Citation: Lu Chenga, Liu Xiang, Tang Yanting, Xu Yongxue, Zhong Weilong, Sun Taoa, Zhou Honggang. Design, Synthesis of a Novel Phosphatase 1B Inhibitor and the Evaluation of Its Biology Activity and Toxicity in vitro[J]. Acta Chimica Sinica, ;2015, 74(2): 155-164. doi: 10.6023/A15090597 shu

Design, Synthesis of a Novel Phosphatase 1B Inhibitor and the Evaluation of Its Biology Activity and Toxicity in vitro

a.
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071
b.
High Throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457

Corresponding author: Zhou Honggang, honggang.zhou@nankai.edu.cn
Received Date: 11 September 2015

Fund Project: the National Natural Science Foundation of China No. 81102374the National Biomedical Special Project of International Innovation Park Nos. 11ZCKFSY06900, 10ZCKFSY08600, 14ZCZDSY00038

Figures(11)

Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the insulin receptor. It has been considered as one of the drug targets of diabetes, and the inhibitors for PTP1B to treat type II diabetes have received considerable attention. The study reports a discovery of a new lead compound inhibiting PTP1B. In this work, PTP1B protein was expressed, purified and crystallized to the resolution of 2.1 Angstrom in the condition of 19%~21% PEG8000, 200 mmol/L Mg(Ac)₂·4H₂O. Structural based fragment screening was then performed against 768 fragment chemical compounds. These small molecular fragments were soaked with the PTP1B crystals, and three of them were found to bind at the active site A of PTP1B in the crystals. Then 14 kinds of published molecules which bind to the second active site (site B) were chosen. With the structures of these bound fragment compounds, hundreds of moleculars were calculated by computer aided drug design. Compound 20 was selected as the target compound, and it was synthesized by 13 steps with the total yield of 1.7%. The structure of compound 20 was characterized by ¹H NMR and HRMS data. Bioassay of inhibition of PTP1B by the new compounds revealed its IC₅₀ at (3.4±1.2) μmol/L, which was better than that of the positive control drug-sodium vanadate. The result of measurement of glucose uptake by insulin resistant HepG2 cells showed that the new compound can improve glucose uptake and had similar effect as Pioglitazone. The acute toxicity of the new compound was tested by using zebrafish larvae at two different concentrations (50 and 500 μmol/L). The results showed there was no significant difference in heart rate, blood flow and morphology between the experiment and control group of zebrafish. All the results above implied the new compound has a good inhibition on PTP1B and low acute toxicity. It may be a potential lead compound for further drug discovery.
- protein tyrosine phosphatase (PTPase) 1B,
- crystal diffraction,
- structure-based drug design,
- synthesis,
- activity
1. [1]
  Tonks, N. K. Nat. Rev. Mol. Cell Biol. 2006, 7, 833.
2. [2]
  Tonks, N. K.; Diltz, C. D.; Fischer, E. H. J. Biol. Chem. 1988, 263, 6731.
3. [3]
  Kenner, K. A.; Anyanwu, E.; Olefsky, J. M.; Kusari, J. J. Biol. Chem. 1996, 271, 19810.
4. [4]
  Ahmad, F.; Li, P. M.; Meyerovitch, J.; Goldstein, B. J. J. Biol. Chem. 1995, 270, 20503.
5. [5]
  Elchebly, M.; Payette, P.; Michaliszyn, E.; Cromlish, W.; Collins, S.; Loy, A. L.; Normandin, D.; Cheng, A.; Himms-Hagen, J.; Chan, C. C.; Ramachandran, C.; Gresser, M. J.; Tremblay, M. L.; Kennedy, B. P. Science 1999, 283, 1544.
6. [6]
  Combs, A. P. J. Med. Chem. 2010, 53, 2333.
7. [7]
  Barford, D.; Flint, A. J.; Tonks, N. K. Science 1994, 263, 1397.
8. [8]
  Renate, R. B.; Dirk, S.; Elke, H. H.; Atanas, G. A.; Markus, G.; Hermann, S.; Verena, M. D. Nat. Prod. 2010, 73, 1578.
9. [9]
  Shen, K.; Keng, Y. F.; Wu, L.; Guo, X. L.; Lawrence, D. S.; Zhang, Z. Y. J. Biol. Chem. 2001, 276, 47311.
10. [10]
  Asante-Appiah, E.; Patel, S.; Dufresne, C.; Roy, P.; Wang, Q.; Patel, V.; Friesen, R. W.; Ramachandran, C.; Becker, J. W.; Leblanc, Y.; Kennedy, B. P.; Scapin, G. Biochemistry 2002, 41, 9043.
11. [11]
  Sun, J. P.; Fedorov, A. A.; Lee, S. Y.; Guo, X. L.; Shen; Lawrence, D. S.; Almo, S. C.; Zhang, Z. Y. J. Biol. Chem. 2003, 278, 12406.
12. [12]
  Szczepankiewicz, B. G.; Liu, G.; Hajduk, P. J.; Abad-Zapatero, C.; Pei, Z.; Xin, Z.; Lubben, T. H.; Trevillyan, J. M.; Stashko, M. A.; Ballaron, S. J.; Liang, H.; Huang, F.; Hutchins, C. W.; Fesik, S. W.; Jirousek, M. R. J. Am. Chem. Soc. 2003, 125, 4087.
13. [13]
  Xin, Z.; Oost, T. K.; Abad-Zapatero, C.; Hajduk, P. J.; Pei, Z.; Szczepankiewicz, B. G.; Hutchins, C. W.; Ballaron, S. J.; Stashko, M. A.; Lubben, T.; Trevillyan, J. M.; Jirousek, M. R.; Liu, G. Bioorg. Med. Chem. Lett. 2003, 13, 1887.
14. [14]
15. [15]
  Liu, G.; Xin, Z. L.; Pei, Z. G.; Hajduk, P. J.; Abad-Zapatero, C.; Hutchins, C. W.; Zhao, H. Y.; Lubben, T. H.; Ballaron, S. J.; Haasch, D. L.; Kaszubska, W.; Rondinone, C. M.; Trevillyan, J. M.; Jirousek, M. R. J. Med. Chem. 2003, 46, 4232.
16. [16]
17. [17]
  Wilson, D. P.; Wan, Z. K.; Xu, W. X.; Kirincich, S. J.; Follows, B. C.; Joseph-McCarthy, D.; Foreman, K.; Moretto, A.; Wu, J.; Zhu, M.; Binnun, E.; Zhang, Y. L.; Tam, M.; Erbe, D. V.; Tobin, J.; Xu, X.; Leung, L.; Shilling, A.; Tam, S. Y.; Mansour, T. S.; Lee, J. J. Med. Chem. 2007, 50, 4681.
18. [18]
  Craig, C. M.; Jaqueline, D. H.; Marjorie, A. J.; Zaneta, D.; Emily, A. B.; Bradley, A. G.; Nicole, A. D.; Mary, A. Y.; Lisa, M. M. J. Inorg. Biochem. 2010, 104, 274.
19. [19]
20. [20]
  Huang, D.; Liu, Y.; Shi, B.; Li, Y.; Wang, G.; Liang, G. J. Mol. Graphics Modell. 2013, 45, 65.
1. [1]
  Jing WU , Puzhen HUI , Huilin ZHENG , Pingchuan YUAN , Chunfei WANG , Hui WANG , Xiaoxia GU . Synthesis, crystal structures, and antitumor activities of transition metal complexes incorporating a naphthol-aldehyde Schiff base ligand. Chinese Journal of Inorganic Chemistry, 2024, 40(12): 2422-2428. doi: 10.11862/CJIC.20240278
2. [2]
  Xinting XIONG , Zhiqiang XIONG , Panlei XIAO , Xuliang NIE , Xiuying SONG , Xiuguang YI . Synthesis, crystal structures, Hirshfeld surface analysis, and antifungal activity of two complexes Na(Ⅰ)/Cd(Ⅱ) assembled by 5-bromo-2-hydroxybenzoic acid ligands. Chinese Journal of Inorganic Chemistry, 2024, 40(9): 1661-1670. doi: 10.11862/CJIC.20240145
3. [3]
  Bin SUN , Heyan JIANG . Glucose-modified bis-Schiff bases: Synthesis and bio-activities in Alzheimer′s disease therapy. Chinese Journal of Inorganic Chemistry, 2025, 41(7): 1338-1350. doi: 10.11862/CJIC.20240428
4. [4]
  Lifang HE , Wenjie TANG , Yaoze LUO , Mingsheng LIANG , Jianxin TANG , Yuxuan WU , Fuxing ZHANG , Xiaoming ZHU . Synthesis, structure, and anticancer activity of two dialkyltin complexes constructed based on 2, 2′-bipyridin-6, 6′-dicarboxylic acid. Chinese Journal of Inorganic Chemistry, 2025, 41(8): 1601-1609. doi: 10.11862/CJIC.20250012
5. [5]
  Lixing ZHANG , Yaowen WANG , Xu HAN , Junhong ZHOU , Jinghui WANG , Liping LI , Guangshe LI . Research progress in the synthesis of fluorine-containing perovskites and their derivatives. Chinese Journal of Inorganic Chemistry, 2025, 41(9): 1689-1701. doi: 10.11862/CJIC.20250007
6. [6]
  Ying Chen , Ronghua Yan , Weiyan Yin . Research Progress on the Synthesis of Metal Single-Atom Catalysts and Their Applications in Electrocatalytic Hydrogen Evolution Reactions. University Chemistry, 2025, 40(9): 344-353. doi: 10.12461/PKU.DXHX202503066
7. [7]
  Jiaming Xu , Yu Xiang , Weisheng Lin , Zhiwei Miao . Research Progress in the Synthesis of Cyclic Organic Compounds Using Bimetallic Relay Catalytic Strategies. University Chemistry, 2024, 39(3): 239-257. doi: 10.3866/PKU.DXHX202309093
8. [8]
  Xinyi Zhang , Kai Ren , Yanning Liu , Zhenyi Gu , Zhixiong Huang , Shuohang Zheng , Xiaotong Wang , Jinzhi Guo , Igor V. Zatovsky , Junming Cao , Xinglong Wu . Progress on Entropy Production Engineering for Electrochemical Catalysis. Acta Physico-Chimica Sinica, 2024, 40(7): 2307057-0. doi: 10.3866/PKU.WHXB202307057
9. [9]
  Lei Feng , Ze-Min Zhu , Ying Yang , Zongbin He , Jiafeng Zou , Man-Bo Li , Yan Zhao , Zhikun Wu . Long-Pursued Structure of Au₂₃(S-Adm)₁₆ and the Unexpected Doping Effects. Acta Physico-Chimica Sinica, 2024, 40(5): 2305029-0. doi: 10.3866/PKU.WHXB202305029
10. [10]
  Chunling Qin , Shuang Chen , Hassanien Gomaa , Mohamed A. Shenashen , Sherif A. El-Safty , Qian Liu , Cuihua An , Xijun Liu , Qibo Deng , Ning Hu . Regulating HER and OER Performances of 2D Materials by the External Physical Fields. Acta Physico-Chimica Sinica, 2024, 40(9): 2307059-0. doi: 10.3866/PKU.WHXB202307059
11. [11]
  Qing ZHANG , Kexin ZHOU , Yanjun GUO , Guangjun CHEN , Bai HE , Bo YU , Songshan JIANG , Guoyuan YUAN , Huidong QIU . Preparation, functional modification, and applications of Fe₃O₄ nanoparticles. Chinese Journal of Inorganic Chemistry, 2026, 42(7): 1383-1411. doi: 10.11862/CJIC.20250344
12. [12]
  Liping GUO . Synthesis and crystal structure characterization of yttrium imido complex: The reactivity of 2-substituted-1-amino-o-carborane with yttrium dialkyl complex. Chinese Journal of Inorganic Chemistry, 2025, 41(7): 1409-1415. doi: 10.11862/CJIC.20250065
13. [13]
  Hongwei Ma , Hui Li . Three Methods for Structure Determination from Powder Diffraction Data. University Chemistry, 2024, 39(3): 94-102. doi: 10.3866/PKU.DXHX202310035
14. [14]
  Lihua HUANG , Jian HUA . Denitration performance of HoCeMn/TiO₂ catalysts prepared by co-precipitation and impregnation methods. Chinese Journal of Inorganic Chemistry, 2024, 40(3): 629-645. doi: 10.11862/CJIC.20230315
15. [15]
  Ping Song , Nan Zhang , Jie Wang , Rui Yan , Zhiqiang Wang , Yingxue Jin . Experimental Teaching Design on Synthesis and Antitumor Activity Study of Cu-Pyropheophorbide-a Methyl Ester. University Chemistry, 2024, 39(6): 278-286. doi: 10.3866/PKU.DXHX202310087
16. [16]
  Wei Li , Guoqiang Feng , Ze Chang . Teaching Reform of X-ray Diffraction Using Synchrotron Radiation in Materials Chemistry. University Chemistry, 2024, 39(3): 29-35. doi: 10.3866/PKU.DXHX202308060
17. [17]
  Qingyu Shi , Yiqing Wang , Ziqian Su , Danzan Fu , Jiajun Qin , Yuetong Liu , Yongce Zhang , Yan Su . AI Titration Analysis Experiment Based on Computer Vision. University Chemistry, 2026, 41(1): 57-63. doi: 10.12461/PKU.DXHX202505001
18. [18]
  Huiru Sheng , Rui Qi , Chao Shen , Hao Xu , Jiabin Shen , Pengfei Zhang . Green synthesis of pyrrolo[1,2-a]quinoxaline derivatives as antineoplastic agents: a comprehensive chemistry laboratory teaching exploration. University Chemistry, 2026, 41(7): 266-273. doi: 10.12461/PKU.DXHX202505015
19. [19]
  Liang TANG , Jingfei NI , Kang XIAO , Xiangmei LIU . Synthesis and X-ray imaging application of lanthanide-organic complex-based scintillators. Chinese Journal of Inorganic Chemistry, 2024, 40(10): 1892-1902. doi: 10.11862/CJIC.20240139
20. [20]
  Chengyan XU , Jiangnan YU , Yu LI , Xizhen PAN , Yinlin HOU , Wenmin WANG . Synthesis, structure, and bioactivity of a Ho₄ complex bridged by azide group. Chinese Journal of Inorganic Chemistry, 2026, 42(7): 1453-1462. doi: 10.11862/CJIC.20260033

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(3541)
HTML views(792)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142