天然蛋白酪氨酸磷酸酶-1B抑制剂的研究进展
Research Progress on Inhibitors of Natural Protein Tyrosine Phosphatase-1B
摘要: 蛋白酪氨酸磷酸酶-1B (PTP1B)是胰岛素信号转导途径中重要的负调控因子。PTP1B通过使胰岛素受体及其底物的酪氨酸残基去磷酸化从而破坏胰岛素信号转导。近年来，作为治疗2型糖尿病的新靶点，有关PTP1B抑制剂的研究引起了广泛关注。中国有丰富的植物资源，通过对天然产物进行提取，可以获得一些有活性的PTP1B抑制剂。高效PTP1B抑制剂的发现可以为2型糖尿病的治疗提供新的途径。本文根据PTP1B抑制剂的结构类型，综述了一些具有代表性的天然PTP1B抑制剂的研究进展，包括溴酚类化合物，黄铜化合物，萜类化合物，香豆素类化合物等。表明深入研究PTP1B及其有效的抑制剂对于治疗2型糖尿病具有很好的发展前景。
Abstract: Protein tyrosine phosphatase-1B (PTP1B) is a major negative regulator in insulin signal transduction pathways. In recent years, as a new target for the treatment of type 2 diabetes, the study of PTP1B inhibitors has attracted extensive attention. PTP1B disrupts the insulin signal transduction by dephosphorylating phosphotyrosine residues of insulin receptor and its substrates. China has plenty of plant resources, through the extraction of natural products, some active PTP1B inhibitors can be obtained. The discovery of highly effective inhibitors of PTP1B can provide a new way to treat type 2 diabetes. In this paper, according to the structural types of PTP1B inhibitors, the research progress of some representative natural PTP1B inhibitors is reviewed, including bromophenol compounds, brass compounds, terpenoid compounds, coumarin compounds and others, which shows that further study of PTP1B and its potent inhibitors have good prospects for the treatment of type 2 diabetes.
文章引用：郭忠秋, 王欣, 韩佳婧, 刘宇. 天然蛋白酪氨酸磷酸酶-1B抑制剂的研究进展[J]. 药物资讯, 2018, 7(6): 129-140. https://doi.org/10.12677/PI.2018.76022

参考文献

[1] 刘永贵, 解学星, 吴疆, 等. 治疗2型糖尿病的新靶点药物研究进展[J]. 现代药物与临床, 2015, 30(2): 222-227.
[2] 孟艳秋, 刘文虎, 刘凤鑫, 等. 抗2型糖尿病药物研究进展[J]. 现代药物与临床, 2013, 28(3): 461-464.
[3] Maheshwari, N., Karthikeyan, C., Trivedi, P., et al. (2018) Recent Advances in Protein Tyrosine Phos-phatase 1B Targeted Drug Discovery for Type II Diabetes and Obesity. Current Drug Targets, 19, 551-575.
[4] Chen, X., Gan, Q., Feng, C.G., et al. (2018) Virtual Screening of Novel and Selective Inhibitors of Protein Tyrosine Phospha-tase 1B over T-Cell Protein Tyrosine Phosphatase Using a Bidentate Inhibition Strategy. The Journal of Chemical In-formation and Modeling, 58, 837-847. [Google Scholar] [CrossRef] [PubMed]
[5] 王欣, 许潇, 孙瑞, 等. 蛋白酪氨酸磷酸酶1B及其小分子抑制剂的研究进展[J]. 北方药学, 2014, 11(11): 92-94.
[6] 刘霞, 冯长根. 蛋白酪氨酸磷酸酶-1B抑制剂研究进展[J]. 科技导报, 2012, 30(10): 72-79.
[7] Hajfg, B.J. (2015) Protein-Tyrosine Phosphatase 1B Substrates and Metabolic Regulation. Seminars in Cell & Developmental Biology, 37, 58-65. [Google Scholar] [CrossRef] [PubMed]
[8] Barford, D., Flint, A.J. and Tonks, N.K. (1994) Crystal Struc-ture of Human Protein Tyrosine Phosphatase 1B. Science, 263, 1397-1404. [Google Scholar] [CrossRef] [PubMed]
[9] Xiao, P., Wang, X., Wang, H.M., et al. (2014) The Second-Sphere Residue T263 Is Important for the Function and Catalytic Activity of PTP1B via Interaction with the WPD-Loop. Inter-national Journal of Biochemistry & Cell Biology, 57, 84-95. [Google Scholar] [CrossRef] [PubMed]
[10] Puius, Y.A., Zhao, Y., Sullivan, M., et al. (1997) Indentification of a Second Aryl Phosphate-Binding Site in Protein-Tyrosine Phosphatase 1B: A Paradigm for Inhibitor Design. Bio-chemistry, 94, 13420-13425.
[11] Panzhinskiy, E., Ren, J. and Nair, S. (2013) Protein Tyrosine Phosphatase 1B and Insulin Resistance: Role of Endoplasmic Reticulum Stress/Reactive Oxygen Species/Nuclear Factor Kappa B Axis. PLoS ONE, 8, e77228. [Google Scholar] [CrossRef] [PubMed]
[12] Mcguire, M.C., Fields, R.M., Nyomba, B.L., et al. (1991) Ab-normal Regulation of Protein Tyrosine Phosphatase Activities in Skeletal Muscle of Insulin-Resistant Humans. Diabetes, 40, 939-942. [Google Scholar] [CrossRef] [PubMed]
[13] Dadke, S.S., Li, H.C., Kusari, A.B., et al. (2000) Elevated Expression and Activity of Protein-Tyrosine Phosphatase 1B in Skeletal Muscle of Insulin-Resistant Type II Diabetic Goto-Kakizaki Rats. Biochemical and Biophysical Research Communications, 274, 583-589. [Google Scholar] [CrossRef] [PubMed]
[14] Chen, H., Wertheimer, S.J., Lin, C.H., et al. (1997) Protein-Tyrosine Phosphatases PTP1B and Syp Are Modulators of Insulin-Stimulated Translocation of GLUT4 in Transfected Rat Adi-pose Cells. Journal of Biological Chemistry, 272, 8026-8031. [Google Scholar] [CrossRef] [PubMed]
[15] Cicirelli, M.F., Tonks, N.K., Diltz, C.D., et al. (1990) Microinjection of a Protein-Tyrosine-Phosphatase Inhibits Insulin Action in Xenopus Oocytes. Proceedings of National Academy of Sciences of USA, 87, 5514-5518. [Google Scholar] [CrossRef] [PubMed]
[16] Klaman, L.D., Boss, O., Peroni, O.D., et al. (2000) Increased Energy Expenditure, Decreased Adiposity, and Tissue Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice. Molecular and Cellular Biology, 20, 5479-5489. [Google Scholar] [CrossRef] 
[17] Fernandez, R.R., Vieira, E., Garcia, R.P.M., et al. (2014) Protein Tyrosine Phosphatase-1B Modulates Pancreatic β-Cell Mass. PLoS ONE, 9, e90344. [Google Scholar] [CrossRef] [PubMed]
[18] 吴鸿. 蛋白酪氨酸磷酸酶1B对β细胞胰岛素分泌功能及其胰岛素信号转导通路的影响[D]: [博士学位论文]. 上海: 第二军医大学内分泌与代谢病专业, 2009.
[19] Kushner, J.A., Haj, F.G., Klaman, L.D., et al. (2004) Islet-Sparing Effects of Protein Tyrosine Phosphatase-1B Deficiency Delays Onset of Diabetes in InsRS2 Knockout Mice. Diabetes, 53, 61-66. [Google Scholar] [CrossRef] [PubMed]
[20] 郭伍斌, 马新, 刘翔. 血清胰岛素、瘦素及CRP在乳腺癌合并2型糖尿病患者中的表达水平及其临床意义[J]. 中国医学创新, 2017, 14(3): 13-16.
[21] Lund, I.K., Hansen, J.A., Andersen, H.S., et al. (2005) Mechanism of Protein Tyrosine Phosphatase 1B-Mediated Inhibition of Leptin Signalling. Journal of Molecular Endocrinology, 34, 339-351. [Google Scholar] [CrossRef] [PubMed]
[22] Cheng, A., Uetanli, E.N., Simoncic, P.D., et al. (2002) Attenuation of Leptin Action and Regulation of Obesity by Protein Tyrosine Phos-phatase 1B. Developmental Cell, 2, 497-503. [Google Scholar] [CrossRef] 
[23] 张雪莲, 郑海洲, 郑智慧. PTP1B作为药物靶点的研究进展[J]. 国外医药抗生素分册, 2017, 38(4): 173-178.
[24] Liu, M., Han-sen, P.E. and Lin, X.K. (2011) Bromophenols in Marine Algae and Their Bioactivities. Marine Drugs, 9, 1273-1292. [Google Scholar] [CrossRef] [PubMed]
[25] Liu, X., Li, X.M., Gao, L.X., et al. (2011) Extraction and PTP1B Inhibi-tory Activity of Bromophenols from the Marine Red Alga Symphyocladia latiuscula. Chinese Journal of Oceanology and Limnology, 29, 686-690. [Google Scholar] [CrossRef] 
[26] 朱承根, 田金英, 叶菲, 等. 溴酚衍生物的合成及其蛋白酪氨酸磷脂酶1B抑制剂活性研究[J]. 中国药物化学杂志, 2015, 25(6): 424-429.
[27] 杨猛, 高天虹. 原料药HPN制备工艺的优化以及新型PTP1B抑制剂的设计、合成以及生物活性研究[D]: [硕士学位论文]. 青岛: 青岛科技大学, 2015.
[28] 吴国耀. 蛋白酪氨酸磷酸酶1B抑制剂的化学合成及活性研究[D]: [硕士学位论文]. 青岛: 青岛科技大学, 2015.
[29] Halbwirth, H. (2010) The Creation and Physiological Relevance of Divergent Hydroxylation Pat-terns in the Flavonoid Pathway. International Journal of Molecular Sciences, 11, 595-621. [Google Scholar] [CrossRef] [PubMed]
[30] Kumar, S. and Pandey, A.K. (2013) Chemistry and Biological Activities of Flavonoids: An Overview. The Scientific World Journal, 2013, Article ID: 162750.
[31] Paoli, P., Cirri, P., Caselli, A., et al. (2013) The Insulin-Mimetic Effect of Morin: A Promising Molecule in Diabetes Treatment. Biochimica et Bio-physica Acta, 1830, 3102-3111. [Google Scholar] [CrossRef] [PubMed]
[32] Jiang, L., Numonov, S., Boba-kulov, K., et al. (2015) Phytochemical Profiling and Evaluation of Pharmacological Activities of Hypericum scabrum L. Molecules, 20, 11257-11271. [Google Scholar] [CrossRef] [PubMed]
[33] Choi, J.S., Islam, M.N., Ali, M.Y., et al. (2014) The Effects of Cglycosylation of Luteolin on Its Antioxidant, Anti-Alzheimer’s Disease, Anti-Diabetic, and Anti-Inflammatory Activities. Archives of Pharmacal Research, 37, 1354-1363. [Google Scholar] [CrossRef] [PubMed]
[34] Choi, J.S., Islam, M.N., Ali, M.Y., et al. (2014) Effects of C-Glycosylation on Anti-Diabetic, Anti-Alzheimer’s Disease and Anti-Inflammatory Potential of Apigenin. Food and Chemical Toxicology, 64, 27-33. [Google Scholar] [CrossRef] [PubMed]
[35] Na, B., Nguyen, P.H., Zhao, B.T., et al. (2016) Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitory Activity and Glucosidase Inhibitory Activity of Compounds Isolated from Agrimo-nia pilosa. Pharmaceutical Biology, 54, 474-480. [Google Scholar] [CrossRef] [PubMed]
[36] Progenca, C., Freitas, M., Ribeiro, D., et al. (2017) Inhibi-tion of Protein Tyrosine Phosphatase 1B by Flavonoids: A Structure-Activity Relationship Study. Food and Chemical Toxicology, 111, 474-481. [Google Scholar] [CrossRef] [PubMed]
[37] Quang, T.H., Ngan, N.T.T., Yoon, C.S., et al. (2015) Protein Tyro-sine Phosphatase 1B Inhibitors from the Roots of Cudrania tricuspidata. Molecules, 20, 11173-11183. [Google Scholar] [CrossRef] [PubMed]
[38] Cui, L., Thuong, P.T., Lee, H.S., et al. (2008) Flavanones from the Stem Bark of Erythrina abyssinica. Bioorganic & Medicinal Chemistry, 16, 10356-10362. [Google Scholar] [CrossRef] [PubMed]
[39] Zhang, L., Ge, Y., Song, H.M., et al. (2018) Design, Synthesis of Novel Azolyl Flavonoids and Their Protein Tyrosine Phosphatase-1B Inhibitory Activities. Bioorganic Chemistry, 80, 195-203. [Google Scholar] [CrossRef] [PubMed]
[40] Huang, X.C., Li, J., Li, Z.Y., et al. (2008) Sesquiter-penes from the Hainan Sponge Dysidea septosa. Journal of Natural Products, 71, 1399-1403. [Google Scholar] [CrossRef] [PubMed]
[41] Choi, J.Y., Na, M., Hwang, I.H., et al. (2009) Isolation of Betulinic Acid, Its Methyl Ester and Guaiane Sesquiterpenoids with Protein Tyrosine Phosphatase 1B Inhibitory Activity from the Roots of Saussurea lappa C.B. Clarke. Molecules, 14, 266-272. [Google Scholar] [CrossRef] [PubMed]
[42] Abdjul, D.B., Yamazaki, H., Takahashi, O., et al. (2016) Sesquiterpene Hydroquinones with Protein Tyrosine Phosphatase 1B Inhibitory Activities from a Dysidea sp. Marine Sponge Collected in Okinawa. Journal of Natural Products, 79, 1842-1847. [Google Scholar] [CrossRef] [PubMed]
[43] Jung, H.J., Jung, H.A., Kang, S.S., et al. (2012) In-hibitory Activity of Aralia continentalis Roots on Protein Tyrosine Phosphatase 1B and Rat Lens Aldose Reductase. Ar-chives of Pharmacal Research, 35, 1771-1777. [Google Scholar] [CrossRef] [PubMed]
[44] Zhang, X.S., Bi, X.L., Wan, X., et al. (2013) Protein Tyrosine Phosphatase 1B Inhibitory Effect by Dammarane-Type Triterpenes from Hydrolyzate of Total Gynostemma pentaphyl-lum Saponins. Bioorganic & Medicinal Chemistry Letters, 23, 297-300. [Google Scholar] [CrossRef] [PubMed]
[45] Li, J.L., Lli, N., Zhang, N., et al. (2014) Lupane Terpenoids Iso-lated from Betula platyphylla Suk of Protein Tyrosine Phosphatase 1B Inhibitory Activity. Natural Product Research and Development, 26, 1398-1401.
[46] Jain, P.K. and Joshi, H. (2012) Coumarin: Chemical and Pharmacological Profile. Journal of Applied Pharmaceutical Science, 2, 236-240.
[47] Ishita, I.J., Nurul, I.M., Kim, Y.S., et al. (2016) Couma-rins from Angelica decursiva Inhibit Lipopolysaccharide-Induced Nitrite Oxide Production in RAW 264.7 Cells. Archives of Pharmacal Research, 39, 115-126. [Google Scholar] [CrossRef] [PubMed]
[48] Nuru, I.M., Jung, H.A., Sohn, H.S., et al. (2013) Potent a-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitors from Artemisia capillaris. Archives of Pharmacal Re-search, 36, 542-552. [Google Scholar] [CrossRef] [PubMed]
[49] Ali, M.Y., Jannat, S., Jung, H.A., et al. (2016) Coumarins from Angelica decursiva Inhibit a-Glucosidase Activity and Protein Tyrosine Phosphatase 1B. Chemico-Biological Interactions, 252, 93-101. [Google Scholar] [CrossRef] [PubMed]
[50] Li, J.L., Gao, L.X., Meng, F.W., et al. (2015) PTP1B Inhibitors from Stems of Angelica keiskei (Ashitaba). Bioorganic & Medicinal Chemistry Letters, 25, 2028-2032. [Google Scholar] [CrossRef] [PubMed]
[51] Henki, R., Hiroyuki, Y., Shino, S., et al. (2018) Cladosporamide A, a New Protein Tyrosine Phosphatase 1B Inhibitor, Produced by an Indonesian Marine Sponge-Derived Cladosporium sp. Journal of Natural Medicines, 72, 779-783. [Google Scholar] [CrossRef] [PubMed]
[52] Feng, Y.J., Carroll, A.R., Addepalli, R., et al. (2017) Vanillic Acid Derivatives from the Green Algae Cladophora socialis as Potent Protein Tyrosine Phosphatase 1B Inhibitors. Journal of Natural Products, 70, 1790-1792. [Google Scholar] [CrossRef] [PubMed]
[53] Liang, L.F., Wang, X.J., Zhang, H.Y., et al. (2013) Bioactive Polyhydrox-ylated Steroids from the Hainan Soft Coral Sinularia depressa Tixier-Durivault. Bioorganic & Medicinal Chemistry Let-ters, 23, 1334-1337. [Google Scholar] [CrossRef] [PubMed]
[54] Yang, H., Liu, D.Q., Liang, T.J., et al. (2014) Racemosin C, a Novel Minor Bisindole Alkaloid with Protein Tyrosine Phosphatase-1B Inhibitory Activity from the Green Alga Caulerpa racemosa. Journal of Asian Natural Products Research, 16, 1158-1165. [Google Scholar] [CrossRef] [PubMed]
[55] Steinmann, D., Baumgarther, R.R., Heiss, E.H., et al. (2012) Bioguided Isolation of (9Z)-Octadec-9-Enoic Acid from Phellodendron amurense Rupr. and Identification of Fatty Acids as PTP1B Inhibitors. Planta Medica, 78, 219-224. [Google Scholar] [CrossRef] [PubMed]
[56] Quang, T.H., Ngan, N.T.T., Ko, W., et al. (2014) Tanzawaic Acid Derivatives from a Marine Isolate of Penicillium sp. (SF-6013) with Anti-Inflammatory and PTP1B Inhibitory Activities. Bioorganic & Medicinal Chemistry Letters, 24, 5787-5791. [Google Scholar] [CrossRef] [PubMed]
[57] Chen, G.C., Li, X.L., Chen, G., et al. (2016) Isolation and Identification of Lignans Chemical Constituents from Coptis chinen-sis and Their Inhibitory Activity to Protein Tyrosine Phosphatase-1B. China Pharm, 27, 2197-2199.