Abstract
Background: Quinoline scaffold acts as “privileged structure” for anticancer drug design. Certain derivatives showed good results through different mechanisms as topoisomerase 1 and kinase inhibition.
Methods: A new series of 2-chloro-3-(2-amino-3-cyano-4H-chromene, 4H-pyranyl and fused 1- cyclohexen-4-yl)quinoline structures (3-5, 6 and 7) were designed, synthesized, and evaluated for their in vitro antitumor activity. All compounds were tested by MTT assay against a panel of four different human tumor cell lines. The inhibitory activity of selected compounds was assessed on topoisomerase 1 and epidermal growth factor receptor tyrosine kinase via ELISA. In addition, compounds 7b and 3a were docked into the X-ray crystal structure of Topo 1 and EGFR enzymes, respectively to explain the molecular basis of the potent activity.
Results: Compounds 3a, 3b and 7b showed characteristic efficacy profile. 7b showed the best cytotoxic activity on all types of tested cell lines with IC50 range (15.8±1.30 to 28.2±3.37 µM), relative to 5-fluoruracil of IC50 range (40.7±2.46 to 63.8±2.69 µM). Via ELISA, 7b and 3a showed characteristic inhibition profile on Topo 1 and EGFR-TK respectively. In addition, 7b has scored binding energy (101.61 kcal/mol) and six hydrogen bonds with amino acids conserved residues in the enzyme pocket.
Conclusion: Analysis of results revealed that compounds 7a and 7b mainly were Topo 1 inhibitors while 3a was mainly EGFR inhibitor. This property may be exploited to design future quinoline derivatives as antitumor agents with enhanced selectivity towards either of the two molecular targets.
Keywords: Antitumor, cell lines, docking, EGFR, ELISA, MTT assay, topo 1, quinoline.
Graphical Abstract
[1]
Yarbro, C.H.; Wujcik, D.; Gobel, B.H. Cancer nursing: Principles and practice; Jones and Bartlett Publishers: Sudbury, Mass., 2011.
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin., 2015, 65, 5-29.
[3]
Dubey, P.; Srinivas Rao, S.; Aparna, V. Synthesis of some novel 3-(2-chloro-3-quinolyl)-5-phenyl [1, 3] thiazolo [2, 3-c][1, 2, 4] triazoles. Heterocycl. Commun., 2003, 9, 281-286.
[4]
Mital, A.; Negi, V.S.; Ramachandran, U. Synthesis and antimycobacterial activities of certain trifluoromethyl-aminoquinoline derivatives. Arkivoc, 2006, 10, 220-227.
[5]
Pandey, V.; Tusi, S.; Misra, R.; Shukla, R. A chemical strategy for the construction of quinoline isoquinoline core units., 2010.
[6]
Pokalwar, R.U.; Hangarge, R.V.; Maske, P.V.; Shingare, M.S. Synthesis and antibacterial activities of α-hydroxyphosphonates and α-acetyloxyphosphonates derived from 2-chloroquinoline-3-carbaldehyde. Arkivoc, 2006, 11, 196-204.
[7]
Srivastava, A.; Chandra, A.; Singh, R. Thiophene-fused quinoline analogues: facile synthesis of 3-amino-2-cyanothieno [2, 3-b] quinolines from 2-chloro-3-cyanoquinolines. Ind J. Chem., 2005, 44B, 2077-2081.
[8]
Foley, M.; Tilley, L. Quinoline antimalarials: Mechanisms of action and resistance and prospects for new agents. Pharmacol. Ther., 1998, 79, 55-87.
[9]
Desai, N.C.; Dodiya, A.; Shihory, N. Synthesis and antimicrobial activity of novel quinazolinone-thiazolidine-quinoline compounds. J. Saudi Chem. Soc., 2013, 17, 259-267.
[10]
Eswaran, S.; Adhikari, A.V.; Chowdhury, I.H.; Pal, N.K.; Thomas, K.D. New quinoline derivatives: Synthesis and investigation of antibacterial and antituberculosis properties. Eur. J. Med. Chem., 2010, 45, 3374-3383.
[11]
Rossiter, S.; Peron, J.M.; Whitfield, P.J.; Jones, K. Synthesis and anthelmintic properties of arylquinolines with activity against drug-resistant nematodes. Bioorg. Med. Chem. Lett., 2005, 15, 4806-4808.
[12]
Kumar, H.; Devaraji, V.; Joshi, R.; Jadhao, M.; Ahirkar, P.; Prasath, R.; Bhavana, P.; Ghosh, S.K. Antihypertensive activity of a quinoline appended chalcone derivative and its site specific binding interaction with a relevant target carrier protein. RSC Advances, 2015, 5, 65496-65513.
[13]
Fernandez-Bachiller, M.I.; Perez, C.; Gonzalez-Munoz, G.C.; Conde, S.; Lopez, M.G.; Villarroya, M.; Garcia, A.G.; Rodriguez-Franco, M.I. Novel tacrine-8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimer’s disease, with neuroprotective, cholinergic, antioxidant, and copper-complexing properties. J. Med. Chem., 2010, 53, 4927-4937.
[14]
Magda, A.; Massoud, M.A.; Tantawy, A.S.; Nasr, M.N.; Barghash, A.E-D.M.; Abou-Zeid, L.A. Synthesis and biological evaluation of new unsaturated derivatives of cyclic compounds as potent antioxidant agent. Der. Pharma. Chemica., 2012, 5, 1785-1797.
[15]
El-Gazzar, A.B.A.; Youssef, M.M.; Youssef, A.M.S.; Abu-Hashem, A.A.; Badria, F.A. Design and synthesis of azolopyrimidoquinolines, pyrimidoquinazolines as anti-oxidant, anti-inflammatory and analgesic activities. Eur. J. Med. Chem., 2009, 44, 609-624.
[16]
El-Emam, A.A.; Massoud, M.A.; El-Bendary, E.R.; El-Sayed, M.A. Synthesis of certain 6-(arylthio) uracils and related derivatives as potential antiviral agents. Bull. Korean Chem. Soc., 2004, 25, 991-996.
[17]
RohitKumar, H.G.; Asha, K.R.; Kiran Kumar Inamdar, L.S.; Rao, G.M. Cell cycle arrest and induction of apoptosis in colon adenocarcinoma cells by a DNA intercalative quinoline derivative, 4-morpholinopyrimido [4′,5′:4,5] selenolo (2,3-b) quinoline. Nucleosi. Nucleoti. Nucleic Acid., 2015, 34, 525-543.
[18]
Borgstrom, P.; Torres Filho, I.P.; Hartley-Asp, B. Inhibition of angiogenesis and metastases of the Lewis-lung cell carcinoma by the quinoline-3-carboxamide, Linomide. Anticancer Res., 1995, 15, 719-728.
[19]
Afzal, O.; Kumar, S.; Haider, M.R.; Ali, M.R.; Kumar, R.; Jaggi, M.; Bawa, S. A review on anticancer potential of bioactive heterocycle quinoline. Eur. J. Med. Chem., 2015, 97, 871-910.
[20]
Arafa, R.K.; Hegazy, G.H.; Piazza, G.A.; Abadi, A.H. Synthesis and in vitro antiproliferative effect of novel quinoline-based potential anticancer agents. Eur. J. Med. Chem., 2013, 63, 826-832.
[21]
Musiol, R. An overview of quinoline as a privileged scaffold in cancer drug discovery. Expert Opin. Drug Discov., 2017, 12, 583-597.
[22]
Samuelsson, G. Drugs of Natural Origin: A Textbook of Pharmacognosy, 5th ed; Swedish Pharmaceutical Press: Stockholm, Sweden, 2004.
[23]
Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Wang, Y.; Zhao, J.; Jia, S.; Herich, J.; Labreque, D.; Storer, R.; Meerovitch, K.; Bouffard, D.; Rej, R.; Denis, R.; Blais, C.; Lamothe, S.; Attardo, G.; Gourdeau, H.; Tseng, B.; Kasibhatla, S.; Cai, S.X. Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 1. Structure-activity relationships of the 4-aryl group. J. Med. Chem., 2004, 47, 6299-6310.
[24]
Kemnitzer, W.; Kasibhatla, S.; Jiang, S.; Zhang, H.; Zhao, J.; Jia, S.; Xu, L.; Crogan-Grundy, C.; Denis, R.; Barriault, N.; Vaillancourt, L.; Charron, S.; Dodd, J.; Attardo, G.; Labrecque, D.; Lamothe, S.; Gourdeau, H.; Tseng, B.; Drewe, J.; Cai, S.X. Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 2. Structure–activity relationships of the 7- and 5-, 6-, 8-positions. Bioorg. Med. Chem. Lett., 2005, 15, 4745-4751.
[25]
Patil, S.A.; Patil, R.; Pfeffer, L.M.; Miller, D.D. Chromenes: Potential new chemotherapeutic agents for cancer. Future Med. Chem., 2013, 5, 1647-1660.
[26]
Sonsona, I.G.; Marqués-López, E.; Herrera, R.P. Enantioselective organocatalyzed synthesis of 2-amino-3-cyano-4H-chromene derivatives. Symmetry , 2015, 7, 1519-1535.
[27]
Lu, X.; Dong, G.; Zheng, Y.; Zhang, C.; Qiu, Y.; Lua, T.; Zhou, X. Synthesis and anticancer study of novel 4H-chromen derivatives. Anticancer. Agents Med. Chem., 2017, 17, 1070-1083.
[28]
Mohareb, R.; Moustafa, H. Use of 2-aminoprop-1-ene-1, 1, 3-tricarbonitrile for the synthesis of tetrahydronaphthalene, hexahydroisoquinoline and hexahydrocinnoline derivatives with potential antitumor activities. Acta Pharmaceutica., 2011, 61, 51-62.
[29]
Aoki, S.; Watanabe, Y.; Sanagawa, M.; Setiawan, A.; Kotoku, N.; Kobayashi, M.; Cortistatins, A. B, C, and D, Anti-angiogenic steroidal alkaloids, from the marine sponge corticium simplex. J. Am. Chem. Soc., 2006, 128, 3148-3149.
[30]
Meth-Cohn, O.; Narine, B.; Tarnowski, B. A versatile new synthesis of quinolines and related fused pyridines, Part 5. The synthesis of 2-chloroquinoline-3-carbaldehydes. J. Chem. Soc., 1981, 1520-1530.
[31]
Jay, P.; Nirmal, M.P.P.; Ranjan, G.P. Microwave-assisted synthesis of some new biquinoline compounds catalyzed by DMAP and their biological activities. Ind J. Chem., 2009, 48B, 712-717.
[32]
Zonouz, A.; Eskandari, I.; Notash, B. An efficient and green procedure for the synthesis of highly substituted polyhydronaphthalene derivatives via a one-pot, multi-component reaction in aqueous media. Curr. Chem. Lett., 2015, 4, 85-92.
[33]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65, 55-63.
[34]
Denizot, F.; Lang, R. Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J. Immunol. Methods, 1986, 89, 271-277.
[35]
Mauceri, H.J.; Hanna, N.N.; Beckett, M.A.; Gorski, D.H.; Staba, M.J.; Stellato, K.A.; Bigelow, K.; Heimann, R.; Gately, S.; Dhanabal, M.; Soff, G.A.; Sukhatme, V.P.; Kufe, D.W.; Weichselbaum, R.R. Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature, 1998, 394, 287-291.
[36]
Giovannetti, E.; Lemos, C.; Tekle, C.; Smid, K.; Nannizzi, S.; Rodriguez, J.A.; Ricciardi, S.; Danesi, R.; Giaccone, G.; Peters, G.J. Molecular mechanisms underlying the synergistic interaction of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, with the multitargeted antifolate pemetrexed in non-small-cell lung cancer cells. Mol. Pharmacol., 2008, 73, 1290-1300.
[38]
Volpe, G.; Draisci, R.; Palleschi, G.; Compagnone, D. 3, 3′, 5, 5′-Tetramethylbenzidine as electrochemical substrate for horseradish peroxidase based enzyme immunoassays. A comparative study. Analyst , 1998, 123, 1303-1307.
[39]
Kiianitsa, K.; Maizels, N. Ultrasensitive isolation, identification and quantification of DNA-protein adducts by ELISA-based RADAR assay. Nucleic Acids Res., 2014, 42, e108.
[40]
Hayakawa, I.; Hasegawa, M.; Takehara, K.; Sato, S. Anti-DNA topoisomerase IIalpha autoantibodies in localized scleroderma. Arthritis Rheum., 2004, 50, 227-232.
[41]
Buck, E.; Eyzaguirre, A.; Brown, E.; Petti, F.; McCormack, S.; Haley, J.D.; Iwata, K.K.; Gibson, N.W.; Griffin, G. Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol. Cancer Ther., 2006, 5, 2676-2684.
[42]
Lawrence, H.R.; Mahajan, K.; Luo, Y.; Zhang, D.; Tindall, N.; Huseyin, M.; Gevariya, H.; Kazi, S.; Ozcan, S.; Mahajan, N.P. Development of novel ACK1/TNK2 inhibitors using a fragment-based approach. J. Med. Chem., 2015, 58, 2746-2763.
[43]
Staker, B.L.; Hjerrild, K.; Feese, M.D.; Behnke, C.A.; Burgin, A.B., Jr; Stewart, L. The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc. Natl. Acad. Sci. USA, 2002, 99, 15387-15392.
[44]
Stamos, J.; Sliwkowski, M.X.; Eigenbrot, C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J. Biol. Chem., 2002, 277, 46265-46272.
[45]
Kidwai, M.; Saxena, S.; Rahman, K.M.K.; Thukral, S.S. Aqua mediated synthesis of substituted 2-amino-4H-chromenes and in vitro study as antibacterial agents. Bioorg. Med. Chem. Lett., 2005, 15, 4295-4298.
[46]
Kidwai, M.; Poddar, R. Transesterification of chromenes employing immobilized lipase in ionic liquids. Catal. Lett., 2008, 124, 311.
[47]
Paplal, B.; Nagaraju, S.; Veerabhadraiah, P.; Sujatha, K.; Kanvah, S.; Kumar, B.V.; Kashinath, D. Recyclable Bi 2 WO 6-nanoparticle mediated one-pot multicomponent reactions in aqueous medium at room temperature. RSC Advances, 2014, 4, 54168-54174.
[48]
Heravi, M.M.; Hosseinnejad, T.; Faghihi, Z.; Shiri, M.; Vazinfard, M. Synthesis of 2-amino-3-cyano 4-H-chromenes containing quinoline in water: Computational study on substituent effects. J. Iran. Chem. Soc., 2017, 14, 823-832.
[49]
Gelfand, R.; Vernet, D.; Bruhn, K.; Vadgama, J.; Gonzalez-Cadavid, N.F. Long-term exposure of MCF-12A normal human breast epithelial cells to ethanol induces epithelial mesenchymal transition and oncogenic features. Int. J. Oncol., 2016, 48, 2399-2414.
[50]
Kollmannsberger, C.; Mross, K.; Jakob, A.; Kanz, L.; Bokemeyer, C. Topotecan-a novel topoisomerase I inhibitor: Pharmacology and clinical experience. Oncology, 1999, 56, 1-12.
[51]
Kiianitsa, K.; Maizels, N. A rapid and sensitive assay for DNA-protein covalent complexes in living cells. Nucleic Acids Res., 2013, 41, 21.
[52]
Sasaki, T.; Hiroki, K.; Yamashita, Y. The role of epidermal growth factor receptor in cancer metastasis and microenvironment. Biomed Res. Int., 2013, 2013, 8.
[53]
Schettino, C.; Bareschino, M.A.; Ricci, V.; Ciardiello, F. Erlotinib: An EGF receptor tyrosine kinase inhibitor in non-small-cell lung cancer treatment. Expert Rev. Respir. Med., 2008, 2, 167-178.
[54]
Bryce, A.H.; Borad, M.J.; Egan, J.B.; Condjella, R.M.; Liang, W.S.; Fonseca, R.; McCullough, A.E.; Hunt, K.S.; Ritacca, N.R.; Barrett, M.T.; Patel, M.D.; Young, S.W.; Silva, A.C.; Ho, T.H.; Halfdanarson, T.R.; Stanton, M.L.; Cheville, J.; Swanson, S.; Schneider, D.E.; McWilliams, R.R.; Baker, A.; Aldrich, J.; Kurdoglu, A.; Izatt, T.; Christoforides, A.; Cherni, I.; Nasser, S.; Reiman, R.; Cuyugan, L.; McDonald, J.; Adkins, J.; Mastrian, S.D.; Von Hoff, D.D.; Craig, D.W.; Stewart, A.K.; Carpten, J.D. Comprehensive genomic analysis of metastatic mucinous urethral adenocarcinoma guides precision oncology treatment: Targetable EGFR amplification leading to successful treatment with erlotinib. Clin. Genitourin. Cancer, 2016.
Related Journals
Anti-Cancer Agents in Medicinal Chemistry
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
Current Computer-Aided Drug Design
Current Bioactive Compounds
Current Cancer Drug Targets
Combinatorial Chemistry & High Throughput Screening
Current Cancer Therapy Reviews
Current Diabetes Reviews
Current Drug Safety
Current Drug Targets
Related Books
Drug Addiction Mechanisms in the Brain
Software and Programming Tools in Pharmaceutical Research
Objective Pharmaceutics: A Comprehensive Compilation of Questions and Answers for Pharmaceutics Exam Prep
Medicinal Chemistry of Drugs Affecting Cardiovascular and Endocrine Systems
Medicinal Plants, Phytomedicines and Traditional Herbal Remedies for Drug Discovery and Development against COVID-19
Advanced Pharmacy
Plant-derived Hepatoprotective Drugs
The Role of Chromenes in Drug Discovery and Development
New Avenues in Drug Discovery and Bioactive Natural Products
Practice and Re-Emergence of Herbal Medicine
Article Metrics
39
4