Synthesis of 5-Phenyl-1,3,4-thiadiazole Derivatives and Their Biochemical Evaluation against Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase 1 (SHP1)

doi:10.6023/cjoc202104041

Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (8): 3097-3105.DOI: 10.6023/cjoc202104041 Previous Articles Next Articles

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5-苯基-1,3,4-噻二唑衍生物的合成及含SH2结构域蛋白酪氨酸磷酸酶1 (SHP1)抑制活性研究

于丽杰^a, 冯勃^b^,^c, 王智佳^a, 高立信^a^,^b, 张纯^a^,^d, Rajendran Satheeshkumar^a, 李佳^b, 周宇波^b^,^c^,^*(), 王文龙^a^,^*()

a 江南大学药学院江苏无锡 214122
b 中国科学院上海药物研究所国家新药筛选中心上海 201203
c 中国科学院药物创新研究院中山研究院广东中山 528400
d 南京大学化学化工学院南京 210023

收稿日期:2021-04-18 修回日期:2021-05-19 发布日期:2021-06-02
通讯作者: 周宇波, 王文龙
作者简介:
† 共同第一作者
基金资助:
国家自然科学基金(21772068); 国家自然科学基金(81773779); 江苏省研究生科研与实践创新计划(KYCX20-1965); 江苏省自然科学基金(BK20190608)

Synthesis of 5-Phenyl-1,3,4-thiadiazole Derivatives and Their Biochemical Evaluation against Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase 1 (SHP1)

Lijie Yu^a, Bo Feng^b^,^c, Zhijia Wang^a, Lixin Gao^a^,^b, Chun Zhang^a^,^d, Rajendran Satheeshkumar^a, Jia Li^b, Yubo Zhou^b^,^c(), Wenlong Wang^a()

a School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122
b National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
c Zhongshan Institute for Drug Discovery, Institutes of Drug Discovery and Development, Chinese Academy of Sciences, Zhongshan, Guangdong 528400
d School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023

Received:2021-04-18 Revised:2021-05-19 Published:2021-06-02
Contact: Yubo Zhou, Wenlong Wang
About author:
† (These authors contributed equally to this work).
Supported by:
National Natural Science Foundation of China(21772068); National Natural Science Foundation of China(81773779); Postgraduate Research & Practice Innovation Program of Jiangsu Province(KYCX20-1965); Natural Science Foundation of Jiangsu Province(BK20190608)

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Abstract

The Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) is a convergent node for oncogenic cell-signaling cascades. Consequently, SHP1 represents a potential target for drug development in cancer treatment. Meanwhile only countable SHP1 inhibitors have been reported. A new type of SHP1 inhibitors with 5-phenyl-1,3,4-thiadiazole scaffold was developed. The representative compound 5b exhibited SHP1 inhibitory activity with IC₅₀ of (1.33±0.16) μmol/L, exhibited about 2-fold selectivity for SHP1 over SHP2, and had no detectable activity against PTP1B and TCPTP, and offered a novel scaffold to develop new SHP1 inhibitors.

Key words: 5-phenyl-1,3,4-thiadiazole derivatives, Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1), inhibitors, structure-activity relationships

Cite this article

Lijie Yu, Bo Feng, Zhijia Wang, Lixin Gao, Chun Zhang, Rajendran Satheeshkumar, Jia Li, Yubo Zhou, Wenlong Wang. Synthesis of 5-Phenyl-1,3,4-thiadiazole Derivatives and Their Biochemical Evaluation against Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase 1 (SHP1)[J]. Chinese Journal of Organic Chemistry, 2021, 41(8): 3097-3105.

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Fig. & Tab. 7

Figure 1. Chemical structures of reported SHP1 inhibitors

Figure 2. Structures of modulators of PTPs

Compd.	R¹	R²	R³	SHP1
Compd.	R¹	R²	R³	Inhibition/% at 50 μmol/L	IC₅₀/(μmol•L^–1)
2a	3-NO₂	4-NHMe	NH₂	27.5±19.1	—
2b	3-NO₂		NH₂	20.9±16.9	—
2c	3-NO₂	4-OMe	NH₂	21.6±5.1	—
2d	3-OMe	4-OMe	NH₂	–2.4±7.2	—
2e	3-OH	3-OH	NH₂	8.6±1.8	—
4	3-NO₂	4-NHMe		80.6±6.5	23.42±3.17
5a	3-NO₂	4-NHMe		64.3±11.0	4.40±1.09
5b	3-NO₂	4-NHMe		92.8±2.1	1.33±0.16
5c	3-NO₂	4-NHMe		69.7±2.7	21.56±2.61
5d	3-NO₂			36.4±8.4	—
5e	3-NO₂	4-OMe		38.6±39.4	—
NSC-87877	—	—	—	—	34.76±4.46

Table 1. SHP1 inhibitory activities of compounds 2a~2e, 4 and 5a~5e

Scheme 1. Synthetic route of compounds 2a~2e, 4 and 5a~5e Reagents and conditions: (a) thiosemicarbazide, POCl3, 80 ℃, 2.5 h, 48%~90%; (b) 3-((tert-butoxycarbonyl)amino)benzoic acid, HATU, DIPEA, DMF, r.t., overnight, 40%; (c) HCl-dioxane, r.t., overnight, 90%; (d) furan-2-carboxylic acid (5-methylfuran-2-carboxylic acid, tetrahydrofuran-2-carboxylic acid) HATU, DIPEA, DMF, r.t., overnight, 64%~68%; (e) 3-(furan-2-carboxamido)benzoic acid, HATU, DIPEA, DMF, r.t., overnight, 49%; (f) 3-(furan-2-carboxamido)benzoic acid, HATU, DIPEA, DMF, r.t., overnight, 26%.

Compd.	SHP1	SHP2	SHP2/SHP1	PTP1B	TCPTP
5b	1.33±0.16	2.99±0.36	2.25	NA^b	NA^b
NSC-87877	34.76±4.46	33.71±0.72		50.04±11.91	40.70±6.50

Table 2. IC50a (μmol•L–1) values of compound 5b against PTPs

Figure 3. Characterization of 5b to SHP1 (A) Time-independent inhibition of SHP1 by 5b; (B) typical competitive inhibition of 5b shown by Lineweaver-Burk plot; (C) the initial velocity determined with various concentrations of 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) at various fixed concentrations of 5b

Figure 4. Calculated results of molecular properties for 5b and docking simulation (A) Molecular electrostatic properties of mapped on the 0.001 a.u. contour of the electronic density at the DFT//B3LYP/6-31G(d) level; (B) docking pose of 5b with SHP1 (PDB Entry: 1FPR): relative position of 5b and WPD_loop (orange), Q_loop (purple), P_loop (Yellow) and PTyr_loop (green) in SHP1; (C) strong interactions between 5b and the nearest residues

References 37

[1]	Tonks, N. K. FEBS J. 2013, 280, 346.
[2]	Hendriks, W.; Elson, A.; Harroch, S.; Pulido, R.; Stoker, A.; Hertog, J. D. FEBS J. 2013, 280, 708. doi: 10.1111/febs.12000 pmid: 22938156
[3]	Frankson, R.; Yu, Z. H.; Bai, Y.; Li, Q.; Zhang, R. Y.; Zhang, Z. Y. Cancer Res. 2017, 77, 5701. doi: 10.1158/0008-5472.CAN-17-1510
[4]	Varone, A.; Spano, D.; Corda, D. Front. Oncol. 2020, 10, 935. doi: 10.3389/fonc.2020.00935
[5]	Sandur, S. K.; Pandey, M. K.; Sung, B.; Aggarwal, B. B. Mol. Cancer Res. 2010, 8, 107. doi: 10.1158/1541-7786.MCR-09-0257
[6]	Sharma, Y.; Bashir, S.; Bhardwaj, P.; Ahmad, A.; Khan, F. Immunol. Res. 2016, 64, 804. doi: 10.1007/s12026-016-8805-y pmid: 27216862
[7]	Yuan, X.; Bu, H.; Zhou, J.; Yang, C. Y.; Zhang, H. J. Med. Chem. 2020, 63, 11368 doi: 10.1021/acs.jmedchem.0c00249
[8]	Dempke, W. M.; Peter, U.; Klaus, F.; Timothy, C. Oncology 2018, 95, 1.
[9]	Song, M.; Park, J. E.; Park, S. G.; Lee, D. H.; Choi, H. K.; Park, B. C. Biochem. Biophys. Res. Commun. 2009, 381, 491. doi: 10.1016/j.bbrc.2009.02.069
[10]	Kundu, S.; Fan, K.; Cao, M.; Lindner, D. J.; Zhao, Z. J.; Borden, E.; Yi, T. L. J. Immunol. 2010, 184, 6529. doi: 10.4049/jimmunol.0903562
[11]	Arabaci, G.; Yi, T.; Fu, H.; Porter, M. E.; Beebe, K. D.; Pei, D. Bioorg. Med. Chem. Lett. 2002, 12, 3047. pmid: 12372498
[12]	Yi, T.; Elson, P.; Mitsuhashi, M.; Jacobs, B.; Hollovary, E.; Budd, G. T.; Spiro, T.; Triozzi, E.; Borden, E. C. Oncotarget 2011, 2, 1155. doi: 10.18632/oncotarget.v2i12
[13]	Lu, L.; Wang, S.; Zhu, M.; Liu, Z.; Guo, M.; Xing, S.; Fu, X. Biometals 2010, 23, 1139. doi: 10.1007/s10534-010-9363-8
[14]	Wang, Q.; Zhu, M.; Lu, L.; Yuan, C.; Fu, X. Dalton. Trans. 2011, 40, 12926. doi: 10.1039/c1dt11006c
[15]	Akiba, H.; Sumaoka, J.; Hamakubo, T.; Komiyama, M. Anal. Bioanal. Chem. 2014, 406, 2957. doi: 10.1007/s00216-014-7707-x
[16]	Frija, L.; Pombeiro, A.; Kopylovich, M. N. Eur. J. Org. Chem. 2017, 19, 2670.
[17]	Yang, H.; Li, C. Y.; Wang, X. M.; Yang, Y. H.; Zhu, H. L. Chem. Rev. 2014. 45, 5572.
[18]	Wang, W. L.; Yang, D. L.; Gao, L. X.; Tang, C. L.; Ma, W. P.; Ye, H. H.; Zhang, S. Q.; Zhao, Y. N.; Xu, H. J.; Hu, Z.; Chen, X.; Fan, W. H.; Chen, H. J.; Li, J. Y.; Nan, F. J.; Li, J.; Feng, B. N. Molecules 2013, 19, 102. doi: 10.3390/molecules19010102
[19]	Wang, W.L; Chen, X.; Gao, L.X; Sheng, L.; Li, J. Y.; Li, J.; Feng, B. N. Chem. Biol. Drug Des. 2015, 86, 1161. doi: 10.1111/cbdd.12587
[20]	Satheeshkumar, R.; Zhu, R.; Feng, B.; Huang, C.; Gao, Y.; Gao, L. X.; Shen, C.; Hou, T. J.; Xu, L.; Li, J.; Zhu, Y. L.; Zhou, Y. B.; Wang, W. L. Bioorg. Med. Chem. Lett. 2020, 30, 127170. doi: S0960-894X(20)30267-5 pmid: 32273218
[21]	Wang, W. L.; Chen, X. Y.; Gao, Y.; Gao, L. X.; Sheng, L.; Zhu, J. Y.; Xu, L.; Ding, Z. Z.; Zhang, C.; Li, J. Y.; Li, J.; Zhou, Y. B. Bioorg. Med. Chem. Lett. 2017, 27, 5154. doi: 10.1016/j.bmcl.2017.10.059
[22]	Wang, W. L.; Huang, C.; Gao, L. X.; Tang, C. L.; Wang, J. Q.; Wu, M. C.; Sheng, L.; Chen, H. J.; Nan, F. J.; Li, J. Y.; Feng, B. N. Bioorg. Med. Chem. Lett. 2014, 24, 1889.
[23]	Wang, W. L.; Luo, H.; Gao, Y.; Gao, L. X.; Sheng, L.; Zhou, Y. B.; Li, J. Y.; Li, J.; Feng, B. N. Chin. J. Org. Chem. 2016, 36, 2142. (in Chinese) doi: 10.6023/cjoc201603045
	(王文龙, 骆欢, 高雅, 高立信, 盛丽, 周宇波, 李佳, 李静雅, 冯柏年, 有机化学, 2016, 36, 2142.) doi: 10.6023/cjoc201603045
[24]	Pac, A.; As, A.; Fal, A.; Mb, B.; Mfe, C. J. Mol. Struct. 2019, 1179, 11. doi: 10.1016/j.molstruc.2018.10.082
[25]	Chen, Y. N.; LaMarche, M. J.; Chan, H. M.; Fekkes, P.; Garcia, F. J.; Acker, M. G.; Antonakos, B.; Chen, C. H.; Chen, Z.; Cooke, V. G.; Dobson, J. R.; Deng, Z.; Fei, F.; Firestone, B.; Fodor, M.; Fridrich, C.; Gao, H.; Grunenfelder, D.; Hao, H. X.; Jacob, J.; Ho, S.; Hsiao, K.; Kang, Z. B.; Karki, R.; Kato, M.; Larrow, J.; LaBonte, L. R.; Lenoir, F.; Liu, G.; Liu, S.; Majumdar, D.; Meyer, M. J.; Palermo, M.; Perez, L.; Pu, M.; Price, E.; Quinn, C.; Shakya, S.; Shultz, M. D.; Slisz, J.; Venkatesan, K.; Wang, P.; Warmuth, M.; Williams, S.; Yang, G.; Yuan, J.; Zhang, J. H.; Zhu, P.; Ramsey, T.; Keen, N. J.; Sellers, W. R.; Stams, T.; Fortin, P. D. Nature 2016, 535, 148. doi: 10.1038/nature18621
[26]	Welte, S.; Baringhaus, K. H.; Schmider, W.; Müller, G.; Petry, S.; Tennagels, N. Anal. Biochem. 2005, 338, 32. doi: 10.1016/j.ab.2004.11.047
[27]	Krishnan, N.; Koveal, D.; Miller, D. H.; Xue, B.; Akshinthala, S. D.; Kragelj, J.; Jensen, M. R.; Gauss, C. M.; Page, R.; Blackledge, M.; Muthuswamy, S. K.; Peti, W.; Tonks, N. K. Nat. Chem. Biol. 2014, 10, 558. doi: 10.1038/nchembio.1528
[28]	Zhang, W.; Hong, D.; Zhou, Y.; Zhang, Y.; Shen, Q.; Li, J. Y.; Hu, L. H.; Li, J. Biochim. Biophys. Acta 2006, 1760, 1505. pmid: 16828971
[29]	McGovern, S. L.; Helfand, B. T.; Feng, B.; Shoichet, B. K. J. Med. Chem. 2003, 46, 4265. pmid: 13678405
[30]	Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision D.01, Gaussian, Inc., Wallingford, CT, 2013.
[31]	Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R. K.; Goodsell, D. S.; Olson, A. J. J. Comput. Chem. 2009, 30, 2785. doi: 10.1002/jcc.v30:16
[32]	Yang, J.; Cheng, Z. L.; Niu, T. Q.; Liang, X. S.; Zhao, Z. Z. J.; Zhou, G. W. J. Biol. Chem. 2000, 275, 4066. pmid: 10660565
[33]	Zhang, B.; Wang, K. B.; Wang, W.; Wang, X.; Liu, F.; Zhu, J. P.; Shi, J.; Li, L. Y.; Han, H.; Xu, K.; Qiao, H. Y.; Zhang, X.; Jiao, R. H.; Houk, K. N.; Liang, Y.; Tan, R. X.; Ge, H. M. Nature 2019, 568, 122. doi: 10.1038/s41586-019-1021-x
[34]	Daina, A.; Michielin, O.; Zoete, V. Sci. Rep. 2017, 7, 1. doi: 10.1038/s41598-016-0028-x
[35]	Vachala, S. D.; Bhargavi, B. J. Chem. Pharm. Res. 2014, 6, 377.
[36]	Guan, P.; Wan, Y. C.; Hou, X. B.; Wang, L; Xu, W. F.; Tang, W. P.; Fang, H. Bioorg. Med. Chem. 2014, 22, 5766.
[37]	Jakovljević, K.; Matić, I. Z.; Stanojković, T.; Krivokuća, A.; Marković, V.; Joksović, M. D.; Mihailović, N.; Nićiforović, M.; Joksović, L. Bioorg. Med. Chem. Lett. 2017, 27, 3709. doi: S0960-894X(17)30696-0 pmid: 28709826

5-苯基-1,3,4-噻二唑衍生物的合成及含SH2结构域蛋白酪氨酸磷酸酶1 (SHP1)抑制活性研究

Synthesis of 5-Phenyl-1,3,4-thiadiazole Derivatives and Their Biochemical Evaluation against Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase 1 (SHP1)

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