CN113444069B - 一类2-芳基-4-(1h-吡唑-3-基)吡啶类lsd1/hdac双靶点抑制剂 - Google Patents
一类2-芳基-4-(1h-吡唑-3-基)吡啶类lsd1/hdac双靶点抑制剂 Download PDFInfo
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- CN113444069B CN113444069B CN202110766449.9A CN202110766449A CN113444069B CN 113444069 B CN113444069 B CN 113444069B CN 202110766449 A CN202110766449 A CN 202110766449A CN 113444069 B CN113444069 B CN 113444069B
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Abstract
本发明涉及一类2‑芳基‑4‑(1H‑吡唑‑3‑基)吡啶类LSD1/HDAC双靶点抑制剂、其制备方法及在制备抗肿瘤药物中的应用，属于药物化学技术领域。所述的化合物具有如下通式：
其中，R1优选CH3、OCH3和H；R2优选F和H。本发明所述化合物对LSD1和HDAC均具有较强的抑制活性，对HDAC1的IC50值小于5 nM，显著优于阳性药物SAHA。对人急性髓系白血病THP‑1细胞株显示出较好的体外抗肿瘤活性，优于阳性药物SAHA，为LSD1/HDAC双靶点抑制剂类药物的研发提供了基础，可作为进一步开发的候选或者先导化合物用于开发抗肿瘤治疗药物。
Description
技术领域
本发明具体涉及一类2-芳基-4-(1H-吡唑-3-基)吡啶类LSD1/HDAC双靶点抑制剂、其制备方法及在制备抗肿瘤药物中的应用，属于药物化学技术领域。
背景技术
表观遗传修饰失调与肿瘤的发生、发展和不良预后密切相关，靶向表观遗传调控蛋白的抗癌药物的研发引起了人们的极大兴趣，并且已经取得了较大进展。
组蛋白赖氨酸特异性去甲基化酶1(LSD1)也被称为KDM1A、CPRF、BHC110和AOF2，是由哈佛大学的施杨团队于2004年发现。LSD1是一个黄素腺嘌呤二核苷酸依赖性的氨基氧化酶，其主要功能是特异性的去除组蛋白H3K4上的一甲基化和二甲基化修饰。LSD1通过去除H3K4me1/2的甲基化标记抑制基因的转录，进而调控细胞周期、增殖、分化和胚胎多能性等多种关键细胞过程。通过和雌激素受体或者雄激素受体相互作用，LSD1还可以去除H3K9上的单、双甲基化修饰，使其从转录抑制因子转变为转录活化因子，激活下游基因的转录。此外，LSD1还能去除非组蛋白如p53、DNMT1、STAT3、E2F1、MYPT1和HIF-1的甲基化修饰，进一步调节其下游基因的稳定性和活性。LSD1在急性髓系白血病、肺癌、胃癌、乳腺癌、结肠癌、前列腺癌、滑膜肉瘤和神经母细胞瘤等多种肿瘤中的表达量显著升高，并且和肺癌、急性髓系白血病、结肠癌和乳腺癌等多种恶性肿瘤的不良预后密切相关。采用小分子化合物抑制LSD1的活性可以有效抑制肿瘤细胞的增殖、转移和侵袭。针对LSD1开发抗肿瘤药物是目前药物化学领域中极具吸引力的策略之一，目前已有IMG-7289，GSK2879552，TAK-418，ORY-2001，INCB059872，CC-90011和SP-2577等七个LSD1小分子抑制剂进入I/II期临床试验，用于治疗急性髓系白血病和非小细胞肺癌。此外，研究表明LSD1与其他疾病，例如代谢紊乱、精神疾病、病毒感染等疾病也是密切相关的。
组蛋白去乙酰化酶(HDAC)主要去除组蛋白N末端尾部赖氨酸残基上的乙酰化修饰，导致基因转录沉默。HDAC不仅能使组蛋白去乙酰化，而且还可以作用于各种非组蛋白蛋白，包括RUNX3，p53，E2F，STAT，NF-κF，HIF-1α，ERα，AR和HSP90等。在白血病、淋巴癌、宫颈癌、结直肠癌，乳腺癌等多种恶性肿瘤中，HDAC家族成员的表达水平与活性都有明显上调，并且白血病、淋巴癌、宫颈癌、结直肠癌等多种恶性肿瘤的不良预后与HDAC的表达水平呈正相关。目前已经有Vorinostat，Romidepsin，Belinostat，Panobinostat和Chidamide等5个HDAC小分子抑制剂被FDA和CFDA批准上市，用于治疗皮肤T细胞淋巴瘤、骨髓瘤等多种肿瘤。此外，还有多个HDAC抑制剂正在进行各期临床试验。此外，HDAC与神经退行性疾病、自体免疫性疾病、急性移植物抗宿主病等众多疾病的发生也有密切的关联，被视为这些疾病的潜在治疗靶点。
虽然LSD1抑制剂和HDAC抑制剂在多种血液肿瘤的治疗中取得了不错效果，但是LSD1和HDAC抑制剂对实体瘤的治疗效果不佳。作为两个重要的组蛋白表观遗传调控蛋白，LSD1和HDAC都与癌症的发生发展密切相关，二者之间存在着密切的串话关联关系。LSD1和HDAC1/2共同存在于NuRD、CoREST、Sin3A多种共抑制复合蛋白中，参与调控多种基因的转录。HDAC1可以去乙酰化LSD1底物结合区的K374，促进LSD1和组蛋白H3的有效结合，增强LSD1的去甲基化酶活性，抑制下游靶基因的表达。在乳腺癌中，LSD1和HDAC5的表达量均明显上调，HDAC5通过上调LSD1的去泛素酶USP28的表达，进而提高LSD1的稳定性和去甲基化活性，从而促进乳腺癌的发生和发展。相反，抑制HDAC5的活性或者敲除HDAC5则促进LSD1的泛素化降解，抑制乳腺癌细胞的增殖和侵袭。联合应用LSD1和HDAC抑制剂对多种恶性肿瘤包括横纹肌肉瘤、胶质母细胞瘤、乳腺癌、尤文氏肉瘤和急性髓系白血病细胞都显示出良好的协同抗肿瘤作用。因此，发现新型、高活性的LSD1/HDAC双靶点抑制剂，通过同时抑制LSD1、HDAC以及互相串话的信号通路转导，有望发现新型高效的抗肿瘤先导化合物，提高对实体瘤的治疗效果，这对于研究LSD1、HDAC的生理功能、研发新型高效的抗肿瘤药物具有十分重要的意义。为了发现新型的LSD1/HDAC双靶点抑制剂，探索合成一类2-芳基-4-(1H-吡唑-3-基)吡啶类化合物，验证其LSD1、HDAC双靶点抑制活性和体外抗肿瘤活性为本申请的出发点，目前尚未见有该类化合物的合成、LSD1/HDAC抑制活性及抗肿瘤活性的报道。
发明内容
由上述可知，本发明的一个目的在于提供一类2-芳基-4-(1H-吡唑-3-基)吡啶类化合物，为新药物筛选提供可能。
本发明的另一个目的在于提供此类2-芳基-4-(1H-吡唑-3-基)吡啶类化合物的制备方法。
本发明的再一个目的在于提供所述2-芳基-4-(1H-吡唑-3-基)吡啶类化合物以LSD1/HDAC为靶点在制备抗肿瘤药物中的应用。
为实现上述目的，本发明所涉及的2-芳基-4-(1H-吡唑-3-基)吡啶类化合物的结构通式为：
通式I中，R1为H、CH3、OCH3中的任意一个；R2为F、H中的任意一个。
优选：通式I中，R1、R2所代表的取代基或原子如下表所示：
为实现上述第二个目的，本发明化合物的合成反应流程如下所示：
通式I化合物的合成路线：
化合物3的制备方法：化合物2-溴-4-碘吡啶(化合物1)和吡唑-3-硼酸(化合物2)，在甲苯中，碱性化合物和钯催化剂存在下，加热搅拌反应，反应结束后，反应体系加入水和乙酸乙酯萃取，合并乙酸乙酯层，分别用水、饱和NaCl水溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩物经硅胶柱柱层析分离，得化合物3。其中，所述碱性化合物选自碳酸钾、碳酸钠、碳酸氢钠、碳酸铯、磷酸钾、氢化钠中的一种，所述的钯催化剂选自四(三苯基膦)钯、醋酸钯、双(二亚苄基丙酮)钯、二氯化钯中的一种；
化合物4的制备方法：在DMF中，碱性化合物存在下，化合物3和4-溴甲基苯甲酸甲酯室温搅拌反应，反应结束后，反应体系加入水和乙酸乙酯萃取，合并乙酸乙酯层，分别用水、饱和NaCl水溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩物经硅胶柱柱层析分离，得化合物4。其中，所述碱性化合物选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾中的一种；
化合物5的制备方法：化合物4和各种取代苯硼酸或取代苯硼酸频那醇酯，在甲苯中，碱性化合物和钯催化剂存在下，加热搅拌反应，反应结束后，反应体系加入水和乙酸乙酯萃取，合并乙酸乙酯层，分别用水、饱和NaCl水溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩物经硅胶柱柱层析分离纯化，得化合物5。其中，所述碱性化合物选自碳酸钾、碳酸钠、碳酸氢钠、碳酸铯、磷酸钾、氢化钠中的一种，所述的钯催化剂选自四(三苯基膦)钯、醋酸钯、双(二亚苄基丙酮)钯、二氯化钯中的一种；
化合物I的制备方法：在二氯甲烷溶液中，化合物5和NH2OK/NH2OH的甲醇溶液反应，反应结束后，反应体系真空浓缩，浓缩物用水溶解，用稀盐酸调pH为5-6，抽滤，洗涤，收集固体，用甲醇重结晶得化合物I。
本发明优点：本发明合成的2-芳基-4-(1H-吡唑-3-基)吡啶类化合物对LSD1和HDAC均具有较强的抑制活性，且对LSD1具有很好的选择性。所有化合物对HDAC1的IC50值小于5nM，显著优于阳性药物SAHA。该类LSD1/HDAC双靶点制剂对人白血病THP-1细胞株显示出较好的体外抗肿瘤活性，优于阳性药物SAHA，特别是化合物I-2对THP-1的抑制活性是SAHA的13倍。本发明化合物代表着一类具有全新结构的高活性的LSD1/HDAC双靶点抑制剂，为LSD1/HDAC双靶点抑制剂类药物的研发提供了基础，为LSD1、HDAC的生物学功能研究提供了有效工具。可作为进一步候选或者先导化合物用于开发抗肿瘤、抗病毒、抗艾滋病等疾病治疗药物，且合成方法简单，有利于推广应用。
具体实施方式
下面举实施例对本发明技术方案作详细说明。
实施例1 2-溴-4-(1H吡唑-3-基)吡啶(3)的合成
在50毫升两口烧瓶中加入化合物2-溴-4-碘吡啶(1212.1mg,6.0mmol),甲苯(20mL),乙醇(25mL),H2O(7.5mL),K2CO3(1.68g,11.1mmol),Pd(PPh3)4(694.0mg,0.6mmol)和吡唑-3-硼酸(1451.9mg,7.2mmol),氮气保护下,92℃搅拌反应4小时.反应结束后,将反应体系冷却至室温,然后向反应体系中加入水和乙酸乙酯萃取,合并乙酸乙酯层,分别用水、饱和NaCl水溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,浓缩物经硅胶柱柱层析分离纯化(石油醚：丙酮＝5:1)得化合物3a(850.4mg),白色固体,产率:65.5％,Mp:140-141℃.1H NMR(400MHz,DMSO-d6)δ13.36(s,1H),8.39(d,1H,J＝5.2Hz),8.03(d,1H,J＝1.6Hz),7.88(s,1H),7.86(dd,1H,J1＝1.6Hz,J2＝5.2Hz),7.03(d,1H,J＝2.0Hz).HRMS(ESI)calcdfor C8H6BrN3Na[M+Na]+:245.9637,Found:245.9639.
实施例2 4-((3-(2-溴-吡啶-4-基)-1H-吡唑-1-基)甲基)苯甲酸甲酯(4)的合成
在50毫升两口烧瓶中加入化合物3(1244.4mg,6.0mmol),4-溴甲基苯甲酸甲酯(1451.9mg,7.2mmol)和碳酸铯(2932.2mg,9.0mmol),加入DMF(8mL),氮气保护下室温搅拌反应5h.然后向反应体系中加入水和乙酸乙酯萃取,合并乙酸乙酯层,分别用水、饱和NaCl水溶液洗涤，无水硫酸钠干燥,过滤,滤液减压浓缩,浓缩物经硅胶柱柱层析分离纯化(石油醚：丙酮＝2:1)得化合物4(1755.4mg),白色固体,产率:78.6％,Mp:127-128℃.1H NMR(400MHz,CDCl3)δ8.36(d,1H,J＝5.2Hz),8.03(d,2H,J＝8.0Hz),7.90(d,1H,J＝1.2Hz),7.64(dd,1H,J1＝1.6Hz,J1＝5.2Hz),7.47(d,1H,J＝2.4Hz),7.29(d,2H,J＝8.4Hz),6.69(d,1H,J＝2.4Hz),5.43(s,2H),3.92(s,3H).13C NMR(101MHz,CDCl3)δ166.57,150.41,147.94,143.43,142.86,140.92,131.57,130.23,130.14,127.45,124.04,119.13,104.82,56.06,52.27.HRMS(ESI)calcd for C17H14BrN3NaO2[M+Na]+:394.0162,Found:394.0167.
实施例3 4-((3-(2-(4-甲基苯基)吡啶-4-基)-1H-吡唑-1-基)甲基)苯甲酸甲酯(5a)的合成
在50毫升两口圆底烧瓶中,加入化合物4(521.1mg,1.4mmol),甲苯(5mL),乙醇(5mL),H2O(1.3mL),K2CO3(359.3mg,2.6mmol),Pd(PPh3)4(162.0mg,0.14mmol)和4-甲基苯硼酸(231.1mg,1.7mmol),氮气保护下,92℃搅拌反应4小时.反应结束后,将反应体系冷却至室温,用水和乙酸乙酯萃取,合并乙酸乙酯层,再分别用水、饱和NaCl水溶液洗涤,无水硫酸钠干燥，干燥完毕，抽滤，滤液减压浓缩,浓缩物用硅胶柱柱层析纯化(石油醚:乙酸乙酯＝2:1),得化合物5a(483.7mg),产率:90.1％,白色固体,Mp:92-93℃.1H NMR(400MHz,CDCl3)δ8.68(dd,1H,J1＝0.8Hz,J2＝4.8Hz),8.13(dd,1H,J1＝0.8Hz,J2＝1.6Hz),8.03(d,2H,J＝8.4Hz),7.96(d,2H,J＝8.4Hz),7.59(dd,1H,J1＝1.6Hz,J2＝5.2Hz),7.46(d,1H,J＝2.4Hz),7.30-7.27(m,4H),6.75(d,1H,J＝2.4Hz),5.44(s,2H),3.90(s,3H),2.41(s,3H).13C NMR(101MHz,CDCl3)δ166.63,158.00,150.03,149.67,141.34,141.29,138.93,136.70,131.33,130.20,130.03,129.44,127.42,126.89,118.32,116.57,104.57,55.94,52.25,21.32.HRMS(ESI)calcd for C24H22N3O2[M+H]+:384.1707,Found:384.1705.
实施例4 4-((3-(2-(4-甲氧基苯基)吡啶-4-基)-1H-吡唑-1-基)甲基)苯甲酸甲酯(5b)的合成
按照实施例3的方法,用4-甲氧基苯硼酸(258.33mg,1.7mmol)替换4-甲基苯硼酸,得化合物5b(201.9mg),白色固体,产率:36.1％,Mp:102-103℃.1H NMR(400MHz,CDCl3)δ8.65(dd,1H,J1＝0.8Hz,J2＝5.2Hz),8.10(dd,1H,J1＝0.8Hz,J2＝1.6Hz),8.03-8.01(m,4H),7.56(dd,1H,J1＝1.2Hz,J2＝4.8Hz),7.47(d,1H,J＝2.4Hz),7.29(d,2H,J＝8.0Hz),7.00(d,2H,J＝8.8Hz),6.74(d,1H,J＝2.4Hz),5.44(s,2H),3.91(s,3H),3.86(s,3H).13CNMR(101MHz,CDCl3)δ166.62,160.45,157.65,149.97,149.70,141.31,141.29,132.14,131.33,130.19,130.03,128.30,127.41,117.97,116.12,114.05,104.55,55.94,55.37,52.24.HRMS(ESI)calcd for C24H22N3O3[M+H]+:400.1656,Found:400.1658.
实施例5 4-((3-(2-(2-氟-4-甲基苯基)吡啶-4-基)-1H-吡唑-1-基)甲基)苯甲酸甲酯(5c)的合成
按照实施例3的方法,用2-氟-4-甲基苯硼酸(261.7mg,1.7mmol)替换4-甲基苯硼酸,得化合物5c(363.1mg),白色固体,产率:64.6％,Mp:129-130℃.1H NMR(400MHz,CDCl3)δ8.71(dd,1H,J1＝1.2Hz,J2＝5.2Hz),8.15(t,1H,J＝2.0Hz),8.02(d,2H,J＝8.4Hz),7.87(t,1H,J＝8.4Hz),7.66(dd,1H,J1＝1.6Hz,J2＝5.2Hz),7.46(d,1H,J＝2.4Hz),7.29(d,2H,J＝8.4Hz),7.08(dt,1H,J1＝1.6Hz,J2＝7.6Hz),6.99(dt,1H,J1＝1.2Hz,J2＝12.4Hz),6.75(d,1H,J＝2.4Hz),5.44(s,2H),3.91(s,3H),2.40(s,3H).13C NMR(101MHz,CDCl3)δ166.64,160.34(d,JC-F＝250.3Hz),154.16(d,JC-F＝2.3Hz),150.07,149.52,141.28,141.14(d,JC-F＝8.4Hz),141.05,131.30,130.68(d,JC-F＝3.4Hz),130.19,130.00,127.43,125.29(d,JC-F＝2.9Hz),124.69(d,JC-F＝11.7Hz),120.66(d,JC-F＝8.7Hz),118.52,116.66(d,JC-F＝22.3Hz),104.65,55.95,52.25,21.20.HRMS(ESI)calcd for C24H21FN3O2[M+H]+:402.1612,Found:402.1614.
实施例6 N-羟基-4-((3-(2-(4-甲基苯基)吡啶-4-基)-1H-吡唑-1-基)甲基)苯甲酰胺(I-1)的合成
在冰浴、搅拌下，将氢氧化钾的无水甲醇溶液(7.0g,45mL甲醇)慢慢滴加入盐酸羟胺的无水甲醇溶液中(5.84g,20mL甲醇),加毕搅拌5min,过滤得NH2OK-NH2OH甲醇溶液,密封保存备用.在50mL两口圆底烧瓶中,加入化合物5a(383.4mg,1.0mmol),用无水二氯甲烷(5mL)溶解,氮气保护,冰浴搅拌下,慢慢滴加上步制备的NH2OK-NH2OH溶液(16.5mL),加毕室温搅拌1.0h.将反应体系减压浓缩,浓缩物用蒸馏水(20mL)溶解,用稀HCl调pH 5-6,有固体析出,过滤,收集固体,用甲醇重结晶得化合物I-1(324.8mg),白色固体,产率:84.7％,Mp:185-186℃.1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),9.05(s,1H),8.63(d,1H,J＝5.2Hz),8.23(t,1H,J＝1.2Hz),8.06-8.02(m,3H),7.73(d,2H,J＝8.4Hz),7.69(dd,1H,J1＝1.2Hz,J2＝5.2Hz),7.34(d,2H,J＝8.4Hz),7.32(d,2H,J＝8.8Hz),7.13(d,1H,J＝2.0Hz),5.50(s,2H),2.37(s,3H).13C NMR(101MHz,DMSO-d6)δ164.35,157.11,150.47,148.96,141.76,140.84,139.10,136.38,133.30,132.67,129.80,127.89,127.68,126.97,118.45,115.84,105.08,55.22,21.31.HRMS(ESI)calcd for C23H21N4O2[M+H]+:385.1659,Found:385.1659.
实施例7 N-羟基-4-((3-(2-(4-甲氧基苯基)吡啶-4-基)-1H-吡唑-1-基)甲基)苯甲酰胺(I-2)的合成
按照实施例6的方法,用化合物5b(399.45mg,1.0mmol)替换5a,得化合物I-2(338.4mg),黄色固体,产率:84.5％,Mp:187-188℃.1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),9.06(s,1H),8.60(d,1H,J＝4.8Hz),8.20(t,1H,J＝1.2Hz),8.11(d,2H,J＝8.8Hz),8.03(d,1H,J＝2.4Hz),7.73(d,2H,J＝8.4Hz),7.65(dd,1H,J1＝1.2Hz,J2＝4.8Hz),7.34(d,2H,J＝8.0Hz),7.12(d,1H,J＝2.4Hz),7.06(d,2H,J＝8.8Hz),5.50(s,2H),3.83(s,3H).13C NMR(101MHz,DMSO-d6)δ164.31,160.64,156.89,150.38,149.02,141.70,140.84,133.27,132.66,131.61,128.45,127.90,127.68,117.99,115.41,114.54,105.05,55.68,55.22.HRMS(ESI)calcd for C23H21N4O3[M+H]+:401.1608,Found:401.1608.
实施例8 N-羟基-4-((3-(2-(2-氟-4-甲基苯基)吡啶-4-基)-1H-吡唑-1-基)甲基)苯甲酰胺(I-3)的合成
按照实施例6的方法,用化合物5c(401.4mg,1.0mmol)替换5a,得化合物I-3(318.7mg),白色固体,产率:79.2％,Mp:114-115℃.1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),9.08(s,1H),8.69(d,1H,J＝5.2Hz),8.13(t,1H,J＝2.0Hz),8.04(d,1H,J＝2.4Hz),7.86(t,1H,J＝8.0Hz),7.75-7.73(m,3H),7.34(d,2H,J＝8.4Hz),7.20-7.15(m,2H),7.02(d,1H,J＝2.4Hz),5.51(s,2H),2.38(s,3H).13C NMR(101MHz,DMSO-d6)δ164.33,160.16(d,JC-F＝248.9Hz),153.66(d,JC-F＝2.3Hz),150.70,148.67,141.76(d,JC-F＝8.6Hz),141.37,140.80,133.41,132.67,131.03(d,JC-F＝3.4Hz),127.89,127.68,125.93(d,JC-F＝2.8Hz),124.58(d,JC-F＝11.5Hz),119.80(d,JC-F＝8.7Hz),118.91,117.03(d,JC-F＝22.7Hz),104.93,55.22,21.08.HRMS(ESI)calcd for C23H20FN4O2[M+H]+:403.1565,Found:403.1569.
本发明所合成化合物的LSD1、HDAC和THP-1抑制活性评价：
(一)LSD1、HDAC和THP-1的抑制活性评价：
1、LSD1抑制活性评价实验方法
样品为实施例所合成的上述化合物纯化而得；样品储备液：称取3-5mg样品置于1.5mL EP管中，然后用DMSO配制成浓度是20mM的溶液，-20℃避光保存，实验时根据所需浓度用DMSO稀释。将待测样品与LSD1蛋白于室温孵育后，加入LSD1反应底物H3K4me2并孵育反应，最后加入荧光染料Amplex和辣根过氧化酶HRP室温孵育，在酶标仪上激发光530nm，发射光590nm检测荧光数值。
试验结果采用SPSS软件计算IC50值。
2、HDAC抑制活性评价实验方法
称取3-5mg样品置于1.5mL EP管中，然后用DMSO配制成浓度是20mM的溶液，-20℃避光保存，实验时根据所需浓度用DMSO稀释。制备1X缓冲液(改良Tris缓冲液)。HDAC酶用1X缓冲液稀释至1.67X终浓度。将胰蛋白酶和乙酰肽底物混合制成底物溶液，用1X缓冲液稀释至2.5X终浓度。用Echo550将250nL待测化合物转移到384孔板上。然后，将15μL的酶液加入384孔板中，与待测化合物在室温下预孵育15min。用15μL 1X缓冲液作为阴性对照。然后将10μL底物溶液加入384孔中以启动反应。用EnVision在激发波长355nm和发射波长460nm处检测荧光强度。
3、重组蛋白水平MAO-A/B抑制活性评价
样品为实施例所合成的上述化合物、纯化而得；样品储备液：称取3-5mg样品置于1.5mL EP管中，然后用DMSO配制成浓度是20mM的溶液，-20℃避光保存，实验时根据所需浓度用DMSO稀释。根据制造商的使用方法，使用Promega的商品化MAO-Glo检测试剂盒测定对MAO-A和MAO-B的抑制活性。
4、体外抗肿瘤活性测定
样品为实施例所合成的化合物；样品储备液:称取3-5mg样品置于1.5mL EP管中，然后用DMSO配制成浓度为10mmol/L溶液，-20℃避光保存放置，实验时根据所需浓度利用培养基稀释。
取对数生长期的细胞，消化计数后，用培养基调整细胞密度，以4000-5000个细胞/孔接种至96孔板中，每孔100μL，培养24h后，加入用培养基稀释好的不同浓度的药物(10μM、2.5μM、0.625μM、0.1563μM、0.0391μM、0.0098μM、0.0024μM、0.006μM)，每个浓度设3个复孔，另设空白对照组及阳性对照组。药物作用72h后，每孔加入40μL CellTiter-Glo Reagent，振荡混匀2分钟，室温继续孵育10分钟后，酶标仪检测荧光强度，计算抑制率，计算公式如下:
抑制率(％)＝(最大荧光强度-给药组荧光强度)/(最大荧光强度-最小荧光强度)×100％。
5、实验结果
表1 LSD1、HDAC1和THP-1抑制活性评价结果
a N.D.:未测定。
b 30nM浓度时的抑制率为83％。
从上表1实验结果可以看出，本发明化合物对LSD1和HDAC1均具有较好的抑制活性。所有化合物对HDAC1的IC50小于5nM,明显优于阳性药物SAHA，特别是化合物I-2对HDAC1的IC50为1.88nM，是阳性药物SAHA的7倍。体外抗肿瘤活性评价显示，所有化合物对THP-1急性髓系白血病细胞的抑制活性均优于SAHA，特别是化合物I-2对THP-1的IC50为0.44μM,是SAHA的13倍。
化合物I-2对其他亚型的HDAC也具有很强的抑制活性，对HDAC2、HDAC5、HDAC6和HDAC8的抑制活性均强于SAHA。化合物I-2对LSD1的同源蛋白MAO-A和MAO-B没有抑制活性，对LSD1具有很好的选择性(表2)。
表2化合物I-2对HDAC亚型和MAO-A/B抑制活性评价结果
a ND:未检测
实验结果表明本发明化合物代表着一类结构全新的LSD1/HDAC双靶点抑制剂，具有很好的体外抗肿瘤活性，可作为进一步开发的候选或者先导化合物，应用于制备抗癌药物，为LSD1/HDAC双靶点抑制剂类药物的研发提供了基础，为LSD1和HDAC的生物学功能研究提供了有效工具。
Claims (5)
1.一类2-芳基-4-(1H-吡唑-3-基)吡啶类化合物，其特征在于，具有通式(I)所示结构：
通式I中，R1为OCH3、CH3、H中的任意一个；R2为F和H中的任意一个。
2.如权利要求1所述的一类2-芳基-4-(1H-吡唑-3-基)吡啶类化合物，其特征在于，选以下化合物其中之一：
3.一种制备如权利要求1或2所述的一类2-芳基-4-(1H-吡唑-3-基)吡啶类化合物的方法，其特征在于，通过如下步骤实现：
(1)化合物3的制备方法：化合物2-溴-4-碘吡啶(化合物1)和吡唑-3-硼酸(化合物2)，在甲苯中，碱性化合物和钯催化剂存在下，加热搅拌反应，反应结束后，反应体系经萃取，洗涤，干燥，过滤，浓缩，柱层析分离，得化合物3；其中，所述碱性化合物选自碳酸钾、碳酸钠、碳酸氢钠、碳酸铯、磷酸钾、氢化钠中的一种，所述的钯催化剂选自四(三苯基膦)钯、醋酸钯、双(二亚苄基丙酮)钯、二氯化钯中的一种；
(2)化合物4的制备方法：在DMF中，碱性化合物存在下，化合物3和4-溴甲基苯甲酸甲酯室温搅拌反应，反应结束后，反应体系经萃取，洗涤，干燥，过滤，浓缩，柱层析分离，得化合物4；其中，所述碱性化合物选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾中的一种；
(3)化合物5的制备方法：化合物4和结构式如下的取代苯硼酸或取代苯硼酸频那醇酯在甲苯中，碱性化合物和钯催化剂存在下，加热搅拌反应，反应结束后，反应体系经萃取，洗涤，干燥，过滤，滤浓缩，柱层析分离纯化，得化合物5；其中，所述碱性化合物选自碳酸钾、碳酸钠、碳酸氢钠、碳酸铯、磷酸钾、氢化钠中的一种，所述的钯催化剂选自四(三苯基膦)钯、醋酸钯、双(二亚苄基丙酮)钯、二氯化钯中的一种；
R1为OCH3，CH3，H；R2为F或H；
(4)化合物I的制备方法：在二氯甲烷溶液中，化合物5和NH2OK/NH2OH的甲醇溶液反应，反应结束后，反应体系减压浓缩，浓缩物用水溶解，调pH为5-6，抽滤，洗涤，收集固体，重结晶得化合物I。
4.如权利要求1-2其中之一所述的一类2-芳基-4-(1H-吡唑-3-基)吡啶类化合物在药物制备中的应用，其特征在于，将其作为活性成分用于LSD1/HDAC双靶点抑制剂类药物的制备。
5.如权利要求4所述的一类2-芳基-4-(1H-吡唑-3-基)吡啶类化合物在药物制备中的应用，其特征在于，将其作为活性成分用于制备急性髓系白血病的治疗药物。
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