Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Design, Synthesis, In Silico and In Vitro Evaluation of Novel Pyrimidine Derivatives as EGFR Inhibitors

Author(s): Gurubasavaraja S.P. Matada*, Nahid Abbas, Prasad S. Dhiwar, Rajdeep Basu and Giles Devasahayam

Volume 21, Issue 4, 2021

Published on: 21 July, 2020

Page: [451 - 461] Pages: 11

DOI: 10.2174/1871520620666200721102726

Price: $65

Abstract

Background: The abnormal signaling from tyrosine kinase causes many types of cancers, including breast cancer, non-small cell lung cancer, and chronic myeloid leukemia. This research reports the in silico, synthesis, and in vitro study of novel pyrimidine derivatives as EGFR inhibitors.

Objective: The objective of the research study is to discover more promising lead compounds using the drug discovery process, in which a rational drug design is achieved by molecular docking and virtual pharmacokinetic studies.

Methods: The molecular docking studies were carried out using discovery studio 3.5-version software. The molecules with good docking and binding energy score were synthesized, and their structures were confirmed by FT-IR, NMR, Mass and elemental analysis. Subsequently, molecules were evaluated for their anti-cancer activity using MDA-MB-231, MCF-7, and A431 breast cancer cell lines by MTT and tyrosine kinase assay methodology.

Results: Pyrimidine derivatives displayed anti-cancer activity. Particularly, compound R8 showed significant cytotoxicity against MDA-MB-231 with an IC50 value of 18.5±0.6μM. Molecular docking studies proved that the compound R8 has good binding fitting by forming hydrogen bonds with amino acid residues at ATP binding sites of EGFR.

Conclusion: Eight pyrimidine derivatives were designed, synthesized, and evaluated against breast cancer cell lines. Compound R8 significantly inhibited the growth of MDA-MB-231 and MCF-7. Molecular docking studies revealed that compound R8 has good fitting by forming different Hydrogen bonding interactions with amino acids at the ATP binding site of epidermal growth factor receptor target. Compound R8 was a promising lead molecule that showed better results as compared to other compounds in in vitro studies.

Keywords: Pyrimidine, cancer, cytotoxic, anti-cancer, molecular docking, EGFR.

« Previous Next »
Graphical Abstract

[1]
Kyriakopoulou, K.; Kefali, E.; Piperigkou, Z.; Bassiony, H.; Karamanos, N.K. Advances in targeting epidermal growth factor receptor signaling pathway in mammary cancer. Cell. Signal., 2018, 51, 99-109.
[http://dx.doi.org/10.1016/j.cellsig.2018.07.010] [PMID: 30071291]
[2]
Sawyers, C. Targeted cancer therapy.Nature, 2004, 432(7015), 294-297.,
[http://dx.doi.org/10.1038/nature03095] [PMID: 15549090]
[3]
Jin, S.; Sun, X.; Liu, D.; Xie, H.; Rao, Y. Design, synthesis and biological study of potent and covalent HER-2 tyrosine kinase inhibitors with low cytotoxicity in vitro. Chem. Pap., 2019, 73(6), 1333-1345.
[http://dx.doi.org/10.1007/s11696-019-00686-0]
[4]
Mendelsohn, J.; Baselga, J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J. Clin. Oncol.,, 2003, 21(14), 2787-2799.
[http://dx.doi.org/10.1200/JCO.2003.01.504] [PMID: 12860957]
[5]
Block, K.I.; Gyllenhaal, C.; Lowe, L.; Amedei, A.; Amin, A.R.; Amin, A.; Aquilano, K.; Arbiser, J.; Bishayee, A.; Block, K.; Ashraf, S.S. A broad-spectrum integrative design for cancer prevention and therapy: The challenge ahead. Semin. Cancer Biol., 2015, 35(Suppl.), S1-S4..
[http://dx.doi.org/10.1016/j.semcancer.2015.08.002] [PMID: 26260004]
[6]
Okamoto, I. Epidermal growth factor receptor in relation to tumor development: EGFR-targeted anticancer therapy. FEBS J., 2010, 277(2), 309-315.
[http://dx.doi.org/10.1111/j.1742-4658.2009.07449.x ] [PMID: 19922468]
[7]
Cao, J.; Fang, H.; Wang, B.; Ma, C.; Xu, W. Epidermal growth factor receptor as a target for anti-cancer agent design. Anticancer Agents Med. Chem., 2010, 10(6), 491-503.,
[http://dx.doi.org/10.2174/1871520611009060491] [PMID: 20698825]
[8]
Esteban-Gamboa, A.; Balzarini, J.; Esnouf, R.; De Clercq, E.; Camarasa, M.J.; Pérez-Pérez, M.J. Design, synthesis, and enzymatic evaluation of multisubstrate analogue inhibitors of Escherichia coli thymidine phosphorylase. J. Med. Chem., 2000, 43(5), 971-983.
[http://dx.doi.org/10.1021/jm9911377 ] [PMID: 10715161]
[9]
Parveen, H.; Hayat, F.; Salahuddin, A.; Azam, A. Synthesis, characterization and biological evaluation of novel 6-ferrocenyl-4-aryl-2-substituted pyrimidine derivatives. Eur. J. Med. Chem., 2010, 45(8), 3497-3503.
[http://dx.doi.org/10.1016/j.ejmech.2010.04.023] [PMID: 20488588]
[10]
Tarnchompoo, B.; Sirichaiwat, C.; Phupong, W.; Intaraudom, C.; Sirawaraporn, W.; Tarnchompoo, B.; Sirichaiwat, C.; Phupong, W.; Intaraudom, C.; Sirawaraporn, W.; Kamchonwongpaisan, S.; Vanichtanankul, J.; Thebtaranonth, Y.; Yuthavong, Y. Development of 2,4-diaminopyrimidines as antimalarials based on inhibition of the S108N and C59R+S108N mutants of dihydrofolate reductase from pyrimethamine-resistant Plasmodium falciparum. J.Med. Chem., 2002, 45(6), 1244-1252..
[http://dx.doi.org/10.1021/jm010131q] [PMID: 11881993]
[11]
Boykin, D.W.; Kumar, A.; Bajic, M.; Xiao, G.; Wilson, W.D.; Bender, B.C.; Mccurdy, D.R.; Hall, J.E.; Tidwell, R.R. Anti-Pneumocystis carinii pneumonia activity of dicationic diaryl methylprimidines. Eur. J. Med. Chem., 1998, 32, 965-972.
[http://dx.doi.org/10.1016/S0223-5234(97)89640-7]
[12]
Palanki, M.S.; Ransone, L.J.; Bennett, B.L.; Manning, A.M.
Suto, M.J. Inhibitors of NF-κB and AP-1 gene expression: SAR studies on the pyrimidine portion of 2-chloro-4-trifluoromethylpyrimidine-5-. J. Med. Chem., 2000, 43(21), 3995-4004.
[http://dx.doi.org/10.1021/jm0001626] [PMID: 11052805]
[13]
Hamby, J.M.; Connolly, C.J.; Schroeder, M.C.; Winters, R.T.; Showalter, H.D.; Panek, R.L.; Major, T.C.; Olsewski, B.; Ryan, M.J.; Dahring, T.; Lu, G.H.; Keiser, J.; Amar, A.; Shen, C.; Kraker, A.J.; Slintak, V.; Nelson, J.M.; Fry, D.W.; Bradford, L.; Hallak, H.; Doherty, A.M. Structure-activity relationships for a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. J. Med. Chem., 1997, 40(15), 2296-2303.
[http://dx.doi.org/10.1021/jm970367n] [PMID: 9240345]
[14]
Liu, Z.; Wu, S.; Wang, Y.; Li, R.; Wang, J.; Wang, L.; Zhao, Y.; Gong, P. Design, synthesis and biological evaluation of novel thieno[3,2-d]pyrimidine derivatives possessing diaryl semicarbazone scaffolds as potent antitumor agents. Eur. J. Med. Chem., 2014, 87, 782-793.,
[http://dx.doi.org/10.1016/j.ejmech.2014.10.022] [PMID: 25440879]
[15]
Bakr, R.B.; Mehany, A.B.M.; Abdellatif, K.R.A. Synthesis, EGFR inhibition and anti-cancer activity of new 3,6-dimethyl-1-phenyl-4-(substituted-methoxy)pyrazolo[3,4-d] pyrimidine derivatives. Anticancer Agents Med. Chem., 2017, 17(10), 1389-1400.,
[http://dx.doi.org/10.2174/1872211311666170213105004] [PMID: 28270084]
[16]
Ismail, Z.H.; Abdel-Gawad, S.M.; Abdel-Aziem, A.; Ghorab, M.M. Synthesis of some new biologically active sulfur compounds containing pyrazolo[3,4-d]pyrimidine moiety. Phosphorus Sulfur Silicon Relat. Elem., 2003, 178(8), 1795-1805.
[http://dx.doi.org/10.1080/10426500307825]
[17]
Carraro, F.; Naldini, A.; Pucci, A.; Locatelli, G.A.; Maga, G.; Schenone, S.; Bruno, O.; Ranise, A.; Bondavalli, F.; Brullo, C.; Fossa, P. Pyrazolo[3,4-d]pyrimidines as potent antiproliferative and proapoptotic agents toward A431 and 8701-BC cells in culture via inhibition of c-Src phosphorylation. J. Med. Chem., 2006, 49(5), 1549-1561.
[http://dx.doi.org/10.1021/jm050603r] [PMID: 16509573]
[18]
el-Enany, M.M.; Kamel, M.M.; Khalil, O.M.; el-Nassan, H.B. Synthesis and antitumor activity of novel 6-aryl and 6-alkylpyrazolo [3,4-d]pyrimidin-4-one derivatives. Eur. J. Med. Chem., 2010, 45(11), 5286-5291.
[http://dx.doi.org/10.1016/j.ejmech.2010.08.048] [PMID: 20846758]
[19]
Peat, A.J.; Garrido, D.; Boucheron, J.A.; Schweiker, S.L.; Dickerson, S.H.; Wilson, J.R.; Wang, T.Y.; Thomson, S.A. Novel GSK-3 inhibitors with improved cellular activity. Bioorg. Med. Chem. Lett., 2004, 14(9), 2127-2130.
[http://dx.doi.org/10.1016/j.bmcl.2004.02.037] [PMID: 15080993]
[20]
Kim, D.C.; Lee, Y.R.; Yang, B.S.; Shin, K.J.; Kim, D.J.; Chung, B.Y.; Yoo, K.H. Synthesis and biological evaluations of pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 inhibitors. Eur. J. Med. Chem., 2003, 38(5), 525-532.
[http://dx.doi.org/10.1016/S0223-5234(03)00065-5] [PMID: 12767603]
[21]
Schenone, S.; Brullo, C.; Bruno, O.; Bondavalli, F.; Mosti, L.; Maga, G.; Crespan, E.; Carraro, F.; Manetti, F.; Tintori, C.; Botta, M. Synthesis, biological evaluation and docking studies of 4-amino substituted 1H-pyrazolo[3,4-d]pyrimidines. Eur. J. Med. Chem., 2008, 43(12), 2665-2676.
[http://dx.doi.org/10.1016/j.ejmech.2008.01.034] [PMID: 18342402]
[22]
Schenone, S.; Bruno, O.; Bondavalli, F.; Ranise, A.; Mosti, L.; Menozzi, G.; Fossa, P.; Manetti, F. Synthesis of 1-(2-chloro-2-phenylethyl)-6-methylthio-1H-pyrazolo[3,4-d]pyrimidines 4-amino substituted and their biological evaluation. Eur. J. Med. Chem., 2004, 39(2), 153-160.
[http://dx.doi.org/10.1016/j.ejmech.2003.11.007] [PMID: 14987824]
[23]
Vigneri, P.; Wang, J.Y. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat. Med., 2001, 7(2), 228-234.http://dx.doi.org/
[http://dx.doi.org/10.1038/84683] [PMID: 11175855]
[24]
Chikhale, R.; Thorat, S.; Choudhary, R.K.; Gadewal, N.; Khedekar, P. Design, synthesis and anticancer studies of novel aminobenzazolyl pyrimidines as tyrosine kinase inhibitors. Bioorg. Chem., 2018, 77, 84-100.
[http://dx.doi.org/10.1016/j.bioorg.2018.01.008] [PMID: 29342447]
[25]
Petrov, K.G.; Zhang, Y.M.; Carter, M.; Cockerill, G.S.; Dickerson, S.; Gauthier, C.A.; Guo, Y.; Mook, R.A., Jr; Rusnak, D.W.; Walker, A.L.; Wood, E.R.; Lackey, K.E. Optimization and SAR for dual ErbB-1/ErbB-2 tyrosine kinase inhibition in the 6-furanylquinazoline series. Bioorg. Med. Chem. Lett., 2006, 16(17), 4686-4691.
[http://dx.doi.org/10.1016/j.bmcl.2006.05.090] [PMID: 16777410]
[26]
Moyer, J.D.; Barbacci, E.G.; Iwata, K.K.; Arnold, L.; Boman, B.; Cunningham, A.; DiOrio, C.; Doty, J.; Morin, M.J.; Moyer, M.P.; Neveu, M. Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res., 1997, 57(21), 4838-4848.
[PMID: 9354447]
[27]
Usha, T.; Middha, S.K.; Goyal, A.K.; Karthik, M.; Manoj, D.A.; Faizan, S.; Goyal, P.; Prashanth, H.P. Molecular docking studies of anti-cancerous candidates in Hippophae rhamnoides and Hippophae salicifolia. J. Biomed. Res., 2014, 28(5), 406-415.https://dx.doi.org/10.7555%2FJBR.28.20130110
[PMID: 25332713]
[28]
Jayaraj, R.L.; Ranjani, V.; Manigandan, K.; Elangovan, N.A. In-silico docking studies to identify potent inhibitors of alpha-synuclein aggregation in Parkinson disease. Asian J. Pharm. Clin. Res., 2013, 6(4), 127-131., https://innovareacademics.in/journals/index.php/ajpcr/article/view/369
[29]
Sogabe, S.; Kawakita, Y.; Igaki, S.; Iwata, H.; Miki, H.; Cary, D.R.; Takagi, T.; Takagi, S.; Ohta, Y.; Ishikawa, T. Structure-based approach for the discovery of pyrrolo[3,2-d]pyrimidine-based EGFR T790M/L858R mutant inhibitors. ACS Med. Chem. Lett., 2012, 4(2), 201-205..
[http://dx.doi.org/10.1021/ml300327z] [PMID: 24900643]
[30]
Hartung, C.G.; Backes, A.C.; Felber, B.; Missio, A.; Philipp, A. Efficient microwave assisted synthesis of highly functionalized pyrimidine derivatives. Tetrahedron, 2006, 62(43), 10055-10064.
[http://dx.doi.org/10.1016/j.tet.2006.08.065]
[31]
Majumder, A.; Gupta, R.; Jain, A. Microwave-assisted synthesis of nitrogen containing heterocycles. Green Chem. Lett. Rev., 2013, 6(2), 151-182.https://www.ijper.org/article/731doi:10.5530/ijper.51.4s.101
[http://dx.doi.org/10.1080/17518253.2012.733032]
[32]
Padarthi, P.; Pavankumar, K.; Chandramohan, V.; Richard, J.; Kaliaperumal, J. Chalcones as effective Antimicrobials a comparative in silico approach. J. Chem. Pharm. Sci., 2012, 3, 67-74.
[33]
Kaur, N.; Aggarwal, A.K.; Sharma, N.; Choudhary, B. Synthesis and in vitro antimicrobial activity of pyrimidine derivatives. Int. J. Pharm. Sci. Drug Res., 2012, 4(3), 199-204.
[34]
Sharma, C.S.; Mishra, S.S.; Singh, H.P.; Kumar, N. In silico ADME and toxicity study of some selected antineoplastic drugs. Int. J. Pharm. Sci. Drug Res., 2016, 8, 65-67.
[http://dx.doi.org/10.25004/IJPSDR.2016.080110]
[35]
Mao, Y.; Zhu, W.; Kong, X.; Wang, Z.; Xie, H.; Ding, J.; Terrett, N.K.; Shen, J.; Shen, J. Design, synthesis and biological evaluation of novel pyrimidine, 3-cyanopyridine and m-amino-N-phenylbenzamide based monocyclic EGFR tyrosine kinase inhibitors. Bioorg. Med. Chem., 2013, 21(11), 3090-3104.
[http://dx.doi.org/10.1016/j.bmc.2013.03.053] [PMID: 23602524]
[36]
Hamed, M.M.; El Ella, D.A.; Keeton, A.B.; Piazza, G.A.; Engel, M.; Hartmann, R.W.; Abadi, A.H. Quinazoline and tetrahydropyridothieno[2,3-d]pyrimidine derivatives as irreversible EGFR tyrosine kinase inhibitors: Influence of the position 4 substituent. MedChemComm, 2013, 4(8), 1202-1207.
[http://dx.doi.org/10.1039/c3md00118k]

Rights & Permissions Print Cite
Article Metrics
40
1
© 2024 Bentham Science Publishers | Privacy Policy