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蛋白质组学在细胞信号通路研究中的应用

谭程宁, 黄靖涵, 李春红, 夏之宁, 杨丰庆

谭程宁, 黄靖涵, 李春红, 夏之宁, 杨丰庆. 蛋白质组学在细胞信号通路研究中的应用[J]. 中国药科大学学报, 2017, 48(4): 384-395. DOI: 10.11665/j.issn.1000-5048.20170402
引用本文: 谭程宁, 黄靖涵, 李春红, 夏之宁, 杨丰庆. 蛋白质组学在细胞信号通路研究中的应用[J]. 中国药科大学学报, 2017, 48(4): 384-395. DOI: 10.11665/j.issn.1000-5048.20170402
TAN Chengning, HUANG Jinghan, LI Chunhong, XIA Zhining, YANG Fengqing. Applications of proteomics in the study of cell signal pathways[J]. Journal of China Pharmaceutical University, 2017, 48(4): 384-395. DOI: 10.11665/j.issn.1000-5048.20170402
Citation: TAN Chengning, HUANG Jinghan, LI Chunhong, XIA Zhining, YANG Fengqing. Applications of proteomics in the study of cell signal pathways[J]. Journal of China Pharmaceutical University, 2017, 48(4): 384-395. DOI: 10.11665/j.issn.1000-5048.20170402

蛋白质组学在细胞信号通路研究中的应用

基金项目: 国家自然科学基金资助项目(No.81202886,No.21275169)

Applications of proteomics in the study of cell signal pathways

  • 摘要: 细胞中各种信号转导与生物学过程密切相关,而蛋白质在信号传导过程中起着至关重要的作用。蛋白质组学从整体水平上研究蛋白质组,可系统地研究生物体生理生化以及与疾病发生发展相关的功能性蛋白的表达,是研究细胞信号通路的有效方法之一。目前,蛋白质组学技术已经应用于各种信号通路研究中,并取得了诸多进展。本文综述了蛋白质组学在肝脏疾病、肿瘤、病原微生物致病机制以及机体代谢相关通路的研究等方面的应用,以期为蛋白质组学在相关领域的进一步应用研究提供参考。
    Abstract: Various signal transduction pathways in cells are closely related to the biological processes, while the proteins play an important role in the process of signal transductions. Proteomics, which is one of the effective methods for the study of cell signal pathways, can conduct proteomic analysis systematically as well as explore the expression of functional proteins related to the physiological characteristics in organism and in the initiation and progression of diseases. Nowadays, proteomics has been successfully applied in the studies of many kinds of signal pathways. In this paper, proteomic study in signal pathways related to liver disease, tumors, pathogenic mechanism of pathogens and metabolism are reviewed, in order to provide a reference for future research and applications of proteomics in the related fields.
  • 癌症作为一种严重危害人类健康的疾病,是世界各国都面临的公共卫生问题[1]。根据国际癌症研究中心的数据显示,全球新发癌症病例和癌症死亡病例逐年增加[2]。药物研发起源于先导物的发现和优化[3],基于药物设计原理,利用现有药物的结构或药效团,从而构建结构新颖的化合物,并利用活性筛选发现先导化合物是目前新药研发最经济有效的策略[45]

    1,2-苯并噻嗪是多个药物的优势骨架,如非甾体抗炎药吡罗昔康等,具有多种生物活性。薁是由一个环庚三烯和一个环戊二烯稠合而成,是萘的同分异构体。由于其特殊的电子结构和物理化学性质,使其广泛应用于医药、农药和光学材料等领域[611],因而受到研究者的广泛关注。为了进一步研究杂环修饰的1,2-苯并噻嗪类化合物的合成及其生物活性,寻找具有生物活性的新化合物,本研究以吡罗昔康合成中间体1(2-甲基-4-羟基-2H-1,2-苯并噻嗪-3-甲酸甲酯-1,1-二氧化物,CAS:35511-15-0)为原料,首次将类薁基引入1,2-苯并噻嗪结构中,制备一系列结构新颖的1,2-苯并噻嗪类化合物6a~6j,合成路线见路线1。

      1.  Synthetic route of the target compounds

    熔点用毛细管法测定,温度未校正; AM2400型核磁共振仪(德国Bruker公司);HP1100型质谱仪(美国Agilent公司);PE2400-Ⅱ元素分析仪(美国PE公司);化合物1为吡罗昔康合成中间体(CAS:35511-15-0)来自商业品,化合物2(2-甲基-4-羟基-2H-1,2-苯并噻嗪-3-甲酰肼-1,1-二氧化物)按文献[12]的方法制备,试剂均为市售分析纯,未经处理,直接使用。

    取氢氧化钾(4.7 g, 0.084 mol),无水乙醇120 mL,依次加入250 mL三口瓶中,完全溶解后,加入化合物2(15 g, 0.056 mol),冰浴降温至0℃左右,控制温度(0~5 ℃),恒压滴液漏斗滴加二硫化碳(5 mL, 0.083 mol),滴加结束后,自然升至室温,搅拌反应4 h后,加热至回流并反应9 h,利用TLC检测(乙酸乙酯-石油醚, 2∶1),反应结束后,自然冷却至室温,调节pH2~3,过滤,用乙醇重结晶,60 ℃鼓风干燥,得黄色化合物12.5 g,收率72%,mp:251~252 ℃。

    取化合物3(10 g, 0.032 mol),80%水合肼(100 mL, 1.651 mol)依次加入250 mL三口瓶中,加热回流(约100 ℃)8 h,TLC检测(乙酸乙酯-石油醚, 3∶1),反应完成后,将反应液浓缩至黏稠状,加水80 mL,调节pH至中性,静置,析出沉淀后,过滤,用乙醇重结晶,60 ℃干燥得到黄色化合物4.8 g,收率46%,mp:208~209 ℃。

    取化合物4(3.5 g, 0.011 mol),无水乙醇20 mL,依次加入250 mL三口瓶中,搅拌均匀,加入1 mol/L氢氧化钠溶液,调节pH至9~10,待完全溶解后,加入3-氯苯乙酮(2.2 g, 0.013 mol),常温下搅拌反应6 h(过程中注意监测溶液的pH,控制pH 9~10),待反应结束后,静置,过滤,用乙醇重结晶,干燥黄色化合物2.2 g,mp:192~193 ℃,收率45%。

    按化合物5a相似的方法分别制备目标物5b~5j

    向100 mL单口瓶中,加入化合物5a(1.1 g, 0.002 mol),无水乙醇10 mL,滴加5~6 滴浓硫酸,加热至回流,反应5 h,TLC检测(乙酸乙酯-石油醚, 1∶1),反应结束后,自然冷却至室温,过滤,得黄色化合物0.7 g。收率64%,mp:229~231 ℃。

    按化合物6a相似的方法分别制备目标物6b6j。理化性质和光谱数据见表1表2

    Table  1.  Physical properties of compounds 5a 5j and 6a6j
    Compd. Formula Yield/% mp/℃ Elemental analysis(%,Calcd.)
    C H N
    5a C20H19N5O4S2 45 192–193 55.52(55.50) 4.21(4.19) 15.27(15.31)
    5b C20H18FN5O4S2 47 196–198 50.48(50.52) 3.78(3.82) 14.81(14.73)
    5c C20H17BrFN5O4S2 45 203–205 43.35(43.33) 3.05(3.09) 12.65(12.63)
    5d C20H19N5O5S2 42 202–204 50.75(50.73) 4.02(4.04) 14.75(14.79)
    5e C21H21N5O4S2 48 198–200 53.53(53.49) 4.55(4.49) 14.81(14.85)
    5f C20H17Cl2N5O4S2 49 210–212 45.65(45.63) 3.32(3.26) 13.34(13.30)
    5g C18H17N5O4S3 52 221–223 46.58(46.64) 3.68(3.70) 15.13(15.11)
    5h C18H22N6O4S2 50 233–235 47.91(47.99) 4.88(4.92) 18.69(18.65)
    5i C23H23N5O4S2 42 228–230 55.48(55.52) 4.68(4.66) 14.03(14.07)
    5j C23H24N6O4S2 41 225–227 53.93(53.89) 4.74(4.72) 16.36(16.40)
    6a C20H17N5O3S2 64 229–231 54.60(54.66) 3.94(3.90) 15.97(15.93)
    6b C20H16FN5O3S2 65 222–224 52.57(52.51) 3.51(3.53) 15.35(15.31)
    6c C20H15BrFN5O3S2 60 224–226 44.86(44.78) 2.86(2.82) 13.12(13.06)
    6d C20H17N5O4S2 61 223–226 52.68(52.74) 3.72(3.76) 15.36(15.38)
    6e C21H19N5O3S2 67 225–227 55.63(55.61) 4.26(4.22) 15.38(15.44)
    6f C20H15Cl2N5O3S2 66 240–242 47.19(47.25) 2.99(2.97) 13.80(13.78)
    6g C18H15N5O3S3 73 249–251 48.57(48.53) 3.35(3.39) 15.70(15.72)
    6h C18H20N6O3S2 71 261–263 49.95(49.99) 4.72(4.66) 19.45(19.43)
    6i C23H21N5O3S2 59 258–260 57.64(57.60) 4.39(4.41) 14.62(14.60)
    6j C23H22N6O3S2 59 252–254 55.82(55.86) 4.54(4.48) 16.95(16.99)
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    Table  2.  Spectral data of compounds 36i
    Compd.1H NMR (400 MHz, DMSO-d6) δ13C NMR (100 MHz , DMSO-d6) δMS m/z [M+H]+
    312.96(1H,s,-OH),7.73-7.95(4H,m,Ph-H),3.00(3H,s,-NCH3)160,156,134,132,129,127,124,110,37312
    412.84(1H,s,-OH),7.69-7.91(4H,m,Ph-H),5.27(2H,s,-NH2),3.11(3H,s,-NCH3)167,156,144,134,132,129,127,124,111,38326
    5a12.88(1H,s,-OH),7.65-7.89(9H,m,Ph-H),5.43(2H,s,-NH2),3.31(2H,t,-SCH2),3.13(3H,s,-NCH3),3.05(2H,t,-CH2-C=O)200,159,156,144,137,134,133,132,129,127,124,111,42,38,27458
    5b12.82(1H,s,-OH),7.45-7.86(8H,m,Ph-H),5.46(2H,s,-NH2),3.35(2H,t,-SCH2),3.12(3H,s,-NCH3),3.02(2H,t,-CH2-C=O)200,162,158,156,143,135,134,133,132,128,127,124,111,41,38,28476
    5c12.78(1H,s,-OH),7.36-8.06(7H,m,Ph-H),5.54(2H,s,-NH2),3.29(2H,t,-SCH2),3.07(3H,s,-NCH3),2.97(2H,t,-CH2-C=O)200,161,159,156,144,138,134,133,132,128,127,124,118,110,41,38,28554
    5d12.77(1H,s,-OH),10.68(1H,s,Ph-OH),7.18-7.86(8H,m,Ph-H),5.48(2H,s,-NH2),3.17(2H,t,-SCH2),3.09(3H,s,-NCH3),2.93(2H,t,-CH2-C=O)200,163,159,156,144,135,133,132,129,127,124,122,118,110,41,38,28474
    5e12.83(1H,s,-OH),7.21-7.87(8H,m,Ph-H),5.64(2H,s,-NH2),3.22(2H,t,-SCH2),3.11(3H,s,-NCH3),2.95(2H,t,-CH2-C=O),1.51(3H,s,Ph-CH3)200,160,156,144,143,135,134,133,132,129,127,124,118,110,42,38,28,21472
    5f12.84(1H,s,-OH),7.66-8.26(7H,m,Ph-H),5.52(2H,s,-NH2),3.27(2H,t,-SCH2),3.07(3H,s,-NCH3),2.98(2H,t,-CH2-C=O)200,159,156,144,138,136,134,133,132,130,128,127,110,41,38,28526
    5g12.80(1H,s,-OH),7.32-7.86(4H,m,Ph-H),7.16-7.66(3H,d,thiophene-H),5.44(2H,s,-NH2),3.27(2H,t,-SCH2),3.11(3H,s,-NCH3),2.98(2H,t,-CH2-C=O)192,159,156,144,134,133,132,129,127,124,110,40,37,27464
    5h12.78(1H,s,-OH),7.34-7.88(4H,m,Ph-H),5.50(2H,s,-NH2),3.23(2H,t,-SCH2),3.10(3H,s,-NCH3),2.95(2H,t,-CH2-C=O),2.69(4H,t,-CH2-N-CH2),1.33(4H,t,pyrrolidine-CH2-CH2)175,159,156,144,142,135,134,132,129,127,124,110,49,38,32,29,25451
    5i12.82(1H,s,-OH),7.34-7.85(7H,m,Ph-H),5.58(2H,s,-NH2),3.19(2H,t,-SCH2),3.11(3H,s,-NCH3),2.89(2H,t,-CH2-C=O),1.35-1.95(6H,m,-CH2-CH2-CH2)200,159,156,148,144,142,135,134,132,129,127,126,124,110,40,38,33,28,25498
    5j12.86(1H,s,-OH),7.26-7.82(8H,m,Ph-H),5.62(2H,s,-NH2),3.32-4.42(6H,m,piperidine-H),3.29(2H,t,-SCH2),3.03(3H,s,-NCH3),2.77(2H,t,-CH2-C=O),172,159,156,144,135,134,132,129,127,126,124,111,49,48,38,32,29513
    6a12.78(1H,s,-OH),7.65-7.94(9H,m,Ph-H),3.23(2H,t,-SCH2),3.07(3H,s,-NCH3),2.75(2H,t,-CH2-C=N)165,159,156,144,135,132,129,128,127,124,111,37,33,31440
    6b12.68(1H,s,-OH),7.46-7.84(8H,m,Ph-H),3.31(2H,t,-SCH2),3.12(3H,s,-NCH3),2.79(2H,t,-CH2-C=N)165,160,159,156,144,135,133,132,131,129,127,124,116,111,37,33,31458
    6c12.74(1H,s,-OH),7.30-7.96(7H,m,Ph-H),3.29(2H,t,-SCH2),3.03(3H,s,-NCH3),2.69(2H,t,-CH2-C=N)165,159,156,144,138,136,135,132,128,124,120,118,110,37,33,31536
    6d12.78(1H,s,-OH),10.66(1H,s,Ph-OH),7.12-7.76(8H,m,Ph-H),3.19(2H,t,-SCH2),3.11(3H,s,-NCH3),2.73(2H,t,-CH2-C=N)165,163,159,156,144,135,132,129,127,124,121,118,110,37,33,31456
    6e12.73(1H,s,-OH),7.18-7.87(8H,m,Ph-H),3.27(2H,t,-SCH2),3.07(3H,s,-NCH3),2.75(2H,t,-CH2-C=N),1.47(3H,s,Ph-CH3)165,159,156,144,141,135,132,131,129,127,124,110,42,37,33,31,21454
    6f12.74(1H,s,-OH),7.56-8.18(7H,m,Ph-H),3.19(2H,t,-SCH2),3.01(3H,s,-NCH3),2.68(2H,t,-CH2-C=N)165,159,156,144,138,136,135,134,132,130,129,126,110,37,33,31508
    6g12.82(1H,s,-OH),7.44-7.84(4H,m,Ph-H),7.10-7.62(3H,d,thiophene-H),3.20(2H,t,-SCH2),2.993H,(s,-NCH3),2.68(2H,t,-CH2-C=N)165,159,156,144,134,132,129,127,126,124,110,37,34,31446
    6h12.74(1H,s,-OH),7.44-7.78(4H,m,Ph-H),3.23(2H,t,-SCH2),3.04(3H,s,-NCH3),2.75(2H,t,-CH2-C=N),2.58(4H,t,-CH2-N-CH2),1.66(4H,t,pyrrolidine-CH2-CH2)159,156,149,144,134,132,129,127,124,110,49,37,31,30,26433
    6i12.76(1H,s,-OH),7.44-7.84(7H,m,Ph-H),3.23(2H,t,-SCH2),3.13(3H,s,-NCH3),2.63(2H,t,-CH2-C=N),1.35-1.87(6H,m,-CH2-CH2-CH2)165,159,156,149,146,144,135,132,129,127,124,110,37,33,31,25480
    6j12.82(1H,s,-OH),7.22-7.78(8H,m,Ph-H),3.36-4.44(6H,m,piperidine-H),3.25(2H,t,-SCH2),3.07(3H,s,-NCH3),2.73(2H,t,-CH2-C=N),159,156,144,140,135,134,132,130,129,126,123,111,45,37,32,27,22495
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    对合成的目标化合物,蒽醌类抗肿瘤药物多柔比星以及母体吡罗昔康合成中间体(化合物1)进行抗肿瘤活性评价。采用MTT法测定对人胰腺癌细胞Capan-1(中国医学科学院协和细胞库)、鼠白血病细胞L1210(中国医学科学院协和细胞库)和人肝癌细胞SMMC-7721(中国医学科学院协和细胞库)的半数抑制浓度(IC50),结果见表3

    Table  3.  Anti-cell proliferative activity of the tested compounds against Capan-1, SMMC-7721 and L1210 tumor cells($\bar{x}\pm s $, n=3)
    Compd. IC50/(μmol/L)
    Capan-1 SMMC-7721 L1210
    6a 15.7±1.4 18.2±1.7 14.6±1.5
    6b 9.8±1.0 8.6±0.9 2.6±0.3
    6c 9.6±1.0* 2.1±0.2* 8.7±0.8*
    6d 10.8±1.1* 11.6±1.2 10.2±1.0*
    6e 14.6±1.5 15.3±1.5 16.2±1.6
    6f 4.8±0.5* 8.7±0.7* 9.4±0.9*
    6g 11.4±1.2 14.1±1.4 15.8±1.6
    6h 11.8±1.2 13.6±1.4* 13.8±1.4
    6i 11.7±1.2 10.7±1.2* 9.2±0.9*
    6j 12.8±1.3 11.6±1.2 13.6±1.4
    Doxorubicin 3.5±0.6 2.7±0.2 1.4±0.2
    1 >100 >100 >100
    2 80.2±8.1 78.5±7.3 77.4±7.3
    3 65.5±6.6 71.7±7.2 73.6±7.5
    4 64.6±6.5 70.3±7.0 72.5±7.2
    5a 15.2±1.4 17.2±1.7 15.6±1.6
    5b 10.2±1.0 9.2±0.9 2.4±0.3
    5c 9.8±1.0* 6.2±0.6* 6.7±0.8*
    5d 10.6±1.1* 10.8±1.2 9.8±1.0*
    5e 15.6±1.5 15.1±1.5 15.4±1.5
    5f 7.6±0.7* 8.2±0.7* 8.8±0.9*
    5g 12.2±1.2 14.3±1.4 14.2±1.4
    5h 12.6±1.2 11.2±1.1* 13.6±1.4
    5i 12.7±1.3 11.6±1.2* 8.6±0.9*
    5j 11.8±1.2 13.6±1.4 15.2±1.5
    *P<0.05 vs doxorubicin
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    体外抗肿瘤实验结果显示,10个目标化合物(6a~6j)对人胰腺癌细胞Capan-1、鼠白血病细胞L1210和人肝癌细胞SMMC-7721呈现出不同程度的抑制作用(IC50均小于20 μmol/L),其中化合物6f6g6h对Capan-1、L1210和SMMC-7721的IC50与对照多柔比星的活性相当。

    初步的构效关系研究表明,薁类衍生物的引入,有利于化合物电荷的分散而更加稳定,对提高该类化合物的抗肿瘤活性有一定的作用。更有意义的是,在稠杂环结构上引入含有吸电子基团的取代基时,化合物的抗肿瘤活性进一步增强,具有进一步研究的价值,这也预示着1,2-苯并噻嗪结构的修饰在肿瘤治疗方面将会有更加广阔的研究前景。

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