CN109761898B - 一种双靶点抑制剂及其制备方法和用途 - Google Patents
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Abstract
本发明公开了一种双靶点抑制剂及其制备方法和用途,该双靶点抑制剂具有如下式(I)所示的结构,其中,R1为H、吸电子基或供电子基;R为烷基;n=1~5。本发明的双靶点抑制剂能够选择性抑制HDAC6,对HDAC1和8的IC50值大于20μM,其作为前药,在细胞内经过水解反应,可以释放出微管蛋白与HDAC双靶点抑制剂,提高了组蛋白去乙酰化酶对实体瘤的抑制活性,对肿瘤细胞具有较好的抑制作用。
Description
技术领域
本发明涉及一种组蛋白去乙酰化酶抑制剂,具体涉及一种双靶点抑制剂及其制备方法和用途。
背景技术
组蛋白去乙酰化酶(histone deacetylases,HDACs)是维持染色体的基本组成单位核小体中组蛋白乙酰化状态平衡的关键酶类之一,其催化组蛋白的去乙酰化作用,与基因转录抑制密切相关,牵扯到促基因沉默的诸多过程,组蛋白及非组蛋白乙酰化状态失衡与肿瘤的发生、发展密切相关,因此组蛋白去乙酰化酶是抗肿瘤药物设计中的热门靶标。
组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitor,HDACi)是一类有干扰组蛋白去乙酰化酶功能的化合物。HDACis通过增加细胞内组蛋白的乙酰化程度,提高p21等基因的表达水平等途径,抑制肿瘤细胞的增殖,诱导肿瘤细胞分化和(或)凋亡,其对肿瘤细胞迁移、侵袭、转移的抑制作用和抗肿瘤血管生成作用也被证实,因此HDACi的开发已成为肿瘤靶向治疗的研究热点。
HDACi的药效团由三部分组成:(1)cap结构,用于识别HDAC活性口袋的入口处;(2)锌离子螯合基团(ZBG),用于螯合HDAC催化口袋底部的锌离子;(3)连接链,用于连接cap与ZBG,并与活性口袋中的疏水性通道相互作用。
根据上述HDACi结构特点,已报道的HDACi可大致分为4个大类:异羟肟酸类、苯甲酰胺类、环肽类和短链脂肪酸类。其中,异羟肟酸类包括:曲古抑菌素和SAHA及其衍生物,这一类HDAC抑制剂的研究倍受瞩目,它被证明可在小剂量、低浓度情况下导致肿瘤分化,并选择性地抑制肿瘤生长而对正常细胞无毒副作用,更适用于临床。
但是,现已上市的HDACis对实体瘤的治疗效果不理想以及伴随多种副作用等,这严重限制了HDACi在临床上的应用范围。为了解决这一难题,双靶点的HDAC抑制剂和设计与合成提供了一种可行的方案。由于肿瘤的发生和发展涉及多个信号传导通路。仅仅抑制一条通路难以完全抑制肿瘤的增殖。而研究表明,多靶点抗癌药物可提高单靶点抗癌药物的治疗效果,并降低耐药性,是抗癌药物研发的重要研究方向。
发明内容
本发明的目的是提供一种双靶点抑制剂及其制备方法和用途,该抑制剂解决了现有组蛋白去乙酰化酶抑制剂治疗效果不理想的问题,能够选择性抑制HDAC6,对肿瘤细胞具有较好的抑制作用。
为了达到上述目的,本发明提供了一种组蛋白去乙酰化酶与微管蛋白双靶点抑制剂,该双靶点抑制剂具有如下式(I)所示的结构:
其中,R1为H、吸电子基或供电子基;R为烷基;n=1~5。
本发明的双靶点抑制剂作为前药,其在细胞内经过水解反应,可以释放出微管蛋白与HDAC双靶点抑制剂,如下式所示:
在细胞内水解得到的化合物F,其喹啉环部分是微管蛋白聚合抑制剂,巯基烷基链(矩形框)部分具有组蛋白去乙酰化酶抑制活性,游离的巯基可与组蛋白去乙酰化酶中的锌离子(Zn2+)发生螯合作用。
优选地,所述供电子基选自甲基。
优选地,所述吸电子基选自卤素。
优选地,所述烷基选自甲基或异丙基。
优选地,该双靶点抑制剂选自以下所示结构中的任意一种:
本发明还提供了一种药物组合物,该药物组合物包含:所述的组蛋白去乙酰化酶与微管蛋白双靶点抑制剂及其药学上可接受的载体。通过将本发明的活性成分与药物可接受的载体混合而形成的组合物,以适合给药途径的各种剂型方便地给予,如片剂、胶囊等。
本发明还提供了一种所述的组蛋白去乙酰化酶与微管蛋白双靶点抑制剂的用途,该抑制剂作为制备治疗肿瘤的药物。
优选地,所述肿瘤包括:血液瘤和实体瘤;所述血液瘤包括:白血病和淋巴瘤;所述实体瘤包括:人乳腺癌、肺癌、胃癌、肝癌、结肠癌、前列腺癌等等。
本发明还提供了一种所述的组蛋白去乙酰化酶与微管蛋白双靶点抑制剂的制备方法,其合成路线为:
将化合物A和B在碱性条件下于干燥的有机溶剂中反应,得到化合物C,化合物C和化合物D在干燥的有机溶剂中于室温反应,得到具有如式(I)所示结构的化合物。
其中,化合物D为钠盐或钾盐,即Y=Na或K。
优选地,当R为异丙基时,化合物C和化合物D反应时在碱性条件下进行。
本发明的双靶点抑制剂及其制备方法和用途,解决了现有组蛋白去乙酰化酶抑制剂治疗效果不理想的问题,具有以下优点:
本发明的双靶点抑制剂能够选择性抑制HDAC6,对HDAC1和8的IC50值大于20μM,其作为前药,在细胞内经过水解反应,可以释放出微管蛋白与HDAC双靶点抑制剂,提高了组蛋白去乙酰化酶对实体瘤的抑制活性,对肿瘤细胞具有较好的抑制作用。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本发明的组蛋白去乙酰化酶与微管蛋白双靶点抑制剂,通过具有如以下合称路线中的化合物A(喹啉化合物)和化合物B(酰氯化合物)在条件a下亲核反应,得到化合物C,化合物C与化合物D(硫代酸盐)在条件b下反应得到化合物E(本发明的双靶点抑制剂)。
反应条件如下:
条件a:三乙胺或二异丙基乙胺,无水二氯甲烷,25℃;
条件b:三乙胺,无水乙醇,25℃,或无水乙醇,25℃,温度太高会产生大量杂质。
以下结合实施例1~20对本发明的组蛋白去乙酰化酶与微管蛋白双靶点抑制剂的制备进行详细阐述。
实施例1
将4-甲氧基-N1-甲基-N1-(2-甲基-喹啉基-4-)-1,3-苯二胺(0.293克,1毫摩尔,1倍量)溶于15毫升的无水二氯甲烷中,分别加入三乙胺(209微升,1.5毫摩尔,1.5倍量)和4-溴丁酰氯(0.278克,1.5毫摩尔,1.5倍量),混合物在25℃下搅拌反应4小时,将反应混合液直接使用硅胶柱层析分离纯化,洗脱液为二氯甲烷:甲醇=40:1,得到化合物0.221克C-1,产率50%。
将化合物C-1(0.221克,0.5毫摩尔,1倍量)与硫代乙酸钾(0.114克,1毫摩尔,2倍量)混合于10毫升无水乙醇中,于25℃搅拌反应24小时,直接经硅胶柱层析分离纯化,洗脱液为二氯甲烷:甲醇=40:1,得到98.5毫克化合物E-1,产率45%。
化合物E-1的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.05(brs,1H),8.29(m,1H),7.91(m,1H),7.71(m,1H),7.46(m,1H),7.35(s,1H),7.32(d,J=1.8Hz,1H),7.10(dd,J=8.8,1.8Hz,1H),7.02(d,J=8.8,1H),3.81(s,3H),3.53(t,J=8.8Hz,2H),3.38(s,3H),2.64(s,3H),2.37(t,J=8.8Hz,2H),2.30(s,3H),1.82(m,2H)。
13C-NMR(101MHz,DMSO-d6),δ193.8,178.6,159.0,149.2,148.9,141.9,138.1,129.1,128.6,127.8,124.6,123.8,119.6,115.2,110.2,106.6,106.1,56.8,43.6,35.2,32.0,30.6,22.6,20.1。
化合物E-1的质谱数据如下:
HRMS:calcd for C24H28N3O3S+[M+H]+:438.1846found:438.1850。
实施例2
实施例2与实施例1的制备方法基本相同,区别在于:以5-溴戊酰氯替换4-溴丁酰氯。
化合物E-2的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.02(brs,1H),8.29(m,1H),7.91(m,1H),7.71(m,1H),7.46(m,1H),7.35(s,1H),7.32(d,J=2.0Hz,1H),7.09(dd,J=8.8,2.0Hz,1H),7.02(d,J=8.8,1H),3.81(s,3H),3.53(t,J=8.8Hz,2H),3.38(s,3H),2.64(s,3H),2.37(t,J=8.8Hz,2H),2.30(s,3H),1.82(m,2H),1.72(m,2H)。
13C-NMR(101MHz,DMSO-d6),δ194.8,179.8,159.1,149.2,148.8,141.6,138.0,129.6,128.6,127.2,124.6,123.7,119.6,115.3,110.1,106.5,106.2,57.0,43.1,38.0,35.2,28.5,27.2,24.7,20.2。
化合物E-2的质谱数据如下:
HRMS:calcd for C25H30N3O3S+[M+H]+:452.2002found:452.2004。
实施例3
实施例3与实施例1的制备方法基本相同,区别在于:以6-溴已酰氯替换4-溴丁酰氯。
化合物E-3的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.02(brs,1H),8.29(m,1H),7.91(m,1H),7.71(m,1H),7.46(m,1H),7.35(s,1H),7.32(d,J=2.0Hz,1H),7.09(dd,J=8.8,2.0Hz,1H),7.02(d,J=8.8,1H),3.95(s,3H),3.50(t,J=8.6Hz,2H),3.32(s,3H),2.62(s,3H),2.35(t,J=8.6Hz,2H),2.30(s,3H),1.86(m,2H),1.69(m,2H),1.29(m,2H)。
13C-NMR(101MHz,DMSO-d6),δ194.8,179.8,159.1,149.2,148.8,141.6,138.0,129.6,128.6,127.2,124.6,123.7,119.6,115.3,110.1,106.5,106.2,57.0,43.1,38.3,30.5,29.5,29.2,25.3,24.7,20.0。
化合物E-3的质谱数据如下:
HRMS:calcd for C26H32N3O3S+[M+H]+:466.2159found:466.2160。
实施例4
实施例4与实施例1的制备方法基本相同,区别在于:以7-溴庚酰氯替换4-溴丁酰氯。
化合物E-4的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.02(brs,1H),8.29(m,1H),7.91(m,1H),7.71(m,1H),7.46(m,1H),7.35(s,1H),7.32(d,J=2.0Hz,1H),7.09(dd,J=8.8,2.0Hz,1H),7.02(d,J=8.8,1H),3.85(s,3H),3.32(s,3H),3.26(t,J=8.8Hz,2H),2.62(s,3H),2.38(t,J=8.8Hz,2H),2.31(s,3H),1.87(m,2H),1.65(m,2H),1.42(m,2H),1.33(m,2H)。
13C-NMR(101MHz,DMSO-d6),δ194.8,179.8,159.1,149.2,148.8,141.6,138.0,129.6,128.6,127.2,124.6,123.7,119.6,115.3,110.1,106.5,106.2,56.8,43.4,38.6,32.5,30.5,29.5,28.3,28.0,25.6,20.3。
化合物E-4的质谱数据如下:
HRMS:calcd for C27H34N3O3S+[M+H]+:480.2315found:480.2316。
实施例5
实施例5与实施例1的制备方法基本相同,区别在于:以8-溴辛酰氯替换4-溴丁酰氯。
化合物E-5的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.04(brs,1H),8.28(m,1H),7.92(m,1H),7.71(m,1H),7.46(m,1H),7.35(s,1H),7.32(d,J=1.8Hz,1H),7.09(dd,J=8.8,1.8Hz,1H),7.01(d,J=8.8,1H),3.86(s,3H),3.34(s,3H),3.25(t,J=8.6Hz,2H),2.63(s,3H),2.36(t,J=8.6Hz,2H),2.30(s,3H),1.88(m,2H),1.60(m,2H),1.42(m,2H),1.33(m,2H),1.26(m,2H)。
13C-NMR(101MHz,DMSO-d6),δ194.8,179.8,159.1,149.2,148.8,141.6,138.0,129.6,128.6,127.2,124.6,123.7,119.6,115.3,110.1,106.5,106.2,55.9,43.1,38.3,32.5,30.5,29.2,28.7,28.5,28.3,25.6,20.1。
化合物E-5的质谱数据如下:
HRMS:calcd for C28H36N3O3S+[M+H]+:494.2472found:494.2476.
实施例6
将4-甲氧基-N1-甲基-N1-(2-氯-喹啉基-4-)-1,3-苯二胺(0.314克,1毫摩尔,1倍量)溶于15毫升的无水二氯甲烷中,分别加入三乙胺(209微升,1.5毫摩尔,1.5倍量)和4-溴丁酰氯(0.278克,1.5毫摩尔,1.5倍量),混合物在25℃下搅拌反应4小时,将反应混合液直接使用硅胶柱层析分离纯化,洗脱液为二氯甲烷:甲醇=40:1,得到0.259克化合物C-6,产率56%。
将化合物C-6(0.232克,0.5毫摩尔,1倍量)与硫代乙酸钾(0.114克,1毫摩尔,2倍量)混合于10毫升无水乙醇中,于25℃搅拌反应24小时,直接经硅胶柱层析分离纯化,洗脱液为二氯甲烷:甲醇=40:1,得到119毫克化合物E-6,产率52%。
化合物E-6的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.06(s,1H),8.31(m,1H),7.95(m,1H),7.77(m,1H),7.45(m,1H),7.30(d,J=1.8Hz,1H),7.06(s,1H),7.04(dd,J=8.8,1.8Hz,1H),7.02(d,J=8.8,1H),3.85(s,3H),3.53(t,J=8.8Hz,2H),3.36(s,3H),2.46(s,3H),2.39(t,J=8.8Hz,2H),2.30(m,2H)。
13C-NMR(101MHz,DMSO-d6),δ194.8,179.8,151.4,151.2,150.6,141.9,138.0,130.7,127.6,125.9,124.3,124.0,119.7,115.3,110.1,106.2,105.2,55.9,43.1,35.5,32.2,30.5,22.7。
化合物E-6的质谱数据如下:
HRMS:calcd for C23H25ClN3O3S+[M+H]+:458.1300found:458.1306。
实施例7
实施例7与实施例6的制备方法基本相同,区别在于:以5-溴戊酰氯替换4-溴丁酰氯。
化合物E-7的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.05(s,1H),8.30(m,1H),7.96(m,1H),7.78(m,1H),7.43(m,1H),7.31(d,J=2.0Hz,1H),7.06(s,1H),7.04(dd,J=8.7,2.0Hz,1H),7.02(d,J=8.7,1H),3.86(s,3H),3.52(t,J=8.8Hz,2H),3.36(s,3H),2.43(s,3H),2.36(t,J=8.8Hz,2H),1.87(m,2H),1.63(m,2H)。
13C-NMR(101MHz,DMSO-d6),δ194.9,179.9,151.4,151.2,150.8,141.8,138.1,130.6,127.7,126.0,124.4,124.1,119.8,115.4,110.2,106.3,105.1,55.8,43.2,38.0,30.5,28.5,27.2,24.6。
化合物E-7的质谱数据如下:
HRMS:calcd for C24H27ClN3O3S+[M+H]+:472.1456found:472.1460.
实施例8
实施例8与实施例6的制备方法基本相同,区别在于:以6-溴己酰氯替换4-溴丁酰氯。
化合物E-8的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.08(s,1H),8.31(m,1H),7.97(m,1H),7.79(m,1H),7.42(m,1H),7.32(d,J=2.0Hz,1H),7.07(s,1H),7.05(dd,J=8.7,2.0Hz,1H),7.03(d,J=8.7,1H),3.86(s,3H),3.52(t,J=8.6Hz,2H),3.36(s,3H),2.44(s,3H),2.35(t,J=8.6Hz,2H),1.87(m,2H),1.63(m,2H),1.29(m,2H)。
13C-NMR(101MHz,DMSO-d6),δ194.9,179.9,151.4,151.2,150.8,141.8,138.1,130.6,127.7,126.0,124.4,124.1,119.8,115.4,110.2,106.3,105.1,56.0,43.1,38.3,30.6,29.2,29.0,25.3,24.4。
化合物E-8的质谱数据如下:
HRMS:calcd for C25H28ClN3O3S+[M+H]+:485.1540found:485.1544。
实施例9
实施例9与实施例6的制备方法基本相同,区别在于:以7-溴庚酰氯替换4-溴丁酰氯。
化合物E-9的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.02(s,1H),8.32(m,1H),7.96(m,1H),7.78(m,1H),7.41(m,1H),7.33(d,J=2.0Hz,1H),7.08(s,1H),7.06(dd,J=8.7,2.0Hz,1H),7.04(d,J=8.7,1H),3.87(s,3H),3.53(t,J=8.6Hz,2H),3.37(s,3H),2.46(s,3H),2.35(t,J=8.6Hz,2H),1.87(m,2H),1.63(m,2H),1.42(m,2H),1.33(m,2H)。
13C-NMR(101MHz,DMSO-d6),δ194.9,179.9,151.4,151.2,150.8,141.8,138.1,130.6,127.7,126.0,124.4,124.1,119.8,115.4,110.2,106.3,105.1,56.0,43.1,38.3,32.6,30.5,29.2,28.6,28.2,25.6。
化合物E-9的质谱数据如下:
HRMS:calcd for C26H31ClN3O3S+[M+H]+:500.1769found:500.1770。
实施例10
实施例10与实施例6的制备方法基本相同,区别在于:以8-溴辛酰氯替换4-溴丁酰氯。
化合物E-10的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.02(s,1H),8.32(m,1H),7.96(m,1H),7.78(m,1H),7.41(m,1H),7.33(d,J=2.0Hz,1H),7.08(s,1H),7.06(dd,J=8.7,2.0Hz,1H),7.04(d,J=8.7,1H),3.87(s,3H),3.53(t,J=8.7Hz,2H),3.37(s,3H),2.46(s,3H),2.35(t,J=8.7Hz,2H),1.87(m,2H),1.58(m,2H),1.42(m,2H),1.30(m,2H),1.26(m,2H)。
13C-NMR(101MHz,DMSO-d6),δ195.0,179.8,151.6,151.1,150.9,141.8,138.1,130.6,127.7,126.0,124.4,124.1,119.8,115.4,110.2,106.3,105.1,55.9,43.2,38.4,32.5,30.6,29.3,28.8,28.6,28.2,25.6。
化合物E-10的质谱数据如下:
HRMS:calcd for C27H33ClN3O3S+[M+H]+:514.1926found:514.1928。
实施例11
将4-甲氧基-N1-甲基-N1-(2-甲基-喹啉基-4-)-1,3-苯二胺(0.293克,1毫摩尔,1倍量)溶于15毫升的无水二氯甲烷中。分别加入三乙胺(209微升,1.5毫摩尔,1.5倍量)和4-溴丁酰氯(0.278克,1.5毫摩尔,1.5倍量),混合物在25℃下搅拌反应4小时,将反应混合液直接使用硅胶柱层析分离纯化,洗脱液为二氯甲烷:甲醇=40:1,得到0.221克化合物C-1,产率50%。
将化合物C-1(0.221克,0.5毫摩尔,1倍量)与硫代异丁酸钾(0.126克,1毫摩尔,2倍量)混合于10毫升无水乙醇中,于25℃搅拌反应24小时,直接经硅胶柱层析分离纯化,洗脱液为二氯甲烷:甲醇=40:1,得到114毫克化合物E-11,产率49%。
化合物E-11的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.00(brs,1H),8.26(m,1H),7.89(m,1H),7.70(m,1H),7.43(m,1H),7.36(s,1H),7.30(d,J=2.0Hz,1H),7.04(dd,J=8.7,2.0Hz,1H),7.02(d,J=8.7,1H),3.87(s,3H),3.54(t,J=8.7Hz,2H),3.36(s,3H),2.66(q,J=7.1Hz,1H),2.53(s,3H),2.39(t,J=8.8Hz,2H),2.34(m,2H),1.12(d,J=7.1Hz,6H)。
13C-NMR(101MHz,DMSO-d6),δ202.6,179.8,159.1,149.2,148.9,141.9,138.0,129.4,128.2,127.6,124.5,123.7,119.6,115.2,110.1,106.6,106.3,57.0,43.1,42.6,35.2,32.6,22.6,20.1,18.9。
化合物E-11的质谱数据如下:
HRMS:calcd for C26H32N3O3S+[M+H]+:466.2159found:466.2162。
实施例12
实施例12与实施例11的制备方法基本相同,区别在于:以5-溴戊酰氯替换4-溴丁酰氯。
化合物E-12的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.08(brs,1H),8.29(m,1H),7.92(m,1H),7.73(m,1H),7.45(m,1H),7.34(s,1H),7.32(d,J=1.8Hz,1H),7.05(dd,J=8.8,1.8Hz,1H),7.03(d,J=8.8,1H),3.85(s,3H),3.54(t,J=8.7Hz,2H),3.38(s,3H),2.65(q,J=7.1Hz,1H),2.52(s,3H),2.35(t,J=8.8Hz,2H),1.87(m,2H),1.63(m,2H),1.13(d,J=7.1Hz,6H)。
13C-NMR(101MHz,DMSO-d6),δ204.0,179.8,159.2,149.3,148.8,142.0,138.0,129.4,128.4,127.5,124.6,123.8,119.8,115.4,110.2,106.3,106.2,56.9,43.1,42.6,38.0,29.1,27.2,24.7,20.0,19.3。
化合物E-12的质谱数据如下:
HRMS:calcd for C27H34N3O3S+[M+H]+:480.2315found:480.2316。
实施例13
实施例13与实施例11的制备方法基本相同,区别在于:以6-溴己酰氯替换4-溴丁酰氯。
化合物E-13的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.02(brs,1H),8.29(m,1H),7.91(m,1H),7.71(m,1H),7.46(m,1H),7.35(s,1H),7.32(d,J=2.0Hz,1H),7.09(dd,J=8.8,2.0Hz,1H),7.02(d,J=8.8,1H),3.95(s,3H),3.54(t,J=8.6Hz,2H),3.38(s,3H),2.65(q,J=7.0Hz,1H),2.52(s,3H),2.36(t,J=8.7Hz,2H),1.87(m,2H),1.63(m,2H),1.29(m,2H),1.13(d,J=7.1Hz,6H)。
13C-NMR(101MHz,DMSO-d6),δ204.0,179.8,159.2,149.3,148.8,142.0,138.0,129.4,128.4,127.5,124.6,123.8,119.8,115.4,110.2,106.3,106.2,56.0,43.1,42.6,38.3,29.8,29.1,25.3,24.4,20.0,19.2。
化合物E-13的质谱数据如下:
HRMS:calcd for C28H36N3O3S+[M+H]+:494.2472found:494.2476.
实施例14
实施例14与实施例11的制备方法基本相同,区别在于:以7-溴庚酰氯替换4-溴丁酰氯。
化合物E-14的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.02(brs,1H),8.29(m,1H),7.91(m,1H),7.71(m,1H),7.46(m,1H),7.35(s,1H),7.32(d,J=2.0Hz,1H),7.09(dd,J=8.8,2.0Hz,1H),7.02(d,J=8.8,1H),3.95(s,3H),3.54(t,J=8.6Hz,2H),3.38(s,3H),2.65(q,J=7.0Hz,1H),2.52(s,3H),2.36(t,J=8.7Hz,2H),1.87(m,2H),1.63(m,2H),1.42(m,2H),1.32(m,2H),1.13(d,J=7.1Hz,6H)。
13C-NMR(101MHz,DMSO-d6),δ204.0,179.8,159.2,149.3,148.8,142.0,138.0,129.4,128.4,127.5,124.6,123.8,119.8,115.4,110.2,106.3,106.2,55.8,43.2,42.7,38.3,32.6,29.8,28.4,28.0,25.3,20.0,19.2。
化合物E-14的质谱数据如下:
HRMS:calcd for C29H38N3O3S+[M+H]+:508.2628found:508.2626。
实施例15
实施例15与实施例11的制备方法基本相同,区别在于:以8-溴辛酰氯替换4-溴丁酰氯。
化合物E-15的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.00(brs,1H),8.29(m,1H),7.91(m,1H),7.71(m,1H),7.46(m,1H),7.35(s,1H),7.32(d,J=2.0Hz,1H),7.09(dd,J=8.8,2.0Hz,1H),7.02(d,J=8.8,1H),3.94(s,3H),3.53(t,J=8.8Hz,2H),3.38(s,3H),2.66(q,J=7.0Hz,1H),2.52(s,3H),2.36(t,J=8.8Hz,2H),1.87(m,2H),1.57(m,2H),1.42(m,2H),1.30(m,2H),1.26(m,2H),1.13(d,J=7.1Hz,6H)。
13C-NMR(101MHz,DMSO-d6),δ204.0,179.8,159.2,149.3,148.8,142.0,138.0,129.4,128.4,127.5,124.6,123.8,119.8,115.4,110.2,106.3,106.2,55.9,43.2,42.8,38.4,32.6,28.8,28.7,28.6,25.6,24.4,20.0,19.3。
化合物E-15的质谱数据如下:
HRMS:calcd for C30H40N3O3S+[M+H]+:522.2785found:522.2781。
实施例16
将4-甲氧基-N1-甲基-N1-(2-氯-喹啉基-4-)-1,3-苯二胺(0.314克,1毫摩尔,1倍量)溶于15毫升的无水二氯甲烷中,分别加入三乙胺(209微升,1.5毫摩尔,1.5倍量)和4-溴丁酰氯(0.278克,1.5毫摩尔,1.5倍量),混合物在25℃下搅拌反应4小时,将反应混合液直接使用硅胶柱层析分离纯化,洗脱液为二氯甲烷:甲醇=40:1,得到化合物0.259克C-6,产率56%。
将化合物C-6(0.232克,0.5毫摩尔,1倍量)与硫代异丁酸钾(0.126克,1毫摩尔,2倍量)混合于10毫升无水乙醇中,于25℃搅拌反应24小时,直接经硅胶柱层析分离纯化,洗脱液为二氯甲烷:甲醇=40:1,得到141毫克化合物E-16,产率58%。
化合物E-16的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.06(s,1H),8.32(m,1H),7.96(m,1H),7.79(m,1H),7.46(m,1H),7.31(d,J=2.0Hz,1H),7.06(s,1H),7.04(dd,J=8.6,2.0Hz,1H),7.02(d,J=8.6,1H),3.85(s,3H),3.52(t,J=8.8Hz,2H),3.36(s,3H),2.56(q,J=7.0Hz,1H),2.39(t,J=8.8Hz,2H),2.34(m,2H),1.12(d,J=7.0Hz,6H)。
13C-NMR(101MHz,DMSO-d6),δ204.8,179.9,151.4,151.2,150.8,141.8,138.2,130.7,127.8,126.0,124.3,124.0,119.8,115.3,110.1,106.2,105.2,56.0,43.2,42.6,35.2,32.6,22.6,19.3。
化合物E-16的质谱数据如下:
HRMS:calcd for C25H29ClN3O3S+[M+H]+:486.1613found:486.1616。
实施例17
实施例17与实施例16的制备方法基本相同,区别在于:以5-溴戊酰氯替换4-溴丁酰氯。
化合物E-17的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.06(s,1H),8.32(m,1H),7.96(m,1H),7.79(m,1H),7.46(m,1H),7.31(d,J=2.0Hz,1H),7.06(s,1H),7.04(dd,J=8.6,2.0Hz,1H),7.02(d,J=8.6,1H),3.86(s,3H),3.53(t,J=8.6Hz,2H),3.34(s,3H),2.58(q,J=7.0Hz,1H),2.38(t,J=8.7Hz,2H),1.87(m,2H),1.63(m,2H),1.13(d,J=7.0Hz,6H)。
13C-NMR(101MHz,DMSO-d6),δ204.8,179.9,151.4,151.2,150.8,141.8,138.2,130.7,127.8,126.0,124.3,124.0,119.8,115.3,110.1,106.2,105.2,56.0,43.2,42.6,38.0,29.3,27.2,24.7,19.4。
化合物E-17的质谱数据如下:
HRMS:calcd for C26H31ClN3O3S+[M+H]+:500.1769found:500.1768。
实施例18
实施例18与实施例16的制备方法基本相同,区别在于:以6-溴己酰氯替换4-溴丁酰氯。
化合物E-18的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.06(s,1H),8.32(m,1H),7.96(m,1H),7.79(m,1H),7.46(m,1H),7.31(d,J=2.0Hz,1H),7.06(s,1H),7.04(dd,J=8.6,2.0Hz,1H),7.02(d,J=8.6,1H),3.86(s,3H),3.53(t,J=8.6Hz,2H),3.34(s,3H),2.57(q,J=7.0Hz,1H),2.36(t,J=8.7Hz,2H),1.87(m,2H),1.63(m,2H),1.29(m,2H),1.12(d,J=7.1Hz,6H)。
13C-NMR(101MHz,DMSO-d6),δ204.8,179.9,151.4,151.2,150.8,141.8,138.2,130.7,127.8,126.0,124.3,124.0,119.8,115.3,110.1,106.2,105.2,56.0,43.1,42.5,38.3,29.8,29.1,25.3,24.6,19.2。
化合物E-18的质谱数据如下:
HRMS:calcd for C27H33ClN3O3S+[M+H]+:514.1926found:514.1924。
实施例19
实施例19与实施例16的制备方法基本相同,区别在于:以7-溴庚酰氯替换4-溴丁酰氯。
化合物E-19的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.05(s,1H),8.31(m,1H),7.95(m,1H),7.78(m,1H),7.46(m,1H),7.31(d,J=2.0Hz,1H),7.07(s,1H),7.05(dd,J=8.6,2.0Hz,1H),7.02(d,J=8.6,1H),3.87(s,3H),3.53(t,J=8.6Hz,2H),3.34(s,3H),2.57(q,J=7.0Hz,1H),2.36(t,J=8.7Hz,2H),1.87(m,2H),1.63(m,2H),1.42(m,2H),1.33(m,2H),1.12(d,J=7.1Hz,6H)。
13C-NMR(101MHz,DMSO-d6),δ204.8,179.9,151.4,151.2,150.8,141.8,138.2,130.7,127.8,126.0,124.3,124.0,119.8,115.3,110.1,106.2,105.2,55.8,43.2,42.6,38.3,32.5,29.8,28.3,28.0,25.6,19.1。
化合物E-19的质谱数据如下:
HRMS:calcd for C28H34ClN3O3S+[M+H]+:527.2009found:527.2012。
实施例20
实施例20与实施例16的制备方法基本相同,区别在于:以8-溴辛酰氯替换4-溴丁酰氯。
化合物E-20的核磁表征数据如下:
1H-NMR(400MHz,DMSO-d6),δ9.05(s,1H),8.31(m,1H),7.95(m,1H),7.78(m,1H),7.46(m,1H),7.31(d,J=2.0Hz,1H),7.07(s,1H),7.05(dd,J=8.6,2.0Hz,1H),7.02(d,J=8.6,1H),3.87(s,3H),3.53(t,J=8.6Hz,2H),3.34(s,3H),2.57(q,J=7.0Hz,1H),2.36(t,J=8.7Hz,2H),1.87(m,2H),1.58(m,2H),1.43(m,2H),1.30(m,2H),1.26(m,2H),1.12(d,J=7.0Hz,6H)。
13C-NMR(101MHz,DMSO-d6),δ204.8,179.9,151.4,151.2,150.8,141.8,138.2,130.7,127.8,126.0,124.3,124.0,119.8,115.3,110.1,106.2,105.2,55.8,43.2,42.6,38.3,32.5,29.8,28.8,28.6,28.4,25.6,19.1。
化合物E-20的质谱数据如下:
HRMS:calcd for C29H37ClN3O3S+[M+H]+:542.2239found:542.2242。
实验例1化合物E-1~E-20对HDAC1、6和8的抑制活性检测
具体方法为:10μL的酶溶液(HDAC1、HDAC6或HDAC8)与不同浓度的化合物(50μL)混合,混合物于37℃孵化5分钟,然后加入40μL荧光底物(HDAC1和HDAC6使用Boc-Lys(acetyl)-AMC为底物,HDAC8使用Boc-Lys(trifluoroacetyl)-AMC为底物),37℃孵化30分钟后猝灭。在37℃另外孵化20分钟后,测量荧光强度,激发波长和发射波长分别为390nm和460nm。通过比较试验组和对照组的荧光强度读数来计算抑制率,并最终计算IC50值。
结果如下表1,从表1中可以看出,化合物E-1~E-20均对HDAC6表现出抑制活性,而对HDAC1和8抑制活性均很差,是HDAC6特异性抑制剂。
表1化合物E-1~E-20对HDAC1、6和8的抑制活性IC50(μM)值
实验例2化合物E-1~E-20对MCF-7细胞(人乳腺癌细胞)的抑制活性检测
采用本领域已知的MTT实验(加入化合物后抚育72小时),计算抑制活性GI50值,在此不做赘述。
结果如下表2和表3,从表2和表3中可以看出,化合物E-3、E-4、E-5、E-9、E-10、E-14、E-15、E-19和E-20均表现出对MCF-7细胞、A549细胞、SGC-7901细胞、HepG2细胞、HCT116细胞、PC-3细胞、HL60细胞和RPMI8226细胞均有很好的抑制活性。
化合物E-1~E-5、E-6~E-10、E-11~E-15、E-16~E-20之间分别比较,发现结构中酰胺羰基到S原子间的碳链越长活性越好。
化合物E-1和E-6,化合物E-5和E-10,化合物E-11和E-16,化合物E-2和E-7,化合物E-12和E-17,化合物E-3和E-8,化合物E-13和E-18,化合物E-4和E-9,化合物E-14和E-19,及化合物E-15和E-20之间分别比较,发现供电子基甲基的活性好于吸电子基Cl。
化合物E-1和E-11,化合物E-2和E-12,化合物E-3和E-13,化合物E-4和E-14,化合物E-5和E-15,化合物E-6和E-16,化合物E-7和E-17,化合物E-8和E-18,化合物E-9和E-19,及化合物E-10和E-20之间分别比较,发现R为甲基的活性好于异丙基。
表2化合物E-1~E-20对六种人实体瘤细胞的抑制活性GI50(nM)值
注:Mcf-7为人乳腺癌细胞;A549为人非小细胞肺癌细胞,SGC-7901为人胃癌细胞;HepG2为人肝肿瘤细胞;HCT116为人结肠癌细胞;PC-3为人前列腺癌细胞。
表3化合物E-1~E-20对两种人血液瘤细胞的抑制活性GI50(nM)值
注:HL60为人早幼粒急性白血病细胞;RPMI8226为人多发性骨髓瘤细胞。
尽管本发明的内容已经通过上述优选实施例作了详细介绍,但应当认识到上述的描述不应被认为是对本发明的限制。在本领域技术人员阅读了上述内容后,对于本发明的多种修改和替代都将是显而易见的。因此,本发明的保护范围应由所附的权利要求来限定。
Claims (8)
2.根据权利要求1所述的组蛋白去乙酰化酶与微管蛋白双靶点抑制剂,其特征在于,所述烷基选自甲基或异丙基。
4.一种药物组合物,其特征在于,该药物组合物包含:如权利要求1-3中任意一项所述的组蛋白去乙酰化酶与微管蛋白双靶点抑制剂及其药学上可接受的载体。
5.一种如权利要求1-3中任意一项所述的组蛋白去乙酰化酶与微管蛋白双靶点抑制剂的用途,其特征在于,该抑制剂用于制备治疗肿瘤的药物。
6.根据权利要求5所述的组蛋白去乙酰化酶与微管蛋白双靶点抑制剂的用途,其特征在于,所述肿瘤包括:血液瘤和实体瘤;所述血液瘤包括:白血病和淋巴瘤。
8.根据权利要求7所述的组蛋白去乙酰化酶与微管蛋白双靶点抑制剂的制备方法,其特征在于,当R为异丙基时,化合物C和化合物D反应时在碱性条件下进行。
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