CN112209888A - 一种4-芳巯基喹唑啉类化合物、制备方法和医药用途 - Google Patents

一种4-芳巯基喹唑啉类化合物、制备方法和医药用途 Download PDF

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CN112209888A
CN112209888A CN202011093788.7A CN202011093788A CN112209888A CN 112209888 A CN112209888 A CN 112209888A CN 202011093788 A CN202011093788 A CN 202011093788A CN 112209888 A CN112209888 A CN 112209888A
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李中华
马金莲
秦婷婷
苗晋鑫
宋军营
谢治深
曾华辉
张振强
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Abstract

本发明公开了一种4‑芳巯基喹唑啉类化合物、制备方法和医药用途，该4‑芳巯基喹唑啉类化合物均为首次报道。研究发现，该4‑芳巯基喹唑啉类化合物具有LSD1抑制活性，具有开发成抗肿瘤药物的前景。以其中的化合物1为例，该化合物对LSD1蛋白抑制作用的IC50值为0.69μM，显著优于阳性对照；抗肿瘤测试中，该化合物对胃癌MGC‑803、胃癌BGC‑823、胃癌SGC‑7901、乳腺癌MCF‑7、肺癌H1650、肺癌A549、肺癌H1975、肺癌H460、食管癌EC‑109、肝癌HepG2、白血病THP‑1细胞均具有较强的抑制活性，具有开发成抗胃癌、乳腺癌、肺癌、食管癌、肝癌和白血病药物的前景。

Description

一种4-芳巯基喹唑啉类化合物、制备方法和医药用途
技术领域
本发明属于药物化学领域，涉及新化合物的合成和活性研究，具体涉及一种4-芳巯基喹唑啉类化合物、制备方法和医药用途。
背景技术
肿瘤严重危害人类的生命健康，给病人家属及社会带来沉重负担。目前已上市的抗肿瘤药物也有很多，但多数药物还存在比如毒性大、靶向性弱以及容易产生耐药性等弊端。因此，新型抗肿瘤药物的研发显得尤为重要，尤其是靶向药物的研究。
组蛋白共价修饰是一种重要的表观遗传模式，包括组蛋白乙酰化、甲基化、磷酸化以及泛素化等，其中乙酰化与甲基化是针对组蛋白修饰机制研究中比较多的组蛋白修饰方式。长期以来，组蛋白的甲基化修饰被认为是稳定的，不可逆的修饰行为，直到赖氨酸特异性组蛋白去甲基化酶(lysine specific demethylase 1，LSD1)的发现才揭开了组蛋白甲基化修饰研究的新篇章。LSD1可以催化去除组蛋白H3K4me1/2和H3K9me1/2的甲基化修饰，从而调节下游靶基因的转录。LSD1在多种肿瘤细胞中的表达量显著高于正常细胞，如神经母细胞瘤、眼癌、前列腺癌、乳腺癌、肺癌、膀胱癌等。研究表明，通过RNAi技术或小分子抑制剂在细胞水平降低LSD1表达量或降低LSD1的活性能抑制细胞增殖并诱导一些细胞分化相关基因的表达；在小分子单胺氧化酶抑制剂PCPA的作用下亦能抑制多种肿瘤细胞和实体瘤的生长。
因此，LSD1抑制剂不仅能作为表观遗传学的研究工具用于阐述其生物学功能，而且能作为表观遗传学药物用于肿瘤的预防和治疗，已经引起科研界的广泛关注，其特异性抑制剂在肿瘤治疗上极具应用前景。
发明内容
本发明的目的在于提供一种4-芳巯基喹唑啉类化合物、制备方法和医药用途。
本发明上述目的通过如下技术方案实现：
一种4-芳巯基喹唑啉类化合物，化学结构如通式I所示：
Figure BDA0002722997250000011
其中：
R1、R2为氢、卤素、甲氧基乙基、N取代的乙(丙)胺基或吗啉基；
R3为如下结构中的一种：
Figure BDA0002722997250000021
Figure BDA0002722997250000022
R为甲基、取代的苯基。
一种上述化合物的合成方法，合成路线如下：
Figure BDA0002722997250000023
其中：
R1、R2为氢、卤素、甲氧基乙基、N取代的乙(丙)胺基或吗啉基；
R3为如下结构中的一种：
Figure BDA0002722997250000024
Figure BDA0002722997250000025
R为甲基、取代的苯基。
上述化合物用于制备LSD1抑制剂药物的医药用途。
上述化合物用于制备抗肿瘤药物的医药用途。
优选地，所述化合物为如下化学结构的化合物，所述肿瘤为胃癌、乳腺癌、肺癌、食管癌、肝癌或白血病：
Figure BDA0002722997250000026
有益效果：
本发明提供的4-芳巯基喹唑啉类化合物均为首次报道。研究发现，该4-芳巯基喹唑啉类化合物具有LSD1抑制活性，具有开发成抗肿瘤药物的前景。以其中的化合物1为例，该化合物对LSD1蛋白抑制作用的IC50值为0.69μM，显著优于阳性对照；抗肿瘤测试中，该化合物对胃癌MGC-803、胃癌BGC-823、胃癌SGC-7901、乳腺癌MCF-7、肺癌H1650、肺癌A549、肺癌H1975、肺癌H460、食管癌EC-109、肝癌HepG2、白血病THP-1细胞均具有较强的抑制活性，具有开发成抗胃癌、乳腺癌、肺癌、食管癌、肝癌和白血病药物的前景。
具体实施方式
下面结合实施例具体介绍本发明实质性内容，但并不以此限定本发明的保护范围。
实施例1：4-(1,2,4-三氮唑-3-硫基)-6,7-二(2-甲氧基乙氧基)喹唑啉(化合物1)的制备
Figure BDA0002722997250000031
将6,7-二(2-甲氧基乙氧基)喹唑啉酮(50mmol)、三氯氧磷(150mmol)和N,N-二甲基苯胺(52.5mmol)加热至回流反应5小时。待反应冷却至室温后，减压蒸馏出过量的三氯氧磷，然后将浓缩液倒入冰水中。用饱和碳酸氢钠水溶液调至pH至中性，用乙酸乙酯萃取后减压蒸馏得4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉，粗品产率95％。直接用于下一步反应。
将4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉(1mmol)、3-巯基-1,2,4-三氮唑(1.05mmol)和无水碳酸钾(2mmol)加入15ml的乙腈中，加热回流3小时。待反应液冷却至室温后，减压蒸馏出乙腈，用水和乙酸乙酯萃取分离。有机相浓缩后抽滤即得纯品，产率68％，黄色固体。1HNMR(400MHz,DMSO-d6)δ8.65(s,1H),8.22(m,1H),7.56(br,1H),7.34(s,1H),7.32(s,1H),4.33(m,2H),4.25(m,2H),3.76–3.74(m,4H),3.36(s,3H),3.35(s,3H).13C NMR(100MHz,DMSO-d6)δ166.59,154.83,152.14,149.96,149.15,147.57,145.83,118.03,107.78,102.77,69.99,69.89,68.34,68.31,58.31.HRMS(ESI):Calcd.C16H19N5O4S,[M+H]+m/z:378.1236,found:378.1234.
实施例2：化合物2的制备
Figure BDA0002722997250000032
按制备化合物1的反应步骤，区别在于将3-巯基-1,2,4-三氮唑替换成4-甲基苯硫酚，得到化合物2，黄色固体,产率80％。1H NMR(400MHz,CDCl3)δ8.73(s,1H),7.51(m,2H),7.40(s,1H),7.29(d,J＝7.8Hz,2H),7.25(s,1H),4.34–4.29(m,4H),3.91–3.87(m,4H),3.51(s,3H),3.49(s,3H),2.42(s,3H).13C NMR(100MHz,DMSO-d6)δ167.01,155.42,152.70,149.83,146.00,140.00,136.18,130.63,124.01,117.95,108.36,102.78,70.54,70.41,68.88,58.84,58.82,21.35.HRMS(ESI):Calcd.C21H24N2O4S,[M+Na]+m/z:423.1354,found:423.1352.
实施例3：化合物3的制备
Figure BDA0002722997250000041
按制备化合物1的反应步骤，区别在于将3-巯基-1,2,4-三氮唑替换成4-甲氧基苯硫酚，得到化合物3，白色固体，产率86％。1H NMR(400MHz,DMSO-d6)δ8.53(s,1H),7.59(s,1H),7.40(s,1H),7.23(m,2H),7.02(m,2H),4.33(m,4H),3.80(s,3H),3.77(m,4H),3.37(s,6H).13C NMR(100MHz,DMSO-d6)δ165.52,157.22,155.44,152.78,149.72,149.12,146.13,123.48,116.14,115.03,110.21,108.09,102.49,70.56,70.46,68.82,68.80,58.84,58.80,55.91.ESI-MS:Calcd.C21H24N2O6,[M+Na]+m/z:423.15,found:423.22.
实施例4：化合物4的制备
Figure BDA0002722997250000042
按制备化合物1的反应步骤，区别在于将3-巯基-1,2,4-三氮唑替换成2-萘硫酚，得到化合物4，白色固体，产率95％。1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.29(m,1H),8.04–7.99(m,3H),7.66–7.59(m,3H),7.43(s,1H),7.38(s,1H),4.35(m,4H),3.77(m,4H),3.38(s,1H),3.36(s,1H).13C NMR(100MHz,DMSO-d6)δ166.32,155.04,152.21,149.44,145.63,135.09,133.29,132.91,132.19,128.75,127.80,127.65,127.39,126.71,124.80,117.59,107.91,102.39,70.06,69.92,68.44,68.41,58.35,58.33.ESI-MS:Calcd.C24H24N2O4S,[M+Na]+m/z:459.13,found:459.21.
实施例5：化合物5的制备
Figure BDA0002722997250000043
按制备化合物1的反应步骤，区别在于将3-巯基-1,2,4-三氮唑替换成2-巯基吡啶，得到化合物5，浅黄色固体，产率66％。1H NMR(400MHz,CDCl3)δ8.79(s,1H),8.65(m,1H),7.80–7.74(m,2H),7.41(s,1H),7.34–7.30(m,1H),7.28(m,1H),4.29–4.33(m,4H),3.89–3.87(m,4H),3.50(s,3H),3.49(s,3H).13C NMR(100MHz,CDCl3)δ165.74,155.64,152.80,152.71,150.52,149.89,146.80,137.14,129.97,123.19,119.48,108.04,103.50,70.60,70.40,68.82,68.59,59.35.HRMS(ESI):Calcd.C19H21N3O4S,[M+H]+m/z:388.1331,found:388.1330.
实施例6：化合物6的制备
Figure BDA0002722997250000051
按制备化合物1的反应步骤，区别在于将3-巯基-1,2,4-三氮唑替换成2-巯基嘧啶，得到化合物6，灰白色固体,产率75％。1H NMR(400MHz,CDCl3)δ9.04(s,1H),8.57(d,J＝4.8Hz,2H),7.49(s,1H),7.34(s,1H),7.13–7.09(m,1H),4.33(m,2H),4.22(m,2H),3.90–3.87(m,2H),3.84–3.82(m,2H),3.49(s,3H),3.47(s,3H).13C NMR(100MHz,CDCl3)δ168.33,160.95,157.07,156.86,155.02,152.15,149.40,147.39,121.51,117.46,106.83,103.53,69.49,69.35,67.75,67.69,58.35,58.34.HRMS(ESI):Calcd.C18H20N4O4S,[M+Na]+m/z:411.1103,found:411.1101.
实施例7：化合物7的制备
Figure BDA0002722997250000052
按制备化合物1的反应步骤，区别在于将3-巯基-1,2,4-三氮唑替换成2-巯基-1,3,4-噻二唑，得到化合物7，白色固体,产率84％。1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.95(s,1H),7.34(s,1H),7.30(s,1H),4.44–4.20(m,4H),4.00–3.79(m,4H),3.52(s,3H),3.50(s,3H).13C NMR(100MHz,DMSO-d6)δ159.91,157.52,157.25,155.65,151.31,149.95,146.12,117.43,107.95,101.89,70.02,69.86,68.62,68.59,58.34.HRMS(ESI):Calcd.C16H18N4O4S2,[M+Na]+m/z:395.0848,found:395.0846.
实施例8：化合物8的制备
Figure BDA0002722997250000053
按制备化合物1的反应步骤，区别在于将3-巯基-1,2,4-三氮唑替换成2-巯基-5-甲基-1,3,4-噻二唑，得到化合物8，白色固体,产率75％。1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),7.47(s,1H),7.40(s,1H),4.39(m,4H),3.78(m,4H),3.38(s,3H),3.36(s,3H),2.83(s,3H).13C NMR(100MHz,CDCl3)δ168.32,161.01,157.56,156.08,151.68,150.41,146.81,118.39,108.21,102.41,70.64,70.36,69.05,68.75,59.39,15.55.HRMS(ESI):Calcd.C17H20N4O4S2,[M+Na]+m/z:431.0824,found:431.0826.
实施例9：化合物9的制备
Figure BDA0002722997250000061
按制备化合物1的反应步骤，区别在于将3-巯基-1,2,4-三氮唑替换成2-巯基噻唑，得到化合物9，浅黄色固体,产率63％。1H NMR(400MHz,CDCl3)δ8.89(s,1H),7.97(d,J＝3.4Hz,1H),7.60(d,J＝3.4Hz,1H),7.31(d,J＝8.5Hz,2H),4.37–4.28(m,4H),3.89(dd,J＝9.3,3.9Hz,4H),3.51(s,3H),3.49(s,3H).13C NMR(100MHz,CDCl3)δ163.45,155.82,155.04,152.13,150.14,146.62,142.98,123.64,118.46,108.17,102.69,70.64,70.38,68.96,68.67,59.39,59.38.HRMS(ESI):Calcd.C17H19N3O4S2,[M+Na]+m/z:416.0715,found:416.0713.
实施例10：化合物10的制备
Figure BDA0002722997250000062
按制备化合物1的反应步骤，区别在于将3-巯基-1,2,4-三氮唑替换成2-巯基-1-甲基咪唑，得到化合物10，白色固体，产率68％。1HNMR(400MHz,CDCl3)δ8.90(s,1H),7.32(s,1H),7.30(s,1H),7.26(m,2H),4.35–4.32(m,4H),3.91–3.88(m,4H),3.51(s,3H),3.49(s,3H),2.86(s,3H).13C NMR(100MHz,CDCl3)δ168.31,160.97,157.55,156.06,151.66,150.39,146.79,118.36,108.19,102.37,70.63,70.36,69.04,68.74,59.38,15.54.ESI-MS:Calcd.C18H22N4O4S,[M+Na]+m/z:413.18,found:413.13.
实施例11：化合物11的制备
Figure BDA0002722997250000063
按制备化合物1的反应步骤，区别在于将3-巯基-1,2,4-三氮唑替换成1-甲基-5-巯基-1H-四氮唑，得到化合物11，浅棕色固体，产率71％。1HNMR(400MHz,CDCl3)δ8.66(s,1H),7.32(s,1H),7.27(s,1H),4.37–4.32(m,4H),4.14(s,3H),3.92–3.88(m,4H),3.52(s,3H),3.49(s,3H).13C NMR(100MHz,CDCl3)δ161.43,156.35,152.31,150.72,147.12,146.44,118.53,108.12,102.42,70.66,70.34,69.17,68.82,59.42,59.38,34.83.HRMS(ESI):Calcd.C16H20N6O4S,[M+Na]+m/z:415.1164,found:415.1164.
实施例12：化合物12的制备
Figure BDA0002722997250000071
按制备化合物1的反应步骤，区别在于将3-巯基-1,2,4-三氮唑替换成1-苯基-5-巯基四氮唑，得到化合物12，白色固体，产率79％。1H NMR(400MHz,CDCl3)δ8.63(s,1H),7.59(m,2H),7.46–7.42(m,3H),7.19(s,1H),4.31–4.29(m,4H),3.89–3.86(m,4H),3.49(s,3H),3.48(s,3H).13C NMR(100MHz,CDCl3)δ161.68,156.23,152.34,150.59,147.06,146.56,133.89,130.56,129.42,124.82,118.72,108.06,102.50,70.64,70.33,69.11,68.78,59.40,59.37.HRMS(ESI):Calcd.C21H22N6O4S,[M+Na]+m/z:477.1321,found:477.1302.
实施例13：化合物13的制备
Figure BDA0002722997250000072
按制备化合物1的反应步骤，区别在于将3-巯基-1,2,4-三氮唑替换成5-巯基-1-对甲氧基苯基四氮唑，得到化合物13，浅黄固体，产率65％。1HNMR(400MHz,CDCl3)δ8.64(s,1H),7.48(d,J＝8.1Hz,2H),7.27(m,1H),7.18(s,1H),6.91(d,J＝8.1Hz,2H),4.30(m,4H),3.87(m,4H),3.80(s,3H),3.49(s,3H),3.48(s,3H).13C NMR(100MHz,DMSO-d6)δ162.33,161.10,156.22,152.50,150.55,147.95,146.71,127.35,126.44,118.13,115.02,108.29,102.60,70.54,70.33,69.10,69.08,58.83,58.82,56.03.ESI-MS:Calcd.C22H24N6O5S,[M+Na]+m/z:507.14,found:507.19.
实施例14：化合物14的制备
Figure BDA0002722997250000081
按制备化合物1的反应步骤，区别在于将3-巯基-1,2,4-三氮唑替换成5-巯基-1-对溴苯基四氮唑，得到化合物14，白色固体，产率71％。1HNMR(400MHz,CDCl3)δ8.60(s,1H),7.59(d,J＝8.6Hz,2H),7.51(d,J＝8.5Hz,2H),7.26(s,1H),7.18(s,1H),4.35–4.26(m,4H),3.87(m,4H),3.50(s,3H),3.48(s,3H).13C NMR(100MHz,CDCl3)δ161.41,156.31,152.27,150.68,147.13,146.52,132.85,132.72,126.30,124.88,118.63,108.11,102.39,70.64,70.32,69.14,68.81,59.41,59.37.HRMS(ESI):Calcd.C21H21BrN6NaO4S,[M+H]+m/z:555.0426,found:555.0425.
实施例15：化合物15的制备
Figure BDA0002722997250000082
按制备化合物1的反应步骤，区别在于将3-巯基-1,2,4-三氮唑替换成5-巯基-1-对氯苯基四氮唑，得到化合物15，浅黄色固体，产率59％。1HNMR(400MHz,CDCl3)δ8.61(s,1H),7.57(m,2H),7.44–7.42(m,2H),7.26(m,1H),7.18(s,1H),4.31(m,4H),3.89–3.86(m,4H),3.50(s,3H),3.48(s,3H).13C NMR(100MHz,CDCl3)δ161.43,156.32,152.29,150.70,147.15,146.56,136.80,132.35,129.73,126.09,118.65,108.14,102.43,70.65,70.33,69.15,68.81,59.41,59.37.HRMS(ESI):Calcd.C21H21ClN6O4S,[M+H]+m/z:489.1112,found:489.1110.
实施例16：化合物16的制备
Figure BDA0002722997250000083
按制备化合物1的反应步骤，区别在于将4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉替换成4-氯喹唑啉，得到化合物16，白色固体，产率71％。1H NMR(400MHz,DMSO-d6)δ9.71(m,1H),9.16(s,1H),8.97(s,1H),8.00–7.95(m,2H),7.78–7.74(m,1H),7.38(br,1H).13C NMR(100MHz,DMSO-d6)δ153.54,152.60,151.62,147.35,134.26,128.41,128.25,127.59,127.24,115.35.ESI-MS:Calcd.C10H7N5S,[M+Na]+m/z:252.03,found:252.08.
实施例17：化合物17的制备
Figure BDA0002722997250000091
按制备化合物1的反应步骤，区别在于将4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉替换成4-氯-6,7-二甲氧基喹唑啉，得到化合物17，白色固体，产率72％。1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.21(s,1H),7.46(br,1H),7.31(s,1H),7.27(s,1H),3.97(s,3H),3.91(s,3H).13C NMR(100MHz,DMSO-d6)δ169.01,155.62,153.22,152.57,149.97,146.50,146.41,118.78,107.32,102.48,56.52,56.29.ESI-MS:Calcd.C12H11N5O2S,[M+H]+m/z:290.07,found:290.06.
实施例18：化合物18的制备
Figure BDA0002722997250000092
按制备化合物1的反应步骤，区别在于将4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉替换成7-苄氧基-4-氯-6-甲氧基喹唑啉，得到化合物18，白色固体，产率65％。1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.79(s,1H),7.50(m,,2H),7.43(m,2H),7.38(m,2H),7.28(m,2H),5.30(s,2H),3.85(s,3H).13C NMR(100MHz,DMSO-d6)δ168.41,154.07,152.52,152.06,150.03,149.63,146.14,145.78,136.03,128.49,128.12,128.05,118.34,108.06,102.18,79.19,70.18,55.85.HRMS(ESI):Calcd.C18H15N5O2S,[M+H]+m/z:366.1025,found:366.1022.
实施例19：化合物19的制备
Figure BDA0002722997250000093
按制备化合物1的反应步骤，区别在于将4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉替换成4-氯-7-甲氧基-6-[3-(吗啉-4-基)丙氧基]喹唑啉，得到化合物19，灰白色固体，产率68％。1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.80(s,1H),7.35(br,1H),7.27(m,2H),4.08(t,J＝6.0Hz,2H),3.96(s,3H),3.59(m,4H),2.51(m,2H),2.39(m,4H),1.99–1.93(m,2H).13C NMR(100MHz,DMSO-d6)δ168.94,155.76,153.24,152.56,149.31,146.27,118.73,107.41,103.15,100.00,67.32,66.69,56.55,55.28,53.86,26.07.HRMS(ESI):Calcd.C18H22N6O3S,[M+H]+m/z:403.1551,found:403.1552.
实施例20：LSD1抑制活性测试
化合物1～19按照实施例1～19制备，纯度不低于98％，作为待测样品。阳性对照品为苯环丙胺(TCP)。
样品储备液：称取适量样品用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。
将不同浓度的待测样品(1.25μL)与LSD1重组蛋白(0.25μM)于HEPES缓冲液中室温孵育10分钟，加入LSD1反应底物H3K4me2(2.5μL，终浓度为25μM)于37℃孵育反应30分钟。最后分别加入荧光染料Amplex Red溶液(0.1μL)和辣根过氧化酶HRP(1μL)室温孵育5分钟。然后在荧光酶标仪上激发光530nm、发射光590nm检测荧光强度。每板同时设定空白对照孔与100％对照孔。空白孔中样品与H3K4me2分别用1.25μL的DMSO与2.5μL的缓冲液代替，100％孔中样品用1.25μL的DMSO替代。根据如下公式计算不同浓度待测样品对LSD1蛋白的抑制率：
Figure BDA0002722997250000101
根据不同浓度待测样品对LSD1蛋白的抑制率，采用SPSS软件计算待测样品对LSD1蛋白抑制作用的IC50值。实验结果如表1所示。
表1化合物1～20对LSD1蛋白的抑制作用
Figure BDA0002722997250000102
Figure BDA0002722997250000111
上述结果表明，化合物1、6、14、18、19具有较强的LSD1抑制活性，且化合物1最强，IC50值为0.69μM，显著优于阳性对照TCP。
实施例21：抗肿瘤活性测试
以LSD1抑制活性最强的化合物1为例，测试了其对不同肿瘤细胞的抑制活性。化合物1按照实施例1制备，纯度不低于98％。
化合物1储备液：称取适量化合物1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。
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4000-8000个cell/孔接种至96孔板中，每孔100μL，培养24h后，弃去培养基，加入用培养基稀释好的药物，每个浓度设3个复孔，另设空白对照组。药物作用72h后，每孔加入20μLMTT溶液，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，计算不同浓度化合物1对不同肿瘤细胞的抑制率，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％
根据不同浓度化合物1对不同肿瘤细胞的抑制率，采用SPSS软件计算化合物1对不同肿瘤细胞抑制作用的IC50值。实验结果如表2所示。
表2化合物1对不同肿瘤细胞抑制作用的IC50值
肿瘤细胞株 肿瘤类型 IC<sub>50</sub>(μM)
MGC-803 胃癌 9.21
BGC-823 胃癌 15.32
SGC-7901 胃癌 10.89
GES-1 正常胃粘膜上皮细胞 >50
MCF-7 乳腺癌 38.52
H1650 肺癌 17.21
A549 肺癌 9.51
H1975 肺癌 26.55
H460 肺癌 28.21
PC-3 前列腺癌 >50
EC-109 食管癌 9.65
HepG2 肝癌 16.22
THP-1 白血病 2.20
结果表明，化合物1对胃癌MGC-803、胃癌BGC-823、胃癌SGC-7901、乳腺癌MCF-7、肺癌H1650、肺癌A549、肺癌H1975、肺癌H460、食管癌EC-109、肝癌HepG2、白血病THP-1细胞具有较强的抑制活性，对前列腺癌PC-3细胞无明显抑制作用，因此，化合物1具有开发成抗胃癌、乳腺癌、肺癌、食管癌、肝癌和白血病药物的前景。同时，该化合物对正常胃粘膜上皮细胞GES-1无明显抑制作用，说明该化合物对正常细胞毒性低，安全性高。
上述实施例的作用在于具体介绍本发明的实质性内容，但本领域技术人员应当知道，不应将本发明的保护范围局限于该具体实施例。

Claims (5)

1.一种4-芳巯基喹唑啉类化合物，其特征在于，化学结构如通式I所示：
Figure FDA0002722997240000011
其中：
R1、R2为氢、卤素、甲氧基乙基、N取代的乙(丙)胺基或吗啉基；
R3为如下结构中的一种：
Figure FDA0002722997240000012
Figure FDA0002722997240000013
R为甲基、取代的苯基。
2.权利要求1所述化合物的合成方法，其特征在于，合成路线如下：
Figure FDA0002722997240000014
其中：
R1、R2为氢、卤素、甲氧基乙基、N取代的乙(丙)胺基或吗啉基；
R3为如下结构中的一种：
Figure FDA0002722997240000015
Figure FDA0002722997240000016
R为甲基、取代的苯基。
3.权利要求1所述化合物用于制备LSD1抑制剂药物的医药用途。
4.权利要求1所述化合物用于制备抗肿瘤药物的医药用途。
5.根据权利要求4所述的医药用途，所述化合物为如下化学结构的化合物，所述肿瘤为胃癌、乳腺癌、肺癌、食管癌、肝癌或白血病：
Figure FDA0002722997240000017
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