Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Author(s): Sachin A. Dhawale, Pratap S. Dabhade and Santosh N. Mokale*

DOI: 10.2174/1871520623666230714152455

DownloadDownload PDF Flyer Cite As
Discovery of New Quinazoline Derivatives as VEGFR-2 Inhibitors: Design, Synthesis, and Anti-proliferative Studies

Page: [2042 - 2055] Pages: 14

  • * (Excluding Mailing and Handling)

Abstract

Background: In cancer, Receptor tyrosine kinases (RTKs) are powerful oncoproteins that can lead to uncontrolled cell proliferation, angiogenesis, and metastasis when mutated or overexpressed, making them crucial targets for cancer treatment. In endothelial cells, one of them is vascular endothelial growth factor receptor 2 (VEGFR2), a tyrosine kinase receptor that is produced and is the most essential regulator of angiogenic factors involved in tumor angiogenesis. So, a series of new N-(4-(4-amino-6,7-dimethoxyquinazolin-2-yloxy)phenyl)-N-phenyl cyclopropane-1,1- dicarboxamide derivatives as VEGFR-2 inhibitors have been designed and synthesized.

Methods: The designed derivatives were synthesized and evaluated using H-NMR, C13-NMR, and Mass spectroscopy. The cytotoxicity was done with HT-29 and COLO-205 cell lines. The potent compound was further studied for Vegfr- 2 kinase inhibition assay. Furthermore, the highest activity compound was tested for cell cycle arrest and apoptosis. The molecular docking investigation was also done with the help of the Glide-7.6 program interfaced with Maestro- 11.3 of Schrodinger 2017. The molecular dynamics simulation was performed on the Desmond module of Schrodinger.

Results: Compound SQ2 was observed to have promising cytotoxic activity (IC50 = 3.38 and 10.55 μM) in comparison to the reference drug Cabozantinib (IC50 = 9.10 and 10.66 μM) against HT-29 and COLO-205, respectively. The synthesized compound SQ2 showed VEGFR-2 kinase inhibition activity (IC50 = 0.014 μM) compared to the reference drug, Cabozantinib (IC50 = 0.0045 μM). Moreover, compound SQ2 strongly induced apoptosis by arresting the cell cycle in the G1 and G2/M phases. The docking study was performed to understand the binding pattern of the new compounds to the VEGFR-2 active site. Docking results attributed the potent VEGFR-2 inhibitory effect of the new compounds as they bound to the key amino acids in the active site, Asp1044, and Glu883, as well as their hydrophobic interaction with the receptor's hydrophobic pocket. The advanced computational study was also done with the help of molecular dynamics simulation.

Conclusion: The findings show that the developed derivatives SQ2 and SQ4 are equally powerful as cabozantinib at cellular and enzymatic levels. The apoptosis and cell cycle results show that the proposed compounds are potent. This research has provided us with identical or more potent VEGFR-2 inhibitors supported by the results of docking studies, molecular dynamics simulation, cytotoxic actions, in vitro VEGFR-2 inhibition, apoptosis, and cell cycle arrest.

Graphical Abstract

[1]
Dokla, E.M.E.; Fang, C.S.; Abouzid, K.A.M.; Chen, C.S. 1,2,4-Oxadiazole derivatives targeting EGFR and c-Met degradation in TKI resistant NSCLC. Eur. J. Med. Chem., 2019, 182, 111607.
[http://dx.doi.org/10.1016/j.ejmech.2019.111607] [PMID: 31446247]
[2]
Gu, W.; Dai, Y.; Qiang, H.; Shi, W.; Liao, C.; Zhao, F.; Huang, W.; Qian, H. Discovery of novel 2-substituted-4-(2-fluorophenoxy) pyridine derivatives possessing pyrazolone and triazole moieties as dual c-Met/VEGFR-2 receptor tyrosine kinase inhibitors. Bioorg. Chem., 2017, 72, 116-122.
[http://dx.doi.org/10.1016/j.bioorg.2017.04.001] [PMID: 28411406]
[3]
Bray, F.; Jemal, A.; Grey, N.; Ferlay, J.; Forman, D. Global cancer transitions according to the Human Development Index (2008–2030): A population-based study. Lancet Oncol., 2012, 13(8), 790-801.
[http://dx.doi.org/10.1016/S1470-2045(12)70211-5] [PMID: 22658655]
[4]
Li, J.; Gu, W.; Bi, X.; Li, H.; Liao, C.; Liu, C.; Huang, W.; Qian, H. Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors. Bioorg. Med. Chem., 2017, 25(24), 6674-6679.
[http://dx.doi.org/10.1016/j.bmc.2017.11.010] [PMID: 29146452]
[5]
Marzouk, A.A.; Abdel-Aziz, S.A.; Abdelrahman, K.S.; Wanas, A.S.; Gouda, A.M.; Youssif, B.G.M.; Abdel-Aziz, M. Design and synthesis of new 1,6-dihydropyrimidin-2-thio derivatives targeting VEGFR-2: Molecular docking and antiproliferative evaluation. Bioorg. Chem., 2020, 102, 104090.
[http://dx.doi.org/10.1016/j.bioorg.2020.104090] [PMID: 32683176]
[6]
Zhang, J.; Jiang, X.; Jiang, Y.; Guo, M.; Zhang, S.; Li, J.; He, J.; Liu, J.; Wang, J.; Ouyang, L. Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs. Eur. J. Med. Chem., 2016, 108, 495-504.
[http://dx.doi.org/10.1016/j.ejmech.2015.12.016] [PMID: 26717201]
[7]
Saavedra, O.; Claridge, S.; Zhan, L.; Raeppel, F.; Granger, M.C.; Raeppel, S.; Mannion, M.; Gaudette, F.; Zhou, N.; Isakovic, L.; Bernstein, N.; Déziel, R.; Nguyen, H.; Beaulieu, N.; Beaulieu, C.; Dupont, I.; Wang, J.; Macleod, A.R.; Besterman, J.M.; Vaisburg, A. N3-Arylmalonamides: A new series of thieno[3,2-b]pyridine based inhibitors of c-Met and VEGFR2 tyrosine kinases. Bioorg. Med. Chem. Lett., 2009, 19(24), 6836-6839.
[http://dx.doi.org/10.1016/j.bmcl.2009.10.095] [PMID: 19896842]
[8]
Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med., 1995, 1(1), 27-30.
[http://dx.doi.org/10.1038/nm0195-27] [PMID: 7584949]
[9]
Kerbel, R.S. Tumor angiogenesis: Past, present and the near future. Carcinogenesis, 2000, 21(3), 505-515.
[http://dx.doi.org/10.1093/carcin/21.3.505] [PMID: 10688871]
[10]
Yang, Y.; Shi, L.; Zhou, Y.; Li, H.Q.; Zhu, Z.W.; Zhu, H.L. Design, synthesis and biological evaluation of quinoline amide derivatives as novel VEGFR-2 inhibitors. Bioorg. Med. Chem. Lett., 2010, 20(22), 6653-6656.
[http://dx.doi.org/10.1016/j.bmcl.2010.09.014] [PMID: 20943391]
[11]
Awazu, Y.; Nakamura, K.; Mizutani, A.; Kakoi, Y.; Iwata, H.; Yamasaki, S.; Miyamoto, N.; Imamura, S.; Miki, H.; Hori, A. A novel inhibitor of c-Met and VEGF receptor tyrosine kinases with a broad spectrum of in vivo antitumor activities. Mol. Cancer Ther., 2013, 12(6), 913-924.
[http://dx.doi.org/10.1158/1535-7163.MCT-12-1011] [PMID: 23548264]
[12]
Qiang, H.; Gu, W.; Huang, D.; Shi, W.; Qiu, Q.; Dai, Y.; Huang, W.; Qian, H. Design, synthesis and biological evaluation of 4-aminopyrimidine-5-cabaldehyde oximes as dual inhibitors of c-Met and VEGFR-2. Bioorg. Med. Chem., 2016, 24(16), 3353-3358.
[http://dx.doi.org/10.1016/j.bmc.2016.03.061] [PMID: 27068889]
[13]
Arora, A.; Scholar, E.M. Role of tyrosine kinase inhibitors in cancer therapy. J. Pharmacol. Exp. Ther., 2005, 315(3), 971-979.
[http://dx.doi.org/10.1124/jpet.105.084145] [PMID: 16002463]
[14]
Cohen, P. Protein kinases-The major drug targets of the twenty-first century? Nat. Rev. Drug Discov., 2002, 1(4), 309-315.
[http://dx.doi.org/10.1038/nrd773] [PMID: 12120282]
[15]
Behdani, M.; Zeinali, S.; Khanahmad, H.; Karimipour, M.; Asadzadeh, N.; Azadmanesh, K.; Khabiri, A.; Schoonooghe, S.; Habibi Anbouhi, M.; Hassanzadeh-Ghassabeh, G.; Muyldermans, S. Generation and characterization of a functional Nanobody against the vascular endothelial growth factor receptor-2; angiogenesis cell receptor. Mol. Immunol., 2012, 50(1-2), 35-41.
[http://dx.doi.org/10.1016/j.molimm.2011.11.013] [PMID: 22208996]
[16]
Folkman, J. Role of angiogenesis in tumor growth and metastasis; Elsevier, 2002.
[17]
Yakes, F.M.; Chen, J.; Tan, J.; Yamaguchi, K.; Shi, Y.; Yu, P.; Qian, F.; Chu, F.; Bentzien, F.; Cancilla, B.; Orf, J.; You, A.; Laird, A.D.; Engst, S.; Lee, L.; Lesch, J.; Chou, Y.C.; Joly, A.H. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol. Cancer Ther., 2011, 10(12), 2298-2308.
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0264] [PMID: 21926191]
[18]
Abdel-Rahman, O. Targeting vascular endothelial growth factor (VEGF) pathway in gastric cancer: Preclinical and clinical aspects. Crit. Rev. Oncol. Hematol., 2015, 93(1), 18-27.
[http://dx.doi.org/10.1016/j.critrevonc.2014.05.012] [PMID: 24970311]
[19]
Des Guetz, G.; Uzzan, B.; Nicolas, P.; Cucherat, M.; Morere, J-F.; Benamouzig, R.; Breau, J-L.; Perret, G-Y. Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature. Br. J. Cancer, 2006, 94(12), 1823-1832.
[http://dx.doi.org/10.1038/sj.bjc.6603176] [PMID: 16773076]
[20]
Mannion, M.; Raeppel, S.; Claridge, S.; Zhou, N.; Saavedra, O.; Isakovic, L.; Zhan, L.; Gaudette, F.; Raeppel, F.; Déziel, R.; Beaulieu, N.; Nguyen, H.; Chute, I.; Beaulieu, C.; Dupont, I.; Robert, M.F.; Lefebvre, S.; Dubay, M.; Rahil, J.; Wang, J.; Ste-Croix, H.; Robert Macleod, A.; Besterman, J.M.; Vaisburg, A.N. -(4-(6,7-Disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: A novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(23), 6552-6556.
[http://dx.doi.org/10.1016/j.bmcl.2009.10.040] [PMID: 19854051]
[21]
Claridge, S.; Raeppel, F.; Granger, M.C.; Bernstein, N.; Saavedra, O.; Zhan, L.; Llewellyn, D.; Wahhab, A.; Deziel, R.; Rahil, J.; Beaulieu, N.; Nguyen, H.; Dupont, I.; Barsalou, A.; Beaulieu, C.; Chute, I.; Gravel, S.; Robert, M.F.; Lefebvre, S.; Dubay, M.; Pascal, R.; Gillespie, J.; Jin, Z.; Wang, J.; Besterman, J.M.; MacLeod, A.R.; Vaisburg, A. Discovery of a novel and potent series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases. Bioorg. Med. Chem. Lett., 2008, 18(9), 2793-2798.
[http://dx.doi.org/10.1016/j.bmcl.2008.04.009] [PMID: 18434145]
[22]
Claesson-Welsh, L.; Welsh, M. VEGFA and tumour angiogenesis. J. Intern. Med., 2013, 273(2), 114-127.
[http://dx.doi.org/10.1111/joim.12019] [PMID: 23216836]
[23]
Lintnerová, L.; García-Caballero, M. Gregáň, F.; Melicherčík, M.; Quesada, A.R.; Dobiaš, J.; Lác, J.; Sališová, M.; Boháč, A. A development of chimeric VEGFR2 TK inhibitor based on two ligand conformers from PDB: 1Y6A complex – Medicinal chemistry consequences of a TKs analysis. Eur. J. Med. Chem., 2014, 72, 146-159.
[http://dx.doi.org/10.1016/j.ejmech.2013.11.023] [PMID: 24368209]
[24]
Abbas, S.E.; Barsoum, F.F.; Georgey, H.H.; Mohammed, E.R. Synthesis and antitumor activity of certain 2,3,6-trisubstituted quinazolin-4(3H)-one derivatives. Bull. Fac. Pharm. Cairo Univ., 2013, 51(2), 273-282.
[http://dx.doi.org/10.1016/j.bfopcu.2013.08.003]
[25]
Kumar, M.; Narasimhan, B.; Kumar, P.; Ramasamy, K.; Mani, V.; Mishra, R.K.; Majeed, A.B.A. 4-(1-Aryl-5-chloro-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzene sulfonamides: Synthesis, antimicrobial, anticancer evaluation and QSAR studies. Arab. J. Chem., 2014, 7(4), 436-447.
[http://dx.doi.org/10.1016/j.arabjc.2013.03.002]
[26]
Garofalo, A.; Farce, A.; Ravez, S.; Lemoine, A.; Six, P.; Chavatte, P.; Goossens, L.; Depreux, P. Synthesis and structure-activity relationships of (aryloxy)quinazoline ureas as novel, potent, and selective vascular endothelial growth factor receptor-2 inhibitors. J. Med. Chem., 2012, 55(3), 1189-1204.
[http://dx.doi.org/10.1021/jm2013453] [PMID: 22229669]
[27]
Barbosa, M.L.C.; Lima, L.M.; Tesch, R.; Sant’Anna, C.M.R.; Totzke, F.; Kubbutat, M.H.G.; Schächtele, C.; Laufer, S.A.; Barreiro, E.J. Novel 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors. Eur. J. Med. Chem., 2014, 71, 1-14.
[http://dx.doi.org/10.1016/j.ejmech.2013.10.058] [PMID: 24269511]
[28]
Morabito, A.; Piccirillo, M.C.; Costanzo, R.; Sandomenico, C.; Carillio, G.; Daniele, G.; Giordano, P.; Bryce, J.; Carotenuto, P.; La Rocca, A.; Di Maio, M.; Normanno, N.; Rocco, G.; Perrone, F. Vandetanib: An overview of its clinical development in NSCLC and other tumors. Drugs Today (Barc), 2010, 46(9), 683-698.
[http://dx.doi.org/10.1358/dot.2010.46.9.1516989] [PMID: 20967300]
[29]
Zhan, Z.; Ai, J.; Liu, Q.; Ji, Y.; Chen, T.; Xu, Y.; Geng, M.; Duan, W. Discovery of anilinopyrimidines as dual inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity. ACS Med. Chem. Lett., 2014, 5(6), 673-678.
[http://dx.doi.org/10.1021/ml500066m] [PMID: 24944742]
[30]
Zhengsheng, Z.; Jing, A.; Qiufeng, L.; Yinchun, J.; Tiantian, C.; Yechun, X.; Meiyu, G.; Wenhu, D. Discovery of anilinopyrimidines as dual inhibitors of c-Met and VEGFR-2: synthesis, SAR, and cellular activity. ACS Med. Chem. Lett., 2014, 5, 673-678.
[31]
Christensen, J.G.; Burrows, J.; Salgia, R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett., 2005, 225(1), 1-26.
[http://dx.doi.org/10.1016/j.canlet.2004.09.044] [PMID: 15922853]
[32]
Yakes, F.M.; Chen, J.; Tan, J.; Yamaguchi, K.; Shi, Y.; Yu, P.; Qian, F.; Chu, F.; Bentzien, F.; Cancilla, B.; and Orf, J. 2011. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol. Cancer Ther., 2011, 10(12), 2298-2308.
[33]
Mohassab, A.M.; Hassan, H.A.; Abdelhamid, D.; Gouda, A.M.; Youssif, B.G.M.; Tateishi, H.; Fujita, M.; Otsuka, M.; Abdel-Aziz, M. Design and Synthesis of Novel quinoline/chalcone/1,2,4-triazole hybrids as potent antiproliferative agent targeting EGFR and BRAFV600E kinases. Bioorg. Chem., 2021, 106, 104510.
[http://dx.doi.org/10.1016/j.bioorg.2020.104510] [PMID: 33279248]
[34]
Abou-Zied, H.A.; Youssif, B.G.M.; Mohamed, M.F.A.; Hayallah, A.M.; Abdel-Aziz, M. EGFR inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and docking studies of novel xanthine derivatives carrying chalcone moiety as hybrid molecules. Bioorg. Chem., 2019, 89, 102997.
[http://dx.doi.org/10.1016/j.bioorg.2019.102997] [PMID: 31136902]
[35]
Wei, D.; Fan, H.; Zheng, K.; Qin, X.; Yang, L.; Yang, Y.; Duan, Y.; Zhang, Q.; Zeng, C.; Hu, L. Synthesis and anti-tumor activity of [1,4] dioxino [2,3-f] quinazoline derivatives as dual inhibitors of c-Met and VEGFR-2. Bioorg. Chem., 2019, 88, 102916.
[http://dx.doi.org/10.1016/j.bioorg.2019.04.010] [PMID: 31026719]
[36]
Alsaif, N.A.; Taghour, M.S.; Alanazi, M.M.; Obaidullah, A.J.; Alanazi, W.A.; Alasmari, A.; Albassam, H.; Dahab, M.A.; Mahdy, H.A. Identification of new [1,2,4]triazolo[4,3-a]quinoxalines as potent VEGFR-2 tyrosine kinase inhibitors: Design, synthesis, anticancer evaluation, and in silico studies. Bioorg. Med. Chem., 2021, 46, 116384.
[http://dx.doi.org/10.1016/j.bmc.2021.116384]
[37]
Ubale, P.; Mokale, S.; More, S.; Waghamare, S.; More, V.; Munirathinam, N.; Dilipkumar, S.; Das, R.K.; Reja, S.; Helavi, V.B.; Kollur, S.P. Evaluation of in vitro anticancer, antimicrobial and antioxidant activities of new Cu(II) complexes derived from 4(3H)-quinazolinone: Synthesis, crystal structure and molecular docking studies. J. Mol. Struct., 2022, 1251, 131984.
[http://dx.doi.org/10.1016/j.molstruc.2021.131984]
[38]
Qian, F.; Engst, S.; Yamaguchi, K.; Yu, P.; Won, K.A.; Mock, L.; Lou, T.; Tan, J.; Li, C.; Tam, D.; Lougheed, J.; Yakes, F.M.; Bentzien, F.; Xu, W.; Zaks, T.; Wooster, R.; Greshock, J.; Joly, A.H. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res., 2009, 69(20), 8009-8016.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-4889] [PMID: 19808973]
[39]
Norman, M.H.; Liu, L.; Lee, M.; Xi, N.; Fellows, I.; D’Angelo, N.D.; Dominguez, C.; Rex, K.; Bellon, S.F.; Kim, T.S.; and Dussault, I. 2012. Structure-based design of novel class II c-Met inhibitors: 1. Identification of pyrazolone-based derivatives. J. Med. Chem., 2012, 55(5), 1858-1867.
[40]
Zhou, S.; Liao, H.; Liu, M.; Feng, G.; Fu, B.; Li, R.; Cheng, M.; Zhao, Y.; Gong, P. Discovery andw biological evaluation of novel 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety as c-Met kinase inhibitors. Bioorg. Med. Chem., 2014, 22(22), 6438-6452.
[http://dx.doi.org/10.1016/j.bmc.2014.09.037] [PMID: 25438768]
[41]
Shaw, D.E. Schrödinger: Desmond Molecular Dynamics System; Schrödinger Release: New York, 2021, p. pp. 4.