Abstract
Small molecule tyrosine kinase inhibitors (TKIs) targeting at epidermal growth factor receptor (EGFR) in recent years have made great progress in the treatment of advanced non-small cell cancer (NSCLC). Although as the first-line treatment for sensitizing EGFR mutation-positive metastatic NSCLC, gefitinib has also behaved quite a lot of side effect and EGFR tolerance. Herein, a novel series of 7-bromo-1,4-dihydrothieno[3’,2’:5,6]thiopyrano[4,3-c]pyrazole-3-carboxamide derivatives were designed and synthesized, and screened for their inhibitory activity on the EGFR high-expressing human lung adenocarcinoma cell line A549 and human large cell lung cancer cell line NCI-H460 by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assay. The calculated IC50 values were reported. Compound 8h demonstrated the most potent inhibitory activity (IC50 = 9.57 ± 2.20 μmol L–1 for A549 and IC50 = 13.04 ± 1.21 μmol L–1 for NCI-H460), comparable to the positive-control gefitinib (IC50 = 8.58 ± 1.65 μmol L–1 for A549 and IC50 = 18.66 ± 5.01 μmol L–1 for NCI-H460). Conclusively, 7-bromo- 1,4-dihydrothieno[3’,2’:5,6]thiopyrano[4,3-c]pyrazole-3-carboxamide derivatives as the EGFR–TKIs were discovered, and could be used as potential leading compounds for further research.
Similar content being viewed by others
References
Adly ME, Gedawy EM, El-Malah AA, El-Telbany FA (2018) Synthesis of novel thieno[2,3-d]pyrimidine derivatives and rvaluation of Theircytotoxicity and EGFR inhibitory activity. Anticancer Agents Med Chem 18(5):747–756
Cagniant P, Cagniant D (1966) Contibution àl’étude des hétérocycles soufrés condensés.Dérivés du dihydro-5,6 4H thiéno-[2,3-b]-thiopyranne, du dihydro-5,6 7H thiéno [3,2-b]-thiopyranne et de la tétrahydro-5,6,7,8 thiéno[3,2-b]-thiépinne. Bull Soc Chim Fr 7:2172–2179
Coumar MS, Chu CY, Lin CW, Shiao HY, Ho YL, Reddy R, Lin WH, Chen CH, Peng YH, Leou JS, Lien TW, Huang CT, Fang MY, Wu SH, Wu JS, Chittimalla SK, Song JS, Hsu JT, Wu SY, Liao CC, Chao YS, Hsieh HP (2010) Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification. J Med Chem 53(13):4980–4988
Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS (2011) Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 29:2866–2874
Guo ZR (2008) Strategy of molecular drug design: pharmacophore and scaffold hopping. Chin J Med Chem 18:147–157
Inoue A, Saijo Y, Maemondo M, Gomi K, Tokue Y, Kimura Y, Ebina M, Kikuchi T, Moriya T, Nukiwa T (2003) Severe acute interstitial pneumonia and gefitinib. Lancet 361:137–139
Ke J, Lu Q, Wang X, Sun R, Jin Z, Zhan X, Hu J, Wan DCC, Hu C (2018) Discovery of 4,5-Dihydro-1H-thieno[2′,3′:2,3]thiepino[4,5-c]pyrazole-3-carboxamide derivatives as the potential epidermal growth factor receptors for tyrosine kinase inhibitors. Molecules 23:1980
Kohno T, Nakaoku T, Tsuta K, Tsuchihara K, Matsumoto S, Yoh K, Goto K (2015) Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer. Transl Lung Cancer Res 4:156–164
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. New Engl J Med 361:947–957
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immun Methods 65:55–63
National Comprehensive Cancer Network. Non-small Cell Lung Cancer (Version 2, 2016). Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed 2015-12-01
Neumann CS, Fujimori DG, Walsh CT (2008) Halogenation strategies in natural product biosynthesis. Chem Biol 15:99–109
Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2(3):e73
Park JH, Liu Y, Lemmon MA, Radhakrishnan R (2012) Erlotinib binds both inactive and active conformations of the EGFR tyrosine kinase domain. Biochem J 448:417–423
Parkin DM, Bray FB, Pisani P (2005) Global cancer statistics. CA Cancer J Clin 55(2):74–108
Ponticello GS, Freedman MB, Habecker CN, Habecker CN, Holloway MK, Amato JS, Conn RS, Baldwin JJ (1988) Utilization of α, β-unsaturated acids as Michael acceptors for the synthesis of thieno[2,3-b]thiopyrans. J Org Chem 1988 53:9–13
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH (2002) Comparison of four chemotherapy regimens for advanced nonsmall cell lung cancer. New Engl J Med 346:92–98
Sharma SV, Bell DW, Settleman J, Haber DA (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7(3):169–181
Sun B, Zhang J, Yin XE, Xu Y, Zhang FR, Huang YS, Wang JH, Wang GQ, Hu C (2016) Synthesis, characterization and biological activity of thieno[2,3-d]pyrimidine derivatives as the epidermal growth factor receptor inhibitors. Lat Am J Pharm 35:570–577
Sun J, Wang XY, Lv PC, Zhu HL (2015) Discovery of a series of novel phenylpiperazine derivatives as egfr tk inhibitors. Sci Rep 5:13934
Sun R, Song J, Zhao H, Yan CL, Zhang AJ, Koirala D, Li DW, Hu C (2011) Synthesis and anti-tumor activity of 1,4-dihydrothieno[3’,2’:5,6]thiopyrano[4,3-c]pyrazole-3-carboxamide derivatives. J Chin Pharm Sci 20:26–34
Thomsen R, Christensen MH (2006) MolDock: a new technique for high-accuracy molecular docking. J Med Chem 49(11):3315–3321
Wang JJ, Yin BZ, Jiang GJ, Imafuku K (1990) Synthesis of isochroman-fused pyrazolone and pyrimidine derivatives. J Heterocycl Chem 27:1181–1184
Wissner A, Mansour TS (2008) The development of HKI-272 and related compounds for the treatment of cancer. Arch Pharm 2008 341(8):465–477
Wood ER, Shewchuk LM, Ellis B, Brignola P, Brashear RL, Caferro TR, Dickerson SH, Dickson HD, Donaldson KH, Gaul M, Griffin RJ, Hassell AM, Keith B, Mullin R, Petrov KG, Reno MJ, Rusnak DW, Tadepalli SM, Ulrich JC, Wagner CD, Vanderwall DE, Waterson AG, Williams JD, White WL, Uehling DE (2008) 6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases. Proc Natl Acad Sci USA 105(8):2773–2778
Wu CH, Coumar MS, Chu CY, Lin WH, Chen YR, Chen CT, Shiao HY, Rafi S, Wang SY, Hsu H, Chen CH, Chang CY, Chang TY, Lien TW, Fang MY, Yeh KC, Chen CP, Yeh TK, Hsieh SH, Hsu JT, Liao CC, Chao YS, Hsieh HP (2010) Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: the role of side chain chirality and Michael acceptor group for maximal potency. J Med Chem 53(20):7316–7326
Zhang HQ, Gong FH, Li CG, Zhang C, Wang YJ, Xu YG, Sun LP (2016) Design and discovery of 4-anilinoquinazoline-acylamino derivatives as EGFR and VEGFR-2 dual TK inhibitors. Eur J Med Chem 109:371–379
Zhang L, Deng XS, Zhang C, Meng GP, Wu JF, Li XS, Zhao QC, Hu C (2017) Design, synthesis and cytotoxic evaluation of a novel series of benzo[d]thiazole-2-carboxamide derivatives as potential EGFR inhibitors. Med Chem Res 26(9):2180–2189
Zhao Y, Wu XR, Yin JG, Wang JJ (2002) Synthesis of isochromano[4,3-C]pyrazole substituted with biheterocycle at 3-position. J Yantai Univ Nat Sci Eng Ed 15:113–117
Zhou W, Ercan D, Jänne PA, Gray NS (2011) Discovery of selective irreversible inhibitors for EGFR-T790M. Bioorg Med Chem Lett 21(2):638–643
Zhou XF, Guo JL, Ji YM, Pan GF, Liu T, Zhu H, Zhao JP (2016) Reciprocal negative regulation between EGFR and DEPTOR plays an important role in the progression of lung adenocarcinoma. Mol Cancer Res 14:448–457
Acknowledgements
This work was supported by the National Science Foundation of China (NSFC) for the grant No. 21342006 and the Program for Innovative Research Team of the Ministry of Education of China for the grant No. IRT_14R36. We thank Molegro ApS for kindly providing a free evaluation copy of their software package and Schrödinger, LLC for allowing the use of PyMOL Molecular Graphics System.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This article does not contain any studies with animals, performed by any of the authors. Informed consent was obtained from all individual participants included in the study.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Rights and permissions
About this article
Cite this article
Xie, Q., Wang, J., Liu, M. et al. Discovery of 7-bromo-1,4-dihydrothieno[3’,2’:5,6]thiopyrano[4,3-c]pyrazole-3-carboxamide derivatives as the potential epidermal growth factor receptors for tyrosine kinase inhibitors. Med Chem Res 28, 1000–1009 (2019). https://doi.org/10.1007/s00044-019-02354-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-019-02354-0