Design, Synthesis and Antitumor Activity of Quinazoline Derivatives Bearing 2,3-Dihydro-indole or 1,2,3,4-Tetrahydroquinoline

Author(s): Yiqiang OuYang, Bingbing Zhao, Xiuying Chen, Caolin Wang, Hong Zhang, Shuang Jia, Wufu Zhu*, Pengwu Zheng*.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 5 , 2019

Submit Manuscript
Submit Proposal

Graphical Abstract:


Abstract:

Background: Cancer continues to pose a great problem and burden on society despite new treatment options. While surgery, radiotherapy, and chemotherapy have led to major improvements in patient prognosis, newer treatments are needed to more effectively manage this disease in its advanced stage. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK), which is catalytically active and under tight regulatory control. Dysregulation of its activity is strongly associated with tumorigenesis and cancer patients with altered EGFR activity tend to have a more aggressive disease, associated with a poor clinical prognosis. The family of EGFR has been intensively studied due to its strong influence on the formulation and deterioration of carcinoma. Thus, it is a good strategy that design anticancer agents by inhibiting the EGFR pathway.

Methods: We group to obtain the six series compounds (8a-f, 9a-f, 10a-f, 11a-f, 12a-b and 13a-d). Hence we disclosed the design, synthesis and antitumor activity of novel quinazoline analogues against EGFR overexpression cancer cells A549 (human lung cancer), HepG-2 (human liver cancer), MCF-7 (human breast cancer) and PC-3 (human prostate cancer) and as well as the inhibitory on EGFR kinase. Moreover, apoptosis by acridine orange single staining and docking studies were presented in this paper as well.

Results: Six series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline (8a-f, 9a-f, 10a-f, 11a-f, 12a-b and 13a-d) were designed, synthesized and evaluated for the half maximal inhibitory concentration (IC50) values against four cancer cell lines (A549, HepG-2, MCF-7 and PC-3). Thirty target compounds showed moderate to excellent (1.49 - 50 µM) cytotoxicity activity against one or several cancer cell lines. The compound 13a showed the best activity against A549, HepG- 2, MCF-7 and PC-3 cancer cell lines, with the IC50 values of 1.49 ± 0.17 µM, 2.90 ± 0.24 µM, 1.85 ± 0.19 µM, 3.30 ± 0.22 µM, respectively. What’s more, the secondary amines were introduced to the target compounds to improve the water-soluble. The results showed that the compounds were beneficial to the cytotoxicity activity. Furthermore, the results prompted us that this series of compounds may be a kind of potential epidermal growth factor receptor (EGFR) kinase inhibitors.

Conclusion: Six series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4- tetrahydroquinoline moiety (8a-f, 9a-f, 10a-f, 11a-f, 12a-b and 13a-d) were designed, synthesized and evaluated for the IC50 values of cytotoxicity against four cancer cell lines (A549, HepG-2, MCF-7 and PC-3). Thirty synthesized compounds showed moderate to excellent cytotoxicity activity against the different cancer cells. Especially, the compound 13a exerted antitumor effects in a dosage-dependent manner and the IC50 values of compound 13a were 1.49 µM, 2.90 µM, 1.85 µM and 3.30 µM against A549, HepG-2, MCF-7 and PC-3, respectively. From the antitumor activity data show that the compounds possessed selectivity for A549 and MCF-7 cancer cell lines. It meant that the compounds had better treatment effect on lung cancer and breast cancer. On the whole, the compounds substituted by 1,2,3,4-tetrahydroquinoline at C-4 position of quinazoline and (S)-tetrahydrofuran-3-ol at C-8 position of quinazoline were beneficial to the cytotoxicity activity. From the result of acridine orange (AO) single staining which indicated the compound 13a could induce apoptosis of A549 cells. From the result of Docking Studies, we hypothesized that the C-4 position of quinazoline were substituted by 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline with the equal influence of the cytotoxicity activity. Overall, the results prompted us that this series of compounds may be a kind of potential EGFR kinase inhibitors.

Keywords: Quinazoline, 2, 3-dihydro-indole, 1, 2, 3, 4-tetrahydroquinoline, cytotoxicity activity, EGFR inhibitors, tyrosine kinase.

[1]
Chang, A. Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. Lung Cancer, 2011, 71(1), 3-10.
[2]
Weaver, K.E.; Rowland, J.H.; Alfano, C.M.; Mcneel, T.S. Parental cancer and the family: A population-based estimate of the number of US cancer survivors residing with their minor children. Cancer, 2010, 116(18), 4395-4401.
[3]
Chandarana, S.P.; Lee, J.S.; Chanowski, E.J.P.; Sacco, A.G.; Bradford, C.R.; Wolf, G.T.; Prince, M.E.; Moyer, J.S.; Avraham, E.; Worden, F.P. Prevalence and predictive role of p16 and epidermal growth factor receptor in surgically treated oropharyngeal and oral cavity cancer. Head Neck, 2013, 35(8), 1083-1090.
[4]
Lynch, T.J.; Bell, D.W.; Sordella, R.; Gurubhagavatula, S.; Okimoto, R.A.; Brannigan, B.W.; Harris, P.L.; Haserlat, S.M.; Supko, J.G.; Haluska, F.G. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New . Eng. J. Med., 2004, 350(350), 2129-2139.
[5]
Phuchareon, J.; Mccormick, F.; Eisele, D.W.; Tetsu, O. EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function. Proc. Natl. Acad. Sci. USA, 2015, 112(29), E3855.
[6]
Wakeling, A.E.; Guy, S.P.; Woodburn, J.R.; Ashton, S.E.; Curry, B.J.; Barker, A.J.; Gibson, K.H. ZD1839 (Iressa): An orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res., 2002, 62(20), 5749-5754.
[7]
Higgins, G.S.; Krause, M.; Mckenna, W.G.; Baumann, M. Personalized radiation oncology: Epidermal growth factor receptor and other receptor tyrosine kinase inhibitors. Rec Result Cancer Res., 2016, 198, 107-122.
[8]
Barbieri, F.; Würth, R.; Favoni, R.E.; Pattarozzi, A.; Gatti, M.; Ratto, A.; Ferrari, A.; Bajetto, A.; Florio, T. Receptor tyrosine kinase inhibitors and cytotoxic drugs affect pleural mesothelioma cell proliferation: Insight into EGFR and ERK1/2 as antitumor targets. Biochem. Pharmacol., 2011, 82(10), 1467-1477.
[9]
Jung, M.; Cho, B.C.; Lee, C.H.; Park, H.S.; Kang, Y.A.; Kim, S.K.; Chang, J.; Kim, D.J.; Sun, Y.R.; Kim, J.H. EGFR Polymorphism as a Predictor of clinical outcome in advanced lung cancer patients treated with EGFR-TKI. Yonsei Med. J., 2012, 53(6), 1128-1135.
[10]
De, R.M.; Loiacono, L.; Fusilli, C.; Poeta, M.L.; Mazza, T.; Sanchez, M.; Marchionni, L.; Signori, E.; Lamorte, G.; Vescovi, A.L. Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer. Clin. Cancer Res., 2017, 23(1), 159-170.
[11]
Wheler, J.J. Combining erlotinib and cetuximab is associated with activity in patients with non-small cell lung cancer (including squamous cell carcinomas) and wild-type EGFR or resistant mutations. Mol. Cancer Therapeut., 2013, 12(10), 2167-2175.
[12]
Schilder, R.J.; Sill, M.W.; Chen, X.; Darcy, K.M.; Decesare, S.L.; Lewandowski, G.; Lee, R.B.; Arciero, C.A.; Wu, H.; Godwin, A.K. Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: A Gynecologic Oncology Group Study. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res., 2005, 11(15), 5539-5548.
[13]
Abu-Yousif, A.O.; Moor, A.C.E.; Zheng, X.; Savellano, M.D.; Yu, W.; Selbo, P.K.; Hasan, T. Epidermal growth factor receptor-targeted photosensitizer selectively inhibits EGFR signaling and induces targeted phototoxicity in ovarian cancer cells. Cancer Lett., 2012, 321(2), 120-127.
[14]
Yang, J.C.; Hirsh, V.; Schuler, M.; Yamamoto, N.; O’Byrne, K.J.; Mok, T.S.; Zazulina, V.; Shahidi, M.; Lungershausen, J.; Massey, D. Symptom control and quality of life in LUX-Lung 3: A phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J. Clin. Oncol., 2013, 31(27), 3342-3350.
[15]
Ruebner, R.; Goldberg, D.; Abt, P.L.; Bahirwani, R.; Levine, M.; Sawinski, D.; Bloom, R.D.; Reese, P.P. Risk of end-stage renal disease among liver transplant recipients with pretransplant renal dysfunction. Am. J. Transplant., 2012, 12(11), 2958.
[16]
Yang, C.H.; Shih, J.Y.; Su, W.C.; Hsia, T.C.; Tsai, C.M.; Ou, S.H.I.; Yu, C.J.; Chang, G.C.; Ho, C.L.; Sequist, L.V. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): A phase 2 trial. Lancet Oncol., 2012, 13(5), 539-548.
[17]
Thongprasert, S. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. J. Evid. Based Med., 2011, 361(10), 947-957.
[18]
Sequist, L.V.; Martins, R.G.; Spigel, D.; Grunberg, S.M.; Spira, A.; Jänne, P.A.; Joshi, V.A.; Mccollum, D.; Evans, T.L.; Muzikansky, A. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J. Clinic. Oncol. Official J. Am. Soc. Clin. Oncol., 2008, 26(15), 2442-2449.
[19]
Pao, W.; Ladanyi, M.; Miller, V.A.; Group, L.C.O. Erlotinib in lung cancer. New. Engl. J. Med., 2005, 353(16), 1739-1741.
[20]
Sequist, L.V.; Yang, J.C.; Yamamoto, N.; Obyrne, K.; Hirsh, V.; Mok, T.; Geater, S.L.; Orlov, S.; Tsai, C.M.; Boyer, M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol., 2013, 31(27), 3327-3334.
[21]
Xu, Z.; Ting, P.; Xun, J.; Jian, L.; Linjiang, T.; Zeng, L.; Wei, Y.; Yungen, X.; Mengyuan, L.; Jian, D. Design, synthesis and biological evaluation of novel 4-anilinoquinazolines with C-6 urea-linked side chains as inhibitors of the epidermal growth factor receptor. Bioorgan. Med. Chem., 2013, 21(24), 7988-7998.
[22]
Yu-Jing, Y.J.; Zhang, C.M.; Liu, Z.P. Recent developments of small molecule EGFR inhibitors based on the quinazoline core scaffolds. Anticancer. Agents Med. Chem., 2012, 12(4), 391-406.
[23]
Mendel, D.B.; Laird, A.D.; Xin, X.; Louie, S.G.; Christensen, J.G.; Li, G.; Schreck, R.E.; Abrams, T.J.; Ngai, T.J.; Lee, L.B. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/ pharmacodynamic relationship. Clin. Cancer Res. Off. J. Am. Associat. Cancer Res., 2003, 9(1), 327-337.
[24]
Motzer, R.J.; Rini, B.I.; Bukowski, R.M.; Curti, B.D.; George, D.J.; Hudes, G.R.; Redman, B.G.; Margolin, K.A.; Merchan, J.R.; Wilding, G. Sunitinib in patients with metastatic renal cell carcinoma. Yearbook Urol., 2006, 295(21), 2516-2524.
[25]
Socinski, M.A.; Novello, S.; Brahmer, J.R.; Rosell, R.; Sanchez, J.M.; Belani, C.P.; Govindan, R.; Atkins, J.N.; Gillenwater, H.H.; Pallares, C. Multicenter, Phase II Trial of Sunitinib in Previously Treated, Advanced Non-Small-Cell Lung Cancer. J. Clin. Oncol., 2008, 26(4), 650-656.
[26]
Yu, Z.; Li, X.M.; Liu, S.H.; Liu, B.; Gao, C.H.; Hou, X. Downregulation of both EGFR and ErbB3 improves the cellular response to pemetrexed in an established pemetrexed-resistant lung adenocarcinoma A549 cell line. Oncol. Rep., 2014, 31(4), 1818-1824.
[27]
Li, X.; Lv, Y.; Yuan, A.; Yi, S.; Ma, Y.; Li, Z. Gastrin-releasing peptide promotes the growth of HepG2 cells via EGFR-independent ERK1/2 activation. Oncol. Rep., 2010, 24(2), 441-448.
[28]
Garcia, R.; Franklin, R.A.; Mccubrey, J.A. Cell death of MCF-7 human breast cancer cells induced by EGFR activation in the absence of other growth factors. Cell Cycle, 2006, 5(16), 1840-1846.
[29]
Kim, J.H.; Xu, C.; Keum, Y.S.; Reddy, B.; Conney, A.; Kong, A.N. Inhibition of EGFR signaling in human prostate cancer PC-3 cells by combination treatment with beta-phenylethyl isothiocyanate and curcumin. Carcinogenesis, 2006, 27(3), 475-482.
[30]
Tu, Y.; Ouyang, Y.; Xu, S.; Zhu, Y.; Li, G.; Sun, C.; Zheng, P.; Zhu, W. Design, synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors. Bioorg. Med. Chem., 2016, 24(7), 1495-1503.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 16
ISSUE: 5
Year: 2019
Page: [533 - 546]
Pages: 14
DOI: 10.2174/1570180815666180801121220
Price: $58

Article Metrics

PDF: 20
HTML: 1