(化合物24)的制备
制备方法同实施例一。以β-萘基的查尔酮代替α-萘基的查尔酮得白色晶体,产率72.8%。m.p.215~217℃;1H NMR(DMSO-d6,300MHz)δ:8.33(s,1H,ArH),8.02(d,J=8.1Hz,1H,ArH),7.87(d,J=8.2Hz,1H,ArH),7.70~7.31(m,4H,ArH),7.42~7.31(m,4H,ArH),7.09~6.70(m,6H,ArH and NH2),6.35(dd,J1=4.7,J2=4.8Hz,1H,5-H),4.21(dd,J1=12.1,J2=11.8Hz,1H,4-Hb),3.80(s,3H,OCH3),3.16(dd,J1=4.9,J2=4.7Hz,1H,4-Ha).ESI-MS:458.1[M+H]+.Anal.Calcd for C26H23N3O3S:C,H,N.
实施例九:4-(5-(β-萘基)-3-(m-甲基苯基)-4,5-二氢吡唑)苯磺酰胺(化合物25)的制备
制备方法同实施例一。以β-萘基的查尔酮代替α-萘基的查尔酮得白色晶体,产率71.3%。m.p.206~207℃;1H NMR(DMSO-d6,300MHz)δ:7.92~7.84(m,4H,ArH),7.68(s,1H,ArH),7.59(t,J=6.8Hz,3H,ArH),7.53~7.48(m,2H,ArH),7.37~7.33(m,2H,ArH),7.14(d,J=8.9Hz,2H,ArH),7.00(s,2H,NH2),5.81(dd,J1=5.2,J2=5.2Hz,1H,5-H),4.05(dd,J1=12.3,J2=12.1Hz,1H,4-Hb),3.28(dd,J1=5.3,J2=5.2Hz,1H,4-Ha),2.37(s,3H,CH3).ESI-MS:442.1[M+H]+.Anal.Calcd for C26H23N3O2S:C,H,N.
实施例十:4-(5-(β-萘基)-3-(m-氯苯基)-4,5-二氢吡唑)苯磺酰胺(化合物26)的制备
制备方法同实施例一。以β-萘基的查尔酮代替α-萘基的查尔酮得白色晶体,产率69.2%。n.p.165~167℃;1H NMR(DMSO-d6,300MHz)δ:8.33(s,1H,ArH),8.02(d,J=8.0Hz,1H,ArH),7.88~7.80(m,2H,ArH),7.77~7.61(m,5H,ArH),7.54~7.38(m,3H,ArH),7.01(s,2H,NH2),7.04(d,J=9.9Hz,1H,ArH),6.39(dd,J1=4.7,J2=4.8Hz,1H,5-H),4.39(dd,J1=12.7,J2=12.4Hz,1H,4-Hb),3.24(dd,J1=4.9,J2=4.7Hz,1H,4-Ha).ESI-MS:462.1[M+H]+.Anal.Calcd for C25H20IN3O2S:C,H,N.
实施例十一:4-(5-(β-萘基)-3-(m-碘基苯基)-4,5-二氢吡唑)苯磺酰胺(化合物27)的 制备
制备方法同实施例一。以β-萘基的查尔酮代替α-萘基的查尔酮得白色晶体,产率71.5%。m.p.216~218℃;1H NMR(DMSO-d6,300MHz)δ:8.31(s,1H,ArH),8.02(d,J=8.0Hz,1H,ArH),7.87(d,J=8.2Hz,1H,ArH),7.77(d,J=8.1Hz,2H,ArH),7.70~7.55(m,6H,ArH),7.39(d,J=6.9Hz,1H,ArH),7.08(s,2H,NH2),7.04(d,J=8.4Hz,3H,ArH),6.34(dd,J1=4.7,J2=4.8Hz,1H,5-H),4.21(dd,J1=12.8,J2=12.5Hz,1H,4-Hb),3.13(dd,J1=4.9,J2=4.7Hz,1H,4-Ha).ESI-MS:554.1[M+H]+.Anal.Calcd for C25H20ClN3O2S:C,H,N.
实施例十二:4-(5-(β-萘基)-3-(m-氟苯基)-4,5-二氢吡唑)苯磺酰胺(化合物28)的制备
制备方法同实施例一。以β-萘基的查尔酮代替α-萘基的查尔酮得白色晶体,产率69.2%。m.p.229~230℃;1H NMR(DMSO-d6,300MHz)δ:8.00(t,J=7.4Hz,1H,ArH),7.93~7.85(m,4H,ArH),7.59(d,J=8.8Hz,2H,ArH),7.53~7.44(m,3H,ArH),7.40~7.28(m,3H,ArH),7.15(d,J=8.8Hz,2H,ArH),7.03(s,2H,NH2),5.81(dd,J1=5.4,J2=5.5Hz,1H,5-H),4.14(dd,J1=12.3,J2=12.3Hz,1H,4-Hb),3.30(dd,J1=3.8,J2=5.3Hz,1H,4-Ha).ESI-MS:446.1[M+H]+.Anal.Calcd for C25H20FN3O2S:C,H,N.
实施例十三:4-(5-(β-萘基)-3-(2.4-二氟苯基)-4,5-二氢吡唑)苯磺酰胺(化合物29)的制备
制备方法同实施例一。以β-萘基的查尔酮代替α-萘基的查尔酮得白色晶体,产率68.3%。m.p.225~227℃;1H NMR(DMSO-d6,300MHz)δ:8.03(q,J=8.7Hz,1H,ArH),7.93~7.85(m,4H,ArH),7.59(d,J=8.9Hz,2H,ArH),7.53~7.35(m,4H,ArH),7.24~7.20(m,1H,ArH),7.14(d,J=8.8Hz,2H,ArH),7.03(s,2H,NH2),5.80(dd,J1=5.5,J2=5.6Hz,1H,5-H),4.12(dd,J1=12.4,J2=12.4Hz,1H,4-Hb),3.29(dd,J1=4.4,J2=5.2Hz,1H,4-Ha).ESI-MS:464.1[M+H]+.Anal.Calcd forC25H19F2N3O2S:C,H,N.
实施例十四:4-(5-(1.3-苯并二噁烷)-5-(α-萘环)-4,5-二氢吡唑)苯磺酰胺(化合物30)的制备
制备方法同实施例一。白色晶体,产率68.2%。m.o.212~213C;1H NMR(DMSO-d6,300MHz)δ:8.31(s,1H,ArH),8.02(d,J=8.1Hz,1H,ArH),7.87(d,J=8.2Hz,1H,ArH),7.70~7.56(m,4H,ArH),7.45~7.39(m,2H,ArH),7.20(d,J=8.0Hz,1H,ArH),7.04(s,2H,NH2),7.02~6.94(m,4H,ArH),6.31(dd,J1=5.4,J2=5.5Hz,1H,5-H),6.09(s,2H,CH2),4.18(dd,J1=12.4,J2=12.2Hz,1H,4-Hb),3.13(dd,J1=3.8,J2=5.3Hz,1H,4-Ha).ESI-MS:472.1[M+H]+.Anal.Calcd for C26H21N3O4S:C,H,N.
实施例十五:4-(5-(1.3苯并二噁烷)-5-(β-萘环)-4,5-二氢吡唑)苯磺酰胺(化合物31)的制备
制备方法同实施例一。以β-萘基的查尔酮代替α-萘基的查尔酮得白色晶体,产率64.1%。m.p.236~238℃;1H NMR(DMSO-d6,300MHz)δ:8.35~7.7.83(m,4H,ArH),7.7.60~7.47(m,6H,ArH),7.37~7.35(m,2H,ArH),7.14~6.98(m,4H,ArH and NH2),6.10(s,2H,CH2),5.77(dd,J1=5.3,J2=5.5Hz,1H,5-H),4.00(dd,J1=12.2,J2=12.0Hz,1H,4-Hb),3.25(dd,J1=5.4,J2=5.3Hz,1H,4-Ha).ESI-MS:472.1[M+H]+.Anal.Calcd for C26H21N3O4S:C,H,N.
实施例十六:含萘环骨架的二氢吡唑磺胺衍生物体外抗肿瘤活性关于抗肿瘤细胞增殖的研究
采用MTT[3-(4,5)-双甲基-2-噻唑-(2,5)-苯基溴化四氮唑蓝]法来测定二氢吡唑磺胺衍生物对人乳腺癌细胞(MCF-7)、***细胞(HeLa)、肺癌细胞(A549)及肝癌细胞(HepG2)的半数抑制浓度(IC50)。
(1)培养液(每升)的配制:①悬浮细胞:DMEM培养粉一袋(10.4g),新生牛血清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,HEPES 2.38g。
(2)D-Hanks缓冲液(每升)的配制:NaCl8.00g,KCl 0.40g,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(MCF-7)、***细胞(HeLa)、肺癌细胞(A549)以及肝癌细胞(HepG2)的培养:为贴壁生长细胞,常规培养于DMEM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。
(7)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。
(8)存活细胞的测定:在培养了48h后的96孔板中,每孔加MTT 40μL(用D-Hanks缓冲液配成4mg/mL)。在37℃放置4h后,移去上清液。每孔加150μLDMSO,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)。
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所示。
表1 本发明所列含萘环骨架的二氢吡唑磺胺衍生物对肿瘤细胞的抑制IC50值(μmol/mL)
α3次平行试验,实验结果取平均值,误差在5%-10%之间
实施例十七:含萘环骨架的二氢吡唑磺胺衍生物体外抗肿瘤活性关于抑制基质金属蛋白酶-2(MMP-2)活性的研究
1.实验材料
试剂:MMP-2蛋白酶rhMMP2,10082-HNAH,北京义翘神州生物技术有限公司;Mca-PLGL-Dpa-AR-NH2(AnaSpec,Catalog#27076),上海吉尔生物化学有限公司。p-aminophenylmercuric acetate(APMA)(Genmed Scientifics Inc.U.S.A,Catalog#GMS12197v.A),Sigma公司生产。其它常用化学试剂为国产分析纯。
仪器:TECANA-5882酶标仪(瑞士),其它仪器同上。
2.实验方法
(1)用含有1mMAPMA的Assay Buffer将rhMMP2蛋白激活,使其最终浓度为100μg/mL。
(2)将rhMMP2蛋白在37℃孵育1h。
(3)用Assay Buffer将激活后的rhMMP2蛋白稀释至0.2μg/mL。
(4)用Assay Buffer将底物稀释至40μM。
(5)在96孔板中加入50μL稀释后的rhMMP2,并加入不同浓度的药液25μL,作用10分钟后在低温下加入25TL,40μM的底物Mca-PLGL-Dpa-AR-NH2。
(6)于Ex320nm,EM450nm处测荧光,动力学检测5min。
活性计算:抑制率=[(Ke-Kc)-(Ks-Kc)]/(Ke-Kc)×100%
Ke:酶活力对照 Kc:空白本底对照 Ks:实验值
测得的IC50见表2所示。
表2 本发明所列含萘环骨架的二氢吡唑磺胺衍生物对基质金属蛋白酶的抑制IC50值(μmol/mL)
α3次平行试验,实验结果取平均值,误差在5%-10%之间
实施例十八:含萘环骨架的二氢吡唑磺胺衍生物体外抗肿瘤活性关于细胞毒性的研究
本发明测试了新合成化合物15-27对人肾上皮细胞(293T)的细胞毒性,细胞毒性结果如表3,以Celecoxib作为阳性对照。每个化合物的毒性用抑制T细胞存活率到50%时的浓度(CC50)来表示。
实验方法:
(1)培养人肾上皮细胞(293T)直至达到其对数生长期末细胞趋于融合,用细胞消化液消化分散细胞,用细胞培养液配制成1×104个/mL的细胞悬液。取96孔培养板,每孔中加入100μL的细胞悬液。轻轻水平转动培养板使细胞均匀地分散在皿孔的表面。
(2)置于含5%CO2细胞培养箱中,在37±2C温度下培养24h。
弃去原培养液,每孔加入100μL的空白对照液,阴性对照液,阳性对照液,100%和50%浓度的试验样品浸提液。每组至少设8孔。注:浸提原液或以培养基作稀释剂的系列浸提稀释液。采用0.9%氯化钠注射液浸提时,在稀释浸提时使用浓缩的2倍培养基。
(3)置于含5%CO2培养箱中,在37±2℃温度下进行培养。培养48h。
(4)每个培养间期后,每孔加入MTT溶液20μL,置于含5%CO2培养箱中,在37±2℃温度下培养5h。
(5)弃去孔内液体,每孔分别加入200μL DMSO,将培养板放置10min,水平摇晃使孔内溶液颜色均匀。
(6)用酶标仪测定吸光度,波长采用570nn。
测得的CC50见表3所示。
表3 本发明所列含萘环骨架的二氢吡唑磺胺衍生物对293T细胞的抑制CC50值(μmol/mL)
α3次平行试验,实验结果取平均值,误差在5%-10%之间。
Claims (2)
1.一类含萘环骨架的二氢吡唑磺胺衍生物的合成,其特征是它有如下通式:
一种上述的二氢吡唑磺胺衍生物的合成,它由下列步骤组成:
步骤1.在室温搅拌下,依次向100mL的圆底烧瓶中加入不同取代基的苯乙酮(10.0mmol)、40%KOH水溶液、不同取代基的萘甲醛(10.0mmol)、乙醇(50mL),继续搅拌反应4h后,将反应液倒入500mL烧杯中,1mol/L盐酸酸化(pH=7.0),过滤,固体依次用蒸馏水(3×100mL)、冷乙醇(3×50mL)、蒸馏水(3×100mL)洗涤,干燥得中间体2-16。
步骤2.依次将不同的查尔酮2-16(4mmol)、无水乙醇(25mL)、对肼基苯磺酰胺(4.5mmol)、乙酸(1.0mL)加入到50mL的圆底烧瓶中,室温搅拌反应1h后,仍有部分固体不溶;将反应烧瓶转移到油浴锅中,回流反应6h,TLC跟踪反应(展开剂VAcOEt∶VPE=1∶2),反应结束后,过滤,固体依次用1mol/L盐酸(3×100mL)、蒸馏水(3×150mL)、冷乙醇(3×50mL)、蒸馏水(3×100mL)洗涤,干燥,将得到的固体粗产物溶于无水乙醇重结晶得到晶体状目标化合物17-31。
2.根据权利要求所述的一类含萘环骨架的二氢吡唑磺胺衍生物的合成及在抗癌药物中的应用。
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