Synthesis and Biological Evaluation of Some Novel Thiophene-bearing Quinazoline Derivatives as EGFR Inhibitors

Author(s): Min Zou, Bo Jin, Yanrong Liu, Huiping Chen, Zhuangli Zhang, Changzheng Zhang, Zhihong Zhao, Liyun Zheng*.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 2 , 2019

Submit Manuscript
Submit Proposal

Graphical Abstract:


Abstract:

Background: With the approval of gefitinib, erlotinib, afatinib, and osimertinib for clinical use, targeting Epidermal Growth Factor Receptor (EGFR) has been intensively pursued. Similar to most therapies, challenges related to the treatment resistance against these drugs have emerged over time, so new EGFR Tyrosine Kinase Inhibitors (TKIs) need to be developed. This study aimed to investigate the potential use of a series of thiophene-bearing quinazoline derivatives as EGFR inhibitors. We designed and synthesized nine quinazolin derivatives, among which five compounds (5e, 5f, 5g, 5h, and 5i) were reported for the first time.

Methods: Two cancer cell lines, A431 (overexpressing EGFR) and A549 (EGFR wild-type and Kras mutation), were treated by these compounds and subjected to MTT assay. The A431 cells were selected for further treatment (5e) and Western blot analysis.

Results: Although the compounds exerted no obvious effects on the proliferation of A549 cells, seven out of the nine compounds significantly inhibited the growth of A431 cells. In particular, the IC50 values of 5e and erlotinib were nearly equal. Western blot results showed that 5e significantly inhibited EGFR autophosphorylation in A431 cells. Structure-activity relationships indicated that quinazolines bearing 6,7-side chains were more potent than those unsubstituted at the 6,7-positions. Moreover, electron-withdrawing hydrophobic groups on the 5-position of the thiophene were preferred, such as chlorine or bromine atom.

Conclusion: Nine 4-aminoquinazolin derivatives were designed, synthesized, and evaluated against A431 and A549 cell lines. Seven compounds significantly inhibited the growth of A431 cells. In particular, 5e possessed similar antitumor potency to that of erlotinib.

Keywords: 4-Aminoquinazoline, non-covalent inhibitors, antiproliferative activity, structure-activity relationships, autophosphorylation, Western blot analysis.

[1]
Citri, A.; Yarden, Y. EGF-ERBB signalling: Towards the systems level. Nat. Rev. Mol. Cell Biol., 2006, 7, 505-516.
[2]
Rego, R.L.; Foster, N.R.; Smyrk, T.C.; Le, M.; O’Connell, M.J.; Sargent, D.J.; Windschitl, H.; Sinicrope, F.A. Prognostic effect of activated EGFR expression in human colon carcinomas: Comparison with EGFR status. Br. J. Cancer, 2010, 102, 165-172.
[3]
Cao, C.; Lu, S.; Sowa, A.; Kivlin, R.; Amaral, A.; Chu, W.; Yang, H.; Di, W.; Wan, Y. Priming with EGFR tyrosine kinase inhibitor and EGF sensitizes ovarian cancer cells to respond to chemotherapeutical drugs. Cancer Lett., 2008, 266, 249-262.
[4]
Wang, J.; Zhang, X.; He, J.; Yang, M.; Tang, J.; Li, X.; Tang, H.; Xie, X. Co-expression of EGFR and CK5/6 in primary squamous cell carcinoma of the breast. Med. Oncol., 2014, 31, 172.
[5]
Cai, J.; Sun, M.; Ge, X.; Sun, Y. EGFR tyrosine kinase inhibitors differentially affect autophagy in head and neck squamous cell carcinoma. Biochem. Biophys. Res. Commun., 2017, 486, 1027-1033.
[6]
Fernandez-Mateos, J.; Seijas-Tamayo, R.; Mesía, R.; Taberna, M.; Pastor Borgonon, M.; Perez-Ruiz, E.; Adansa Klain, J.C.; Vazquez Fernandez, S.; Del Barco Morillo, E.; Lozano, A.; Gonzalez Sarmiento, R.; Cruz-Hernandez, J.J. Epidermal Growth Factor Receptor (EGFR) pathway polymorphisms as predictive markers of cetuximab toxicity in locally advanced Head and Neck Squamous Cell Carcinoma (HNSCC) in a Spanish population. Oral Oncol., 2016, 63, 38-43.
[7]
Amin, K.M.; Georgey, H.H.; Awadallah, F.M. EGFR tyrosine kinase targeted compounds: Synthesis, docking study, and in vitro antitumor activity of some new quinazoline and benzo[d] isothiazole derivatives. Med. Chem. Res., 2011, 20, 1042-1053.
[8]
Xia, G.; Chen, W.; Zhang, J.; Shao, J.; Zhang, Y.; Huang, W.; Zhang, L.; Qi, W.; Sun, X.; Li, B.; Xiang, Z.; Ma, C.; Xu, J.; Deng, H.; Li, Y.; Li, P.; Miao, H.; Han, J.; Liu, Y.; Shen, J.; Yu, Y. A chemical tuned strategy to develop novel irreversible EGFR-TK inhibitors with improved safety and pharmacokinetic profiles. J. Med. Chem., 2014, 57, 9889-9900.
[9]
Kawahara, A.; Yamamoto, C. Nakashima1, K.; Azuma, K.; Hattori, S.; Kashi-hara, M.; Aizawa, H.; Basaki, Y.; Kuwano, M.; Kage, M.; Mitsudomi, T.; Ono, M. Molecular diagnosis of activating EGFR mutations in non-small cell lung cancer using mutation-specific antibodies for immunohistochemical analysis. Clin. Cancer Res., 2010, 16(12), 3164.
[10]
Dowell, J.; Minna, J.D.; Kirkpatrick, P. Erlotinib hydrochloride. Nat. Rev. Drug Discovery., 2005, 4, 13-14.
[11]
Cohen, M.H.; Williams, G.A.; Sridhara, R.; Chen, G.; Pazdur, R. FDA drug approval summary: Gefitinib (ZD1839) (Iressa) tablets. Oncologist, 2003, 8, 303-306.
[12]
Lee, J.K.; Shin, J.Y.; Kim, S.; Lee, S.; Park, C.; Kim, J.Y.; Koh, Y.; Keam, B.; Min, H.S.; Kim, T.M.; Jeon, Y.K.; Kim, D.W.; Chung, D.H.; Heo, D.S.; Lee, S.H.; Kim, J.I. Primary resistance to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: An exploratory study. Ann. Oncol., 2013, 24, 2080-2087.
[13]
Kobayashi, S.; Boggon, T.J.; Dayaram, T.; Janne, P.A.; Kocher, O.; Meyerson, M.; Johnson, B.E.; Eck, M.J.; Tenen, D.G.; Halmos, B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med., 2005, 352, 786-792.
[14]
Bowles, D.W.; Weickhardt, A.; Jimeno, A. Afatinib for the treatment of patients with EGFR-positive non-small cell lung cancer. Drugs Today , 2013, 49, 523-535.
[15]
Heuckmann, J.M.; Rauh, D.; Thomas, R.K. Epidermal Growth Factor Receptor (EGFR) signaling and covalent EGFR inhibition in lung cancer. J. Clin. Oncol., 2012, 30, 3417-3420.
[16]
Singh, J.; Petter, R.C.; Baillie, T.A.; Whitty, A. The resurgence of covalent drugs. Nat. Rev. Drug Discovery., 2011, 10, 307-317.
[17]
Ramalingam, S.S.; Blackhall, F.; Krzakowski, M.; Barrios, C.H.; Park, K.; Bover, I.; Heo, D.S.; Rosell, R.; Talbot, D.C.; Frank, R.; Letrent, S.P.; Ruiz-Garcia, A.; Taylor, I.; Liang, J.Q.; Campbell, A.K.; O’Connell, J.; Boyer, M. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-smallcell lung cancer. J. Clin. Oncol., 2012, 30, 3337-3344.
[18]
Katakami, N.; Atagi, S.; Goto, K. A phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J. Clin. Onco., 2013, l31, 3335-3341
[19]
Janne, P.A.; Yang, J.C.; Kim, D.W.; Planchard, D.; Ohe, Y.; Ramalingam, S.S.; Ahn, M.J.; Kim, S.W.; Su, W.C.; Horn, L.; Haggstrom, D.; Felip, E.; Kim, J.H.; Frewer, P.; Cantarini, M.; Brown, K.H.; Dickinson, P.A.; Ghiorghiu, S.; Ranson, M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med., 2015, 372, 1689-1699.
[20]
Wang, H.; Cai, Z.; Zheng, S.; Ma, H.; Lin, H.; Zheng, X. Design, synthesis and biological evaluation of some novel thiazole-2-carboxamide derivatives as antitumor agents. Lett. Drug Des. Discov., 2018, 15, 388-397.
[21]
Wang, S.; Cang, S.; Liu, D. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J. Hematol. Oncol., 2016, 9, 34.
[22]
Yu, H.A.; Tian, S.K.; Drilon, A.E.; Borsu, L.; Riely, G.J.; Arcila, M.E.; Ladanyi, M. Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor. JAMA Oncol., 2015, 7, 982-984.
[23]
Thress, K.S.; Paweletz, C.P.; Felip, E.; Cho, B.C.; Stetson, D.; Dougherty, B.; Lai, Z.; Markovets, A.; Vivancos, A.; Kuang, Y.; Ercan, D.; Matthews, S.E.; Cantarini, M.; Barrett, J.C.; Janne, P.A.; Oxnard, G.R. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med., 2015, 21, 560-564.
[24]
Abdel-Wahab, B.F.; Farahat, A.A.; Awad, G.E.A.; El-Hiti, G.A. Synthesis and antimicrobial activity of some novel substituted 3-(thiophen-2-yl)pyrazole-based heterocycles. Lett. Drug Des. Discov., 2017, 14(1), 1316-1323.
[25]
Saravanan, M.A.J.; Mohan, S.; Bhattacharjee, S. Synthesis, characterization and antimicrobial activity of some schiff bases of 2-amino-n-(p-acetamidophenyl carboxamido)-4, 5, 6, 7-tetramethylene thiophenes. Int. J. Pharm. Pharm. Sci., 2013, 5(1), 315-319.
[26]
Jamalis, J.; Al-Maqtari, H.M.; Chander, S.; Sirat, H.M.; Naveen, S.; Lokanath, N.K.; Bohari, S.P.M.; Bhagwat, D.P.; Sankaranarayanan, M. Synthesis, in silico and antifungal studies of novel thiophene analogues containing pyrazole ring. Lett. Drug Des. Discov., 2018, 15, 1-9.
[27]
Rao, S.D.; Rasheed, S.; Basha, T.S.K.; Raju, N.C.; Naresh, K. SiO2/ZnCl2 catalyzed a -aminophosphonates and phosphonated N-(substitued phenyl) sulfonamides of 2-aminothiophene synthesis and biological evaluation. Der Pharma Chem., 2013, 5(1), 61-74.
[28]
Lu, X.; Tang, J.; You, Q.; Wan, B.; Franzblau, S.G. Design, synthesis and antitubercular evaluation of new 2-amino-5-(4- (benzyloxy)benzyl)thiophene-3-carboxylic acid derivatives. Part 3. Lett. Drug Des. Discov., 2015, 12(7), 29-37.
[29]
Khan, K.M.; Nullah, Z.; Lodhi, M.A.; Jalil, S.; Choudhary, M.I. Synthesis and anti-inflammatory activity of some selected aminothiophene analogs. J. Enzyme Inhib. Med. Chem., 2006, 21(2), 139-143.
[30]
Abo-Salem, H.M.; El-Sawy, E.R.; Fathy, A.; Mandour, A.H. Synthesis, antifungal activity, and molecular docking study of some novel highly substituted 3- indolylthiophene derivatives. Egypt. Pharmaceut. J., 2014, 13(2), 71-86.
[31]
Gouda, M.A.; Eldien, H.F.; Girges, M.M.; Berghot, M.A. Synthesis and antioxidante activity of novel series of naphthoquinone derivatives attached to benzothiophene moiety. Med. Chem., 2013, 3(2), 2228-2232.
[32]
Jagadish, E.R.; Mohan, S.; Saravanan, J.; Satyendra, D.; Sree, S.P.; Apurba, T.; Manoj, K.; Rama Kanta, S. Synthesis and in-vitro anti-platelet aggregation activity of some new substituted thiophenes. Hyg. J. Drugs Med, 2013, 5(2), 87-96.
[33]
Romagnoli, R.; Salvador, M.K.; Ortega, S.S. Baraldi. P.G.; Oliva, P.; Baraldi, S.; Lopez-Cara, L.C.; Brancale, A.; Ferla, S.; Hamel, E.; Balzarini, J.; Liekens, S.; Mattiuzzo, E.; Basso, G.; Viola, G. 2-alkoxycarbonyl-3-arylamino-5-substituted thiophenes as a novel class of antimicrotubule agents: Design, synthesis, cell growth and tubulin polymerization inhibition. Eur. J. Med. Chem., 2018, 143, 683-698.
[34]
Kaplan, A.P.; Keenan, T.; Scott, R.; Zhou, X.; Bourchouladze, R.; McRiner, A.J.; Wilson, M.E.; Romashko, D.; Miller, R.; Bletsch, M. Identification of 5-(1-methyl-5-(trifluoromethyl)-1h-pyrazol-3-yl) thiophene-2-carboxamides as novel and selective monoamine oxidase B inhibitors used to improve memory and cognition. ACS Chem. Neurosci., 2017, 8, 2746-2758.
[35]
Hovhannisyan, A.A.; Pham, T.H.; Bouvier, D.; Tan, X.; Touhar, S.; Mkryan, G.G.; Dallakyan, A.M.; Amri, C.E.; Melikyan, G.S.; Reboud-Ravaux, M.; Bouvier-Durand, M. Phenoxypropanolamine derivatives as selective inhibitors of the 20S proteasome β1 and β5 subunits. Bioorg. Med. Chem. Lett., 2017, 27, 5172-5178.
[36]
Rodrigues, K.A.D.F.; Dias, C.N.D.S.; Neris, P.L.D.N.; Rocha, J.D.C.; Scotti, M.T.; Scotti, L.; Mascarenhas, S.R.; Veras, R.C.; Medeiros, I.A.D.; Medeiros, T.D.S.L.; Oliveira, T.B.D. 2-Amino-thiophene derivatives present antileishmanial activity mediated by apoptosis and immunomodulation in vitro. Eur. J. Med. Chem., 2015, 106, 1-14.
[37]
Aguiar, A.C.V.; Moura, R.O.; Junior, J.F.B.M.; Rocha, H.A.D.O.; Câmara, R.B.G.; Schiavon, M.D.S.C. Evaluation of the antiproliferative activity of 2-amino thiophene derivatives against human cancer cells lines. Biomed. Pharmacother., 2016, 84, 403-414.
[38]
Sara, B.; Massimo, C.M.; Chiara, D.P.; Silvia, P.; Alessandra, R.; Chiara, R.; Emilio, C.; Dario, C. Intraindividual and interindividual variability of olanzapine trough concentrations in patients treated with the long-acting injectable formulation. J. Clin. Psychopharmacol., 2018, 38(4), 365-369.
[39]
Kalariya, P.D.; Patel, P.N.; Kavya, P.; Sharma, M.; Garg, P.; Srinivas, R.; Talluri, M.V.N.K. Rapid structural characterization of in vivo and in vitro metabolites of tinoridine using UHPLC-QTOF-MS/MS and in silico toxicological screening of its metabolites. J. Mass Spectrom., 2015, 50, 1222-1233.
[40]
Li, D.D.; Fang, F.; Li, J.R.; Du, Q.R.; Sun, J.; Gong, H.B.; Zhu, H.L. Discovery of 6-substituted 4-anilinoquinazolines with dioxygenated rings as novel EGFR tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett., 2012, 22, 5870-5875.
[41]
Wu, J.; Chen, W.; Xia, G.; Zhang, J.; Shao, J.; Tan, B.; Zhang, C.; Yu, W.; Weng, Q.; Liu, H.; Hu, M.; Deng, H.; Hao, Y.; Shen, J.; Yu, Y. Design, synthesis, and biological evaluation of novel conformationally constrained inhibitors targeting EGFR. ACS Med. Chem. Lett., 2013, 4, 974-978.
[42]
Jiang, Y.; Yuan, Q.; Fang, Q. Schedule-dependent synergistic interaction between docetaxel and gefitinib in NSCLC cell lines regardless of the mutation status of EGFR and KRAS and its molecular mechanisms. J. Cancer Res. Clin. Oncol., 2014, 140, 1087-1095.
[43]
Klare, J.E.; Murray, I.P.; Goldberger, J.; Stupp, S.I. Assembling p-type molecules on single wall carbon nanotubes for photovoltaic devices. Chem. Commun. , 2009, 25, 3705-3707.
[44]
Zhang, L.; Yang, Y.; Zhou, H.; Zheng, Q.; Li, Y.; Zheng, S.; Zhao, S.; Chen, D.; Fan, C. Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors. Eur. J. Med. Chem., 2015, 102, 445-463.
[45]
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[46]
Sanner, M.F. Python: A programming language for software integration and development. J. Mol. Graph. Model., 1999, 17(1), 57-61.
[47]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[48]
Sato, T.; Watanabe, H.; Tsuganezawa, K.; Yuki, H.; Mikuni, J.; Yoshikawa, S.; Kukimoto-Niino, M.; Fujimoto, T.; Terazawa, Y. Identification of novel drug-resistant EGFR mutant inhibitors by in silico screening using comprehensive assessments of protein structures. Bioorg. Med. Chem., 2012, 20, 3756-3767.
[49]
Bridges, A.J.; Zhou, H.; Cody, D.R.; Rewcastle, G.W.; McMichael, A.; Showalter, H.D.H.; Fry, D.W.; Kraker, A.J.; Denny, W.A. Tyrosine kinase inhibitors. 8. An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD153035), a potent inhibitor of the epidermal growth factor receptor. J. Med. Chem., 1996, 39, 267-276.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 16
ISSUE: 2
Year: 2019
Page: [102 - 110]
Pages: 9
DOI: 10.2174/1570180815666180803125935

Article Metrics

PDF: 31
HTML: 7