Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Author(s): Youstina W. Rizzk*, Ibrahim M. El-Deen, Faten Z. Mohammed, Moustafa S. Abdelhamid and Amgad I.M. Khedr

DOI: 10.2174/1871520619666190930143856

DownloadDownload PDF Flyer Cite As
In Vitro Antitumor Evaluation of Some Hybrid Molecules Containing Coumarin and Quinolinone Moieties

Page: [2010 - 2018] Pages: 9

  • * (Excluding Mailing and Handling)

Abstract

Background: Hybrid molecules furnished by merging two or more pharmacophores is an emerging concept in the field of medicinal chemistry and drug discovery. Currently, coumarin hybrids have attracted the keen attention of researchers to discover their therapeutic capability against cancer.

Objective: The present study aimed to evaluate the in vitro antitumor activity of a new series of hybrid molecules containing coumarin and quinolinone moieties 4 and 5 against four cancer cell lines.

Materials and Methods: A new series of hybrid molecules containing coumarin and quinolinone moieties, 4a-c and 5a-c, were synthesized and screened for their cytotoxicity against prostate PC-3, breast MCF-7, colon HCT- 116 and liver HepG2 cancer cell lines as well as normal breast Hs-371 T.

Results: All the synthesized compounds were assessed for their in vitro antiproliferative activity against four cancer cell lines and several compounds were found to be active. Further in vitro cell cycle study of compounds 4a and 5a revealed MCF-7 cells arrest at G2 /M phase of the cell cycle profile and induction apoptosis at pre-G1 phase. The apoptosis-inducing activity was evidenced by up-regulation of Bax protein together with the downregulation of the expression of Bcl-2 protein. The mechanism of cytotoxic activity of compounds 4a and 5a correlated to its topoisomerase II inhibitory activity.

Conclusion: Hybrid molecules containing coumarin and quinolinone moieties represents a scaffold for further optimization to obtain promising anticancer agents.

Keywords: Hybrid molecules, coumarin, quinolinone, cell cycle analysis, apoptosis, Bcl-2, Bax.

Graphical Abstract

[1]
Zaki, I.; Abdelhameid, M.K.; El-Deen, I.M.; Abdel Wahab, A.H.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.
[http://dx.doi.org/10.1016/j.ejmech.2018.07.003] [PMID: 30025350]
[2]
Belluti, F.; Fontana, G.; Dal Bo, L.; Carenini, N.; Giommarelli, C.; Zunino, F. Design, synthesis and anticancer activities of stilbene-coumarin hybrid compounds: Identification of novel proapoptotic agents. Bioorg. Med. Chem., 2010, 18(10), 3543-3550.
[http://dx.doi.org/10.1016/j.bmc.2010.03.069] [PMID: 20409723]
[3]
Mulakayala, N.; Rambabu, D.; Raja, M.R. M, C.; Kumar, C.S.; Kalle, A.M.; Rama Krishna, G.; Malla Reddy, C.; Basaveswara Rao, M.V.; Pal, M. Ultrasound mediated catalyst free synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-ones leading to novel quinoline derivatives: Their evaluation as potential anti-cancer agents. Bioorg. Med. Chem., 2012, 20(2), 759-768.
[http://dx.doi.org/10.1016/j.bmc.2011.12.001] [PMID: 22202437]
[4]
Fylaktakidou, K.C.; Hadjipavlou-Litina, D.J.; Litinas, K.E.; Nicolaides, D.N. Natural and synthetic coumarin derivatives with anti-inflammatory/antioxidant activities. Curr. Pharm. Des., 2004, 10(30), 3813-3833.
[http://dx.doi.org/10.2174/1381612043382710] [PMID: 15579073]
[5]
Bansal, V.; Sethi, F.; Bansal, G. Coumarin: A potential nucleus for anti-inflammatory molecules. Med. Chem. Res., 2013, 22, 3049-3060.
[http://dx.doi.org/10.1007/s00044-012-0321-6]
[6]
Riveiro, M.E.; Moglioni, A.; Vazquez, R.; Gomez, N.; Facorro, G.; Piehl, L.; de Celis, E.R.; Shayo, C.; Davio, C. Structural insights into hydroxycoumarin-induced apoptosis in U-937 cells. Bioorg. Med. Chem., 2008, 16(5), 2665-2675.
[http://dx.doi.org/10.1016/j.bmc.2007.11.038] [PMID: 18060791]
[7]
Curini, M.; Epifano, F.; Maltese, F.; Marcotillio, M.C.; Gonzales, S.P.; Rodriguez, J.C. Synthesis of collinin, an antiviral coumarin. Aust. J. Chem., 2003, 56, 59-60.
[http://dx.doi.org/10.1071/CH02177]
[8]
Ostrov, D.A.; Hernández Prada, J.A.; Corsino, P.E.; Finton, K.A.; Le, N.; Rowe, T.C. Discovery of novel DNA gyrase inhibitors by high-throughput virtual screening. Antimicrob. Agents Chemother., 2007, 51(10), 3688-3698.
[http://dx.doi.org/10.1128/AAC.00392-07] [PMID: 17682095]
[9]
Gormley, N.A.; Orphanides, G.; Meyer, A.; Cullis, P.M.; Maxwell, A. The interaction of coumarin antibiotics with fragments of DNA gyrase B protein. Biochemistry, 1996, 35(15), 5083-5092.
[http://dx.doi.org/10.1021/bi952888n] [PMID: 8664301]
[10]
Fesik, S.W. Promoting apoptosis as a strategy for cancer drug discovery. Nat. Rev. Cancer, 2005, 5(11), 876-885.
[http://dx.doi.org/10.1038/nrc1736] [PMID: 16239906]
[11]
Sloane, D. Cancer epidemiology in the United States: Racial, social, and economic factors. Methods Mol. Biol., 2009, 471, 65-83.
[http://dx.doi.org/10.1007/978-1-59745-416-2_4] [PMID: 19109775]
[12]
Agarwal, R. Synthesis and biological screening of some novel coumarin derivatives. Biochem. Pharmacol., 2000, 6, 1042-1051.
[13]
Jayashree, B.S.; Manpreet, K.; Aravinda, P. Synthesis, characterisation, antioxidant and anticancer evaluation of novel schiff’s bases of 2-quinolones. Org. Chem., 2012, 52, 11317-11322.
[14]
Han, J.; Talorete, T.P.N.; Yamada, P.; Isoda, H. Anti-proliferative and apoptotic effects of oleuropein and hydroxytyrosol on human breast cancer MCF-7 cells. Cytotechnology, 2009, 59(1), 45-53.
[http://dx.doi.org/10.1007/s10616-009-9191-2] [PMID: 19353300]
[15]
Topcu, Z. DNA topoisomerases as targets for anticancer drugs. J. Clin. Pharm. Ther., 2001, 26(6), 405-416.
[http://dx.doi.org/10.1046/j.1365-2710.2001.00368.x] [PMID: 11722677]
[16]
Mohamed, K.O.; Zaki, I.; El-Deen, I.M.; Abdelhameid, 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.
[http://dx.doi.org/10.1016/j.bioorg.2018.12.007] [PMID: 30551066]
[17]
El-Deen, I.M.; Elgareib, M.S.A.; Mahey, A.R.E.; Al-Saleem, M.M.S. NMR spectra investigation of some new prepared tetrasubstituted coumarin derivatives. Mens Agitat., 2018, 13, 1-5.
[18]
El-Deen, I.M.; Ibrahim, H.K. Phosphorus, Sulphur. Silicon Relat., 2001, 179, 195-204.
[19]
El-Deen, I.M.; Ibrahim, H.K. Synthesis and some reactions of 2-mercapto-4-hydroxypyrimidine [3,4-(b)under-bar]coumarin. phosphorus, sulphur. Silicon Relat., 2000, 160, 241-250.
[http://dx.doi.org/10.1080/10426500008043684]
[20]
El-Deen, I.M.; Ibrahim, H.K.; Mahmoud, F.F. Synthesis of some new fused coumarin derivatives. Chin. J. Chem., 2000, 18, 590-595.
[21]
El-Deen, I.M.; Ibrahim, H.K. Synthesis and investigation of mass spectra of 3-(substituent)-benzopyran [3,2-c]-[1]-benzopyran-6,7- diones. J. Korean Chem. Soc., 2003, 27, 137-146.
[http://dx.doi.org/10.5012/jkcs.2003.47.2.137]
[22]
Pradhan, A.; Vishwakarma, K.S. Synthesis, characterisation and antimicrobial activity of schiff base of 7-Hydroxy-3-Methyl-2-Quinolone. Int. J. Theor. Appl. Sci., 2018, 10, 40-43.