CN101985449B - 一种香豆素衍生物及其制备方法和作为抗癌药物的用途 - Google Patents
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Abstract
Description
技术领域
本发明属于药物与化工领域,涉及一种香豆素衍生物及其制备方法,以及其在制备用于抗癌药物中的用途。
背景技术
癌症是威胁人类健康和生命安全的主要疾病,据统计,全世界每年新增癌症患者达400万人左右。抗癌药物的研究与开发一直是化学家和药物学家关注的热点。寻找高效、高选择性、毒副作用小的抗癌药物是药物研究开发的重要方向之一。以DNA为靶点设计合成抗癌药物,特别是针对具有重要生理意义的端粒DNA及c-myc等原癌基因DNA的特殊高级结构设计合成小分子抑制剂,是发展新型抗癌药物的重要方法。
香豆素是一类母核为苯并吡喃酮的天然产物,广泛存在于植物界,特别是在伞形科、芸香科、菊科、豆科、茄科等植物。香豆素类化合物具有抗肿瘤、抗艾滋病、抗氧化、抗炎、抗微生物、抗凝血等多方面的生物活性。但是天然香豆素类化合物的抗肿瘤活性不够高,目前未能在临床上作为抗癌药物使用。
发明内容
本发明的目的在于针对现有技术的不足,提供一种毒性小、抗癌效果好的香豆素衍生物。
本发明的另一个目的在于提供该香豆素衍生物的制备方法。
本发明还有一个目的在于提供该香豆素衍生物的应用。
本发明通过以下技术方案实现上述目的:
本发明提供了一种香豆素衍生物,其结构式为:
式中R1为H、OBn、O(CH2)nNR3;
R2为H、OBn、O(CH2)nNR3;且R1或R2中至少有一个为O(CH2)nNR3·。
其中n=1、2、3、4或5;NR3表示C1-6的烷基胺、C3-6的环烷基胺、哌啶基、吗啉基、哌嗪基或吡噁啉基。
本发明同时提供了该香豆素衍生物的制备方法,表示如下:
(1)当R1=H或OBn,R2=O(CH2)nNR3时,合成过程为:
其步骤为:水杨醛或4-苄氧基水杨醛、单羟基取代苯甲醛、氰基乙酸乙酯和醋酸铵反应,得到化合物a1,a1与Br(CH2)nBr发生取代反应,得到化合物a2,a2再与取代胺化合物(NHR3)作用,通过柱层析得到目标产物,结构式为其中n=1、2、3、4或5;NR3表示C1-6的烷基胺、C3-6的环烷基胺、哌啶基、吗啉基、哌嗪基或吡噁啉基。
(2)当R1=O(CH2)nNR3,R2=H时,合成过程为:
其步骤为:4-苄氧基水杨醛、苯甲醛、氰基乙酸乙酯和醋酸铵反应,得到化合物b1,b1在三氟乙酸中回流得到b2,再与Br(CH2)nBr发生取代反应,得到化合物b3,b3再与取代胺化合物(NR3)作用,通过柱层析得到目标产物,结构式为其中n=1、2、3、4或5;NR3表示C1-6的烷基胺、C3-6的环烷基胺、哌啶基、吗啉基、哌嗪基或吡噁啉基。
(3)当R1=O(CH2)nNR3,R2=O(CH2)nNR3时,合成过程为:
其步骤为:4-苄氧基水杨醛、单羟基取代苯甲醛、氰基乙酸乙酯和醋酸铵反应,得到化合物c1,c1在三氟乙酸中回流得到c2,再与Br(CH2)nBr发生取代反应,得到化合物c3,c3再与取代胺化合物(NHR3)作用,通过柱层析得到目标产物,结构式为其中n=1、2、3、4或5;NR3表示C1-6的烷基胺、C3-6的环烷基胺、哌啶基、吗啉基、哌嗪基或吡噁啉基。
本发明同时公开和保护了该香豆素衍生物在制备抗癌药物上的用途;以及含有该香豆素衍生物的抗癌药物。
与现有技术相比,本发明具有以下有益效果:
(1)实验证明,本发明所公开的新型香豆素衍生物与富含鸟嘌呤的端粒DNA以及c-myc等原癌基因DNA具有很强的相互作用,显示对癌细胞中的端粒/端粒酶具有很好的抑制活性,对原癌基因c-myc的表达有很强的抑制作用,表现出显著的抗癌作用,可用于制备具有选择性抗癌药物。
(2)进一步实验证明,本发明涉及的新型香豆素衍生物对多种癌细胞株具有显著的抑制作用,而对正常细胞毒性小,在制备抗癌药物上有着广阔的应用空间。
具体实施方式
以下通过具体的实施例进一步说明本发明的技术方案。
实施例一:化合物a1-1的合成
将100mmol水杨醛、100mmol 3-羟基苯甲醛、100mmol氰基乙酸乙酯和200mmol醋酸铵溶于50mL乙醇,回流1.5小时,反应过程有黄色固体析出。待反应液降到室温后抽滤,用乙醇洗至滤液无色,真空干燥得到黄色固体化合物a1。
产率:22%;m.p.284-285℃;1H NMR(400MHz,DMSO)8.60-8.49(m,2H),8.21(s,1H),8.03-7.93(m,2H),7.79-7.70(m,1H),7.48(td,J=8.6,0.7Hz,2H),7.36(t,J=7.9Hz,1H),7.00(ddd,J=8.1,2.4,1.0Hz,1H).13C NMR(101MHz,DMSO)166.06,163.13,160.79,158.97,157.49,153.35,138.13,133.74,129.41,124.94,124.72,119.54,118.78,118.12,116.84,115.36,95.38.MS(ESI+)m/z 306[M+H]+
化合物a1-1
实施例二:化合物b1的合成
方法同实施例一,所不同的是用4-苄氧基水杨醛代替水杨醛,苯甲醛代替3-羟基苯甲醛,得黄色固体b1。
产率:13%;m.p.205-206℃;1H NMR(400MHz,DMSO)8.54-8.45(m,3H),8.39(d,J=8.7Hz,1H),8.11(d,J=2.6Hz,1H),7.57-7.46(m,5H),7.43-7.34(m,3H),7.06(dd,J=8.8,2.4Hz,1H),7.03(d,J=2.3Hz,1H),5.20(s,2H).13C NMR(101MHz,DMSO)165.86,163.11,162.73,160.97,158.94,154.91,136.81,136.12,131.57,128.55,128.47,128.37,128.08,127.90,126.31,113.29,111.20,101.56,93.87,69.95.MS(ESI+)m/z 396[M+H]+
化合物b1
实施例三:化合物c1-1的合成
方法同实施例一,所不同的是用4-苄氧基水杨醛代替水杨醛,,得黄色固体c1-1。
产率:17%;m.p.280-281℃;1H NMR(400MHz,DMSO)8.45(s,1H),8.38(d,J=8.8Hz,1H),8.12(s,1H),8.04-7.92(m,2H),7.50(d,J=7.1Hz,2H),7.43(t,J=7.2Hz,2H),7.36(dd,J=15.8,7.7Hz,2H),7.09(dd,J=8.8,2.2Hz,1H),7.04(d,J=2.1Hz,1H),7.00(dd,J=7.9,1.4Hz,1H),5.21(s,2H).13C NMR(101MHz,DMSO)165.99,163.07,162.70,160.98,158.83,157.43,154.88,138.25,136.09,129.30,128.45,128.07,127.93,126.12,119.54,118.65,115.36,113.27,111.21,101.52,93.82,69.95.MS(ESI+)m/z 412[M+H]+
化合物c1-1
实施例四:化合物b2的合成
将10mmol化合物b1溶于20mL三氟乙酸,回流3小时。减压除去溶剂,加入100mL水,用饱和碳酸钾溶液调pH值至7,再用乙酸乙酯萃取(3×50mL)。合并有机层,减压出去溶剂,得到橘红色固体b2。
产率:99%;m.p.299-301℃;1H NMR(400MHz,DMSO)8.52(dd,J=8.0,1.5Hz,2H),8.46(s,1H),8.40(d,J=8.7Hz,1H),8.16(s,1H),7.62-7.52(m,3H),7.33(d,J=4.5Hz,1H),6.93(dd,J=8.7,2.3Hz,1H),6.77(d,J=2.2Hz,1H).13C NMR(101MHz,DMSO)165.81,163.15,162.72,161.17,159.18,155.06,136.88,131.49,128.52,128.33,127.95,126.63,126.35,113.48,109.84,102.30,93.47.MS(ESI+)m/z 306[M+H]+
化合物b2
实施例五:化合物c2-1的合成
方法同实施例四,所不同的是用c1-1代替b1,,得橘红色固体c2-1。
产率:99%;m.p.311-312℃;1H NMR(400MHz,DMSO-d6)8.42(br d,J=2.6Hz,1H),8.39(d,J=8.7Hz,1H),8.14(br d,J=2.6Hz,1H),8.03-7.89(m,2H),7.35(t,J=7.8Hz,1H),6.98(ddd,J=8.1,2.4,0.9Hz,1H),6.94(dd,J=8.7,2.3Hz,1H),6.78(d,J=2.2Hz,1H).13C NMR(101MHz,DMSO)165.98,163.14,162.70,161.20,159.14,157.43,155.09,138.32,129.33,126.53,119.49,118.63,115.33,113.52,109.89,102.36,93.47.MS(ESI+)m/z 322[M+H]+
化合物c2-1
实施例六:化合物a2-1的合成
将3mmol化合物a1与30mmol 1,2-二溴乙烷溶于100mL丙酮,加入15mmol无水碳酸钾后回流18小时。抽滤除去碳酸钾,减压除去溶剂,真空干燥得到浅黄色固体a2-1。
产率:81%;m.p.214-215℃;1H NMR(400MHz,DMSO)8.60(d,J=2.7Hz,1H),8.57(dd,J=7.9,1.5Hz,1H),8.21(d,J=2.8Hz,1H),8.17-8.14(m,1H),8.07(dd,J=2.6,1.5Hz,1H),7.75(ddd,J=8.3,7.3,1.7Hz,1H),7.51-7.43(m,3H),7.20(ddd,J=8.2,2.7,0.9Hz,1H),4.44(t,J=5.2Hz,2H),3.88(t,J=5.4Hz,2H).13C NMR(101MHz,DMSO)165.53,163.11,160.74,159.05,158.08,153.33,138.27,133.78,129.68,125.13,124.76,121.49,118.03,117.79,116.79,114.64,95.51,67.87,31.45.MS(ESI+)m/z 412and 414[M+H]+
化合物a2-1
实施例七:化合物a2-2的合成
方法同实施例六,所不同的是用1,3-二溴丙烷代替1,2-二溴乙烷,,得橘红色固体a2-2。
产率:73%;m.p.188-190℃;1H NMR(400MHz,DMSO)8.56(d,J=2.6Hz,1H),8.53(dd,J=7.9,1.5Hz,1H),8.19(d,J=2.6Hz,1H),8.14-8.09(m,1H),8.03(dd,J=2.5,1.5Hz,1H),7.73(ddd,J=8.8,7.4,1.7Hz,1H),7.50-7.41(m,3H),7.17(ddd,J=8.2,2.7,0.9Hz,1H),4.18(t,J=6.0Hz,2H),3.74(t,J=6.5Hz,2H),2.38-2.28(m,2H).13C NMR(101MHz,DMSO)165.57,163.08,160.72,158.97,158.45,153.29,138.17,133.71,129.53,125.08,124.68,121.20,118.01,117.75,116.74,114.24,95.43,65.35,31.86,31.26.MS(ESI+)m/z 426 and 428[M+H]+
化合物a2-2
实施例八:化合物b3-1的合成
方法同实施例六,所不同的是用化合物b2代替化合物a1,得橙色固体b3-1。
产率:68%;m.p.206-208℃;1H NMR(400MHz,DMSO)8.54-8.46(m,3H),8.38(d,J=8.8Hz,1H),8.12(d,J=2.8Hz,1H),7.60-7.51(m,3H),7.01(dd,J=8.8,2.4Hz,1H),6.96(d,J=2.4Hz,1H),4.43(t,2H),3.85(t,J=5.4Hz,2H).13C NMR(101MHz,DMSO)165.83,163.07,162.21,160.91,158.85,154.86,136.77,131.56,128.53,128.36,126.32,113.01,111.37,101.31,93.88,68.32,30.87.MS(ESI+)m/z 412and 414[M+H]+
化合物b3-1
实施例九:化合物b3-2的合成
方法同实施例六,所不同的是用化合物b2代替化合物a1用1,3-二溴丙烷代替1,2-二溴乙烷,,得橙色固体b3-2。
产率:75%;m.p.207-208℃;1H NMR(400MHz,DMSO)8.51-8.47(m,2H),8.46(d,J=3.3Hz,1H),8.31(d,J=8.8Hz,1H),8.10(d,J=2.9Hz,1H),7.60-7.52(m,3H),6.94(dd,J=8.8,2.4Hz,1H),6.87(d,J=2.4Hz,1H),4.14(t,J=6.0Hz,2H),3.68(t,J=6.6Hz,2H),2.31-2.24(m,2H).13C NMR(101MHz,DMSO)165.77,163.04,162.64,160.89,158.81,154.81,136.79,131.48,128.52,128.29,126.17,112.81,111.06,101.04,93.75,66.08,31.60,30.86.MS(ESI+)m/z426and 428[M+H]+
化合物b3-2
实施例十:化合物c3-1的合成
方法同实施例六,所不同的是用化合物c2-1代替化合物a1,且1,2-二溴乙烷用量改为60mmol,得沙棕色固体c3-1。
产率:34%;m.p.121-122℃;1H NMR(400MHz,DMSO)8.52(d,J=2.7Hz,1H),8.42(d,J=8.8Hz,1H),8.17-8.09(m,2H),8.04(dd,J=2.5,1.5Hz,1H),7.47(t,J=8.0Hz,1H),7.19(ddd,J=8.2,2.6,0.7Hz,1H),7.06(dd,J=8.8,2.4Hz,1H),7.02(d,J=2.4Hz,1H),4.51-4.39(m,4H),3.92-3.81(m,4H).13CNMR(101MHz,DMSO)165.48,163.06,162.29,160.93,158.91,158.04,154.94,138.36,129.62,126.45,121.47,117.69,114.64,113.14,111.40,101.39,94.04,68.39,67.85,31.45,30.93.MS(ESI+)m/z 534,536and 538[M+H]+
化合物c3-1
实施例十一:化合物c3-2的合成
方法同实施例六,所不同的是用化合物c2-1代替化合物a1用1,3-二溴丙烷代替1,2-二溴乙烷,且用量改为60mmol,得橙色固体c3-2。
产率:33%;m.p.110-111℃;1H NMR(400MHz,DMSO)8.41(s,1H),8.27(d,J=8.8Hz,1H),8.08-8.01(m,2H),7.96(dd,J=2.4,1.5Hz,1H),7.40(t,J=7.9Hz,1H),7.11(dd,J=8.1,2.0Hz,1H),6.91(dd,J=8.8,2.4Hz,1H),6.85(d,J=2.3Hz,1H),4.14(t,J=5.9Hz,2H),4.11(t,J=5.9Hz,2H),3.70(t,J=6.5Hz,2H),3.65(t,J=6.6Hz,2H),2.34-2.27(m,2H),2.27-2.20(m,2H).13C NMR(101MHz,DMSO)165.45,162.98,162.64,160.88,158.77,158.37,154.82,138.26,129.39,126.22,121.16,117.56,114.21,112.83,111.05,101.04,93.81,66.11,65.32,31.88,31.60,31.24,30.86.MS(ESI+)m/z 562,564and 566[M+H]+
化合物c3-2
实施例十二:化合物1的合成
将1mmol化合物a2-1与5mmol碳酸钾混悬于干燥的50mL乙腈中,再加入5mmol N-甲基哌嗪,回流6小时。抽滤除去碳酸钾,滤液减压除去溶剂,得粗产品。粗产品通过硅胶柱层析纯化,洗脱剂为氯仿/甲醇/氨水=50/1/0.1,纯化之后可得白色固体。
产率:29%;熔点:204-206℃;1H NMR(400MHz,CDCl3)8.65(dd,J=7.9,1.5Hz,1H),8.34(d,J=3.7Hz,1H),8.20-8.15(m,1H),8.12(dd,J=2.5,1.5Hz,1H),7.65(ddd,J=8.3,7.3,1.7Hz,1H),7.46-7.33(m,3H),7.10(ddd,J=8.2,2.7,0.9Hz,1H),6.14(d,J=3.8Hz,1H),4.25(t,J=5.8Hz,2H),2.90(t,J=5.8Hz,2H),2.82-2.40(m,8H),2.32(s,3H).13C NMR(101MHz,CDCl3)167.25,163.52,161.85,159.88,158.97,153.81,138.42,133.62,129.43,125.75,124.79,121.81,118.57,117.03,114.64,95.97,66.02,57.23,55.06,53.59,46.02.HRMS(ESI+)m/z:Calc.for C24H25N5O3:432.2036[M+H]+.Found 432.2030[M+H]+.
化合物1
实施例十三:化合物2的合成
方法同实施例十二,所不同的是用化合物a2-2代替化合物a2-1,得白色固体。
产率:27%;熔点:192-195℃;1H NMR(400MHz,CDCl3)8.66(dd,J=7.9,1.6Hz,1H),8.34(d,J=3.5Hz,1H),8.20-8.14(m,1H),8.10(dd,J=2.5,1.5Hz,1H),7.65(ddd,J=8.4,7.3,1.7Hz,1H),7.46-7.34(m,3H),7.08(ddd,J=8.2,2.6,0.9Hz,1H),6.14(d,J=3.7Hz,1H),4.15(t,J=6.3Hz,2H),2.76-2.45(m,10H),2.33(s,3H),2.12-1.99(m,2H).13C NMR(101MHz,CDCl3)167.32,163.53,161.84,159.88,159.20,153.83,138.42,133.60,129.42,125.74,124.77,121.65,118.55,118.39,117.03,114.69,95.96,66.35,55.12,54.98,52.98,45.86,26.75.HRMS(ESI+)m/z:Calc.for C25H27N5O3:446.2192[M+H]+.Found446.2191[M+H]+.
化合物2
实施例十四:化合物3的合成
方法同实施例十二,所不同的是用化合物b3-1代替化合物a2-1,得白色固体。
产率:10%;熔点:190-192℃;1H NMR(400MHz,CDCl3)8.59-8.52(m,3H),8.28(s,1H),7.55-7.49(m,3H),6.98(dd,J=8.9,2.4Hz,1H),6.83(d,J=2.3Hz,1H),6.02(s,1H),4.20(t,J=5.7Hz,2H),2.88(t,J=5.7Hz,2H),2.68(s,4H),2.55(s,4H),2.34(s,3H).13C NMR(101MHz,CDCl3)167.55,163.62,163.41,162.17,159.91,155.49,137.20,131.72,129.11,128.44,126.97,113.38,111.87,101.46,94.63,66.69,56.84,54.95,53.41,45.85.HRMS(ESI+)m/z:Calc.forC24H25N5O3:432.2036[M+H]+.Found 432.2020[M+H]+.
化合物3
实施例十五:化合物4的合成
方法同实施例十二,所不同的是用化合物b3-2代替化合物a2-1,得白色固体。
产率:34%;熔点:208-209℃;1H NMR(400MHz,CDCl3)8.56(dd,J=7.9,1.7Hz,2H),8.52(d,J=8.8Hz,1H),8.27(s,1H),7.56-7.46(m,3H),6.95(dd,J=8.8,2.4Hz,1H),6.81(d,J=2.3Hz,0H),6.05(s,0H),4.11(t,J=6.3Hz,1H),2.73-2.36(m,5H),2.31(s,2H),2.07-1.99(m,1H).13C NMR(101MHz,CDCl3)167.48,163.72,163.59,162.19,159.91,155.51,137.21,131.69,129.09,128.43,126.87,113.34,111.61,101.28,94.54,66.93,55.14,54.85,53.21,46.03,26.54.HRMS(ESI+)m/z:Calc.for C25H27N5O3:446.2192[M+H]+.Found 446.2178[M+H]+.
化合物4
实施例十六:化合物5的合成
方法同实施例十二,所不同的是用化合物c3-1代替化合物a2-1,二乙胺代替N-甲基哌嗪且用量改为10mmol,得浅黄色固体。
产率:18%;熔点:94-96℃;1H NMR(400MHz,CDCl3)8.37(d,J=8.8Hz,1H),8.17(s,1H),8.07(d,J=7.6Hz,1H),8.02(s,1H),7.33(t,J=7.9Hz,1H),7.03(dd,J=8.0,1.7Hz,1H),6.87(dd,J=8.8,2.1Hz,1H),6.69(d,J=1.9Hz,1H),6.39(s,1H),4.18(t,J=6.1Hz,2H),4.07(t,J=5.7Hz,2H),2.96(t,J=6.0Hz,2H),2.89(t,J=5.9Hz,2H),2.72(q,J=14.3,7.2Hz,4H),2.66(q,J=14.4,7.2Hz,4H),1.12(t,J=8.0Hz,6H),1.08(t,J=8.0Hz,6H).13C NMR(101MHz,CDCl3)166.90,163.42,163.31,162.00,159.58,158.80,155.26,138.54,129.29,126.73,121.70,118.37,114.27,113.14,111.53,101.19,94.43,67.12,66.17,51.64,51.49,47.81,47.70,11.67,11.48.HRMS(ESI+)m/z:Calc.for C27H39N5O4:520.2900[M+Na]+.Found 520.2918[M+Na]+.
化合物5
实施例十七:化合物6的合成
方法同实施例十二,所不同的是用化合物c3-1代替化合物a2-1,四氢吡咯代替N-甲基哌嗪且用量改为10mmol,得浅黄色固体。
产率:31%;熔点:124-125℃;1H NMR(400MHz,CDCl3)8.44(t,J=8.8Hz,1H),8.22(d,J=4.0Hz,1H),8.11(d,J=7.8Hz,1H),8.08(s,1H),7.37(t,J=7.9Hz,1H),7.08(dd,J=8.2,1.8Hz,1H),6.94(dd,J=8.9,2.4Hz,1H),6.76(d,J=2.3Hz,1H),6.32(d,J=4.0Hz,1H),4.24(t,J=5.9Hz,2H),4.17(t,J=5.8Hz,2H),2.99(t,J=5.9Hz,2H),2.94(t,J=5.8Hz,2H),2.70(t,J=6.8Hz,4H),2.67(t,J=6.9Hz,5H),1.91-1.84(m,4H),1.84-1.77(m,4H).13C NMR(101MHz,CDCl3)167.04,163.47,163.37,162.08,159.67,158.92,155.31,138.54,129.30,126.81,121.68,118.39,114.52,113.25,111.62,101.26,94.49,67.67,66.98,55.09,54.75,54.72,23.51.HRMS(ESI+)m/z:Calc.for C29H33N5O4:516.2611[M+H]+.Found 516.2610[M+H]+.
化合物6
实施例十八:化合物7的合成
方法同实施例十二,所不同的是用化合物c3-1代替化合物a2-1,哌啶代替N-甲基哌嗪且用量改为10mmol,得浅黄色固体。
产率:35%;熔点:127-129℃;1H NMR(400MHz,CDCl3)8.52(d,J=8.8Hz,1H),8.29(d,J=3.4Hz,1H),8.17(d,J=7.8Hz,1H),8.11(s,1H),7.41(t,J=7.9Hz,1H),7.09(dd,J=8.0,2.1Hz,1H),6.98(dd,J=8.9,2.3Hz,1H),6.82(d,J=2.3Hz,1H),6.05(d,J=4.3Hz,1H),4.33(t,J=5.7Hz,2H),4.23(t,J=5.8Hz,2H),2.96(t,J=5.3Hz,2H),2.86(t,J=5.8Hz,2H),2.69(s,4H),2.58(s,4H),1.81-1.68(m,J=12.3,7.0Hz,4H),1.69-1.59(m,J=11.0,5.5Hz,4H),1.56-1.41(m,4H).13C NMR(101MHz,CDCl3)165.90,162.40,162.25,161.00,158.54,157.83,154.23,137.51,128.26,125.70,120.65,117.31,113.45,112.16,110.52,100.18,93.41,65.45,64.78,56.92,56.63,54.09,54.03,24.80,24.77,23.10,23.09.HRMS(ESI+)m/z:Calc.for C31H37N5O4:544.2924[M+H]+.Found544.2926[M+H]+.
化合物7
实施例十九:化合物8的合成
方法同实施例十二,所不同的是用化合物c3-1代替化合物a2-1,且N-甲基哌嗪用量改为10mmol,得浅黄色固体。
产率:45%;熔点:141-142℃;1H NMR(400MHz,CDCl3)8.45(d,J=8.8Hz,1H),8.23(d,J=4.3Hz,1H),8.12(d,J=7.8Hz,1H),8.08-8.02(m,J=2.3,1.5Hz,1H),7.39(t,J=7.9Hz,1H),7.06(dd,J=7.8,2.2Hz,1H),6.91(dd,J=8.8,2.4Hz,1H),6.75(d,J=2.3Hz,1H),6.40(d,J=4.3Hz,1H),4.13(t,J=6.3Hz,2H),4.07(t,J=6.3Hz,2H),2.75-2.41(m,20H),2.31(s,3H),2.30(s,3H),2.08-1.98(m,4H).13C NMR(101MHz,CDCl3)167.00,163.46,163.25,162.04,159.64,158.87,155.30,138.56,129.34,126.80,121.74,118.36,114.55,113.25,111.65,101.24,94.51,66.49,65.92,57.21,56.86,55.00,54.96,53.57,53.56,45.99.HRMS(ESI+)m/z:Calc.for C31H39N7O4:574.3142[M+H]+.Found 574.3155[M+H]+.
化合物8
实施例二十:化合物9的合成
方法同实施例十二,所不同的是用化合物c3-1代替化合物a2-1,N-(2-羟乙基)哌嗪代替N-甲基哌嗪且用量改为10mmol,得浅黄色固体。
产率:19%;熔点:156-158℃;1H NMR(400MHz,CDCl3)8.49(d,J=8.8Hz,1H),8.26(d,J=4.0Hz,1H),8.15(d,J=7.7Hz,1H),8.09(s,1H),7.40(t,J=7.9Hz,1H),7.08(dd,J=8.1,2.3Hz,1H),6.96(dd,J=8.9,2.3Hz,1H),6.80(d,J=2.3Hz,1H),6.16(d,J=4.2Hz,1H),4.24(t,J=5.7Hz,2H),4.18(t,J=5.6Hz,2H),3.63(t,J=5.4Hz,4H),2.89(t,J=4.2Hz,2H),2.86(t,J=4.1Hz,2H),2.70-2.34(m,21H).13C NMR(101MHz,CDCl3)166.13,162.47,162.31,161.08,158.75,157.88,154.38,137.57,128.40,125.89,120.77,117.38,113.60,112.30,110.71,100.33,93.57,76.33,76.21,76.01,75.69,65.55,64.95,58.25,58.22,56.71,56.20,55.85,52.67,52.63,51.78,51.73.HRMS(ESI+)m/z:Calc.for C33H43N7O6:634.3353[M+H]+.Found 634.3378[M+H]+.
化合物9
实施例二十一:化合物10的合成
方法同实施例十二,所不同的是用化合物c3-2代替化合物a2-1,二乙胺代替N-甲基哌嗪且用量改为10mmol,得浅棕色固体。
产率:15%;熔点:91-92℃;1H NMR(400MHz,CDCl3)8.52(d,J=8.9Hz,1H),8.27(s,1H),8.15(d,J=7.8Hz,1H),8.10(s,1H),7.40(t,J=7.9Hz,1H),7.08(dd,J=8.1,1.8Hz,1H),6.96(dd,J=8.8,2.4Hz,1H),6.82(d,J=2.3Hz,1H),6.03(s,1H),4.21-4.04(m,4H),2.70(t,J=7.4Hz,2H),2.64(t,2H),2.63-2.51(m,8H),2.05-1.93(m,4H),1.08(t,J=4.7Hz,6H),1.05(t,J=4.7Hz,6H).13CNMR(101MHz,CDCl3)167.27,163.76,163.51,162.17,159.85,159.23,155.48,138.58,129.34,126.85,121.54,118.33,114.61,113.28,111.51,101.27,94.54,67.02,66.52,49.47,49.18,47.02,47.00,26.98,26.86,11.75,11.63.HRMS(ESI+)m/z:Calc.for C31H41N5O4:548.3237[M+H]+.Found 548.3248[M+H]+.
化合物10
实施例二十二:化合物11的合成
方法同实施例十二,所不同的是用化合物c3-2代替化合物a2-1,四氢吡咯代替N-甲基哌嗪且用量改为10mmol,得浅棕色固体。
产率:33%;熔点:136-138℃;1H NMR(400MHz,CDCl3)8.38(d,J=8.8Hz,1H),8.17(d,J=4.2Hz,1H),8.11(d,J=7.8Hz,1H),8.04(s,1H),7.38(t,J=7.9Hz,1H),7.06(dd,J=7.4,2.6Hz,1H),6.85(dd,J=8.8,2.4Hz,1H),6.67(d,J=2.3Hz,1H),6.60(d,J=4.1Hz,1H),4.15(t,J=6.3Hz,2H),4.07(t,J=6.2Hz,2H),2.72(t,2H),2.68(t,2H),2.65-2.51(m,8H),2.14-2.00(m,4H),1.88-1.72(m,8H).13C NMR(101MHz,CDCl3)166.97,163.50,163.46,162.04,159.56,159.12,155.27,138.60,129.28,126.70,121.55,118.28,114.41,113.03,111.39,101.12,94.36,77.36,77.25,77.04,76.73,66.73,66.41,54.25,54.17,53.20,52.72,28.81,28.46,23.47,23.46.HRMS(ESI+)m/z:Calc.for C31H37N5O4:544.2924[M+H]+.Found 544.2932[M+H]+.
化合物11
实施例二十三:化合物12的合成
方法同实施例十二,所不同的是用化合物c3-2代替化合物a2-1,哌嗪代替N-甲基哌嗪且用量改为10mmol,得浅棕色固体。
产率:30%;熔点:118-120℃;1H NMR(400MHz,CDCl3)8.40(d,J=8.8Hz,1H),8.20(d,J=4.1Hz,1H),8.11(d,J=7.8Hz,1H),8.04(s,1H),7.37(t,J=7.9Hz,1H),7.06(dd,J=8.1,2.5Hz,1H),6.87(dd,J=8.8,2.4Hz,1H),6.70(d,J=2.3Hz,1H),6.45(d,J=4.0Hz,1H),4.12(t,J=6.3Hz,2H),4.04(t,J=6.3Hz,2H),2.56(t,2H),2.51(t,2H),2.50-2.32(m,J=16.4Hz,8H),2.10-1.97(m,4H),1.69-1.57(m,J=10.5,5.2Hz,8H),1.52-1.39(m,J=4.6Hz,4H).13CNMR(101MHz,CDCl3)166.96,163.53,163.42,162.04,159.58,159.10,155.29,138.54,129.28,126.69,121.54,118.23,114.47,113.09,111.39,101.10,94.38,66.91,66.50,56.02,55.59,54.60,26.71,26.43,25.84,25.77,24.36,24.32.HRMS(ESI+)m/z:Calc.for C33H41N5O4:572.3237[M+H]+.Found 572.3249[M+H]+.
化合物12
实施例二十四:化合物13的合成
方法同实施例十二,所不同的是用化合物c3-2代替化合物a2-1,且N-甲基哌嗪用量改为10mmol,得浅棕色固体。
产率:31%;熔点:115-117℃;1H NMR(400MHz,CDCl3)8.45(d,J=8.8Hz,1H),8.23(d,J=4.3Hz,1H),8.12(d,J=7.8Hz,1H),8.08-8.02(m,J=2.3,1.5Hz,1H),7.39(t,J=7.9Hz,1H),7.06(dd,J=7.8,2.2Hz,1H),6.91(dd,J=8.8,2.4Hz,1H),6.75(d,J=2.3Hz,1H),6.40(d,J=4.3Hz,1H),4.13(t,J=6.3Hz,2H),4.07(t,J=6.3Hz,2H),2.75-2.41(m,20H),2.31(s,3H),2.30(s,3H),2.08-1.98(m,4H).13C NMR(101MHz,CDCl3)167.08,163.56,163.47,162.09,159.69,159.11,155.36,138.56,129.33,126.78,121.56,118.21,114.56,113.20,111.47,101.14,94.45,66.79,66.33,55.16,54.99,54.78,53.08,45.93,26.76,26.43.HRMS(ESI+)m/z:Calc.for C33H43N7O4:602.3455[M+H]+.Found 602.3472[M+H]+.
化合物13
实施例二十五:化合物14的合成
方法同实施例十二,所不同的是用化合物c3-1代替化合物a2-1,N-(2-羟乙基)哌嗪代替N-甲基哌嗪且用量改为10mmol,得浅棕色固体。
产率:26%;熔点:116-118℃;1H NMR(400MHz,CDCl3)8.34(d,J=8.8Hz,1H),8.16(d,J=3.8Hz,1H),8.05(d,J=7.8Hz,1H),7.98(s,1H),7.33(t,J=7.9Hz,1H),7.01(dd,J=8.1,2.0Hz,1H),6.82(dd,J=8.8,2.3Hz,1H),6.65(d,J=2.3Hz,1H),6.57(d,J=3.5Hz,1H),4.07(t,J=6.1Hz,2H),3.99(t,J=6.2Hz,2H),3.66-3.56(m,J=5.5,2.5Hz,4H),3.15(s,2H),2.65-2.36(m,24H),2.03-1.92(m,4H).13C NMR(101MHz,CDCl3)166.92,163.46,163.40,161.98,159.54,159.05,155.27,138.53,129.29,126.69,121.54,118.09,114.55,113.09,111.39,101.05,94.36,66.68,66.25,59.47,57.83,55.18,54.76,53.19,53.16,52.86,26.74,26.37.HRMS(ESI+)m/z:Calc.for C35H47N7O6:662.3666[M+H]+.Found662.3670[M+H]+.
化合物14
实施例二十六:本专利所述香豆素衍生物对端粒酶的抑制作用
选择部分具有代表性的化合物,采用TRAP法进行无细胞体系端粒酶活性测定。从人乳腺癌细胞株MCF-7中提取总蛋白(内含端粒酶),将一定量的总蛋白提取液与待测药物混合加入TRAP反应混合液中,PCR反应后利用荧光凝胶成像仪或荧光酶标仪进行检测,结果如表1所示。结果表明,本专利所述的化合物在浓度为10μmol/L时,在体外对端粒酶有明显抑制作用。因此本发明的新型香豆素衍生物可用于制备以端粒酶为靶点的抗癌药物。
表1化合物在10μmol/L时对端粒酶活性的抑制作用
注:抑制率大于30%为有效
实施例二十七:本专利所述香豆素衍生物对肿瘤细胞生长的抑制作用
选择部分具有代表性的化合物,以三种肿瘤细胞株A549(人肺腺癌细胞株)、HepG2(人肝癌细胞株)、K562(人白血病细胞株),采用MTT法进行体外细胞毒测定。对数生长期细胞加入不同浓度的新型香豆素衍生物,作用48小时后,测定其吸光度。分别计算抑制细胞生长达50%时的化合物浓度,以IC50值表示,结果如表2所示。结果表明本专利所述化合物在体外对这三种肿瘤细胞株均具有较强的抑制作用。因此本发明所述的香豆素衍生物可用于制备抗癌的药物。
表2式I化合物对肿瘤细胞株生长的抑制作用(IC50/μM)
实施例二十八:本专利所述香豆素衍生物急性毒性试验
选择部分具有代表性的化合物(如化合物5),进行急性毒性试验。取18-22克小鼠随机分六组,每组10只小鼠,分别用生理盐水、DMSO 2.5ml/kg、化合物5500mg/kg、化合物5200mg/kg、化合物5100mg/kg、化合物550mg/kg处理,观察14天,结果可见500mg/kg组小鼠45%死亡,即化合物5对小鼠的急性毒性LD50值大约为500mg/kg。因此本发明所述的香豆素衍生物的急性毒性较小,可用于制备口服抗癌药物。
Claims (4)
2.一种如权利要求1所述的香豆素衍生物的制备方法,其特征在于:
(1)当R1=H,R2=O(CH2)nNR3时,制备方法包括以下步骤:将水杨醛、氰基乙酸乙酯、单羟基取代苯甲醛、醋酸铵进行反应,得到化合物 然后与Br(CH2)nBr反应得到化合物 再与NHR3反应获得香豆素衍生物,结构式为 其中n=1、2、3、4或5;NR3表示C1-6的烷基胺、C3-6的环烷基胺或哌嗪基;
(2)当R1=O(CH2)nNR3,R2=H时,制备方法包括以下步骤:将4-苄氧基水杨醛、氰基乙酸乙酯、苯甲醛、醋酸铵进行反应,得到化合物 然后在三氟乙酸中回流,得到化合物 再与Br(CH2)nBr反应得到化合物 再与NHR3反应获得香豆素衍生物,结构式为 其中n=1、2、3、4或5;NR3表示C1-6的烷基胺、C3-6的环烷基胺或哌嗪基;
3.如权利要求2所述的制备方法,其特征在于所述反应获得的香豆素衍生物经过柱层析纯化得到纯品。
4.如权利要求1所述的香豆素衍生物在制备抗癌药物中的用途。
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