Design, Synthesis, Anti-Proliferative Evaluation and Cell Cycle Analysis of Hybrid 2-Quinolones

Author(s): Heba A.E. Mohamed*, Hossa F. Al-Shareef

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 9 , 2019

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Graphical Abstract:


Background: Quinolones are a significant group of nitrogen heterocyclic compounds that exist in therapeutic agents, alkaloids, and synthetic small molecules that have important biological activities. A wide range of quinolones have been used as antituberculosis, antibacterial, anti-malarial, antifungal, anticonvulsant, anticancer agents and urease inhibitors.

Methods: Ethyl 3,3-disubstituted-2-cyano propionates containing hybride quinolones derivatives were synthesized by the reaction of 1-amino-7-hydroxy-4-methylquinolin-2(1H)-one and its dibromo derivative with α, β-unsaturated carbonyl in ethanol.

Results: A novel series of hybrid 2-quinolone derivatives was designed and synthesized. The compounds structures were confirmed using different spectroscopic methods and elemental analysis. The cytotoxic activities of all the compounds were assessed against HepG2 cell line in comparison with doxorubicin as a standard drug.

Conclusion: Most compounds revealed superior anti-proliferative activity than the standard. Compound 4b, is the most active compound (IC50 = 0.39mM) compared with doxorubicin (IC50 = 9.23mM). DNA flow cytometric analysis of compound 4b showed cell cycle arrest at G2/M phase with a concomitant increase of cells in apoptotic phase. Dual annexin-V/ propidium iodide staining assay of compound 4b revealed that the selected candidate increased the apoptosis of HepG-2 cells more than control.

Keywords: HepG2 cell line, α, β-unsaturated carbonyl, DNA flow cytometric analysis, apoptosis, Dual annexin-V-IP, DNA immunofluorescence.

Bhatti, H.S.; Seshadri, S. Chromophoric potential of the 4(3H)‐quinazolinones. Color. Technol., 2004, 120(3), 101-107.
Blunt, J.W.; Cop, B.R.; Munro, M.H.G.; Northcot, P.T.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep., 2005, 22, 15-61.
Marella, A.; Tanwar, O.P.; Ali, M.R.; Srivastava, S.; Akhteer, M.; Shaquiquzzaman, M.; Alam, M.M. Quinoline: A versatile heterocyclic. Saudi Pharm. J., 2013, 21, 1-12.
Khokra, S.L. Jyoti; Chetan; Kaushik, P.; Alam, M.M.; Zaman, M.S.; Ahmad, A.; Khan, S.A.; Husain, A. Quinoline based furanones and their nitrogen analogues: Docking, synthesis and biological evaluation. Saudi Pharm. J., 2016, 24(6), 705-717.
Savegnago, L.; Vieria, A.I.; Seus, N.; Goldani, B.S.; Castro, M.R.; Lenardao, E.J.; Alves, D. Synthesis and antioxidant properties of novel quinoline–chalcogenium compounds. Tetrahedron Lett., 2013, 54, 40-44.
Afzal, O.; Kumar, S.; Haider, M.R.; Ali, M.R.; Kumar, R.; Jaggi, M.; Bawa, S. Review on anticancer potential of bioactive heterocycle quinolone. Eur. J. Med. Chem., 2015, 97, 871-910.
Franck, X.; Fournet, A.; Prina, E.; Mahieux, R.; Hoquemiller, R.; Figadere, B. Biological evaluation of substituted quinolones. Bioorg. Med. Chem. Lett., 2004, 14, 3635-3638.
Founet, A.; Mahieux, R.; Fakhfakh, M.A.; Franck, X.; Hocquemiller, R.; Figadere, B. Substituted quinolines induce inhibition of proliferation of HTLV-1 infected cells. Bioorg. Med. Chem. Lett., 2003, 13, 891-894.
Kumar, S.; Bawa, S.; Gupta, H. Biological activities of quinoline derivatives. Mini Rev. Med. Chem., 2009, 9(14), 1648-1654.
Mahajan, A.; Kremer, L.; Louw, S.; Guéradel, Y.; Chibale, K.; Biot, C. Synthesis and in vitro antitubercular activity of ferrocene-based hydrazones. Bioorg. Med. Chem. Lett., 2011, 21, 2866-2868.
Eswaran, S.; Adhikari, A.V.; Chowdhury, I.H.; Pal, N.K.; Thomas, K.D. New quinolone derivatives: Synthesis and investigation of antibacterial and antituberculosis properties. Eur. J. Med. Chem., 2010, 45(8), 3374-3383.
Wise, R.; Andrews, J.M.; Edwards, L.J. In vitro activity of Bay 09867, a new quinoline derivative, compared with those of other antimicrobial agents. Antimicrob. Agents Chemother., 1983, 23(4), 559-564.
Eswaran, S.; Adhikari, A.V.; Pal, N.K.; Chowdhury, I.H. Design and synthesis of some new quinoline-3-carbohydrazone derivatives as potential antimycobacterial agents. Bioorg. Med. Chem. Lett., 2010, 20(3), 1040-1044.
Upadhayaya, R.S.; Vandavasi, J.K.; Vasireddy, N.R.; Sharma, V.; Dixit, S.S.; Chattopadhyaya, J. Design, synthesis, biological evaluation and molecular modelling studies of novel quinoline derivatives against mycobacterium tuberculosis. Bioorg. Med. Chem., 2009, 17(7), 2830-2841.
Sureshkumar, B.; Mary, Y.S.; Panicker, C.Y.; Suma, S.; Armakovic´, S.; Armakovic´, S.J.; Alsenoy, C.V.; Narayan, B. Quinoline derivatives as possible lead compounds for anti-malarial drugs: Spectroscopic, DFT and MD study. Arab. J. Chem., 2017. (In Press)
Musiol, R.; Jampilek, J.; Buchta, V.; Silva, L.; Niedbala, H.; Podeszwa, B.; Palka, A.; Majerz-Maniecka, K.; Oleksyn, B.; Polanski, J. Antifungal properties of new series of quinoline derivatives. Bioorg. Med. Chem., 2006, 14(10), 3592-3598.
Ryu, C.K.; Lee, J.Y.; Jeong, S.H.; Nho, J.H. Synthesis and antifungal activity of 1H-pyrrolo[3,2-g]quinoline-4,9-diones and 4,9-dioxo-4,9-dihydro-1H-benzo[f]indoles. Bioorg. Med. Chem. Lett., 2009, 19(1), 146-148.
Hoogkamp-Korstanje, J.A. Comparative in vitro activity of five quinoline derivatives and five other antimicrobial agents used in oral therapy. Eur. J. Clin. Microbiol., 1984, 3(4), 333-338.
Thumar, N.J.; Patel, M.P. Synthesis and antimicrobial activity of some new N-Substituted quinoline derivatives of 1H-Pyrazole. Arch. Pharm. Chem. Life Sci, 2011, 344(2), 91-101.
Abdel-Wadood, F.K.; Abdel-Monem, M.I.; Fahmy, A.M.; Ahmed, A.G. Synthesis, reactions, and biological activities of some new thieno[3,2-c]quinoline and pyrrolo[3,2-c]quinoline derivatives. Arch. Pharm. Chem. Life Sci, 2014, 347(2), 142-152.
El-sayed, O.A.; Al-Bassam, B.A.; Hussien, M.E. Synthesis of some novel quinoline-3-carboxylic acids and pyrimidoquinoline derivatives as potential antimicrobial agents. Arch. Pharm. Pharm. Med. Chem, 2002, 335(9), 403-410.
Wei, C.; Li, F.; Zhao, L.; Quan, Z. Synthesis of 2-substituted-7-heptyloxy-4,5-dihydro-[1,2,4]-triazolo[4,3-a]quinolin-1(2H)-ones with anticonvulsant activity. Arch. Pharm. Chem. Life Sci, 2007, 340(9), 491-495.
Xiao, Z.; Lei, F.; Chen, X.; Wang, X.; Cao, L.; Ye, K.; Zhu, W.; Xu, S. Design, synthesis, and antitumor evaluation of quinolone-imidazole derivatives. Arch. Pharm. Chem. Life Sci, 2018, 351(6)e1700407
Rashad, A.E.; El-Sayed, W.A.; Mohamed, A.M.; Ali, M.M. Synthesis of new quinoline derivatives as inhibitors of human tumor cells growth. Arch. Pharm. Chem. Life Sci, 2010, 343(8), 440-448.
Miri, R.; Motamedi, R.; Rezaei, M.R.; Firuzi, O.; Javidnia, A.; Shafiee, A. Design, synthesis and evaluation of cytotoxicity of novel chromeno[4,3-b]quinoline derivatives. Arch. Pharm. Chem. Life Sci, 2011, 344(2), 111-118.
Warshakoon, N.C.; Sheville, J.; Bhatt, R.T.; Ji, W.; Mendez-Andino, J.L.; Meyers, K.M.; Kim, N.; Wos, J.A.; Mitchell, C.; Paris, J.L.; Piney, B.B.; Reizes, O.; Hu, X.E. Design and synthesis of substituted quinolines as novel and selective melanin concentrating hormone antagonists as anti-obesity agents. Bioorg. Med. Chem. Lett., 2006, 16(19), 5207-5211.
Sun, X.; Wei, C.; Chai, K.; Piao, H.; Quan, Z. Synthesis and anti-inflammatory activity evaluation of novel 7-alkoxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3 a]quinolones. Arch. Pharm. Chem. Life Sci, 2008, 341(5), 288-293.
Chen, S.; Chen, R.; He, M.; Pang, R.; Tan, Z.; Yang, M. Design, synthesis, and biological evaluation of novel quinoline derivatives as HIV-1 Tat-TAR interaction inhibitors. Bioorg. Med. Chem., 2009, 17(5), 1948-1956.
Li, G.X.; Liu, Z.Q.; Luo, X.Y. Dichloro-4-quinolinol-3-carboxylic acid: synthesis and antioxidant abilities to scavenge radicals and to protect methyl linoleate and DNA. Eur. J. Med. Chem., 2010, 45(5), 1821-1827.
Menteşe, E.; Akyüz, G.; Yılmaz, F.; Baltaş, N.; Emirik, M. Synthesis of some novel quinazolin-4(3H)-one hybrid molecules as potent urease inhibitors. Arch. Pharm. Chem. Life Sci, 2018, 351(2)e1800182
Abe, H.; Kawada, M.; Hiroyuki, I.; Ohba, S.; Nomato, A.; Watanabe, T.; Shibasaki, M. Synthesis of intervenolin, an antitumor natural quinolone with unusual substituents. Org. Lett., 2013, 15(9), 2124-2127.
Chen, P.C.; Lu, P.H.; Pan, S.L.; Teng, C.M.; Kuo, S.C.; Lin, T.P.; Ho, P.F.; Huang, P.C.; Guh, J.H. Quinolone analogue inhibits tubulin polymerization and induces apoptosis via Cdk1-involved signaling pathways. Biochem. Pharmacol., 2007, 74(1), 10-19.
Joseph, B.; Darro, F.; Behard, A.; Lesur, B.; Collignon, F.; Decaestecker, C.; Frydman, A.; Guill-Aumet, G.; Kiss, R. 3-Aryl-2-quinolone derivatives: Synthesis and characterization of in vitro and in vivo antitumor effects with emphasis on a new therapeutical target connected with cell migration. J. Med. Chem., 2002, 45(12), 2543-2555.
Andricopulo, A.D.; Salum, L.B.; Abrham, D.J. Structure-based drug design strategies in medicinal hemistry. Curr. Top. Med. Chem., 2009, 9, 771-790.
Roviello, G.N. Novel insights into nucleoamino acids: Biomolecular recognition and aggregation studies of a thymine-conjugated L-phenyl alanine. Amino Acids, 2018, 50(7), 933-941.
Musumeci, D.; Roviello, V.; Roviello, G.N. DNA- and RNA-binding ability of oligoDapT, a nucleobase-decorated peptide, for biomedical applications. Int. J. Nanomedicine, 2018, 13, 2613.
Platella, C.; Guida, S.; Bonmassar, L.; Aquino, A.; Bonmassar, E.; Ravagnan, G.; Montesarchio, D.; Roviello, G.N.; Musumeci, D.; Fuggetta, M.P. Antitumour activity of resveratrol on human melanoma cells: A possible mechanism related to its interaction with malignant cell telomerase. Biochim. Biophys. Acta, Gen. Subj., 2017, 1861(11 Pt A), 2843-2851.
Roviello, G.N.; Iannitti, R.; Palumbo, R.; Simonyan, H.; Vicidomini, C.; Roviello, V. Lac-L-TTA, a novel lactose-based amino acid-sugar conjugate for anti-metastatic applications. Amino Acids, 2017, 49(8), 1347-1353.
Roviello, G.N.; Vicidomini, C.; Costanzo, V.; Roviello, V. Nucleic acid binding and other biomedical properties of artificial oligolysines. Int. J. Nanomedicine, 2016, 11, 5897-5904.
Roviello, G.N.; Iannitti, R.; Roviello, V.; Palumbo, R.; Simonyan, H.; Vicidomini, C. Synthesis and biological evaluation of a novel Amadori compound. Amino Acids, 2017, 49(2), 327-335.
Giovanni, N.R.; Giorgia, O.; Antonella, D.N.; Nicola, B.; Gennaro, P. Synthesis, self-assembly-behavior and biomolecular recognition properties of thyminyl dipeptides. Arab. J. Chem., (2018). In Press
Bansal, Y.; Silakari, O. Multifunctional compounds: Smart molecules for multifactorial diseases. Eur. J. Med. Chem., 2014, 76, 31-42.
Geldenhuys, W.J.; Youdim, M.B.; Carroll, R.T.; Van der Schyf, C.J. The emergencey of designedmultiple ligands for neurodegenerative disorders. Prog. Neurobiol., 2011, 94(4), 347-359.
Aly, H.M.; Saleh, N.M.; El Hady, H.A. Design and synthesis of some new thiophene, thienopyrimidine and thienothiadiazine derivatives of antipyrine as potential antimicrobial agents. Eur. J. Med. Chem., 2011, 46(9), 4566-4572.
Hussein, E.; Al-Shareef, H.F.; Aboellil, A.H.; Elhady, H.A. Synthesis of some novel 6′-(4-chlorophenyl)-3,4′-bipyridine-3′-carbonitriles: Assessment of their antimicrobial and cytotoxic activity. Z. Naturforsch, 2015, 70(11), 783.
Alshareef, H.F.; Mohamed, H.A.; Salaheldin, A. Synthesis and biological evaluation of new tacrine analogues under microwave irradiation. Chem. Pharm. Bull., 2017, 65(8), 732-738.
Elhady, H.A.; El-Sayed, R.; Al-Nathali, H.S. Design, synthesis and evaluation of anticancer activity of novel 2-thioxoimidazolidin-4-one derivatives bearing pyrazole, triazole and benzoxazole moieties. Chem. Cent. J., 2018, 12, 51.
Pardahan, A.; Vishwakarma, S.K. Synthesis, Characterisation and antimicrobial activity of Schiff base of 7-Hydroxy-3-Methyl-2-Quinolone. Inter. Theor. Appl. Sci, 2018, 10(1), 40-43.
Al-Bayati, R.I.H.; Mahdi, F.R. Synthesis of novel 2-quinolone derivatives. Afr. J. Pure Appl. Chem., 2010, 4(10), 228-232.
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
Gomha, S.M.; Riyadh, S.M.; Mahmmoud, E.A.; Elaasser, M.M. Synthesis and anticancer activities of thiazoles, 1,3-thiazines, and thiazolidine using chitosan-grafted-poly(vinyl pyridine) as basic catalyst. Heterocycles, 2015, 91(6), 1227.
Bolaños, G.J.M.; Balao da Silva, C.M.; Muñoz, M.P.; Rodríguez, M.A.; Dávila, P.M.; Rodríguez-Martínez, H.; Aparicio, I.M.; Tapia, J.A.; Ortega Ferrusola, C.; Peña, F.J. Phosphorylated AKT preserves stallion sperm viability and motility by inhibiting caspases 3 and 7. Reproduction, 2014, 148(2), 221-235.
Zaki, I.; Abdelhameid, M.K.; El-Deen, I.M.; Abdel Hady, A.A.; Ashmawy, A.M.; Mohamed, K.O. Design, synthesis and screening of 1, 2, 4-triazinone derivatives as potential antitumor agents with apoptosis inducing activity on MCF-7 breast cancer cell line. Eur. J. Med. Chem., 2018, 156, 563-579.
Mohamed, K.O.; Zaki, I.; El-Deen, I.M.; Abdel-Hameid, M.K. A new class of diamide scaffold: Design, synthesis and biological evaluation as potent antimitotic agents, tubulin polymerization inhibition and apoptosis inducing activity studies. Bioorg. Chem., 2019, 84, 399-409.

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Article Details

Year: 2019
Published on: 22 October, 2019
Page: [1132 - 1140]
Pages: 9
DOI: 10.2174/1871520619666190319142934
Price: $65

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