CN109942547B - 具有生物活性的新型喹啉取代三氮唑类化合物及其合成方法和应用 - Google Patents
具有生物活性的新型喹啉取代三氮唑类化合物及其合成方法和应用 Download PDFInfo
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Abstract
本发明公开了一种具有生物活性的新型喹啉取代三氮唑类化合物及其合成方法和应用,属于具有生物活性的喹啉及三氮唑衍生物技术领域。本发明的技术方案要点为:具有生物活性的新型喹啉取代三氮唑类化合物,其结构式为:
Description
技术领域
本发明属于具有生物活性的喹啉及三氮唑衍生物技术领域,具体涉及一种具有生物活性的新型喹啉取代三氮唑类化合物及其合成方法和应用。
背景技术
目前,非传染性疾病已经成为全球人群的主要死因,癌症也将预计成为21世纪全球范围内致死率第一的疾病。而且在经济发展水平较高的国家中,脑卒和冠心病的死亡率相对下降,导致癌症将会是阻碍寿命增长的主要和唯一的的疾病[1]。因此,加紧展开预防和治疗癌症的各种工作,如何有效治疗癌症已成为当前的热点研究领域。
含氮杂环化合物因为具有在自然界中广泛存在、是药物的重要组成结构等特点而备受关注[2-4]。其中,喹啉及其衍生物是一类具有生物活性的含氮杂环化合物,该类化合物会表现出抗菌[5]、抗HIV-1[6]、抗结核[7]等活性。另外,由于喹啉及其衍生物的低毒、高效、对环境友好、结构变化多样等特点,还被广泛的应用于农药研究。
1,2,3-三氮唑类化合物具有抗真菌、抗肿瘤和抗炎等多种生物活性。而且,1,2,3-三氮唑类化合物还拥有稳定性较好、易于制备等特点,在药物化学领域备受青睐,引起了药物化学家的持续关注[8]。
参考文献:
[1]王宁,刘硕,杨雷.等2018全球癌症统计报告解读[J].肿瘤综合治疗电子杂志,2019, 5(1):87-97。
[2]BrichacekM,Villalobos M,Plichta A,et al.Stereospecificringexpansion of chiral vinyl aziridines[J].Org Lett,2011,13:1110-1113。
[3]Mack D,Njardarson J.New mechanistic insightsinto the coppercatalyzed ring expansion of vinyl aziridines:evidence in support of a copper(I)mediated pathway[J].ChemSci,2012,3: 3321-3325。
[4]周红,张颖,周元敬.等含氮杂环化合物的烷基化反应及其医学应用[J].贵州科学,2016, 34(6):51-56。
[5]Dolan N,Gavind P,Eshwika A,et al.Synthesis,antibacterial and anti-MRSA activity, in vivo toxicity and a structure-activity relationship studyof a quinolinethiourea[J].Bioorg Med ChemLett,2016,26(2):630-635。
[6]Moret V,Dereudre-bosquet N,Clayette P,et al.Synthesis and anti-HIVproperties of new hydroxyquinolinepolyamine conjugates on cells infected byHIV-1LAV and HIV-1BaL viral strains[J].Bioorg Med ChemLett,2006,16(23):5 988-5 992。
[7]Jain P P,Degani M S,Raju A,et al.Identification of a novel classof quinoline-oxadiazole hybrids as anti-tuber-culosis agents[J].Bioorg MedChemLett,2016,26(2):645-64。
[8]郭新乐,于志,鄢笑非.等1,2,3-三氮唑类化合物的生物活性[J].World Noteson Antibiotics, 2018,39(4):286-298。
发明内容
本发明解决的技术问题是提供了一种具有生物活性的新型喹啉取代三氮唑类化合物及其合成方法,该新型喹啉取代三氮唑类化合物对SHP1(含有SH2结构域的蛋白酪氨酸磷酸酶1)和SHP2(含有SH2结构域的蛋白酪氨酸磷酸酶2)均具有较好的抑制作用,能够作为SHP1靶点的酶活抑制剂和SHP1靶点的酶活抑制剂进一步用于制备抗癌类药物。
本发明为解决上述技术问题采用如下技术方案,具有生物活性的新型喹啉取代三氮唑类化合物,其特征在于该新型喹啉取代三氮唑类化合物的结构式为:
其中R为氢、氟、氯、溴、甲基、三氟甲基或甲氧基;
其中R为氢、氟、氯、溴、甲基、甲氧基或三氟甲基,R1为氯或甲氧基;
其中R为氢、氟、氯、溴、甲基、三氟甲基或甲氧基;
该新型喹啉取代三氮唑类化合物作为SHP1靶点的酶活抑制剂通过直接去磷酸化调节细胞内信号蛋白分子的酪氨酸磷酰化水平抑制细胞的有丝分裂增殖、分化和生物活性,在造血系统中抑制白细胞生长,在乳腺癌、卵巢癌或前列腺癌细胞中,抑制SHP1表达量下调,进而抑制对应癌症的发生;该新型喹啉取代三氮唑类化合物作为SHP2靶点的酶活抑制剂通过参与多个信号传导通路介导细胞的生长、分化、迁移、粘附和调亡,在肺癌、胃癌、宫颈癌、甲状腺癌和乳腺癌细胞中,抑制SHP2表达量下调,进而抑制对应癌症的发生。
本发明所述的具有生物活性的新型喹啉取代三氮唑类化合物合成方法,其特征在于具体合成路线为:
本发明所述的具有生物活性的新型喹啉取代三氮唑类化合物在制备抗癌药物中的应用。
本发明所述的具有生物活性的新型喹啉取代三氮唑类化合物作为SHP1靶点的酶活抑制剂和SHP1靶点的酶活抑制剂用于制备抗癌药物。
本发明鉴于喹啉基团和三氮唑类化合物的良好活性,根据活性拼接原理,将喹啉基团引入到三氮唑中获得具有生物活性的新型喹啉取代三氮唑类化合物,该新型喹啉取代三氮唑类化合物作为SHP1靶点的酶活抑制剂通过直接去磷酸化调节细胞内信号蛋白分子的酪氨酸磷酰化水平抑制细胞的有丝分裂增殖、分化和生物活性,在造血系统中抑制白细胞生长,在乳腺癌、卵巢癌或前列腺癌细胞中,抑制SHP1表达量下调,进而抑制对应癌症的发生;该新型喹啉取代三氮唑类化合物作为SHP2靶点的酶活抑制剂通过参与多个信号传导通路介导细胞的生长、分化、迁移、粘附和调亡,在肺癌、胃癌、宫颈癌、甲状腺癌和乳腺癌细胞中,抑制SHP2表达量下调,进而抑制对应癌症的发生,在抗癌药物制备领域具有较好的应用前景。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明,但不应该将此理解为本发明上述主题的范围仅限于以下的实施例,凡基于本发明上述内容实现的技术均属于本发明的范围。
1、化合物的合成
4-(2-芳基)喹啉甲酸1的合成
反应步骤:
向250mL圆底烧瓶中加入27mmol 2,3-吲哚二酮和23mmol取代基苯乙酮,再加入20mL无水乙醇将两者溶解,然后加入14mL 34wt%KOH水溶液,于80℃回流反应,每小时 TLC监测一次,反应结束后在冰浴条件下加入2M盐酸中和反应体系至弱酸性,此时反应体系有大量固体析出,真空抽滤所得滤饼用大量水洗处理盐,再用二氯甲烷洗去未反应的原料及副产物,收集并烘干滤饼得到化合物1。
4-(2-芳基)喹啉甲酸甲酯2的合成
反应步骤:
向100mL圆底烧瓶中加入24mmol化合物1,再加入25mL甲醇将其溶解,在冰浴条件下缓慢滴加7.4mL浓硫酸,于70℃油浴锅磁力搅拌回流反应约8h,反应结束后加20mL 水淬灭反应,然后向反应体系加入饱和碳酸钠水溶液调节反应体系的pH呈弱碱性,然后用(5×30mL)乙酸乙酯萃取,合并有机相并用无水硫酸钠干燥,减压蒸馏,再采用柱色谱分离(石油醚与乙酸乙酯的体积比为100:1)得到化合物2。
4-(2-芳基)喹啉甲醇3的合成
反应步骤:
在250mL圆底烧瓶中加入20mmol化合物2和60mmol硼氢化钠,再加入180mL无水乙醇将两者溶解,于80℃回流反应,每小时采用薄层色谱监测法监测一次至反应结束。将反应体系冷却至室温,后加入约100mL水淬灭反应,有白色固体析出,抽滤并真空干燥得到化合物3。
4-((丙-2-炔-1-基氧基)甲基)喹啉4的合成
反应步骤:
在氮气保护下将20mmol化合物3和氢化钠溶解在25mL干燥四氢呋喃中,放入25℃油浴锅中搅拌1小时后,滴加等当量的溴丙炔,每6小时采用薄层色谱监测法监测一次至反应结束。向反应体系加饱和氯化铵淬灭反应,然后用乙酸乙酯(3×40mL)萃取水相,合并有机相并用无水硫酸钠干燥除水,减压蒸馏得到粗产物,然后采用柱色谱分离(石油醚:乙酸乙酯=40:1)粗产物得到产物4。
4-(((1-R’基-1H-1,2,3-三唑-4-基)甲氧基基)甲基)-2-(R苯基)喹诺酮5的合成
反应步骤:
将0.55mmol化合物4溶于6mL的THF溶液中,再加入0.66mmol抗坏血酸钠,将0.33mmol无水硫酸铜用0.5mL水溶解后加入到上述混合溶液中,在N2氛围下反应,每 20min采用薄层色谱监测法监测一次至反应结束。加入饱和氯化铵溶液淬灭反应,然后用 (3×10mL)二氯甲烷萃取,合并有机相并用无水硫酸钠干燥,减压蒸馏,采用柱色谱分离(石油醚与乙酸乙酯的体积比为2:1)得到化合物5。
化合物的数据表征:
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-氟苯基)喹啉(VI-5a):淡绿色固体,收率:93%;m.p.122-123℃;1H NMR(600MHz,DMSO)δ8.31(dd,J=9.0,5.4Hz,2H),8.26(s, 1H),8.11(s,1H),8.09(d,J=8.4Hz,1H),8.03(d,J=7.8Hz,1H),7.78(t,J=7.2Hz,1H),7.58 (t,J=7.2Hz,1H),7.39–7.33(m,4H),7.31(dd,J=13.8,6.8Hz,3H),5.61(s,2H),5.11(s,2H), 4.76(s,2H).13C NMR(151MHz,CDCl3)δ164.6,162.9,156.0,148.2,145.0,143.7,135.7, 134.4,130.2,129.49,129.4,129.3,129.1,128.8,128.1,126.4,125.0,123.0,122.6,117.0,115.7, 115.6,69.1,64.2,54.2.HRMS(ESI),m/zcalcd.forC26H22FN4O([M+H]+)425.1772,found: 425.1774。
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-氯苯基)喹啉(VI-5b):土黄色固体,收率:81%;m.p.142-144℃;1H NMR(400MHz,CDCl3)8.15(d,J=8.4Hz,1H),8.11(d,J=8.6 Hz,2H),7.90(t,J=3.6Hz,2H),7.70(t,J=8.2Hz,1H),7.50(d,J=8.2Hz,1H),7.46(d,J= 9.4Hz,3H),7.37–7.33(m,3H),7.25(d,J=3.2Hz,1H),5.50(s,2H),5.08(s,2H),4.82(s, 2H).13C NMR(151MHz,CDCl3)δ155.8,148.1,145.0,143.9,137.9,135.5,134.3,130.3,129.6, 129.1,128.9,128.8,128.1,126.5,125.1,123.0,122.6,117.0,69.0,64.2,54.2.HRMS(ESI),m/z calcd.forC26H22ClN4O([M+H]+)441.1477,found:441.1488。
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-溴苯基)喹啉(VI-5c):橘黄色固体,收率:89;m.p.145-146℃;1H NMR(400MHz,CDCl3)δ8.16(d,J=8.2Hz,1H),8.06(d,J=8.6 Hz,2H),7.92(t,J=3.8Hz,2H),7.72(t,J=7.2Hz,1H),7.64(d,J=8.6Hz,2H),7.52(t,J= 8.2Hz,1H),7.48(s,1H),7.40–7.34(m,3H),7.28(d,J=3.5Hz,2H),5.53(s,2H),5.11(s,2H), 4.84(s,2H).13C NMR(151MHz,CDCl3)δ155.9,148.2,145.0,144.0,138.4,134.4,131.9, 130.4,129.6,129.19,129.1,128.9,128.2,126.6,125.2,124.0,123.0,122.7,117.0,69.1,64.3, 54.3。
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(对甲苯基)喹啉(VI-5d):淡棕色固体,收率:95%;m.p.113-115℃;1H NMR(400MHz,CDCl3)δ8.17(d,J=8.24Hz,1H),8.07(d,J= 8.0Hz,2H),7.92(t,J=3.8Hz,2H),7.70(t,J=8.2Hz,1H),7.50(s,1H),7.48(d,J=5.2Hz, 2H),7.38–7.30(m,5H),7.27(s,1H),7.25(d,J=2.0Hz,1H),5.51(s,2H),5.09(s,2H),4.82 (s,2H),2.43(s,3H).13C NMR(151MHz,CDCl3)δ159.9,157.2,148.3,143.5,139.5,136.8, 130.3,129.6,129.4,127.5,126.3,123.0,122.3,117.5,114.8,69.5,64.3,55.6,21.4.HRMS (ESI),m/z calcd.forC27H25N4O([M+H]+)421.2023,found:421.2030。
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-(三氟甲基)苯基)喹啉(VI-5e):白色固体,收率:81%;m.p.129-130℃;1H NMR(400MHz,CDCl3)δ8.29(d,J=8.0Hz,2H),8.20(d, J=8.0Hz,1H),7.98(s,1H),7.94(d,J=8.8Hz,1H),7.77(d,J=8.4Hz,2H),7.73(d,J=6.8 Hz,1H),7.54(t,J=7.2Hz,1H),7.49(s,1H),7.36(dd,J=5.0,1.8Hz,3H),7.28(d,J=3.2Hz, 2H),5.53(s,2H),5.13(d,J=0.7Hz,2H),4.85(s,2H).13C NMR(151MHz,CDCl3)δ155.5, 148.2,144.9,144.2,142.87,134.4,130.5,129.7,129.1,128.8,128.1,127.8,126.9,125.7,125.6, 125.3,123.0,122.6,117.1,69.0,64.3,54.2.HRMS(ESI),m/zcalcd.forC27H23F3N4O([M+H]+) 475.1740,found:475.1742。
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-甲氧基苯基)喹啉(VI-5f):淡黄色固体,收率:95%;m.p.109-110℃;1H NMR(400MHz,CDCl3)δ8.14(d,J=8.8Hz,3H),7.91(d,J =7.6Hz,2H),7.69(t,J=8.2Hz,1H),7.53–7.43(m,2H),7.36(dd,J=5.0,1.8Hz,3H),7.27 (d,J=6.4Hz,2H),7.04(d,J=9.0Hz,2H),5.52(s,2H),5.09(s,2H),4.83(s,2H).3.89(s, 3H).13C NMR(151MHz,CDCl3)δ160.9,156.7,148.3,145.2,143.4,134.5,132.2,130.2,129.4, 129.2,128.9,128.8,128.2,126.0,124.9,123.1,122.7,117.2,114.2,69.3,64.3,55.4,54.2.HRMS (ESI),m/z calcd.forC27H25N4O2([M+H]+)437.1972,found:437.1986。
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-苯基喹啉(VI-5g):米黄色固体,收率:88%;m.p.131-132℃;1H NMR(400MHz,CDCl3)δ8.22–8.13(m,3H),7.94(d,J=7.2Hz, 2H),7.71(t,J=8.4Hz,1H),7.56–7.43(m,5H),7.36(d,J=5.2Hz,3H),7.27(d,J=3.2Hz, 2H),5.52(s,2H),5.11(s,2H),4.83(s,2H).13C NMR(151MHz,CDCl3)δ157.1,148.2,145.0, 143.6,139.5,134.3,130.3,129.4,129.3,129.1,128.8,128.8,128.1,127.5,126.3,125.1,123.0, 122.6,117.6,77.2,77.0,76.7,69.2,64.2,54.2.HRMS(ESI),m/zcalcd.forC26H23N4O([M+H]+) 407.1866,found:407.1873。
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(2-氯苯基)喹啉(VI-5h):橘黄色固体,收率:78%;m.p.91-92℃;1H NMR(400MHz,CDCl3)δ8.19(d,J=8.0Hz,1H),7.99(d,J=8.4 Hz,1H),7.80(s,1H),7.74(t,J=8.4Hz,1H),7.67(dd,J=7.2,2.1Hz,1H),7.56(t,J=8.4Hz, 1H),7.52–7.48(m,1H),7.47(s,2H),7.43–7.32(m,5H),7.27(d,J=6.4Hz,2H),5.52(s,2H), 5.12(s,2H),4.82(s,2H).13C NMR(151MHz,CDCl3)δ157.3,148.1,145.2,142.7,139.6, 134.4,132.4,131.7,130.4,130.1,129.9,129.5,129.2,128.8,128.2,127.2,126.9,125.2,123.2, 122.6,121.2,69.2,64.4,54.2.HRMS(ESI),m/zcalcd.forC26H22ClN4O([M+H]+)441.1477, found:441.1477。
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(3-氯苯基)喹啉(VI-5i):橘黄色油状物;收率:80%;1H NMR(600MHz,CDCl3)δ8.17(d,J=12.6Hz,2H),8.01(d,J=5.0Hz,1H), 7.90(d,J=7.2Hz,2H),7.70(t,J=7.2Hz,1H),7.53–7.46(t,J=7.2Hz,2H),7.41(s,2H), 7.34(d,J=5.4Hz,3H),7.25(s,2H),5.50(s,2H),5.09(s,2H),4.83(s,2H).13C NMR(151 MHz,CDCl3)δ155.5,148.1,145.0,144.0,141.3,134.8,134.3,130.3,130.0,129.6,129.3, 129.1,128.8,128.1,127.6,126.7,125.6,125.2,123.0,122.6,117.0,69.0,64.3,54.2.HRMS (ESI),m/z calcd.forC26H22ClN4O([M+H]+)441.1477,found:441.1479。
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(3-溴苯基)喹啉(VI-5j):橘黄色油状物;收率:83%;1H NMR(400MHz,CDCl3)δ8.35(t,J=1.8Hz,1H),8.18(d,J=8.4Hz,1H),8.08 (d,J=8.0Hz,1H),7.93(d,J=11.2Hz,2H),7.73(t,J=8.2Hz,1H),7.58(d,J=8.0Hz,1H), 7.52(t,J=7.2Hz,1H),7.49(s,1H),7.41–7.33(m,4H),7.28(d,J=3.0Hz,2H),5.53(s,1H), 5.11(s,1H),4.84(s,1H).13C NMR(151MHz,CDCl3)δ155.4,148.1,145.0,144.0,141.6, 134.3,132.2,130.6,130.4,130.3,129.6,129.1,128.8,128.1,126.7,126.1,125.2,123.1,130.0, 122.6,117.1,69.0,64.3,54.2。
2-(4-氟苯基)-4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)喹啉(VI-6a):白色固体;收率:92%;m.p.134-136℃;1H NMR(400MHz,CDCl3)δ8.18(t,J=7.2Hz,3H),7.97 (d,J=10.4Hz,2H),7.93(s,1H),7.72(t,J=7.6Hz,1H),7.60(d,J=8.8Hz,2H),7.54(t,J= 7.2Hz,1H),7.19(t,J=8.6Hz,2H),7.00(d,J=8.8Hz,2H),5.17(s,2H),4.93(s,2H),3.85(s, 3H).13C NMR(151MHz,CDCl3)δ164.7,163.0,159.9,156.1,148.2,143.8,135.8,130.3,129.6, 129.5,129.4,126.5,125.1,123.1,122.3,117.2,115.8,115.7,114.8,69.3,64.3,55.6.HRMS (ESI),m/z calcd.forC26H22FN4O2([M+H]+)441.1721,found:441.1718。
2-(4-氯苯基)-4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)喹啉(VI-6b):白色固体;收率:90%;m.p.141-142℃;1H NMR(400MHz,CDCl3)δ8.21–8.10(m,3H),7.98(d, J=7.6Hz,2H),7.92(s,1H),7.72(t,J=8.4Hz,1H),7.60(d,J=8.8Hz,2H),7.54(t,J=7.2Hz, 1H),7.48(d,J=8.4Hz,2H),7.00(d,J=9.2Hz,2H),5.17(s,2H),4.93(s,2H),3.86(s,3H).13C NMR(151MHz,CDCl3)δ159.9,155.8,148.2,145.1,143.9,137.9,135.5,130.3,129.6,128.9, 128.8,126.6,125.1,123.1,122.2,121.2,117.0,114.8,69.2,64.3,55.6.HRMS(ESI),m/z calcd. forC26H22ClN4O2([M+H]+)457.1426,found:457.1418。
2-(4-溴苯基)-4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)喹啉(VI-6c):橘黄色固体;收率:88%;m.p.133-135℃;1H NMR(400MHz,CDCl3)δ8.10(d,J=8.4Hz,1H),8.00 (d,J=10.9Hz,2H),7.90(d,J=7.4Hz,2H),7.85(s,1H),7.65(t,J=8.4Hz,1H),7.56(d,J= 8.6Hz,2H),7.53(d,J=9.0Hz,2H),7.47(t,J=8.2Hz,1H),6.93(d,J=9.0Hz,2H),5.10(s, 2H),4.86(s,2H),3.78(s,3H).13C NMR(151MHz,CDCl3)δ159.9,155.9,148.2,145.1,143.9, 138.4,131.9,130.4,129.6,129.1,126.6,125.2,123.9,123.0,122.2,121.2,117.0,114.8,69.2, 64.3,55.6.HRMS(ESI),m/zcalcd.forC26H22BrN4O2([M+H]+)501.0921,found:501.0913。
4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(对甲苯基)喹啉(VI-6d):土黄色固体;收率:91%;m.p.120-122℃;1H NMR(400MHz,CDCl3)δ8.18(d,J=8.4Hz,1H), 8.09(d,J=8.0Hz,2H),7.98(s,3H),7.71(t,J=7.6Hz,1H),7.60(d,J=9.0Hz,2H),7.52(t,J =7.6Hz,1H),7.32(d,J=7.8Hz,2H),6.99(d,J=8.8Hz,2H),5.17(s,2H),4.91(s,2H),3.85 (s,3H),2.42(s,3H).13C NMR(151MHz,CDCl3)δ157.1,148.3,145.1,143.4,139.4,136.7, 134.4,130.2,129.5,129.3,129.1,128.8,128.1,127.4,126.2,125.1,123.0,122.6,117.4,69.3, 64.3,54.2,21.3.HRMS(ESI),m/zcalcd.forC27H25N4O2([M+H]+)437.1972,found: 437.1968.HRMS(ESI),m/zcalcd.forC27H25N4O2([M+H]+)437.1972,found:437.1968。
4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-(三氟甲基)苯基)喹啉 (VI-6e):土黄色固体;收率:87%;m.p.120-122℃;1H NMR(400MHz,CDCl3)δ8.31(d,J=8.0 Hz,2H),8.21(d,J=8.4Hz,1H),8.03(s,1H),8.00(d,J=8.0Hz,1H),7.94(s,1H),7.76(t,J= 9.6Hz,3H),7.61(d,J=8.8Hz,2H),7.57(d,J=7.2Hz,1H),7.01(d,J=8.8Hz,2H),5.21(s, 2H),4.95(s,2H),3.87(s,3H).13C NMR(151MHz,CDCl3)δ158.9,154.5,147.2,144.1,143.2, 141.9,129.5,128.8,126.9,126.0,124.70(d,J=3.7Hz),124.4,122.0,121.2,120.2,116.2,113.8, 68.1,63.3,54.6.HRMS(ESI),m/zcalcd.forC27H22F3N4O2([M+H]+)491.1689,found:491.1687。
2-(4-甲氧基苯基)-4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)喹啉(VI-6f): 淡黄色固体;收率:98%;m.p.153-155℃;1H NMR(400MHz,CDCl3)δ8.09(d,J=6.8Hz,3H), 7.90(d,J=10.0Hz,2H),7.85(s,1H),7.63(t,J=7.2Hz,1H),7.54(d,J=8.8Hz,2H),7.44(t, J=8.2Hz,1H),6.96(dd,J=12.4,8.0Hz,1H),5.10(s,2H),4.86(s,2H),3.81(s,3H),3.79(s, 3H).13C NMR(151MHz,CDCl3)δ160.8,159.8,156.7,148.2,143.4,132.1,130.1,129.4,128.9, 126.0,124.9,123.0,122.2,117.2,114.76,114.2,69.4,64.2,55.6,55.4.HRMS(ESI),m/z calcd. forC27H25N4O3([M+H]+)453.1921,found:453.1918。
4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-苯基喹啉(VI-6g):橘黄色固体;收率:90%;m.p.96-98℃;1H NMR(400MHz,CDCl3)δ8.19(t,J=7.2Hz,3H),8.00(d,J =6.4Hz,2H),7.92(s,1H),7.73(t,J=7.0Hz,1H),7.61(d,J=8.8Hz,2H),7.53(dd,J=14.4, 7.2Hz,3H),7.47(d,J=7.2Hz,1H),7.01(d,J=8.8Hz,2H),5.19(s,2H),4.94(s,2H),3.86(s, 3H).13C NMR(151MHz,CDCl3)δ159.8,157.2,148.3,145.2,143.5,139.6,130.4,129.5,129.4, 128.8,127.6,126.4,125.2,123.0,122.2,121.1,117.6,114.7,69.4,64.3,55.6.HRMS(ESI),m/z calcd.forC26H23N4O3([M+H]+)423.1816,found:423.1823。
2-(2-氯苯基)-4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)喹啉(VI-6h):橘黄色固体;收率:96%;m.p.145-147℃;1H NMR(400MHz,CDCl3)δ8.21(d,J=8.0Hz,1H),8.04 (d,J=8.4Hz,1H),7.91(s,1H),7.86(s,1H),7.75(t,J=8.4Hz,1H),7.68(dd,J=7.2,2.0Hz, 1H),7.60(d,J=8.8Hz,3H),7.50(dd,J=7.0,2.4Hz,1H),7.44–7.33(m,2H),7.01(d,J=9.0 Hz,2H),5.19(s,2H),4.92(s,2H),3.86(s,3H).13C NMR(151MHz,CDCl3)δ159.8,157.3, 148.0,142.7,139.6,132.3,131.6,130.3,130.0,129.9,129.5,127.2,126.9,125.2,123.2,122.2, 121.2,114.8,69.2,64.3,55.6.HRMS(ESI),m/zcalcd.forC26H22ClN4O2([M+H]+)457.1426, found:457.1425。
2-(3-氯苯基)-4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)喹啉(VI-6i):橘黄色固体;收率:89%;m.p.146-148℃;1H NMR(400MHz,CDCl3)δ8.21(s,1H),8.19(d,J=8.0 Hz,1H),8.05(d,J=6.8Hz,1H),7.98(d,J=9.2Hz,2H),7.93(s,1H),7.73(t,J=8.2Hz,1H), 7.61(d,J=9.2Hz,2H),7.55(t,J=8.4Hz,1H),7.48–7.40(m,2H),7.00(d,J=8.8Hz,2H), 5.18(s,2H),4.94(s,2H),3.85(s,3H).13C NMR(151MHz,CDCl3)δ159.9,155.6,148.2,145.1, 144.0,141.4,134.9,130.4,130.4,130.0,129.6,129.3,127.7,126.8,125.6,125.3,123.0,122.2, 121.2,117.1,114.8,69.2,64.3,55.6.HRMS(ESI),m/zcalcd.forC26H22ClN4O2([M+H]+) 457.1415,found:457.1425。
2-(3-溴苯基)-4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)喹啉(VI-6j):白色固体;收率:96%;m.p.112-114℃;1H NMR(400MHz,CDCl3)δ8.37(s,1H),8.19(d,J=8.4Hz, 1H),8.10(d,J=7.8Hz,1H),7.98(d,J=12.4Hz,2H),7.93(s,1H),7.74(t,J=7.8Hz,1H), 7.65–7.51(m,4H),7.38(t,J=7.8Hz,1H),7.00(d,J=9.0Hz,2H),5.18(s,2H),4.94(s,2H), 3.85(s,3H).13C NMR(151MHz,CDCl3)δ159.9,155.5,148.2,145.1,144.1,141.7,132.3, 130.6,130.5,130.4,130.3,129.7,126.8,126.2,125.3,123.1,123.1,122.3,121.2,117.2,114.8, 77.3,77.1,76.9,69.2,64.4,55.7.HRMS(ESI),m/zcalcd.forC26H22BrN4O2([M+H]+)501.0921, found:501.0919。
4-(((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(对甲苯基)喹啉(VI-7d):白色固体;收率:92%;m.p.124-126℃;1H NMR(400MHz,CDCl3)δ8.18(d,J=8.4Hz,1H),8.08(d,J= 8.4Hz,2H),7.99(s,1H),7.96(d,J=4.0Hz,2H),7.71(t,J=8.0Hz,1H),7.65(d,J=8.8Hz, 2H),7.52(t,J=8.2Hz,1H),7.48(d,J=9.0Hz,2H),7.32(d,J=8.0Hz,2H),5.16(s,2H),4.92 (s,2H),2.43(s,3H).13C NMR(151MHz,CDCl3)δ157.2,148.4,145.8,143.3,139.5,136.8, 135.4,134.7,130.4,130.0,129.6,129.5,127.5,126.3,125.1,123.1,121.7,120.8,117.5,77.3, 77.1,76.8,69.6,64.2,21.4.HRMS(ESI),m/zcalcd.forC26H22ClN4O2([M+H]+)441.1477,found: 441.1468。
4-(((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-(三氟甲基)苯基)喹啉(VI-7e): 淡黄色固体;收率:90%;m.p.145-147℃;1H NMR(400MHz,CDCl3)δ8.31(d,J=8.0Hz,2H), 8.21(d,J=8.4Hz,1H),8.02(s,1H),8.00(d,J=9.2Hz,2H),7.76(t,J=8.2Hz,3H),7.67(d,J =8.8Hz,2H),7.58(t,J=8.2Hz,1H),7.50(d,J=9.0Hz,2H),5.20(s,2H),4.95(s,2H).13C NMR(151MHz,CDCl3)δ155.5,148.2,145.6,144.0,142.8,135.4,134.7,130.5,130.0,129.8, 127.8,127.0,125.68(d,J=3.6Hz),125.3,123.0,121.7,120.9,117.2,69.3,64.2.HRMS (ESI),m/z calcd.forC26H19ClF3N4O2([M+H]+)495.1194,found:495.1181。
4-(((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-甲氧基苯基)喹啉(VI-7f):白色固体;收率:92%;m.p.149-151℃;1H NMR(400MHz,CDCl3)δ8.16(d,J=8.8Hz,3H),7.97(d, J=8.0Hz,2H),7.94(s,1H),7.70(t,J=8.2Hz,1H),7.66(d,J=8.8Hz,2H),7.50(t,J=10.8 Hz,3H),7.04(d,J=8.8Hz,2H),5.16(s,2H),4.92(s,2H),3.88(s,3H).13C NMR(151MHz, CDCl3)δ160.8,156.7,148.3,145.8,143.2,135.4,134.6,132.1,130.2,129.9,129.4,128.9, 126.1,124.9,123.0,121.7,120.8,117.2,114.2,69.6,64.2,55.4.HRMS(ESI),m/z calcd. forC26H22ClN4O2([M+H]+)457.1426,found:457.1417。
4-(((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-苯基喹啉(VI-7g):橘黄色固体;收率:87%;m.p.95-97℃;1H NMR(400MHz,CDCl3)δ8.19(t,J=8.2Hz,3H),7.99(d,J=5.2Hz, 2H),7.96(s,1H),7.72(t,J=7.0Hz,1H),7.65(d,J=8.8Hz,2H),7.55(d,J=7.2Hz,1H),7.51 (d,J=7.6Hz,2H),7.46(dd,J=13.2,8.0Hz,3H),5.18(s,2H),4.93(s,2H).13C NMR(151 MHz,CDCl3)δ157.2,148.3,145.7,143.4,139.6,135.4,134.6,130.4,129.9,129.4,128.8, 127.6,126.4,125.16,123.03,121.68,120.81,117.61,69.5,64.20.HRMS(ESI),m/z calcd. forC25H20ClN4O([M+H]+)427.1320,found:427.1321。
2-(2-氯苯基)-4-(((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)喹啉(VI-7h):淡黄色固体;收率:86%;m.p.154-156℃;1H NMR(400MHz,CDCl3)δ8.21(d,J=8.4Hz,1H),8.04(d,J =8.4Hz,1H),7.99(s,1H),7.86(s,1H),7.75(t,J=7.4Hz,1H),7.68(t,J=8.8Hz,3H),7.60(t, J=7.6Hz,1H),7.50(t,J=8.0Hz,3H),7.44–7.34(m,2H),5.19(s,2H),4.92(s,2H).13C NMR(151MHz,CDCl3)δ157.3,148.0,142.6,139.6,135.4,134.6,132.3,131.6,130.4,130.1, 129.9,129.5,127.2,127.0,125.1,123.1,121.7,121.2,69.4,64.2.HRMS(ESI),m/z calcd. forC25H19Cl2N4O([M+H]+)461.0930,found:461.0918。
2-(3-氯苯基)-4-(((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)喹啉(VI-7i):淡黄色固体;收率:91%;m.p.170-172℃;1H NMR(400MHz,CDCl3)δ8.19(d,J=8.8Hz,2H),8.05(d,J =6.4Hz,1H),7.98(d,J=4.8Hz,2H),7.96(s,1H),7.74(t,J=8.4Hz,1H),7.66(d,J=8.8Hz, 2H),7.56(t,J=8.2Hz,1H),7.49(d,J=8.8Hz,2H),7.44(d,J=6.0Hz,2H),5.18(s,2H),4.94 (s,2H).13C NMR(151MHz,CDCl3)δ155.6,148.2,145.6,143.9,141.3,135.4,134.9,134.7, 130.5,130.0,129.9,129.7,129.3,127.6,126.8,125.6,125.3,123.0,121.7,120.8,117.1,69.3, 64.2.HRMS(ESI),m/zcalcd.forC25H19Cl2N4O([M+H]+)461.0930,found:461.0916。
2-(3-溴苯基)-4-(((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)喹啉(VI-7j):白色固体;收率:94%;m.p.186-187℃;1H NMR(400MHz,CDCl3)δ8.36(s,1H),8.19(d,J=8.1Hz,1H), 8.10(d,J=8.0Hz,1H),7.97(d,J=6.0Hz,2H),7.95(s,1H),7.74(t,J=8.2Hz,1H),7.66(d,J =9.0Hz,2H),7.56(dd,J=13.6,6.8Hz,2H),7.49(d,J=8.9Hz,2H),7.38(t,J=7.9Hz,1H), 5.18(s,2H),4.94(s,2H).13C NMR(101MHz,CDCl3)δ155.4,148.2,145.6,143.9,141.6, 135.4,134.7,132.3,130.6,130.5,130.3,129.9,129.7,126.8,126.1,125.3,123.1,121.7,120.8, 117.1,69.3,64.3.HRMS(ESI),m/zcalcd.forC25H19BrClN4O([M+H]+)505.0425,found: 505.0418。
3-(4-(((2-(4-氟苯基)喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(VI-8a):黄绿色油状物;收率:97%;1H NMR(400MHz,CDCl3)δ8.20–8.12(m,3H),7.94(d,J=8.4Hz, 1H),7.91(s,1H),7.71(t,J=8.2Hz,1H),7.59(s,1H),7.52(t,J=8.0Hz,1H),7.19(t,J=8.6 Hz,2H),5.11(s,2H),4.84(s,2H),4.47(t,J=6.8Hz,2H),3.58(t,J=5.8Hz,2H),2.15–1.95 (m,2H).13C NMR(151MHz,CDCl3)δ164.7,163.1,156.2,148.1,144.1,135.7,130.2,129.8, 129.59(d,J=8.4Hz),126.6,125.1,123.2,117.3,115.9,115.8,69.3,64.4,58.6,47.2, 32.6.HRMS(ESI),m/z calcd.forC26H22ClN4O2([M+H]+)457.1415,found:457.1425.HRMS (ESI),m/z calcd.forC22H22FN4O2([M+H]+)393.1721,found:393.1714。
3-(4-(((2-(4-氯苯基)喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(VI-8b):黄绿色油状物;收率:96%;1H NMR(400MHz,H2O+D2O)δ8.17(d,J=8.4Hz,1H),8.12(d,J=7.2Hz, 2H),7.95(s,2H),7.72(t,J=7.3Hz,1H),7.53(t,J=7.2Hz,1H),7.47(d,J=7.2Hz,2H),5.15 (s,2H),4.84(s,2H),4.51(s,2H),3.58(s,2H),2.36(s,1H),2.09(s,2H),1.83(s,1H).13C NMR (151MHz,CDCl3)δ155.8,148.0,144.0,137.8,135.5,130.1,129.6 128.9,128.8,126.6,125.1, 123.0,117.0,69.1,64.2,58.3,47.0,32.4.HRMS(ESI),m/z calcd.forC22H22ClN4O2([M+H]+) 409.1426,found:409.1413。
3-(4-(((2-(4-溴苯基)喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(VI-8c):黄色油状物;收率:92%;1H NMR(400MHz,CDCl3)δ8.16(d,J=8.4Hz,1H),8.05(d,J=8.3Hz,2H),7.95(d,J =8.6Hz,2H),7.72(t,J=7.6Hz,1H),7.64(s,1H),7.62(s,1H),7.53(t,J=7.5Hz,1H),5.13(s,2H),4.84(s, 2H),4.49(t,J=6.6Hz,2H),3.59(t,J=5.7Hz,2H),2.33–2.00(m,2H),1.88(s,1H).13C NMR(151MHz, CDCl3)δ156.0,148.2,144.2,138.4,132.0,130.3,129.8,129.3,126.8,125.3,124.1,123.2,117.1,69.3,64.4, 58.6,47.6,32.5.HRMS(ESI),m/z calcd.forC22H22BrN4O2([M+H]+)453.0921,found:453.0903。
3-(4-(((2-(对甲苯基)喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(VI-8d):黄绿色油状物;收率:95%;1H NMR(400MHz,CDCl3)δ8.18(d,J=8.0Hz,1H),8.06(d,J=8.2Hz, 2H),7.95(d,J=8.4Hz,1H),7.92(s,1H),7.70(t,J=7.0Hz,1H),7.55(s,1H),7.51(t,J=7.1 Hz,1H),7.32(d,J=8.0Hz,2H),5.10(s,2H),4.83(s,2H),4.46(t,J=6.8Hz,2H),3.57(t,J= 5.8Hz,2H),2.42(s,3H),2.13–2.00(m,2H),1.91(s,1H).13C NMR(151MHz,CDCl3)δ157.2, 148.1,143.8,139.6,136.6,130.0,129.6,127.6,126.4,125.1,123.2,117.6,69.4,64.3,58.4,47.1, 32.6,21.4.HRMS(ESI),m/z calcd.forC23H25N4O2([M+H]+)389.1972,found:389.1973。
3-(4-(((2-(4-(三氟甲基)苯基)喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(VI-8e):黄绿色油状物;收率:92%;1H NMR(400MHz,CDCl3)δ8.30(d,J=7.9Hz,1H),8.19 (d,J=8.4Hz,1H),8.01(s,1H),7.97(d,J=8.2Hz,1H),7.76(d,J=7.6Hz,1H),7.73(d,J= 8.2Hz,1H),7.56(t,J=7.4Hz,1H),5.17(s,1H),4.85(s,1H),4.52(d,J=6.2Hz,1H),3.61(s, 1H),2.21(s,1H),2.07-2.12(m,2H),1.80(s,1H).13C NMR(101MHz,CDCl3)δ155.9,148.1, 144.1,137.9,135.6,130.2,129.71,129.0,128.9,126.7,125.2,123.1,117.2,69.3,64.5,58.6, 47.7,32.5.HRMS(ESI),m/z calcd.forC23H22F3N4O2([M+H]+)463.1689,found:463.1688。
3-(4-(((2-(4-甲氧基苯基)喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(VI-8f):黄色油状物;收率:94%;1H NMR(400MHz,CDCl3)δ8.15(d,J=8.8Hz,1H),8.12(d,J=8.7Hz, 2H),7.92(d,J=8.4Hz,1H),7.89(s,1H),7.68(t,J=7.6Hz,1H),7.57(s,1H),7.48(t,J=7.4 Hz,1H),7.02(d,J=7.2Hz,1H),5.08(s,2H),4.81(s,2H),4.44(t,J=6.8Hz,2H),3.85(s,3H), 3.55(t,J=5.8Hz,2H),2.13–1.92(m,2H).13C NMR(151MHz,CDCl3)δ160.9,156.8,148.0, 131.9,129.8,129.5,129.0,126.1,124.9,123.1,117.3,114.2,69.3,64.2,58.4,55.4,47.2, 32.6.HRMS(ESI),m/z calcd.forC23H25N4O3([M+H]+)405.1921,found:405.1918。
3-(4-(((2-苯基吡啶-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(VI-8g):黄色油状物;收率:92%;1H NMR(400MHz,CDCl3)δ8.19(d,J=8.8Hz,1H),8.15(d,J=7.6Hz,2H),7.96 (s,1H),7.94(s,1H),7.71(t,J=7.4Hz,1H),7.60–7.48(m,4H),7.46(d,J=7.2Hz,1H),5.11 (s,2H),4.83(s,2H),4.46(t,J=6.8Hz,2H),3.56(t,J=5.8Hz,2H),2.06(dd,J=12.4,6.2Hz, 2H).13C NMR(151MHz,CDCl3)δ157.4,148.2,144.0,139.6,130.3,129.7,129.6,129.0,128.9, 127.7,127.6,126.6,123.2,117.8,69.4,64.5,58.7,47.5,32.6.HRMS(ESI),m/z calcd. forC22H23N4O2([M+H]+)375.1816,found:375.1816。
3-(4-(((2-(2-氯苯基)喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(VI-8h):橘黄色油状物;收率:93%;1H NMR(400MHz,CDCl3)δ8.19(d,J=8.4Hz,1H),7.99(d,J=8.4Hz, 1H),7.80(s,1H),7.73(t,J=8.4Hz,1H),7.66(d,J=7.2Hz,1H),7.60–7.54(m,2H),7.48(d, J=7.2Hz,1H),7.37(p,J=7.4Hz,2H),5.12(s,2H),4.82(s,2H),4.45(t,J=6.8Hz,2H),3.56 (t,J=5.6Hz,2H),2.15–1.95(m,3H).13C NMR(151MHz,CDCl3)δ155.9,148.2,144.1, 138.0,135.7,130.3,129.8,129.0,128.9,126.7,125.2,123.1,117.2,69.2,64.4,58.4,47.2, 32.6.HRMS(ESI),m/z calcd.forC22H22ClN4O2([M+H]+)409.1426,found:409.1425。
3-(4-(((2-(3-氯苯基)喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(VI-8i):橘黄色油状物;收率:91%;1H NMR(400MHz,CDCl3)δ8.29(d,J=8.0Hz,2H),8.19(d,J=8.4Hz, 1H),8.00(s,1H),7.97(d,J=8.0Hz,1H),7.76(d,J=7.8Hz,2H),7.73(d,J=8.0Hz,1H), 7.56(t,J=7.6Hz,1H),5.16(s,1H),4.85(s,1H),4.51(t,J=6.4Hz,1H),3.61(t,J=5.6Hz, 1H),2.29(s,1H),2.17–1.89(m,1H),1.84(s,1H).HRMS(ESI),m/zcalcd. forC22H22ClN4O2([M+H]+)409.1426,found:409.1433。
3-(4-(((2-(3-溴苯基)喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(VI-8j):黄绿色油状物;收率:90%;1H NMR(400MHz,CDCl3)δ8.29(d,J=8.0Hz,2H),8.19(d,J=8.4Hz, 1H),8.00(s,1H),7.97(d,J=8.4Hz,1H),7.76(d,J=7.8Hz,2H),7.73(d,J=8.0Hz,1H), 7.56(t,J=7.6Hz,1H),5.16(s,2H),4.85(s,2H),4.51(t,J=6.4Hz,2H),3.61(t,J=5.4Hz, 2H),2.29(s,1H),2.08-2.13(m,2H),1.84(s,2H).13C NMR(151MHz,CDCl3)δ132.2,130.5, 130.3,130.2,129.7,126.8,126.1,125.2,123.2,123.0,123.0,117.1,69.1,64.3,58.4,47.0, 32.4.HRMS(ESI),m/z calcd.forC22H22BrN4O2([M+H]+)453.0921,found:453.0912。
2、活性研究
SHP-1作为筛选模型
SHP1是含有SH2结构域的蛋白酪氨酸磷酸酶1,其通过直接去磷酸化调节细胞内信号蛋白分子的酪氨酸磷酸化水平抑制细胞的有丝分裂增殖,分化和生物活性。SHP1是近年来发现的重要抑癌基因之一,它在造血系统中抑制白血病细胞生长已经得到证实。而且在乳腺癌、卵巢癌、前列腺癌细胞中,SHP1的的表达量均发生了下调,说明了SHP1在癌症发生中的重要性,所以关于SH P1靶点的激活剂对这些癌症病人有很高的临床应用价值。
测试过程:采用荧光底物D iFM U P,观察不同化合物对重组酶活性的抑制。D iFMU P水解后得到的产物D iFM U在被358nM激发光激发后可发射出波长为455nM的可检测的荧光信号,通过检测荧光信号的变化,反应酶的活性,从而观察酶的活性变化以及化合物对其的抑制情况。
表1部分化合物5a-8j对SH P1靶点的酶活抑制率如下:
SHP-2作为筛选模型
SHP2是含有SH2结构域的蛋白酪氨酸磷酸酶2,其在各种细胞和组织中均有广泛的表达,参与多个信号传导通路,介导细胞的生长、分化、迁移、粘附及凋亡,目前SHP2 在血液肿瘤细胞中的作用相对而言已比较清楚,近来又发现SHP2在肺癌、胃癌、宫颈癌、甲状腺癌和乳腺癌等多种实体肿瘤组织中呈现高表达,并且这种高表达与肿瘤的发生、发展和预后有关,所以SHP2很可能是个很有潜力的靶分子。
采用荧光底物D iFM U P,观察不同化合物对重组酶活性的抑制。D iFM U P水解后得到的产物D iFM U在被358nM激发光激发后可发射出波长为455nM的可检测的荧光信号,通过检测荧光信号的变化,反应酶的活性,从而观察酶的活性变化以及化合物对其的抑制情况。
表2化合物5a-8j对SHP2靶点的酶活抑制率如下:
以上实施例描述了本发明的基本原理、主要特征,本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明原理的范围下,本发明还会有各种变化和改进,这些变化和改进均落入本发明保护的范围内。
Claims (3)
2.权利要求1所述的具有生物活性的喹啉取代三氮唑类化合物在制备抗癌药物中的应用。
3.权利要求1所述的具有生物活性的喹啉取代三氮唑类化合物作为SHP1靶点的酶活抑制剂和SHP2靶点的酶活抑制剂用于制备抗癌药物。
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