CN107474011B - 一类2-苯基-4-苯乙烯基吡啶类lsd1抑制剂、其制备方法及应用 - Google Patents

一类2-苯基-4-苯乙烯基吡啶类lsd1抑制剂、其制备方法及应用 Download PDF

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CN107474011B
CN107474011B CN201710750072.1A CN201710750072A CN107474011B CN 107474011 B CN107474011 B CN 107474011B CN 201710750072 A CN201710750072 A CN 201710750072A CN 107474011 B CN107474011 B CN 107474011B
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段迎超
关圆圆
刘兆敏
翟晓雨
秦文平
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Xinxiang Medical University
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Abstract

本发明公开了一类具有2‑苯基‑4‑苯乙烯基吡啶结构的LSD1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。本发明所述的化合物具有如下通式：

Description

一类2-苯基-4-苯乙烯基吡啶类LSD1抑制剂、其制备方法及 应用
技术领域
本发明具体涉及一类具有2-苯基-4-苯乙烯基吡啶结构的LSD1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
组蛋白赖氨酸特异性去甲基化酶1(Lysine specific histone demethylase 1，LSD1)是第一个被报道的组蛋白去甲基化酶。LSD1属于黄素腺嘌呤二核苷酸(FAD)依赖的胺氧化酶超家族，LSD1可以特异性的去除组蛋白赖氨酸H3K4 和H3K9的单、双甲基。LSD1还可以作用于非组蛋白底物，比如LSD1可以去除抑癌蛋白p53K370位点的甲基，抑制p53靶基因的表达；LSD1还可以使 DNA甲基转移酶(DNMT1)去甲基化，从而维持DNA的整体甲基化水平。LSD1与肿瘤、病毒性感染、代谢性疾病、炎症等多种疾病的发生均有紧密的关系，其中与肿瘤的发生发展尤为密切。
LSD1在乳腺癌、膀胱癌、急性粒细胞白血病、食管癌、胃癌、视网膜母细胞瘤、卵巢癌等多种肿瘤中的表达量显著升高，与这些肿瘤的生长、转移和侵袭等过程呈正相关。用RNA干扰技术降低LSD1的表达量或者用小分子抑制剂抑制LSD1的活性能够降低相关致癌基因的表达，抑制肿瘤的增殖、转移和侵袭。因此，LSD1已经成为目前肿瘤表观遗传学治疗的热点靶标之一，吸引了西班牙Oryzon、葛兰素史克和日本武田制药等众多国际医药公司的关注。目前已有多个LSD1小分子抑制剂被报道，西班牙Oryzon公司报道的苯环丙胺类 LSD1抑制剂目前正在进行II期临床试验，用于治疗白血病。
因此，发现新型、高活性的LSD1小分子抑制剂，对于研究LSD1的生物学功能、研发多种疾病尤其是肿瘤的治疗药物具有十分重要意义。为了发现新型的LSD1小分子抑制剂，本发明合成了一类2-苯基-4-苯乙烯基吡啶化合物，该类化合物具有显著的LSD1抑制活性和体外抗肿瘤活性，目前尚未见有该类化合物的合成、LSD1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-苯基-4-苯乙烯基吡啶类化合物，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-苯基-4-苯乙烯基吡啶类化合物的制备方法及其作为组蛋白赖氨酸特异性去甲基化酶1(LSD1)抑制剂的应用。
本发明的再一个目的在于提供所述化合物以LSD1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-苯基-4-苯乙烯基吡啶类化合物的结构通式为：
Figure BDA0001388737380000021
通式I中，R1为单取代或多取代，取代基指：NH2、
Figure BDA0001388737380000022
中的任意一个； R2为H、OH、CN、F、Cl、Br、I中的任意一个；R3为H、OH、CN、F、Cl、 Br、I中的任意一个。
优选：通式I中，R1为单取代，取代基指：NH2、
Figure BDA0001388737380000023
中的任意一个； R2为H、F、Cl、Br、I中的任意一个；R3为H、F、Cl、Br、I中的任意一个。
更优选地，R1、R2、R3代表的取代基和取代位置如下表所示：
Figure BDA0001388737380000024
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式所示：
通式I化合物的合成路线：
Figure BDA0001388737380000031
R4为硝基或者氰基，R1，R2，R3同上。
化合物1的制备方法:取代2-甲氧基苯硼酸和2-溴吡啶-4-甲醛在甲苯中，碱性化合物和钯催化剂存在下，回流搅拌反应，得化合物1。其中，所述碱性化合物选自碳酸钾、碳酸钠、碳酸铯、磷酸钾中的一种，所述的钯催化剂选四(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2的制备方法:化合物1和取代苄基膦酸二乙酯在DMF中，强碱性化合物存在下，室温搅拌反应，反应结束后，将反应体系倾入冰水中，抽滤，洗涤，收集固体，干燥，得化合物2。其中，所述强碱性化合物选自叔丁醇钾、甲醇钠、氢化钠、叔丁醇钠中的一种。
化合物3的制备方法:当化合物2中R4为硝基，则在有机溶剂中，SnCl2存在下，回流搅拌反应，反应结束后，反应体系真空浓缩，浓缩物加入乙酸乙酯、饱和碳酸氢钠水溶液搅拌，分取有机相，洗涤，干燥，柱层析分离，得化合物 3。其中，所述有机溶剂选自乙醇、乙酸乙酯、四氢呋喃中的一种。
化合物4的制备方法:当化合物2中R4为氰基，在无水二氯甲烷中，三溴化硼存在下，-35℃-室温过夜反应，反应结束后，将反应体系倾入到饱和碳酸氢钠水溶液中，抽滤，收集固体，柱层析分离分别得化合物4。
化合物I的制备方法:化合物4在甲醇中，碱性化合物存在下，和盐酸羟胺回流搅拌反应，反应结束后，反应体系真空浓缩，浓缩物加入乙酸乙酯和水萃取，洗涤，有机相经柱层析分离，得化合物I。其中，所述碱性化合物选自碳酸钾、碳酸铯、三乙胺、N,N-二异丙基乙胺中的一种；
或者将化合物3，在无水二氯甲烷中，三溴化硼存在下，-35℃-室温反应，反应结束后，反应体系倾入到饱和碳酸氢钠水溶液中，抽滤，收集固体，经柱层析分离，得化合物I。
本发明优点：本发明合成的2-苯基-4-苯乙烯基吡啶类化合物均具有较强的 LSD1抑制活性和体外抗肿瘤活性。化合物的LSD1抑制活性均强于阳性对照药物苯环丙胺，多个化合物的LSD1抑制IC50小于1μM，体外抗肿瘤活性优于阳性对照5-氟尿嘧啶。本发明的化合物代表着一类具有全新结构的LSD1小分子抑制剂，为LSD1抑制剂类药物的研发提供了基础，为LSD1的生物学功能研究提供了有效工具。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、抗病毒、抗艾滋病等疾病治疗药物，且合成方法简单，收率高，总收率达40％以上，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-(2-甲氧基苯基)异烟醛(1a)
Figure BDA0001388737380000041
在50毫升两口烧瓶中加入2-溴吡啶-4-甲醛(376mg,2.021mmol)，甲苯 (7mL)，K2CO3水溶液(2.76g碳酸钾溶于10mL水，2mL)，四(三苯基膦)钯 (45.2mg,0.04mmol)，氮气保护下室温搅拌反应15分钟，然后加入2-甲氧基苯硼酸(407.6mg,2.682mmol)的无水乙醇溶液(3mL)，92℃加热反应3个小时，将反应体系倾入水中，乙酸乙酯萃取，合并乙酸乙酯层，依次用水，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩后，浓缩物柱层析分离纯化(石油醚：乙酸乙酯＝6:1)得白色固体406.2mg，产率73.6％，Mp:51-52℃。1H NMR (400MHz,CDCl3)δ10.12(s,1H),8.93(d,1H,J＝4.8Hz),8.27(s,1H),7.84(dd, 1H,J1＝2.0Hz,J2＝8.0Hz),7.61(dd,1H,J1＝1.2Hz,J2＝4.8Hz),7.44(td,1H,J1＝1.6Hz,J2＝8.8Hz),7.11(t,1H,J＝7.2Hz),7.04(d,1H,J＝8.4Hz),3.90(s,3H). 13C NMR(101MHz,CDCl3)δ192.15,157.86,157.07,150.62,141.48,131.16, 130.75,127.80,124.57,121.18,119.51,111.41,55.64.HRMS(ESI)calcd for C13H12NO2[M+H]+:214.0868,Found:214.0866.
实施例2 2-(5-氟-2-甲氧基苯基)异烟醛(1b)
Figure BDA0001388737380000051
按照实施例1的方法，用5-氟-2-甲氧基苯硼酸(455.8mg,2.682mmol)替换 2-甲氧基苯硼酸，得淡黄白色固体389.8mg，收率83.4％，Mp:72-73℃。1H NMR(400MHz,CDCl3)δ10.13(s,1H),8.93(d,1H,J＝4.8Hz),8.34(s,1H), 7.63-7.68(m,2H),7.13(ddd,1H,J1＝3.2Hz,J2＝7.6Hz,J3＝8.8Hz),6.97(dd, 1H,J1＝4.4Hz,J2＝9.2Hz),3.89(s,3H).13C NMR(101MHz,CDCl3)δ191.90, 158.53,156.50,156.48,156.16,153.40,153.38,150.70,141.65,124.32,120.08, 117.72,117.47,116.86,116.63,112.67,112.59,56.25.HRMS(ESI)calcd for C13H11FNO2[M+H]+:232.0768,Found:232.0770.
实施例3(E)-2-(2-甲氧基苯基)-4-(4-硝基苯乙烯基)吡啶(2a)
Figure BDA0001388737380000052
在25毫升两口瓶中加入化合物1a(319.8mg,1.50mmol)和4-硝基苄基膦酸二乙酯(430.3mg,1.575mmol)，用无水DMF(6mL)溶解，冰浴下慢慢加入叔丁醇钾(336.6mg,3.0mmol)，加毕，室温搅拌反应4小时，将反应体系慢慢倾入冰水中，析出固体，抽滤，收集固体，用乙酸乙酯重结晶得白色固体352mg，产率70.7％，Mp:116-117℃。1H NMR(400MHz,CDCl3)δ8.71(d,1H,J＝5.2 Hz),8.25(d,2H,J＝8.4Hz),7.90(s,1H),7.78(d,1H,J＝6.4Hz),7.69(d,2H,J＝ 8.4Hz),7.33-7.41(m,3H),7.24(d,1H,J＝16.4Hz),7.10(t,1H,J＝7.2Hz),7.04 (d,1H,J＝8.0Hz),3.90(s,3H).13C NMR(101MHz,CDCl3)δ157.05,156.93,149.96,147.40,143.13,142.76,131.23,131.17,130.26,130.21,128.84,127.49,124.22,122.99,121.13,118.83,111.45,55.76.HRMS(ESI)calcd for C20H17N2O3 [M+H]+:333.1234,Found:333.1233.
实施例4(E)-2-(5-氟-2-甲氧基苯基)-4-(4-硝基苯乙烯基)吡啶(2b)
Figure BDA0001388737380000061
按照实施例3的方法，用化合物1b(347mg,1.5mmol)替换1a，得白色固体 332mg，产率63.1％，Mp:140-141℃。1H NMR(400MHz,DMSO-d6)δ8.71(d, 1H,J＝5.2Hz),8.26(d,2H,J＝8.8Hz),7.96(s,1H),7.70(d,2H,J＝8.8Hz),7.58 (dd,1H,J1＝3.2Hz,J2＝9.6Hz),7.34-7.38(m,2H),7.24(d,1H,J＝16.4Hz),7.08 (td,1H,J1＝3.2Hz,J2＝8.8Hz),6.97(dd,1H,J1＝4.4Hz,J2＝9.2Hz),3.88(s,3H). 13C NMR(101MHz,CDCl3)δ158.54,156.17,155.70,155.69,153.23,153.21, 150.01,147.46,143.37,142.65,131.02,130.49,130.04,129.96,127.52,124.23, 122.89,119.27,117.79,117.55,116.27,116.04,112.78,112.70,56.42.HRMS(ESI) calcd for C20H15FN2NaO3[M+Na]+:373.0959,Found:373.0959.
实施例5(E)-3-(2-(2-(2-甲氧基苯基)吡啶-4-基)乙烯基)苯甲腈(2c)
Figure BDA0001388737380000062
按照实施例3的方法，用3-氰基苄基膦酸二乙酯(399mg,1.575mmol)替换 4-硝基苄基膦酸二乙酯，得白色固体426mg，产率88.3％，Mp:90-91℃。1H NMR(400MHz,CDCl3)δ8.71(d,1H,J＝5.2Hz),7.87(s,1H),7.82(s,1H),7.77 (d,1H,J＝1.6Hz),7.75(d,1H,J＝1.6Hz),7.60(d,1H,J＝8.0Hz),7.49(t,1H,J＝ 8.0Hz),7.42(td,1H,1H,J1＝1.6Hz,J2＝9.2Hz),7.32(dd,1H,J1＝1.6Hz,J2＝5.2 Hz),7.28(d,1H,J＝16.0Hz),7.07-7.15(m,2H),7.04(d,1H,J＝8.4Hz),3.89(s, 3H).13C NMR(101MHz,CDCl3)δ156.93,156.90,149.81,143.42,137.66,131.62, 131.18,131.02,130.33,130.29,130.18,129.68,129.34,128.81,122.90,121.10, 118.78,118.56,113.17,111.44,55.74.HRMS(ESI)calcd forC21H17N2O[M+H]+:313.1335,Found:313.1337.
实施例6(E)-3-(2-(2-(2-甲氧基苯基)吡啶-4-基)乙烯基)苯甲腈(2d)
Figure BDA0001388737380000063
按照实施例3的方法，用4-氰基苄基膦酸二乙酯(399mg,1.575mmol)替换 4-硝基苄基膦酸二乙酯，得白色固体286mg，产率59.2％，Mp:120-121℃。1H NMR(400MHz,CDCl3)δ8.70(d,1H,J＝5.2Hz),7.88(s,1H),7.77(dd,1H,J1＝2.0Hz,J2＝7.6Hz),7.70(d,2H,J＝8.4Hz),7.64(d,2H,J＝8.4Hz),7.42(ddd,1H, J1＝2.0Hz,J2＝7.6Hz,J3＝8.4Hz),7.27-7.33(m,2H),7.20(d,1H,J＝16.4Hz), 7.10(td,1H,J1＝0.8Hz,J2＝7.2Hz),7.03(d,1H,J＝8.4Hz),3.89(s,3H).13C NMR(101MHz,CDCl3)δ157.00,156.93,149.92,143.26,140.81,132.61,131.17, 130.72,130.39,130.18,128.89,127.40,122.92,121.12,118.80,111.44,55.75. HRMS(ESI)calcd for C21H17N2O[M+H]+:313.1335,Found:313.1338.
实施例7(E)-3-(2-(2-(5-氟-2-甲氧基苯基)吡啶-4-基)乙烯基)苯甲腈(2e)
Figure BDA0001388737380000071
按照实施例3的方法，用化合物1b(347mg,1.5mmol)替换1a，用3-氰基苄基膦酸二乙酯(399mg,1.575mmol)替换4-硝基苄基膦酸二乙酯，得白色固体 398mg，产率80.3％，Mp:185-186℃。1H NMR(400MHz,CDCl3)δ8.69(d,1H,J ＝5.2Hz),7.93(s,1H),7.83(s,1H),7.77(d,1H,J＝8.0Hz),7.55-7.61(m,2H), 7.50(t,1H,J＝8.0Hz),7.34(dd,1H,J1＝1.6Hz,J2＝5.2Hz),7.30(d,1H,J＝16.0 Hz),7.15(d,1H,J＝16.0Hz),7.10(ddd,1H,J1＝3.2Hz,J2＝8.0Hz,J3＝9.2Hz), 6.98(dd,1H,J1＝4.4Hz,J2＝8.8Hz),3.87(s,3H).13C NMR(101MHz,CDCl3) δ158.53,156.16,155.59,153.22,153.20,149.96,143.56,137.58,131.69,131.04, 130.44,130.34,130.09,130.02,129.70,129.18,122.77,119.18,118.55,117.78, 117.54,116.21,115.98,113.18,112.73,112.65,56.40.HRMS(ESI)calcd forC21H16FN2O[M+H]+:331.1241,Found:331.1241.
实施例8(E)-4-(2-(2-(2-甲氧基苯基)吡啶-4-基)乙烯基)苯胺(3a)
Figure BDA0001388737380000072
在25毫升圆底烧瓶中，加入化合物2a(249mg,0.75mmol)和无水氯化亚锡(713.1mg,3.75mmol)，用无水乙醇10mL溶解，100℃回流反应2个小时。反应结束后，将反应体系真空浓缩，浓缩物加乙酸乙酯超声分散，加饱和碳酸氢钠水溶液搅拌30分钟，抽滤，将滤液分取乙酸乙酯层，依次用水，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液真空浓缩，浓缩物柱层析分离纯化(石油醚：丙酮＝5:1)，得黄色固体 155.6mg，收率68.6％，Mp:142-143℃。1H NMR(400MHz,CDCl3)δ8.61(d,1H, J＝5.2Hz),7.78(s,1H),7.72(d,1H,J＝7.2Hz),7.35-7.40(m,3H),7.26(d,1H,J＝ 5.6Hz),7.23(d,J＝16.4Hz,1H),7.08(t,1H,J＝7.2Hz),7.01(d,1H,J＝8.4Hz), 6.87(d,1H,J＝16.4Hz),6.67(d,2H,J＝8.4Hz),3.87(s,3H).13C NMR(101MHz, CDCl3)δ156.93,156.56,149.52,147.13,145.16,132.90,131.16,129.85,129.40, 128.45,126.88,122.69,122.30,121.00,118.45,115.13,111.41,55.75.HRMS(ESI) calcd for C20H19N2O[M+H]+:303.1492,Found:303.1497.
实施例9(E)-4-(2-(2-(5-氟-2-甲氧基苯基)吡啶-4-基)乙烯基)苯胺(3b)
Figure BDA0001388737380000081
按照实施例8的方法，用化合物2b(263mg,0.75mmol)替换2a，得黄色固体 145mg，收率60.3％，Mp:152-153℃。1H NMR(400MHz,DMSO-d6)δ8.54(d, 1H,J＝5.2Hz),7.90(s,1H),7.54(dd,1H,J1＝3.2Hz,J2＝10.0Hz),7.45(dd,1H, J1＝1.2Hz,J2＝5.2Hz),7.36(m,3H),7.25(ddd,1H,J1＝3.2Hz,J2＝8.0Hz,J3＝ 9.2Hz),7.18(dd,1H,J1＝4.8Hz,J2＝9.2Hz),6.93(d,1H,J＝16.0Hz),6.58(d, 2H,J＝8.8Hz),5.51(s,2H),3.86(s,3H).13C NMR(101MHz,DMSO-d6)δ158.00, 155.65,154.73,154.71,153.70,153.68,150.29,149.92,145.87,134.27,130.42, 130.35,129.06,124.11,122.02,120.55,118.96,117.23,116.99,116.46,116.23, 114.24,114.03,113.95,56.76.HRMS(ESI)calcd forC20H17FN2NaO[M+Na]+:343.1223,Found:343.1225.
实施例10(E)-3-(2-(2-(2-羟基苯基)吡啶-4-基)乙烯基)苯甲腈(4a)
Figure BDA0001388737380000082
在25毫升圆底烧瓶中加入化合物2c(469mg,1.5mmol)，用无水二氯甲烷 (5mL)溶解，氮气保护，-35℃搅拌下，慢慢加入三溴化硼的二氯甲烷溶液(1.13g, 4.5mmol,5mL)，加毕，将反应体系缓慢升至室温，室温搅拌过夜。将反应体系加入到饱和碳酸氢钠水溶液中，析出黄色固体，抽滤，水洗，收集黄色固体，柱层析分离纯化(石油醚：丙酮＝6:1)得白色固体375mg，产率83.8％，Mp:178- 179℃。1H NMR(400MHz,CDCl3)δ14.27(s,1H),8.49(d,1H,J＝5.2Hz),7.95 (s,1H),7.84-7.87(m,2H),7.80(d,1H,J2＝8.0Hz),7.62(d,1H,J＝8.0Hz),7.53(t, 1H,J＝8.0Hz),7.33-7.36(m,2H),7.31(d,1H,J＝16.0Hz),7.15(d,1H,J＝16.0 Hz),7.04(dd,1H,J1＝0.8Hz,J2＝8.0Hz),6.96(td,1H,J1＝1.2Hz,J2＝8.4Hz). 13CNMR(101MHz,CDCl3)δ160.15,158.51,146.32,145.37,137.23,132.01, 131.72,131.49,131.12,130.46,129.80,128.59,126.07,118.85,118.74,118.72, 118.45,116.84,113.31.HRMS(ESI)calcd for C20H15N2O[M+H]+:299.1179, Found:299.1180.
实施例11(E)-4-(2-(2-(2-羟基苯基)吡啶-4-基)乙烯基)苯甲腈(4b)
Figure BDA0001388737380000091
按照实施例10的方法，用化合物2d(469mg,1.5mmol)替换2c，得白色固体 300mg，产率67.1％，Mp:189-190℃.1H NMR(400MHz,CDCl3)δ8.63(d,1H,J ＝5.2Hz),8.43(s,1H),8.13(d,1H,J＝7.2Hz),7.93(d,2H,J＝8.4Hz),7.83-7.88 (m,3H),7.65(d,1H,J＝4.8Hz),7.58(d,1H,J＝16.4Hz),7.35(t,1H,J＝6.8Hz), 6.93-6.99(m,2H).13C NMR(101MHz,DMSO-d6)δ159.79,157.89,147.15,146.39, 141.26,133.31,133.04,131.98,129.95,128.28,127.44,120.11,119.28,119.25, 118.44,117.57,111.21.HRMS(ESI)calcd forC20H14N2NaO[M+Na]+:321.0998, Found:321.0999.
实施例12(E)-3-(2-(2-(5-氟-2-羟基苯基)吡啶-4-基)乙烯基)苯甲腈(4c)
Figure BDA0001388737380000092
按照实施例10的方法，用化合物2e(496mg,1.5mmol)替换2c，得黄色固体229mg，产率48.3％，Mp:184-185℃。1H NMR(400MHz,DMSO-d6)δ13.99 (s,1H),8.64(d,1H,J＝5.2Hz),8.45(s,1H),8.17(s,1H),7.97-8.03(m,2H),7.86(d, 1H,J＝16.8Hz),7.84(d,1H,J＝7.6Hz),7.68(t,1H,J＝8.0Hz),7.61(d,1H,J＝ 5.2Hz),7.52(d,1H,J＝16.8Hz),7.22(td,1H,J1＝3.2Hz,J2＝8.8Hz),6.95(dd, 1H,J1＝4.8Hz,J2＝8.8Hz).13C NMR(101MHz,DMSO-d6)δ156.84,156.68, 156.65,155.99,154.52,147.37,146.70,137.90,132.82,132.50,132.24,130.86, 130.67,128.62,120.84,119.78,119.71,119.58,119.50,119.07,118.82,118.59, 117.56,113.29,113.05,112.57.HRMS(ESI)calcd for C20H13FN2NaO[M+Na]+:339.0900,Found:339.0903.
实施例13(E)-2-(4-(3-氨基苯乙烯基)吡啶-2-基)苯酚(I-1)
Figure BDA0001388737380000093
在25毫升圆底烧瓶中加入将化合物3a(02mg,1mmol)用无水二氯甲烷(5mL) 溶解，氮气保护，-35℃搅拌下，慢慢加入三溴化硼的二氯甲烷溶液(0.75g, 3.0mmol,5mL)，加毕，将反应体系慢慢升至室温，室温搅拌过夜反应。将反应体系慢慢加入饱和碳酸氢钠水溶液中，析出黄色固体，抽滤，收集固体，柱层析分离纯化(石油醚：丙酮＝4:1)得黄色固体134mg，产率46.4％，Mp:151-152℃。1H NMR(400MHz,DMSO-d6)δ14.52(s,1H),8.49(d,1H,J＝7.2Hz),8.27(s,1H), 8.13(dd,1H,J1＝1.2Hz,J2＝8.0Hz),7.60(d,1H,J＝16.4Hz),7.52(dd,1H,J1＝ 1.2Hz,J2＝5.6Hz),7.39(d,2H,J＝8.8Hz),7.31(m,1H),6.98(d,1H,J＝16.4Hz),6.96-6.90(m,2H),6.61(d,2H,J＝8.4Hz),5.59(s,2H).13C NMR(101 MHz,DMSO-d6)δ159.97,157.56,150.61,148.26,146.50,135.77,131.72,129.24, 127.30,123.97,120.00,119.29,119.11,119.05,118.38,116.23,114.27.HRMS(ESI) calcd for C19H17N2O[M+H]+:289.1341,Found:289.1338.
实施例14(E)-2-(4-(4-氨基苯乙烯基)吡啶-2-基)-4-氟苯酚(I-2)
Figure BDA0001388737380000101
按照实施例13的方法，用化合物3b(320mg,1mmol)替换化合物3a，得黄色固体126mg，产率41.2％，Mp:180-181℃。1H NMR(400MHz,DMSO-d6)δ 14.34(s,1H),8.50(d,1H,J＝5.6Hz),8.32(s,1H),8.03(dd,1H,J1＝3.2Hz,J2＝ 10.8Hz),7.65(d,1H,J＝16.4Hz),7.52(dd,1H,J1＝0.8Hz,J2＝5.2Hz),7.38(d, 2H,J＝8.4Hz),7.17(td,1H,J1＝3.2Hz,J2＝8.8Hz),6.97(d,1H,J＝16.4Hz), 6.93(dd,1H,J1＝5.2Hz,J2＝9.2Hz),6.61(d,2H,J＝8.4Hz),5.60(s,2H).13C NMR (101MHz,DMSO-d6)δ156.78,156.43,156.41,156.19,154.47,150.66,148.48, 146.68,136.06,129.24,123.95,119.81,119.77,119.70,119.47,119.40,118.57, 118.34,116.47,114.28,113.20,112.96.HRMS(ESI)calcd for C19H16FN2O[M+H]+:307.1241,Found:307.1237.
实施例15N'-羟基-3-((E)-2-(2-(2-羟基苯基)吡啶-4-基)乙烯基)苯甲酰胺(I-3)
Figure BDA0001388737380000102
在25毫升圆底烧瓶中，加入化合物4a(298mg,1mmol)、盐酸羟胺(208.5mg,3mmol)，用甲醇10mL溶解，室温搅拌下加入三乙胺(313mg,3.1mmol)，加毕，回流反应6个小时。反应结束后，将体系真空浓缩，浓缩物柱层析分离纯化(石油醚：丙酮＝3:1)得白色固体231mg，产率69.8％，Mp:185-186℃。1H NMR(400 MHz,DMSO-d6)δ14.32(s,1H),9.70(s,1H),8.60(d,1H,J＝5.2Hz),8.43(s,1H), 8.17(d,1H,J＝6.8Hz),8.04(s,1H),7.83(d,1H,J＝16.8Hz),7.69(t,2H,J＝8.0 Hz),7.64(d,1H,J＝4.4Hz),7.48(t,1H,J＝7.6Hz),7.41(d,1H,J＝16.8Hz),7.35 (td,1H,J1＝1.2Hz,J2＝8.4Hz),6.93-6.98(m,2H),5.92(s,2H).13CNMR(101 MHz,DMSO-d6)δ159.86,157.83,151.11,147.07,146.96,136.44,134.68,134.51,131.90,129.20,128.19,127.46,126.61,126.40,124.62,119.84,119.28,119.23,118.42,117.20.HRMS(ESI)calcd for C20H18N3O2[M+H]+:332.1394, Found:332.1390.
实施例16N'-羟基-4-((E)-2-(2-(2-羟基苯基)吡啶-4-基)乙烯基)苯甲酰胺(I-4)
Figure BDA0001388737380000111
按照实施例15的方法，用化合物4b(298mg,1mmol)替换4a，得白色固体 217mg，产率65.6％，Mp:205-206℃。1H NMR(400MHz,DMSO-d6)δ14.32(s, 1H),9.75(s,1H),8.59(d,1H,J＝5.2Hz),8.41(s,1H),8.16(dd,1H,J1＝1.2Hz,J2＝8.0Hz),7.82(d,1H,J＝16.8Hz),7.78(d,2H,J＝8.8Hz),7.71(d,2H,J＝8.8 Hz),7.64(d,1H,J＝7.6Hz),7.44(d,1H,J＝16.8Hz),7.35(td,1H,J1＝1.2Hz,J2＝ 8.4Hz),6.93-6.98(m,2H),5.88(s,2H).13C NMR(101MHz,DMSO-d6)δ159.85, 157.81,150.87,147.08,146.95,137.03,134.28,134.02,131.90,127.41,126.64, 126.26,119.81,119.27,119.23,118.42,117.20.HRMS(ESI)calcd for C20H17N3NaO2[M+Na]+:354.1213,Found:354.1211.
实施例17N'-羟基-3-((E)-2-(2-(5-氟-2-羟基苯基)吡啶-4-基)乙烯基)苯甲酰胺(I-5)
Figure BDA0001388737380000112
按照实施例15的方法，用化合物4c(316mg,1mmol)替换4a，得白色固体 120mg，产率34.4％，Mp:220-221℃。1H NMR(400MHz,DMSO-d6)δ14.13(s, 1H),9.70(s,1H),8.62(d,1H,J＝4.8Hz),8.48(s,1H),8.02-8.08(m,2H),7.89(d, 1H,J＝16.4Hz),7.64-7.70(m,3H),7.48(t,1H,J＝7.6Hz),7.41(d,1H,J＝16.4 Hz),7.21(t,1H,J＝7.2Hz),6.96(dd,1H,J1＝4.8Hz,J2＝8.4Hz),5.92(s,2H).13C NMR(101MHz,DMSO-d6)δ156.84,156.69,156.66,156.08,154.53,151.08, 147.26,147.17,136.41,134.95,134.53,129.22,128.17,126.43,124.62,120.66, 119.76,119.68,119.55,119.47,118.77,118.54,117.40,113.35,113.10.HRMS(ESI) calcd for C20H17FN3O2[M+H]+:350.1299,Found:350.1306.
实施例18本发明所合成的2-苯基-4-苯乙烯基吡啶化合物的LSD1抑制活性评价(一)酶水平LSD1抑制活性评价：
1、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，4℃保存放置，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:
Figure BDA0001388737380000121
试验结果采用SPSS软件计算IC50值。
2、实验结果
表1LSD1抑制活性测定结果
Figure BDA0001388737380000122
an.t.:未测定
从上表实验结果可以看出，本发明大部分的化合物具有较好的LSD1抑制活性，多个化合物的IC50小于1μM，活性强于阳性对照药物2-PCPA。其中活性最强是化合物I-3，LSD1抑制活性是2-PCPA的100多倍。本发明的化合物代表着一类结构全新的LSD1抑制剂，为LSD1抑制剂类药物的研发提供了基础，为LSD1的生物学功能研究提供了有效工具。
(二)体外抗肿瘤活性测定
1、实验方法
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128μmol/L溶液，4℃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150μL，培养24h后，弃去培养基，加入用培养基稀释好的不同浓度的药物(128μM、64μM、32μM、16μM、8μM、4μM、2μM、 1μM、0.5μM)，每个浓度设6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20μLMTT，继续培养4h后，吸去液体，加入150μL的DMSO，振荡均匀，酶标仪490nm处检测吸光度值，计算抑制率，计算公式如下:
抑制率(％)＝(1-给药组吸光度值/空白组吸光度值)×100％
2、实验结果
表2体外抗肿瘤活性评价结果
Figure BDA0001388737380000131
a人类结肠癌细胞，b人类乳腺癌细胞，c人类肝癌细胞
实验结果表明:所测试化合物均表现出较好的抗肿瘤活性，其中化合物I-3和 I-4对所测试的三种肿瘤细胞的抑制活性均优于阳性对照5-Fu，化合物I-3对SW- 620癌细胞的抑制活性是5-Fu的5倍，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。

Claims (2)

1.2-苯基-4-苯乙烯基吡啶类化合物，其特征在于，选自如下化合物：
Figure FDA0002362745330000011
Figure FDA0002362745330000012
2.如权利要求1所述的2-苯基-4-苯乙烯基吡啶类化合物，其特征在于，选自化合物I-3或I-4。
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