Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Research Article

Hybridized Quinoline Derivatives as Anticancer Agents: Design, Synthesis, Biological Evaluation and Molecular Docking

Author(s): Mohamed R. Selim, Medhat A. Zahran, Amany Belal*, Moustafa S. Abusaif*, Said A. Shedid, Ahmed B.M. Mehany, Gameel A.M. Elhagali and Yousry A. Ammar*

Volume 19, Issue 4, 2019

Page: [439 - 452] Pages: 14

DOI: 10.2174/1871520618666181112121058

Price: $65

Abstract

Objective: Conjugating quinolones with different bioactive pharmacophores to obtain potent anticancer active agents.

Methods: Fused pyrazolopyrimidoquinolines 3a-d, Schiff bases 5, 6a-e, two hybridized systems: pyrazolochromenquinoline 7 and pyrazolothiazolidinquinoline 8, different substituted thiazoloquinolines 13-15 and thiazolo[3,2-a]pyridine derivatives 16a-c were synthesized. Their chemical structures were characterized through spectral and elemental analysis, cytotoxic activity on five cancer cell lines, caspase-3 activation, tubulin polymerization inhibition and cell cycle analysis were evaluated.

Results: Four compounds 3b, 3d, 8 and 13 showed potent activity than doxorubicin on HCT116 and three compounds 3b, 3d and 8 on HEPG2. These promising derivatives showed increase in the level of caspase-3. The trifloromethylphenyl derivatives of pyrazolopyrimidoquinolines 3b and 3d showed considerable tubulin polymerization inhibitory activity. Both compounds arrested cell cycle at G2/M phase and induced apoptosis.

Conclusion: Compounds 3b and 3d can be considered as promising anticancer active agents with 70% of colchicine activity on tubulin polymerization inhibition and represent hopeful leads that deserve further investigation and optimization.

Keywords: Quinoline, pyrazolone, chromene, thizolidinone, pyridine, pyrimidine, anticancer, caspase-3, tubulin polymerization, cell cycle analysis.

Graphical Abstract
[1]
Ma, L.Y.; Wang, B.; Pang, L.P.; Zhang, M.; Wang, S.Q.; Zheng, Y.C.; Shao, K.P.; Xue, D.Q.; Liu, H.M. Design and synthesis of novel 1,2,3-triazole-pyrimidine-urea hybrids as potential anticancer agents. Bioorg. Med. Chem. Lett., 2015, 25(5), 1124-1128.
[2]
Zwick, E.; Bange, J.; Ullrich, A. Receptor tyrosine kinase signalling as a target for cancer intervention strategies. Endocr. Relat. Cancer, 2001, 8(3), 161-173.
[3]
Duan, Y.C.; Zheng, Y.C.; Li, X.C.; Wang, M.M.; Ye, X.W.
Guan, Y.Y.; Liu, G.Z.; Zheng, J.X.; Liu, H.M. Design, synthesis and antiproliferative activity studies of novel 1,2,3-triazole-dithiocarbamate-urea hybrids. Eur. J. Med. Chem., 2013, 64, 99-110.
[4]
Ilango, K.; Valentina, P.; Subhakar, K.; Kathiravan, M.K. Design, synthesis and biological screening of 2, 4-disubstituted quinolines. Austin J. Anal. Pharm. Chem., 2015, 2(4), 1048.
[5]
Firestone, G.; Sundar, S. Anticancer activities of artemisinin and its bioactive derivatives. Expert Rev. Mol. Med., 2009, 11, E32.
[6]
Lu, J.J.; Meng, L.H.; Cai, Y.J.; Chen, Q.; Tong, L.J.; Lin, L.P.; Ding, J. Dihydroartemisinin induces apoptosis in HL-60 leukemia cells dependent of iron and p38 mitogen-activated protein kinase activation but independent of reactive oxygen species. Cancer Biol. Ther., 2008, 7(7), 1017-1023.
[7]
Kouznetsov, V.V.; Rojas, F.A. Méndeza, L.Y.; Gupta, M.P. Simple C-2-substituted quinolines and their anticancer activity. Lett. Drug Des. Discov., 2012, 9, 680-686.
[8]
Afzal, O.; Kumar, S.; Haider, M.R.; Ali, M.R.; Kumar, R.; Jaggi, M.; Bawa, S. A review on anticancer potential of bioactive heterocyclequinoline. Eur. J. Med. Chem., 2015, 97, 871.
[9]
Montoya, A.; Quiroga, J.; Abonia, R.; Derita, M.; Sortino, M.; Ornelas, A.; Zacchino, S.; Insuasty, B. Hybrid molecules containing a 7-chloro-4-aminoquinoline nucleus and a substituted 2-pyrazoline with antiproliferative and antifungal activity. Molecule, 2016, 21, 969.
[10]
Zhuang, L.; Wai, J.S.; Embrey, M.W.; Fisher, T.E.; Egbertson, M.S.; Payne, L.S.; Guare, J.P.; Vacca, J.P.; Hazuda, P.J.; Felock, A.L.; Wolfe, K.A.; Stillmock, M.V.; Witmer, G.; Moyer, W.A.; Schleif, L.J.; Gabryelski, Y.M.; Leonard, J.J.; Lynch, J.; Michelson, S.R.; Young, S.D. Design and synthesis of 8-hydroxy-[1,6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells. J. Med. Chem., 2003, 46(4), 453.
[11]
Shaw, A.Y.; Chang, C.Y.; Hsu, M.Y.; Lu, P.J.; Yang, C.N.; Chen, H.L.; Chern, M.K. Synthesis and structure-activity relationship study of 8-hydroxyquinoline-derived Mannich bases as anticancer agents. Eur. J. Med. Chem., 2010, 45(7), 2860.
[12]
Bakker, P.A.; Ran, L.; Blanco, J. Rhizobacterial salicylate production provokes headaches. Plant Soil, 2014, 382, 1-16.
[13]
Negm, N.A.; Said, M.M.; Morsy, S.M. Synthesis, characterization, surface and biological activity of diquaternary cationic surfactants containing ester linkage. J. Surfactants Deterg., 2005, 13(4), 521.
[14]
Weinberg, E.D.; Moon, J. Malaria and iron: History and review. Drug Metab. Rev., 2009, 41(4), 644.
[15]
Gu, W.; Jin, X.Y.; Li, D.D.; Wang, S.F.; Tao, X.B.; Chen, H. Design, synthesis and in vitro anticancer activity of novel quinoline and oxadiazole derivatives of ursolic acid. Bioorg. Med. Chem. Lett., 2017, 27(17), 4128.
[16]
Moret, V.; Laras, Y.; Cresteil, T.; Aubert, G.; Ping, D.Q.; Di, C.; Requin, C.; Béclin, V.; Peyrot, D.; Allegro, A.; Rolland, F.; Angelis, E.; Gatti, P.; Pierre, E.; Pasquini, L.; Petrucci, E.; Testa, U.; Kraus, J.L. Discovery of a new family of bis-8-hydroxyquinoline substituted benzylamines with pro-apoptotic activity in cancer cells: Synthesis, structure-activity relationship, and action mechanism studies. Eur. J. Med. Chem., 2009, 44(2), 558.
[17]
Jampilek, J.; Dolezal, M.; Kunes, J.; Buchta, V.; Silva, L.; Kralova, K. Quinaldine derivatives: Preparation and biological activity. J. Med. Chem., 2005, 1(6), 591.
[18]
Chang, P.T.; Kung, F.L.; Talekar, R.S.; Chen, C.S.; Lai, S.Y.; Lee, H.Y.; Chern, J.W. An improved screening model to identify inhibitors targeting zinc-enhanced amyloid aggregation. Anal. Chem., 2009, 81(16), 6944-6951.
[19]
Fakhfakh, M.A.; Fournet, A.; Prina, E.; Mouscadet, J.F.; Franck, X.; Hocquemiler, R.; Figadère, B. Synthesis and biological evaluation of substituted quinolines: potential treatment of protozoal and retroviral co-infections. Bioorg. Med. Chem., 2003, 11(23), 5013.
[20]
Jain, S.; Chandra, V.; Jain, P.K.; Pathak, K.; Pathak, D.; Vaidya, A. Comprehensive review on current developments of quinoline-based anticancer agents. Arab. J. Chem., 2016, 2(2), 64-71.
[21]
Bindu, P.J.; Mahadevan, K.M.; Satyanarayan, N.D.; Naik, T.R.R. Synthesis and DNA cleavage studies of novel quinolineoxime esters. Bioorg. Med. Chem. Lett., 2012, 22, 898.
[22]
Broch, S.; Aboab, B.; Anizon, F.; Moreau, P. Synthesis and in vitro antiproliferative activities of quinoline derivatives. Eur. J. Med. Chem., 2010, 45, 1657.
[23]
Srivastava, B.K.R.; Joharapurkar, A.; Raval, S.; Patel, J.Z.; Soni, R.; Raval, P.; Gite, A.; Goswami, A.; Sadhwani, N.; Gandhi, N.; Patel, H.; Mishra, B.; Solanki, M.; Pandey, B.; Jainand, M.P.; Patel, R. Biarylpyrazole inverse agonists at the cannabinoid cb1 receptor: importance of the c-3 carboxamide oxygen/lysine3.28(192) interaction. J. Med. Chem., 2007, 50, 5951.
[24]
Kim, M.; Park, S.B. An improved synthesis of pyrimidine-and pyrazole-based acyclo-C-nucleosides as carbohybrids. Tetrahedron Lett., 2008, 49, 5080.
[25]
Prekupec, S.; Makuc, D.; Plavec, J.; Suman, L.; Kral, M.J.; Pavelic, K.; Balzarin, J.I.; Clercq, E.D.; Mintas, M.; Malic, S. Novel C-6 fluorinated acyclic side chain pyrimidine derivatives: Synthesis, (1)H and (13)C NMR conformational studies, and antiviral and cytostatic evaluations. J. Med. Chem., 2007, 50, 3037.
[26]
Agarwal, A.; Srivastava, K.; Puri, S.K. Chauhan, P.M.S. Synthesis of 2, 4, 6-trisubstituted pyrimidines as antimalarial agents. Bioorg. Med. Chem. Lett., 2005, 13(15), 4645.
[27]
Singh, S.K.; Vobbalareddy, S.; Shivaramakrishna, S.; Krishnamraju, A.; Rajjak, S.A.; Casturi, S.R.; Akhilaband, Y.V.; Raoa, K. Methanesulfonamide group at position-4 of the C-5-phenyl ring of 1,5-diarylpyrazole affords a potent class of cyclooxygenase-2 (COX-2) inhibitors. Bioorg. Med. Chem. Lett., 2004, 14, 1683.
[28]
de-Oliveira, M.R.; Alves, T.R.; Pinto, A.C.; Pereira, H.S.; Leão-Ferreira, L.R.; Moussatché, N.; de-Frugulhetti, I.C.; Ferreira, V.F.; de-Souza, M.C. Synthesis and antiviral activities of new pyrazolo[4,3c] quinolin‐3-ones and their ribonucleoside derivatives. Nucleosides Nucleo. Nuc. Acids, 2004, 23(5), 735.
[29]
Bekhit, A.A.; El-Sayad, O.A.; Aboul-Enein, H.Y.; Siddiqui, Y.M.; Al-Ahdal, M.N. Synthesis of aldehydo-sugar derivatives of pyrazoloquinoline as inhibitors of herpes simplex virus type 1 replication. J. Enzyme Inhib. Med. Chem., 2004, 19, 33.
[30]
Zhang, H.Z.; Claassen, G.; Crogran-Grundy, C.; Tseng, B.; Drewe, J.; Cai, S.X. Discovery and structure-activity relationship of N-phenyl-1H-pyrazolo[3,4-b]quinolin-4-amines as a new series of potent apoptosis inducers. Bioorg. Med. Chem., 2008, 16(1), 222.
[31]
Dai, Y.Q.; Li, D.; Du, X.; Qin, X.; Zhang, H.B.; Yuand, J.X.; Fang, J. Synthesis and biological activities of novel pyrazoleoxime derivatives containing a 2-chloro-5-thiazolyl moiety. Agric. Food Chem., 2008, 56, 10805.
[32]
Ahn, J.H.; Kim, S.J.; Park, W.S.; Cho, S.Y.; Ha, J.D.; Kim, S.S.; Kang, S.K.; Jeong, D.G.; Jung, S.K.; Lee, S.H.; Kim, H.M.; Park, S.K.; Lee, K.H.; Lee, C.W.; Ryu, S.E.; Choi, J.K. Synthesis and biological evaluation of rhodanine derivatives as PRL-3 inhibitors. Bioorg. Med. Chem. Lett., 2006, 16, 2996.
[33]
Wang, S.; Zhao, Y.; Zhang, G.; Ying, X.L.; Zhang, N.; Gong, P. Design, synthesis and biological evaluation of novel 4-thiazolidinones containing indolin-2-one moiety as potential antitumor agent. Eur. J. Med. Chem., 2011, 46, 3509.
[34]
French, K.J.; Schrecengos, R.S.; Lee, B.D.; Zhuang, Y.; Smith, S.N.; Eberly, J.L.; Yun, J.K.; Smith, C.D. Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res., 2003, 63, 5962.
[35]
Cutshall, N.S.; Day, C.O.; Prezhdo, M. Rhodanine derivatives as inhibitors of JSP-1. Bioorg. Med. Chem. Lett., 2005, 15, 3374.
[36]
Geronikaki, A.; Eleftheriou, P.; Vicini, P.; Alam, I.; Dixit, A.; Saxena, A.K. 2-Thiazolylimino/heteroarylimino-5-arylidene-4-thiazolidinones as new agents with SHP-2 inhibitory action. J. Med. Chem., 2008, 51, 5221.
[37]
Zhou, H.Y.; Wu, S.H.; Zhai, S.M.; Liu, A.F.; Sun, Y.; Li, R.S.; Zhang, Y.; Ekins, S.; Swaan, P.W.; Fang, B.L.; Zhang, B.; Yan, B. Design, synthesis, cytoselective toxicity, structure-activity relationships, and pharmacophore of thiazolidinone derivatives targeting drug-resistant lung cancer cells. J. Med. Chem., 2008, 51, 1242.
[38]
Ottana, R.; Carotti, S.; Maccari, R.; Landini, I.; Chiricosta, G.; Caciagli, B.; Vigorita, M.G.; Mini, E. In vitro antiproliferative activity against human colon cancer cell lines of representative 4-thiazolidinones. Part I. Bioorg. Med. Chem. Lett., 2005, 15, 3930.
[39]
Hebat-Allah, S.A.; Al-Marhabi, A.R.M.; Eissa, S.I.; Ammar, Y.A. Molecular modeling studies and synthesis of novel quinoxaline derivatives with potential anticancer activity as inhibitors of c-Met kinase. Bioorg. Med. Chem., 2015, 23, 6560.
[40]
Al-Marhabi, A.R.; Hebat-Allah, S.A.; Ammar, Y.A. Synthesis, characterization and biological evaluation of some quinoxaline derivatives: A promising and potent new class of antitumor and antimicrobial agents. Molecules, 2015, 20, 19805.
[41]
Cai, S.X.; Drewe, J.; Kemnitzer, W. Discovery of 4-aryl-4H-chromenes as potent apoptosis inducers using a cell- and caspase-based Anti-cancer Screening Apoptosis Program (ASAP): SAR studies and the identification of novel vascular disrupting agents. Anticancer. Agents Med. Chem., 2009, 9, 437-456.
[42]
Akhtar, J.; Khan, A.A.; Ali, Z.; Haider, R.; Yar, M.S. Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. Eur. J. Med. Chem., 2017, 125, 143-189.
[43]
Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A. mahon, M.J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenny, S.; Boyd, M.R. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst., 2003, 82, 1107.
[44]
Rudel, T. Caspase inhibitors in prevention of apoptosis. Herz, 1999, 24, 236.
[45]
Ravelli, R.B.; Gigant, B.; Curmi, P.A.; Jourdain, I.; Lachkar, S.; Sobel, A.; Knossow, M. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature, 2004, 428, 198.
[46]
Available at: https://www.rcsb.org/pdb/explore.do?structureId=1SA0 (accessed on 5 Nov 2017).
[47]
Available at: https://www.chemcomp.com/MOE-Molecular_
Operating_Environment.htm (Last accessed on 6 Nov 2017).
[48]
Shehata, A.Z.; Mehany, A.B.; El-Sheikh, T.M. Excretion/ secretion of Lucilia sericata and Chrysomya albiceps (Diptera: Calliphoridae) maggots as potential anticancer agent and kinases inhibitor. N.Y. Sci. J., 2016, 9(12), 95-101.
[49]
[50]
Available at: https://pubchem.ncbi.nlm.nih.gov/compound/31703 (Accessed on 21 May 2018).
[51]
Bonne, D.; Heusele, C.; Simon, C.; Pantaloni, D. 4′,6-Diamidino-2-phenylindole, a fluorescent probe for tubulin and microtubules. J. Biol. Chem., 1985, 260, 2819-2825.
[52]
Lo, K.K.W.; Lee, T.K.M.; Lau, J.S.Y.; Poon, W.L.; Cheng, S.H. Luminescent biological probes derived from ruthenium(II) estradiol polypyridine complexes. Inorg. Chem., 2008, 47, 200.
[53]
Srivastava, A.; Singh, M.K.; Singh, R.M. Pyrazolo-fused quinoline analogues: Synthesis of 1H-pyrazolo [3, 4-b] quinolines and 3-amino-1H-pyrazolo [3, 4-b] quinolines from 3-formyl and 3-cyano-2- chloroquinolines. Indian J. Chem., 2006, 45B(1), 292.
[54]
Elkholy, Y.M.; Morsy, M.A. Facile Synthesis of 5, 6, 7, 8-Tetrahydropyrimido [4, 5-b]-quinoline Derivatives. Molecules, 2006, 11, 890.
[55]
Cheng, L.; Tang, J.; Luo, H.; Jin, X.; Dai, F.; Yang, J.; Qian, Y.; Li, X.; Zhou, B. Antioxidant and antiproliferative activities of hydroxyl-substituted Schiff bases. Bioorg. Med. Chem. Lett., 2010, 20, 2417.
[56]
Bondock, S.; Rabie, R.; Etman, H.A.; Fadda, A.A. Synthesis and antimicrobial activity of some new heterocycles incorporating antipyrine moiety. Eur. J. Med. Chem., 2007, 43, 2122.
[57]
Jain, S.C.; Sinha, J.; Bhagat, S.; Errington, W.; Olsen, C.E. A facile synthesis of novel spiro[indole-pyrazolinyl-thiazolidine]-2,40 –dione. Synth. Commun., 2003, 33, 563.
[58]
Nirmal, J.P.; Patel, M.P.; Patel, R.G.; Nirmal, J.P.; Patel, M.P.; Patel, R.G. Microwave-assisted synthesis of some new biquinoline compounds catalyzed by DMAP and their biological activities. Indian J. Chem., 2009, 48B, 712.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy