

Citation: Lei Shi, Xiaolan Yang, Jingjing Xu, Jingjing Bi, Zhiguo Zhang, Guisheng Zhang. Syntheses and Activities of Novel Quinohydrazone and Acylhydrazone Compounds as PTP 1B Inhibitors[J]. Chemistry, 2021, 84(1): 81-89.

新型PTP 1B抑制剂喹啉腙及酰腙化合物的合成与活性研究
English
Syntheses and Activities of Novel Quinohydrazone and Acylhydrazone Compounds as PTP 1B Inhibitors
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Key words:
- Quinoline derivatives
- / Hydrazine
- / Hydrazide
- / PTP 1B
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蛋白质酪氨酸磷酸酶1B(PTP 1B)是一种信号传导酶,在蛋白质酪氨酸磷酸化水平的调控以及多种细胞过程的调控中起着重要的作用[1]。PTP活动异常涉及许多人类疾病,例如糖尿病、肥胖症、癌症、炎症和自身免疫性疾病[2]。PTP 1B是胰岛素信号转导通路中的关键的负调节蛋白,PTP-1B抑制剂通过阻断胰岛素刺激的胰岛素受体(IR)的酪氨酸磷酸化,进而影响胰岛素受体(IRS-1)的磷酸化,使类胰岛素和胰岛素增敏,降低血糖。同时,该酶能使瘦素信号表达增强,诱导脂肪代谢水平升高,体重下降。PTP 1B靶向过表达会驱动乳腺癌、结肠癌、胃癌、前列腺癌发生或转移,提示PTP 1B在各种癌症中起关键作用[3~7]。目前,研究者已在合成化学、药物和天然产物等化学领域进行了许多研究以开发PTP 1B抑制剂[8~11]。
喹啉核是生物活性分子研究中很重要且被广泛利用的杂环之一,喹啉衍生物广泛存在于天然产物中,也可以通过合成得到,构造喹啉环的经典方法常涉及Skraup和Doebner-Miller[12, 13]或Pfitzinger[14, 15]等方法。化学工作者设计、合成的新型喹啉衍生物具有多种生物活性,如抗炎[16]、抗氧化[17]、抗肿瘤[18]、抗真菌[19]、抗HIV-1[20]、抗结核[21, 22]、抗疟疾[23]等活性。腙是通过肼与醛或酮之间的亲核加成反应后脱水而制得的,是一类特殊的席夫碱化合物。这些化合物稳定性好,并且具有多种生物活性,例如抗菌、杀虫、抗肿瘤等[24, 25]。其中,在酰腙类化合物的分子结构中由于同时含有酰胺基和席夫碱基这两类活性亚结构基团,常具有增强的生物活性[26~31],所以酰腙也是目前药物研究的热点之一[32]。
喹啉腙及喹啉酰腙类化合物具有广泛的生物活性[33, 34],所以这两类化合物的合成与生物活性研究备受关注。Raja等[35]通过使2-氧代喹啉-3-甲醛与苯甲酰肼反应得到酰腙配体,再分别与CuCl· 2H2O和Cu(NO3)2·3H2O反应合成了两种铜(Ⅱ)配合物(化合物Ⅰ和Ⅱ,见图式 1)。铜(Ⅱ)配合物可嵌入小牛胸腺DNA中,从而显示出良好的抗氧化活性及对一系列癌细胞(HeLa、HEp-2和Hep G2癌细胞)的抑制活性。
图式 1
通过许多生化和遗传研究的验证,PTP 1B可以作为人类疾病(例如糖尿病、肥胖症、癌症、炎症和自身免疫性疾病)的治疗靶标,再考虑到喹啉和腙优异的抗肿瘤活性,本文以2, 3-二酮-吲哚和取代苯乙酮为起始原料,经四步反应合成4-(2-芳基)喹啉甲醛,再与不同的芳肼盐酸盐或酰肼反应生成29个未见报道的4-(2-芳基)喹啉芳腙和芳酰腙类化合物(反应路线见图式 2),以期得到具有良好抑制活性的新型PTP 1B抑制剂,为潜在的新抗糖尿病、抗肥胖或抗癌药物的发现提供一定研究基础。此工作已申请了中国发明专利[36]。
图式 2
图式 2. 目标化合物6a~6s和7a~7j的合成路线Scheme 2. Synthetic routes of the target compounds 6a~6s and 7a~7j6a: R1=F, R2=H; 6b: R1=F, R2=OCH3; 6c: R1=F, R2=CH3; 6d: R1=F, R2=F; 6e: R1=F, R2=Cl; 6f: R1=F, R2=CN; 6g: R1=F, R2=CF3; 6h: R1=F, R2=NO2; 6i: R1=H, R2=H; 6j: R1=H, R2=NO2; 6k: R1=H, R2=OCH3; 6l: R1=H, R2=F; 6m: R1=H, R2=CF3; 6n: R1=CF3, R2=NO2; 6o: R1=CF3, R2=CH3; 6p: R1=CF3, R2=F; 6q: R1=CF3, R2=Cl; 6r: R1=CF3, R2=CF3; 6s: R1=CF3, R2=H; 7a: R1=F, R3=2-Furyl; 7b: R1=F, R3=2-Thienyl; 7c: R1=F, R3=4-Pyridyl; 7d: R1=F, R3=2-hydroxyphenyl; 7e: R1=H, R3=2-Furyl; 7f: R1=H, R3=2-Thienyl; 7g: R1=H, R3=4-Pyridyl; 7h: R1=H, R3=2-hydroxyphenyl; 7i: R1=CF3, R3=2-Furyl; 7j: R1=CF3, R3=2-Thienyl.
1. 实验部分
1.1 仪器与试剂
1H NMR和13C NMR由Bruker DPX-400M、Bruker DPX-600M核磁共振谱仪测定,TMS作为内标,DMSO-d6为溶剂;HR-MS由瑞士布鲁克公司高分辨率质谱仪测定;化合物熔点由仪电物理光学仪器有限公司X-4B显微熔点测定仪测定。所用试剂均为市售分析纯级,原料1, 3-吲哚二酮、取代苯乙酮均购于阿拉丁试剂公司。
1.2 实验方法
4-(2-芳基)喹啉甲酸(1)的合成:向250mL圆底烧瓶中加入40mmol 2, 3-吲哚二酮和48mmol取代苯乙酮,用15mL无水乙醇溶解,然后加入28mL 34% KOH水溶液,85℃下回流反应,TLC监测至反应完成,在冰浴条件下滴加浓盐酸中和反应体系至pH约为2,此时体系中有大量固体析出,减压抽滤,水洗,再用二氯甲烷洗去未反应的原料及副产物。收集并烘干滤饼得化合物1。
4-(2-芳基)喹啉甲酸甲酯(2)的合成:向250mL圆底烧瓶中加入30mmol化合物1,再加入30mL甲醇溶解,在冰浴条件下缓慢滴加7mL浓硫酸,70℃下磁力搅拌回流反应约8h,反应结束后,在冰浴条件下向体系加入饱和碳酸钠的水溶液调pH呈弱碱性,然后用乙酸乙酯萃取,合并有机相并用无水硫酸钠干燥,有机相减压蒸馏,后采用柱色谱(洗脱剂:石油醚/乙酸乙酯)分离化合物,得化合物2。
4-(2-芳基)喹啉甲醇(3)的合成:向250mL圆底烧瓶中依次加入135mL无水乙醇、30mmol化合物1和90mmol硼氢化钠,85℃下回流反应,TLC监至反应结束。将反应体系冷却至室温,后加入约80mL水淬灭反应,此时体系中有大量白色固体析出,减压抽滤并真空干燥得化合物3。
4-(2-芳基)喹啉甲醛(4)的合成:在氮气氛围下,将20mmol化合物2和40mmol氯铬酸吡啶盐加入到250mL圆底烧瓶中,再加入65mL干燥的二氯甲烷,室温下搅拌反应。反应结束后,减压抽滤除去盐,滤液减压蒸馏得粗产物4,后采用柱色谱分离纯化(洗脱剂:石油醚/乙酸乙酯)得产物4。
目标化合物6a~6s的合成:在25mL圆底烧瓶中加入0.3mmol化合物4和等摩尔比的不同取代的苯肼盐酸盐,然后加入10mL甲醇,室温下反应,TLC跟踪监测。反应结束后,加20mL水猝灭反应,反应液中出现大量沉淀,减压抽滤,分别用水和石油醚洗涤,真空干燥,得到目标化合物6a~6s。
目标化合物7a~7j的合成:在25mL圆底烧瓶中加入0.15mmol化合物4和等摩尔比的不同取代的酰肼,然后加入5mL无水乙醇,85℃下回流反应,TLC跟踪监测。反应结束后冷至室温,加20mL水猝灭反应,体系中出现了大量沉淀,减压抽滤,分别用水和石油醚洗涤,真空干燥,得到目标化合物7a~7j。
1.3 目标化合物数据
2-(4-氟苯基)-4-((2-苯基亚肼基)甲基)喹啉(6a):黄色固体,产率88%。熔点111~113℃:1H NMR (600MHz,DMSO-d6)δ:11.00(s,1H),8.75(d,J=8.4Hz,1H),8.54(s,1H),8.38~8.36(m,2H),8.32(s,1H),8.10(d,J=8.4Hz,1H),7.81(t,J=7.2Hz,1H),7.69(t,J=7.2Hz,1H),7.40(t,J=8.4Hz,2H),7.32(t,J=7.8Hz,2H),7.24(d,J=7.8Hz,2H),6.87(t,J=7.2Hz,1H);13C NMR(151MHz,DMSO-d6)δ:164.0,162.4,153.1,146.2,144.4,140.3,135.3,135.3,133.2,132.8,131.2,129.4,129.3,128.5,127.8,127.6,127.2,124.6,121.3,121.2,120.0,115.9,115.7,114.7,112.7;HRMS (ESI),m/z:C22H16FN3 ([M+H]+),理论值342.1401,实测值342.1401。
2-(4-氟苯基)-4-((2-(4-甲氧基苯基)亚肼基)甲基)喹啉(6b):黄色固体,产率85%,熔点220~222℃;1H NMR(400MHz,DMSO-d6)δ:11.70(s,1H),8.73(d,J=8.4Hz,1H),8.54(s,1H),8.34(s,1H),8.25(dd,J=15.8、7.4 Hz,3H),7.99(t,J=7.8Hz,1H),7.82(t,J=7.8Hz,1H),7.51(t,J=8.8Hz,2H),7.29(d,J=8.8Hz,2H),6.96(d,J=8.8Hz,2H),3.74(s,3H);13C NMR (151MHz,DMSO-d6)δ:155.3,152.1,136.9,133.5,132.6,132.0,129.4,129.0,128.5,128.2,127.2,124.8,122.9,115.4,115.0,114.0,55.4;HRMS (ESI),m/z:C23H18FN3O ([M+H]+),理论值372.1507,实测值372.1508。
2-(4-氟苯基)-4-((2-(4-甲基苯基)亚肼基)甲基)喹啉(6c):黄色固体,产率71%,熔点216~218℃;1H NMR(400MHz,DMSO-d6)δ:11.69(s,1H),8.73(d,J=8.6Hz,1H),8.60(s,1H),8.32(m,4H),7.98(t,J=7.4Hz,1H),7.83(t,J=7.4Hz,1H),7.52(t,J=8.6Hz,2H),7.24(d,J=8.2Hz,2H),7.16(d,J=8.2Hz,2H),2.27(s,3H);13C NMR(151MHz,DMSO-d6)δ:164.9,163.2,152.4,141.3,132.4,131.1,131.1,130.6,130.1,130.0,128.1,124.7,123.1,116.3,116.2,114.6,113.7,20.5;HRMS(ESI),m/z:C23H18FN3 ([M+H]+),理论值356.1558,实测值356.1556。
2-(4-氟苯基)-4-((2-(4-氟苯基)亚肼基)甲基)喹啉(6d):黄色固体,产率73%,熔点181~183℃;1H NMR (600MHz,DMSO-d6)δ:11.36(s,1H),8.73(d,J=8.4Hz,1H),8.62(s,1H),8.42~8.33(m,3H),8.11(d,J=7.8Hz,1H),7.83(t,J=7.8Hz,1H),7.71(t,J=7.8Hz,1H),7.64(d,J=9.0Hz,2H),7.41(t,J=9.0Hz,2H),7.37(d,J=8.4Hz,2H);13C NMR(151MHz,DMSO-d6)δ:164.0,162.4,157.4,155.8,153.0,146.2,141.1,140.2,135.3,135.3,133.1,132.8,131.2,129.4,129.3,128.5,127.8,127.6,127.1,124.6,121.3,121.1,116.0,115.8,115.7,114.6,113.8,113.7;HRMS(ESI),m/z:C22H15F2N3 ([M+H]+),理论值360.1307,实测值360.1316。
2-(4-氟苯基)-4-((2-(4-氯苯基)亚肼基)甲基)喹啉(6e):黄色固体,产率79%,熔点248~250℃;1H NMR (400MHz,DMSO-d6)δ:11.63(s,1H),8.79~8.58(m,2H),8.49~8.19(m,4H),7.95(s,1H),7.81(s,1H),7.49(s,2H),7.38(d,J=8.8Hz,2H),7.31(d,J=8.4,2H);13C NMR (151MHz,DMSO-d6)δ:164.0,162.4,153.0,146.2,143.4,140.0,135.3,135.3,133.7,133.1,131.1,129.4,129.3,129.2,128.5,127.8,127.4,127.1,124.6,123.3,121.2,121.1,115.8,115.7,114.7,114.1;HRMS(ESI),m/z:C22H15ClFN3 ([M+H]+),理论值376.1011,实测值376.1011。
2-(4-氟苯基)-4-((2-(4-腈基苯基)亚肼基)甲基)喹啉(6f):橘色固体,产率64%,熔点250~252℃;1H NMR(400MHz,DMSO-d6)δ:11.63(s,1H),8.72(d,J=8.2Hz,1H),8.63(s,1H),8.38(d,J=27.8Hz,3H),8.25(s,1H),7.95(s,1H),7.81(s,1H),7.49(s,2H),7.38(d,J=7.6Hz,2H),7.31(d,J=6.8Hz,2H);13C NMR (151MHz,DMSO-d6)δ:164.0,162.4,153.1,147.9,146.2,139.4,139.4,136.6,135.2,135.1,133.8,133.1,131.1,129.4,129.3,128.6,127.9,127.8,127.2,124.5,121.4,121.0,119.9,115.8,115.7,115.3,112.9,100.7;HRMS(ESI),m/z:C23H15FN4 ([M+H]+),理论值367.1354,实测值367.1359。
2-(4-氟苯基)-4-((2-(4-三氟甲基苯基)亚肼基)甲基)喹啉(6g):橘黄色固体,产率78%,熔点238~240℃:1H NMR (400MHz,DMSO-d6)δ:11.76 (s,1H),8.80~8.65(m,2H),8.43(s,1H),8.41~8.30(m,2H),8.23(s,1H),7.93(s,1H),7.80(s,1H),7.66(d,J=8.4Hz,2H),7.48(d,J=8.0Hz,2H),7.45(d,J=8.4Hz,2H);HRMS(ESI),m/z:C23H15F4N3 ([M+H]+),理论值410.1275,实测值410.1275。
2-(4-氟苯基)-4-((2-(4-硝基苯基)亚肼基)甲基)喹啉(6h):橘黄色固体,产率69%,熔点234~236℃;1H NMR(400MHz,DMSO-d6)δ:11.76(s,1H),8.72(d,J=6.8Hz,2H),8.39(dd,J=8.0、4.8 Hz,3H),8.22(d,J=9.2Hz,2H),8.13(d,J=8.4Hz,1H),7.84(t,J=7.4Hz,1H),7.73(t,J=7.4Hz,1H),7.47~7.29(m,4H);13C NMR(101MHz,DMSO-d6)δ:154.8,150.0,148.5,139.4,139.0,138.8,130.1,130.0,129.6,129.5,127.4,126.2,124.2,123.5,116.3,115.9,115.7,112.2;HRMS(ESI),m/z:C22H15FN4O2 ([M+H]+),理论值387.1252,实测值387.1262。
2-苯基-4-((2-苯基亚肼基)甲基)喹啉(6i):棕红色固体,产率91%,熔点226~228℃;1H NMR (600MHz,DMSO-d6)δ:11.06(s,1H),8.76(d,J=8.4Hz,1H),8.55(s,1H),8.34(s,1H),8.30(d,J=7.2Hz,2H),8.12(d,J=8.4Hz,1H),7.83(t,J=7.8Hz,1H),7.71(t,J=7.8Hz,1H),7.59(t,J=7.8Hz,2H),7.54(t,J=7.2Hz,1H),7.33(t,J=7.8Hz,2H),7.25(d,J=7.8Hz,2H),6.88(t,J=7.2Hz,1H);13C NMR (151 MHz,DMSO-d6)δ:155.5,144.3,133.1,130.1,129.8,129.4,128.9,127.3,127.0,124.4,123.5,120.2,115.3,112.8;HRMS(ESI),m/z:C22H17N3 ([M+H]+),理论值324.1495,实测值324.1494。
4-((2-(4-硝基苯基)亚肼基)甲基)-2-苯基喹啉(6j):橙黄色固体,产率80%,熔点226~228℃;1H NMR(600MHz,DMSO-d6)δ:11.76(s,1H),8.72(s,2H),8.41(s,1H),8.32(d,J=7.2Hz,2H),8.22(d,J=8.4Hz,2H),8.14(d,J=7.8Hz,1H),7.87~7.80(m,1H),7.76~7.67 (m,1H),7.62~7.57(m,2H),7.54(d,J=6.6Hz,1H),7.35(d,J=6.6Hz,2H);13C NMR (151 MHz,DMSO-d6)δ:155.8,150.0,148.5,139.4,138.9,138.8,138.5,130.0,130.0,129.7,128.9,127.4,127.2,126.2,124.2,123.6,116.4,112.1;HRMS(ESI),m/z:C22H16N4O2 ([M+H]+),理论值369.1346,实测值369.1337。
4-((2-(4-甲氧基苯基)亚肼基)甲基)-2-苯基喹啉(6k):棕红色固体,产率95%,熔点210~212℃;1H NMR(600MHz,DMSO-d6)δ:12.15(s,1H),8.70(d,J=8.4Hz,1H),8.64(s,1H),8.41(d,J=8.4Hz,1H),8.38(s,1H),8.23~8.19(m,2H),8.07~8.01(m,1H),7.87(t,J=7.8Hz,1H),7.76~7.69(m,3H),7.34(d,J=8.4Hz,2H),6.97(d,J=9.0Hz,2H),3.75(s,3H);13C NMR(151MHz,DMSO-d6)δ:165.1,163.5,155.1,151.1,136.9,133.2,131.7,131.6,128.3,124.7,122.8,116.4,116.2,115.3,114.9,113.9,55.3;HRMS(ESI),m/z:C23H19N3O ([M+H]+),理论值354.1601,实测值354.1607。
4-((2-(4-氟苯基)亚肼基)甲基)-2-苯基喹啉(6l):橘黄色固体,产率98%,熔点95~97℃;1H NMR (600MHz,DMSO-d6)δ:11.83(s,1H),8.69(d,J=7.8Hz,1H),8.65(s,1H),8.38(s,1H),8.31(d,J=8.4Hz,1H),8.23(d,J=7.8Hz,2H),7.96(t,J=7.2Hz,1H),7.81(t,J=7.2Hz,1H),7.66(d,J=7.2Hz,3H),7.33(dd,J=9.0、4.8 Hz,2H),7.18(t,J=8.4Hz,2H);13C NMR (151MHz,DMSO-d6)δ:157.4,155.8,155.7,148.4,141.1,140.0,138.6,133.3,129.8,129.7,129.6,128.8,127.2,126.9,125.2,124.2,123.5,123.4,116.0,115.8,115.2,113.8,113.7;HRMS(ESI),m/z:C22H16FN3 ([M+H]+),理论值342.1401,实测值342.1408。
2-苯基-4-((2-(4-(三氟甲基)苯基)亚肼基)甲基)喹啉(6m):黄色固体,产率89%,熔点236~238℃:1H NMR (400MHz,DMSO-d6)δ:12.36(s,1H),8.88(s,1H),8.73(d,J=8.4Hz,1H),8.46(d,J=12.8Hz,2H),8.29(dd,J=6.6、2.8 Hz,2H),8.00(t,J=7.8Hz,1H),7.85(t,J=7.8Hz,1H),7.67~7.65(m,5H),7.48(d,J=8.4Hz,2H);13C NMR(151MHz,DMSO-d6)δ:154.2,148.5,144.4,142.5,140.3,133.0,130.1,130.0,129.4,127.9,127.4,125.7,124.3,123.8,120.1,115.3,112.7;HRMS(ESI),m/z:C23H16F3N3 ([M+H]+),理论值392.1369,实测值392.1361。
4-((2-(4-硝基苯基)亚肼基)甲基)-2-(4-(三氟甲基)苯基)喹啉(6n):橘黄色固体,产率92%,熔点208~210℃;1H NMR (400MHz,DMSO-d6)δ:12.27(s,1H),8.83(s,1H),8.65(d,J=8.0Hz,1H),8.56~8.40(m,3H),8.15(dd,J=21.8、8.6 Hz,3H),7.90(d,J=8.0Hz,2H),7.83(t,J=7.2Hz,1H),7.72(t,J=7.2Hz,1H),7.35(d,J=8.4Hz,2H);13C NMR(151MHz,DMSO-d6) δ:153.2,147.2,134.4,131.4,131.4,128.8,128.2(d,J=1.8Hz),126.7,125.8,125.8,125.0,124.4,123.9,123.8,120.5,120.2,116.0,113.0;HRMS(ESI),m/z:C23H15F3N4O2 ([M+H]+),理论值437.1220,实测值437.1213。
4-((2-(对甲苯基)亚肼基)甲基)-2-(4-(三氟甲基)苯基)喹啉(6o):黄色固体,产率95%,熔点213~215℃;1H NMR (600MHz,DMSO-d6)δ:11.50(s,1H),8.74(d,J=7.8Hz,1H),8.60(s,1H),8.47(d,J=7.8Hz,2H),8.43(s,1H),8.26(d,J=8.4Hz,1H),8.00(d,J=7.8Hz,2H),7.98~7.91(m,1H),7.82(t,J=7.2Hz,1H),7.22(d,J=7.8Hz,2H),7.15(d,J=7.8Hz,2H),2.27(s,3H);13C NMR(151MHz,DMSO-d6)δ:141.6,140.6,131.6,130.8,130.1,130.1,129.9,128.9,128.1,125.92(d,J=3.6Hz),125.1,124.6,123.6,20.4;HRMS(ESI),m/z:C24H18F3N3 ([M+H]+),理论值406.1526,实测值406.1517。
4-((2-(4-氟苯基)亚肼基)甲基)-2-(4-(三氟甲基)苯基)喹啉(6p):黄色固体,产率90%,熔点222~224℃;1H NMR (400MHz,DMSO-d6)δ:11.70(s,1H),8.71(d,J=8.4Hz,1H),8.64(s,1H),8.47(d,J=11.2Hz,3H),8.29(d,J=4.4Hz,1H),7.97(dd,J=20.8、7.6 Hz,3H),7.82(t,J=7.6Hz,1H),7.37~7.27(m,2H),7.19(t,J=8.8Hz,2H);13C NMR (151MHz,DMSO-d6) δ:158.1,156.5,152.6,140.5,131.8,131.2,129.0,128.2,125.85(d,J=3.4Hz),125.8,125.0,124.5,123.6,123.2,116.1,116.0,115.1,114.6,114.6;HRMS (ESI),m/z:C23H15F4N3 ([M+H]+),理论值410.1275,实测值410.1267。
4-((2-(4-氯苯基)亚肼基)甲基)-2-(4-(三氟甲基)苯基)喹啉(6q):黄色固体,产率92%,熔点226~228℃;1H NMR (400MHz,DMSO-d6)δ:11.67(s,1H),8.70(d,J=8.6Hz,1H),8.64(s,1H),8.51~8.42(m,3H),8.26(d,J=8.4Hz,1H),8.02~7.90(m,3H),7.80(t,J=7.6Hz,1H),7.33(dd,J=24.8、8.8 Hz,4H);13C NMR (151MHz,DMSO-d6)δ:153.1,143.0,132.6.0,131.4,129.2,128.8,128.1,125.83(d,J=3.7Hz),125.8,125.1,124.4,124.2,123.7,123.3,115.4,114.7;HRMS(ESI),m/z:C23H15ClF3N3 ([M+H]+),理论值426.0979,实测值426.0976。
2-(4-(三氟甲基)苯基)-4-((2-(4-(三氟甲基)苯基)亚肼基)甲基)喹啉(6r):黄色固体,产率90%,熔点232~234℃;1H NMR (400MHz,DMSO-d6)δ:12.05(s,1H),8.82(s,1H),8.71(d,J=8.6Hz,1H),8.58~8.43(m,3H),8.21(d,J=8.4Hz,1H),8.01~7.84(m,3H),7.76(t,J=7.8Hz,1H),7.63(d,J=8.6Hz,2H),7.42(d,J=8.4Hz,2H);13C NMR (151MHz,DMSO-d6) δ:154.2,150.0,148.4,142.3,139.3,138.3,130.1,130.1,129.7,129.5,128.0,127.8,126.1,125.70 (d,J=3.7Hz),125.7,125.2,124.1,123.9,123.4,116.2,112.1;HRMS (ESI),m/z:C24H15F6N3 ([M+H]+),理论值460.1243,实测值460.1236。
2-苯基-4-((2-苯基亚肼基)甲基)-2-(4-(三氟甲基)苯基)喹啉(6s):黄色固体,产率92%,熔点236~238℃;1H NMR (600MHz,DMSO-d6)δ:11.05(s,1H),8.76(d,J=7.8Hz,1H),8.56(s,1H),8.53(d,J=7.8Hz,2H),8.41(s,1H),8.14(d,J=8.4Hz,1H),7.94(d,J=8.4Hz,2H),7.84(t,J=7.8Hz,1H),7.74(t,J=7.8Hz,1H),7.35~7.30(m,2H),7.25(d,J=7.8Hz,2H),6.88(t,J=7.2Hz,1H);13C NMR (151MHz,DMSO-d6) δ:154.2,148.5,144.4,142.5,140.3,133.0,130.1,130.0,129.4,128.0,127.4,125.8,125.7(d,J=3.6Hz),124.4,123.8,120.1,115.3,112.7;HRMS(ESI),m/z:C23H16F3N3 ([M+H]+),理论值392.1369,实测值392.1352。
N′-((2-(4-氟苯基)喹啉-4-基)亚甲基)呋喃-2-甲酰肼(7a):黄色固体,产率70%;熔点180~182℃:1H NMR (600MHz,DMSO-d6)δ:12.27(s,1H),9.14(s,1H),8.78(s,1H),8.34(d,J=7.4Hz,3H),8.14(d,J=7.8Hz,1H),8.02(s,1H),7.84(d,J=6.8Hz,1H),7.72(s,1H),7.41(s,3H),6.76(s,1H);13C NMR (151MHz,DMSO-d6)δ:154.8,146.3,138.6,130.1,129.9,129.5,127.5,124.4,117.3,115.8,112.3;HRMS(ESI),m/z:C21H14FN3O2 ([M+Na]+),理论值382.0962,实测值382.0962。
N′-((2-(4-氟苯基)喹啉-4-基)亚甲基)噻吩-2-甲酰肼(7b):黄色固体,产率78%,熔点257~259℃;1H NMR (400MHz,DMSO-d6)δ:12.29(s,1H),9.08(s,1H),8.85(s,1H),8.35(dd,J=8.8、5.6 Hz,3H),8.15(d,J=8.4Hz,1H),7.99(d,J=25.6Hz,2H),7.86(t,J=7.6Hz,1H),7.72(t,J=7.6Hz,1H),7.42(t,J=8.8Hz,2H),7.34~7.23(m,1H);13C NMR (151MHz,DMSO-d6) δ:164.2,162.5,154.8,148.4,145.2,138.7,135.2,134.8,132.5,130.2,129.9,129.6,129.4,128.3,127.5,124.6,123.7,117.6,115.9(d,J=23.0Hz);HRMS(ESI),m/z:C21H14FN3OS ([M+Na]+),理论值398.0734,实测值398.0731。
N′-((2-(4-氟苯基)喹啉-4-基)亚甲基)苯甲酰肼(7c):黄色固体,产率72%,熔点252~254℃;1H NMR (400MHz,DMSO-d6)δ:12.30(s,1H),9.13(s,1H),8.86(d,J=8.0Hz,1H),8.35(d,J=8.0Hz,3H),8.15(d,J=8.4Hz,1H),8.00(d,J=7.0Hz,2H),7.85(t,J=7.4Hz,1H),7.73(t,J=7.2Hz,1H),7.65(t,J=7.2Hz,1H),7.59(t,J=7.22Hz,2H),7.41(t,J=8.8Hz,2H);13C NMR(151MHz,DMSO-d6)δ:164.2,163.5,162.5,154.9,148.4,145.5,138.7,134.8,134.8,133.1,132.2,130.2,130.0,129.52,129.5,128.6,127.8,127.6,124.6,123.7,117.6,115.85(d,J=21.6Hz);HRMS(ESI),m/z:C23H16FN3O ([M+Na]+),理论值392.1170,实测值392.1170。
N′-((2-(4-氟苯基)喹啉-4-基)亚甲基)-2-羟基苯甲酰肼(7d):蓝绿色固体,产率78%,熔点255~257℃:1H NMR (600MHz,DMSO-d6)δ:12.19(s,1H),11.66(s,1H),9.12(s,1H),8.92(d,J=8.4Hz,1H),8.39(s,1H),8.38~8.34(m,2H),8.16(d,J=8.4Hz,1H),7.95(d,J=7.2Hz,1H),7.86(t,J=7.2Hz,1H),7.73(t,J=7.2Hz,1H),7.48(t,J=7.2Hz,1H),7.42(t,J=9.0Hz,2H),7.04(d,J=7.8Hz,1H),7.01(d,J=7.8Hz,1H);13C NMR (101MHz,DMSO-d6)δ:155.9,148.4,146.3,145.4,138.6,138.3,130.1,130.0,129.8,128.9,127.5,127.2,124.4,123.8,117.4,115.7,115.7,112.3;HRMS(ESI),m/z:C23H16FN3O2 ([M+H]+),理论值386.1299,实测值386.1299。
N′-((2-苯基喹啉-4-基)亚甲基)呋喃-2-甲酰肼(7e):黄色固体,产率68%,熔点213~215℃;1H NMR (400MHz,DMSO-d6)δ:12.26(s,1H),9.16(s,1H),8.78(d,J=6.0Hz,1H),8.35(s,1H),8.28(d,J=7.0Hz,2H),8.16(d,J=8.4Hz,1H),8.02(d,J=0.8Hz,1H),7.90~7.80(m,1H),7.72(t,J=7.4Hz,1H),7.59(t,J=7.6Hz,2H),7.53(t,J=7.2,1H),7.42(s,1H),6.76(d,J=3.6Hz,1H);13C NMR(101MHz,DMSO-d6) δ:155.91,148.44,146.29,138.55,138.31,130.04,129.79,128.94,127.47,127.17,124.34,123.78,117.37,112.27;HRMS (ESI),m/z:C21H15N3O2 ([M+H]+),理论值342.1237,实测值342.1247。
N′-((2-苯基喹啉-4-基)亚甲基)噻吩-2-甲酰肼(7f):黄色固体,产率88%,熔点238~240℃;1H NMR (400MHz,DMSO-d6)δ:12.29(s,1H),9.27~8.72(m,2H),8.37(s,1H),8.29(d,J=7.2Hz,2H),8.16(d,J=8.0Hz,1H),7.99(m,2H),7.86(t,J=7.6Hz,1H),7.72(t,J=7.6Hz,1H),7.60(t,J=7.6Hz,2H),7.54 (t,J=7.2Hz,1H),7.28(t,J=4.4Hz,1H);13C NMR (101MHz,DMSO-d6) δ:155.9,148.4,146.3,138.5,138.3,130.0,129.8,128.9,127.5,127.2,124.3,123.8,117.4,112.3;HRMS (ESI),m/z:C21H15FN3OS ([M+Na]+),理论值380.0828,实测值380.0826。
N′-((2-苯基喹啉-4-基)亚甲基)苯甲酰肼(7g):黄色固体,产率87%,熔点223~225℃;1H NMR (400 MHz,DMSO-d6)δ:12.74(s,1H),9.47(d,J=11.4Hz,1H),9.02~8.74(m,1H),8.45~8.20(m,3H),8.20~8.04(m,3H),7.93~7.66(m,2H),7.57(dd,J=13.9、7.0 Hz,6H);13C NMR(151MHz,DMSO-d6)δ:163.5,156.0,148.5,145.5,138.8,138.4,132.9,132.2,130.1,130.0,129.8,129.0,128.6,128.0,127.5,127.2,124.4,124.0,117.2;HRMS(ESI),m/z:C23H17N3O ([M+H]+),理论值352.1444,实测值352.1449。
2-羟基-N′-((2-苯基喹啉-4-基)亚甲基)苯并酰肼(7h):黄色固体,产率97%,熔点213~215℃;1H NMR(400MHz,DMSO-d6)δ:12.22(s,1H),11.72(s,1H),9.15(d,J=19.2Hz,1H),8.89(dd,J=18.8、8.0 Hz,1H),8.54~8.09(m,4H),7.99~7.67(m,3H),7.62~7.29(m,4H),7.22~6.85(m,2H);13C NMR (101MHz,DMSO-d6)δ:164.6,158.5,155.9,155.3,148.4,146.2,138.5,138.8,134.0,132.9,129.8,129.1,128.9,127.5,127.2,124.7,123.7,119.1,118.0,117.2;HRMS (ESI),m/z:C23H17N3O2 ([M+H]+),理论值368.1394,实测值368.1400。
N′-((2-(4-(三氟甲基)苯基)喹啉-4-基)亚甲基)呋喃-2-甲酰肼(7i):黄色固体,产率89%,熔点110~112℃;1H NMR(400MHz,DMSO-d6)δ:12.46(s,1H),9.25(s,1H),8.75(d,J=7.6Hz,1H),8.47(d,J=8.2Hz,2H),8.39(s,1H),8.16(d,J=8.4Hz,1H),8.03(s,1H),7.97~7.81(m,3H),7.74(t,J=7.6Hz,1H),7.49(d,J=2.2Hz,1H),6.76(dd,J=3.4、1.6 Hz,1H);13C NMR(101MHz,DMSO-d6)δ:154.3,146.4,145.0,138.9,130.2,128.0,127.3,126.6,126.1,125.2,124.2,117.2,115.8,112.3;HRMS(ESI),m/z:C22H14F3N3O2 ([M+H]+),理论值410.1111实测值410.1107。
N′-((2-(4-三氟甲基)苯基)喹啉-4-基)亚甲基)噻吩-2-甲酰肼(7j):黄色固体,产率80%,熔点286~288℃:1H NMR (400MHz,DMSO-d6)δ:12.60(s,1H),9.26(s,1H),8.89(d,J=49.8Hz,1H),8.50(d,J=8.2Hz,2H),8.44(s,1H),8.19(d,J=8.4Hz,1H),8.13(d,J=3.4Hz,1H),7.96(s,3H),7.89(t,J=7.4Hz,1H),7.76(t,J=7.6Hz,1H),7.33~7.24(m,1H);13C NMR (101MHz,DMSO-d6)δ:158.2,148.4,144.8,142.1,139.0,137.9,135.3,132.5,130.1,128.4,127.9,125.7,124.2;HRMS(ESI),m/z:C22H14F3N3OS([M+H]+),理论值426.0882,实测值426.0886。
1.4 活性测试模型
PTP 1B抑制活性测试:样品用DMSO溶解,采用光吸收检测法,在96孔或384孔平底透明微孔板中检测酶活性。底物pN PP经PTP 1B水解得到的游离产物在405nm处有很强的光吸收。通过酶标仪监测405nm处光吸收强度的变化,计算得到反应初速度。实验中采用的对照化合物为齐墩果酸。
2. 结果与讨论
2.1 目标化合物数据解析
以2, 3-二酮-吲哚和取代苯乙酮为起始原料,经Pfitzinger反应得4-(2-芳基)喹啉甲酸,先酯化得到4-(2-芳基)喹啉甲酸甲酯,再还原得到4-(2-芳基)喹啉甲醇,然后氧化得到4-(2-芳基)喹啉甲醛,最后与不同取代的芳肼盐酸盐、酰肼进行缩合反应,得到目标化合6a~6s和7a~7j。
以目标化合物6a的1H NMR数据为例进行解析。δ 11.00处的单峰归属于-NH-上的活泼氢;δ 8.75处的d峰归属于喹啉环中5位上的氢;δ 8.54处的单峰归属于喹啉环中3位上的氢;δ 8.38处的dd峰归属于2-位取代芳环上的2位和5位上的氢;δ 8.32处的单峰归属于—HC=N—上的活泼氢;δ 8.10处的双峰归属于喹啉环中8位上的氢;δ 7.81~7.69处的两个三重峰归属于喹啉环中6位和7位上的氢;δ 7.40~7.32处的两个三重峰归属于苯肼环上的4个氢;δ 7.24处的双重峰归属于氟代环上4位和5位的两个氢;δ 6.87处的三重峰归属于苯肼环上的另外一个氢。在HRMS谱图中,目标产物的HRMS [M+H]+实测值是342.1401,理论计算值是342.1401,误差在m/z ±0.003内,进一步确证了目标化合物的结构。
2.2 目标化合物的活性测试
PTP 1B是第一个被鉴定的蛋白酪氨酸磷酸酯酶,通过PTP 1B剔除的老鼠实验表明,PTP 1B通过对胰岛素受体的脱磷酰化,进而在调节胰岛素敏感性和脂肪代谢过程中起着非常重要的作用。PTP 1B的过表达也会促进各种人体肿瘤的发生。因而,选择性的、高活性的PTP 1B抑制剂在糖尿病、肥胖症、肿瘤的治疗中有重要的价值。
活性测试结果表明,目标化合物对PTP 1B具有较显著的抑制活性,具有潜在的调节代谢功能或抗肥胖或抗癌的药物活性。其中化合物6q、6f、6e、6j、6c、6i在20μg/mL浓度时对PTP 1B的抑制活性分别为97.98%、96.40%、96.34%、96.13%、95.45%、95.03%,见表 1。
表 1
表 1 目标化合物6a~6s和7a~7j对PTP 1B活性(抑制率/%)Table 1. Activity of target compounds 6a~6s and 7a~7j PTP 1B (inhibition rate/%)Compd. Inhibition rate/% Compd. Inhibition rate/% 6a 80.64±1.57 6p 73.58±16.29 6b 90.50±11.51 6q 97.98±2.36 6c 95.45±12.97 6r 94.85±2.95 6d 92.07±1.47 6s 83.47±1.38 6e 96.34±1.48 7a 76.70±4.74 6f 96.40±2.88 7b 86.58±6.02 6g 90.68±1.00 7c 93.68±5.69 6h 73.33±16.92 7d 90.25±2.86 6i 95.03±0.82 7e 75.16±14.99 6j 96.13±0.06 7f 77.40±4.34 6k 91.97±2.90 7g 71.72±5.92 6l 92.31±2.33 7h 83.77±1.40 6m 93.14±3.96 7i 88.67±3.21 6n 78.04±7.94 7j 84.10±4.29 6o 83.48±0.38 oleanolic acida 1.63±0.01(IC50) a Sodium orthovanadate were used as positive control. 活性测试表明,化合物系列6比化合物系列7的活性要好。对于系列6来说,当取代基R1为H时,R2是吸电子基还是给电子基或者是H时,化合物的抑制活性均在90%以上;另外,喹啉2位的苯环上不带取代基时活性较优;但当R2是H时,化合物的抑制活性下降较为明显,R2是CF3时,化合物活性基本在90%以上。因此,对于系列6来说,CF3是R2的最佳取代基。对于系列7来说,当R1是吸电子基时,化合物活性要普遍高于R1是H的化合物。
3. 结论
本文以1, 3-吲哚二酮、取代苯乙酮、苯肼盐酸盐、酰肼等价廉易得的化合物为原料合成了29个新型4-(2-芳基)喹啉芳腙和芳酰腙类化合物。初步活性测试结果表明,目标化合物对PTP 1B均具有较强的抑制活性。在检测浓度为20μg/mL时目标化合物对PTP 1B的抑制率大多在80%以上;6系列的化合物比7系列的化合物抑制率相对更高。研究结果为改变代谢功能或抗癌活性的喹啉腙类先导药物分子的发现提供了一定的研究依据。
致谢: 感谢上海国家药物筛选中心免费进行了化合物的活性测试工作! -
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图式 2 目标化合物6a~6s和7a~7j的合成路线
Scheme 2 Synthetic routes of the target compounds 6a~6s and 7a~7j
6a: R1=F, R2=H; 6b: R1=F, R2=OCH3; 6c: R1=F, R2=CH3; 6d: R1=F, R2=F; 6e: R1=F, R2=Cl; 6f: R1=F, R2=CN; 6g: R1=F, R2=CF3; 6h: R1=F, R2=NO2; 6i: R1=H, R2=H; 6j: R1=H, R2=NO2; 6k: R1=H, R2=OCH3; 6l: R1=H, R2=F; 6m: R1=H, R2=CF3; 6n: R1=CF3, R2=NO2; 6o: R1=CF3, R2=CH3; 6p: R1=CF3, R2=F; 6q: R1=CF3, R2=Cl; 6r: R1=CF3, R2=CF3; 6s: R1=CF3, R2=H; 7a: R1=F, R3=2-Furyl; 7b: R1=F, R3=2-Thienyl; 7c: R1=F, R3=4-Pyridyl; 7d: R1=F, R3=2-hydroxyphenyl; 7e: R1=H, R3=2-Furyl; 7f: R1=H, R3=2-Thienyl; 7g: R1=H, R3=4-Pyridyl; 7h: R1=H, R3=2-hydroxyphenyl; 7i: R1=CF3, R3=2-Furyl; 7j: R1=CF3, R3=2-Thienyl.
表 1 目标化合物6a~6s和7a~7j对PTP 1B活性(抑制率/%)
Table 1. Activity of target compounds 6a~6s and 7a~7j PTP 1B (inhibition rate/%)
Compd. Inhibition rate/% Compd. Inhibition rate/% 6a 80.64±1.57 6p 73.58±16.29 6b 90.50±11.51 6q 97.98±2.36 6c 95.45±12.97 6r 94.85±2.95 6d 92.07±1.47 6s 83.47±1.38 6e 96.34±1.48 7a 76.70±4.74 6f 96.40±2.88 7b 86.58±6.02 6g 90.68±1.00 7c 93.68±5.69 6h 73.33±16.92 7d 90.25±2.86 6i 95.03±0.82 7e 75.16±14.99 6j 96.13±0.06 7f 77.40±4.34 6k 91.97±2.90 7g 71.72±5.92 6l 92.31±2.33 7h 83.77±1.40 6m 93.14±3.96 7i 88.67±3.21 6n 78.04±7.94 7j 84.10±4.29 6o 83.48±0.38 oleanolic acida 1.63±0.01(IC50) a Sodium orthovanadate were used as positive control. -

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