Utility of Certain 2-Furanone Derivatives for Synthesis of Different
Heterocyclic Compounds and Testing their Anti-Cancer Activity

Rania    Helmy Abd    El-Hameed; Hend   Medhat   El-Shanbaky; Mosaad   Sayed   Mohamed

doi:10.2174/1573406417666210604103135

Abstract

Background: 2-Furanones have attracted great attention due to their biological activities. They also have the ability to be converted to several biologically active heterocyclic and nonheterocyclic compounds, especially as anti-cancer agents.

Objectives: This research aims to share in the development process of novel cytotoxic agents by synthesizing certain 2-furanone derivatives and using them as starting materials for the preparation of novel heterocyclic and non-heterocyclic compounds, then testing the synthesized derivatives for their anti-cancer activities.

Methods: All the newly synthesized compounds were fully characterized by elemental analysis, IR, Mass, and ¹H-NMR spectroscopy. 18 synthesized compounds were selected by National Cancer Institute (NCI) for testing against 60 cell lines, and the active compound was tested as MAPK14 and VEGFR2-inhibitor using Staurosporine as standard.

Results: Compound 3a showed the higher activity against several cell lines; Leukemia (SR), Non- Small Cell Lung Cancer (NCI-H460), colon cancer (HCT-116), ovarian cancer (OVCAR-4), renal cancer (786-0, ACHN and UO-31) and, finally breast cancer (T-47D). It also has better inhibition activity against MAPK14 than the used reference.

Conclusion: Compound 3a has promising anti-cancer activities compared to the used standards and may need further modification and investigations.

Keywords: 2-furanone, 2-pyrrolone, pyridazinone, synthesis, anti-cancer activity, MAPK14 inhibitor.

« Previous Next »

Graphical Abstract

[1] 
Abou-Elmagd, W.S.I.; El-Ziaty, A.K.; Abdalha, A.A. Ring transformation and antimicrobial activity of indolyl-substituted 2(3H)-furanones. Heterocycl. Commun.,  2015, 21(3), 179-184.
[http://dx.doi.org/10.1515/hc-2015-0008] 
[2] 
Ahmad, A.; Husain, A.; Khan, S.A.; Mujeeb, M.; Bhandari, A. Design, synthesis, molecular properties and antimicrobial activities of some novel 2(3H) pyrrolone derivatives. J. Saudi Chem. Soc.,  2015, 19, 340-346.
[http://dx.doi.org/10.1016/j.jscs.2014.05.007] 
[3] 
Husain, A.; Khan, M.S.Y.; Hasan, S.M.; Alam, M.M. Synthesis, reactions and biological activity of 2-Arylidene-4-(4-phenoxy-phenyl)but-3-en-4-olides. Eur. J. Med. Chem.,  2005, 40, 1394-1404.
[http://dx.doi.org/10.1016/j.ejmech.2005.03.012] [PMID: 15878219] 
[4] 
Husain, A.; Alam, M.M.; Siddiqui, N. Synthesis, reactions and biological activity of 3-arylidene-5-(4-methylphenyl)-2(3H)-furanones. J. Serb. Chem. Soc.,  2009, 74(2), 103-115.
[http://dx.doi.org/10.2298/JSC0902103H] 
[5] 
Alam, M.M.; Husain, A.; Hasan, S.M. Suruchi; Anwer, T. Synthesis and pharmacological evaluation of 2(3H)-furanones and 2(3H)-pyrrolones, combining analgesic and anti-inflammatory properties with reduced gastrointestinal toxicity and lipid peroxidation. Eur. J. Med. Chem.,  2009, 44(6), 2636-2642.
[http://dx.doi.org/10.1016/j.ejmech.2008.10.030] [PMID: 19059680] 
[6] 
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.
[http://dx.doi.org/10.1016/j.jsps.2015.05.002] [PMID: 27829814] 
[7] 
Flefel, E.M.; Abdel-Mageid, R.E.; Tantawy, W.A.; Ali, M.A. Amr, Ael-G. Heterocyclic compounds based on 3-(4-bromophenyl) azo-5-phenyl-2(3H)-furanone: Anti-avian influenza virus (H5N1) activity. Acta Pharm.,  2012, 62(4), 593-606.
[http://dx.doi.org/10.2478/v10007-012-0037-7] [PMID: 23333891] 
[8] 
Hashem, A.I.; Youssef, A.S.A.; Kandeel, K.A.; Abou-Elmagd, W.S.I. Conversion of some 2(3H)-furanones bearing a pyrazolyl group into other heterocyclic systems with a study of their antiviral activity. Eur. J. Med. Chem.,  2007, 42(7), 934-939.
[http://dx.doi.org/10.1016/j.ejmech.2006.12.032] [PMID: 17321008] 
[9] 
Sayed, H.H.; Hashem, A.I.; Yousif, N.M.; El-Sayed, W.A. Conversion of 3-arylazo-5-phenyl-2(3H)-furanones into other heterocycles of anticipated biological activity. Arch. Pharm. (Weinheim),  2007, 340(6), 315-319.
[http://dx.doi.org/10.1002/ardp.200700043] [PMID: 17562565] 
[10] 
Husain, A.; Ahmad, A.; Bhandari, A.; Ram, V. synthesis and antitubercular activity of pyridazinone derivatives. J. Chil. Chem. Soc.,  2011, 56(3), 778-780.
[http://dx.doi.org/10.4067/S0717-97072011000300013] 
[11] 
Husain, A.; Alam, M.M.; Hasan, S.M.; Yar, M.S. 2(3H)-furanones and 2(3H)-pyrrolones: synthesis and antimycobacterial evaluation. Acta Poloniae Pharmaceutica and Drug Research,  2009, 66(2), 173-180.
[12] 
Abou-Elmagd, W.S.I.; Hashem, A.I. Synthesis and antitumor activity evaluation of some novel fused and spiro heterocycles derived from a 2(3H)-furanone derivative. J. Heterocycl. Chem.,  2016, 53, 202-208.
[http://dx.doi.org/10.1002/jhet.2401] 
[13] 
Abou-Elmagd, W.S.I. EL-Ziaty, A.K.; El-Zahar, M.I.; Ramadan, S.K.; Hashem, A.I. synthesis and antitumor activity evaluation of some N-Heterocycles derived from pyrazolyl-substituted 2(3H)-furanone. Synth. Commun.,  2016, 46(14), 1197-1208.
[http://dx.doi.org/10.1080/00397911.2016.1193755] 
[14] 
Wu, Y.C.; Cao, L.; Mei, W.J.; Wu, H.Q.; Luo, S.H.; Zhan, H.Y.; Wang, Z.Y. Bis-2(5H)-furanone derivatives as new anticancer agents: Design, synthesis, biological evaluation, and mechanism studies. Chem. Biol. Drug Des.,  2018, 92(1), 1232-1240.
[http://dx.doi.org/10.1111/cbdd.13183] [PMID: 29469985] 
[15] 
Liu, G.; Guan, Y.; Wu, Y.; Liu, H. Synthesis and biological evaluation of novel γ-alkylidene butenolides. Hindawi Publishing Corporation. J. Chem.,  2013, 926723, 1-8.
[http://dx.doi.org/10.1155/2013/926723] 
[16] 
Wu, Y.; Luo, S.; Mei, W.; Cao, L.; Wu, H.; Wang, Z. Synthesis and biological evaluation of 4-biphenylamino-5-halo-2(5H)-furanones as potential anticancer agents. Eur. J. Med. Chem.,  2017, 139, 84-94.
[17] 
Lane, M.E.; Yu, B.; Rice, A.; Lipson, K.E.; Liang, C.; Sun, L.; Tang, C.; McMahon, G.; Pestell, R.G.; Wadler, S. A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells. Cancer Res.,  2001, 61(16), 6170-6177.
[PMID: 11507069] 
[18] 
Jin, X.; Wang, Y.; Tan, L.; He, Y.; Peng, J.; Hai, L.; Wu, Y.; Qian, Z. An efficient injectable formulation with block copolymer micelles for hydrophobic antitumor candidate-pyridazinone derivatives. Nanomedicine (Lond.),  2015, 10(14), 2153-2165.
[http://dx.doi.org/10.2217/nnm.15.66] [PMID: 26214355] 
[19] 
Martinez-Botella, G.; Hale, M.; Maltais, F.; Tang, Q.; Straub, J. pyrrole compounds as inhibtors of ERK protein kinase , synthesis
	and intermediates thereto. Canadian intellectual property office,
	patent, 2005.
[20] 
Tynebor, R.M.; Chen, M.H.; Natarajan, S.R.; O’Neill, E.A.; Thompson, J.E.; Fitzgerald, C.E.; O’Keefe, S.J.; Doherty, J.B. Synthesis and biological activity of pyridopyridazin-6-one p38 MAP kinase inhibitors. Part 1. Bioorg. Med. Chem. Lett.,  2011, 21(1), 411-416.
[http://dx.doi.org/10.1016/j.bmcl.2010.10.128] [PMID: 21084192] 
[21] 
Coghlan, M.P.; Culbert, A.A.; Cross, D.A.; Corcoran, S.L.; Yates, J.W.; Pearce, N.J.; Rausch, O.L.; Murphy, G.J.; Carter, P.S.; Roxbee Cox, L.; Mills, D.; Brown, M.J.; Haigh, D.; Ward, R.W.; Smith, D.G.; Murray, K.J.; Reith, A.D.; Holder, J.C. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem. Biol.,  2000, 7(10), 793-803.
[http://dx.doi.org/10.1016/S1074-5521(00)00025-9] [PMID: 11033082] 
[22] 
Elagawany, M.; Ibrahim, M.A.; Ali Ahmed, H.E.; El-Etrawy, A. Sh.; Ghiaty, A.; Abdel-Samii, Z.K.; El-Feky, S.A.; Bajorath, J. Design, synthesis, and molecular modelling of pyridazinone and phthalazinone derivatives as protein kinases inhibitors. Bioorg. Med. Chem. Lett.,  2013, 23(7), 2007-2013.
[http://dx.doi.org/10.1016/j.bmcl.2013.02.027] [PMID: 23453843] 
[23] 
Kuznietsova, H.; Dziubenko, N.; Byelinska, I.; Hurmach, V.; Bychko, A.; Lynchak, O.; Milokhov, D.; Khilya, O.; Rybalchenko, V. Pyrrole derivatives as potential anti-cancer therapeutics: Synthesis, mechanisms of action, safety. J. Drug Target.,  2020, 28(5), 547-563.
[http://dx.doi.org/10.1080/1061186X.2019.1703189] [PMID: 31814456] 
[24] 
Peifer, C.; Selig, R.; Kinkel, K.; Ott, D.; Totzke, F.; Schächtele, C.; Heidenreich, R.; Röcken, M.; Schollmeyer, D.; Laufer, S. Design, synthesis, and biological evaluation of novel 3-aryl-4-(1H-indole-3yl)-1,5-dihydro-2H-pyrrole-2-ones as vascular endothelial growth factor receptor (VEGF-R) inhibitors. J. Med. Chem.,  2008, 51(13), 3814-3824.
[http://dx.doi.org/10.1021/jm8001185] [PMID: 18529047] 
[25] 
Abdelbaset, M.S.; Abuo-Rahma, G.E.A.; Abdelrahman, M.H.; Ramadan, M.; Youssif, B.G.M.; Bukhari, S.N.A.; Mohamed, M.F.A.; Abdel-Aziz, M. Novel pyrrol-2(3H)-ones and pyridazin-3(2H)-ones carrying quinoline scaffold as anti-proliferative tubulin polymerization inhibitors. Bioorg. Chem.,  2018, 80, 151-163.
[http://dx.doi.org/10.1016/j.bioorg.2018.06.003] [PMID: 29920422] 
[26] 
Fatahala, S.S.; Mohamed, M.S.; Youns, M.; Abd-El Hameed, R.H. Synthesis and evaluation of cytotoxic activity of some pyrroles and fused pyrroles. Anticancer. Agents Med. Chem.,  2017, 17(7), 1014-1025.
[http://dx.doi.org/10.2174/1871520617666170102152928] [PMID: 28042776] 
[27] 
Abd El-Hameed, R.H.; Sayed, A.I. synthesis of novel pyrrolopyrimidine derivatives as CDK2 inhibitors. Pharmacophore,  2018, 9(5), 29-49.
[28] 
Awad, S.M.; Mohamed, M.S.; Khodair, M.A.; Abd El-Hameed, R.H. Synthesis and evaluation of cytotoxic activity of certain benzo[h]chromene derivatives. Anticancer. Agents Med. Chem.,  2021, 21, 1-24.
[29] 
Soliman, A.Y.; Attia, I.A.; Salem, M.A.; Soliman, E.A.; Gaber, A.M. synthesis and reactions of 2-[α-(3,4-disubstituted phenacyl)-p-substitutedstyryl]-4H-3,1-benzoxazin-4-ones. Chin. J. Chem.,  1996, 14(5), 437-446.
[30] 
Soliman, F.M.A.; Dawoud, N.T.A.; Abdel-Ghaffar, N.F.; El-Guindy, M.I.; Naguib, H. Synthesis, characterization and antimicrobial activity of some new heterocyclic compounds incorporating pyridazine moiety. Am. Chem. Sci. J.,  2016, 13(1), 1-14.
[http://dx.doi.org/10.9734/ACSJ/2016/23961] 
[31] 
Abd Alla, M.M.; Soliman, E.A.; Hamed, A.A.; Osman, M.W. Cheminform abstract: Reactions of some arylidenefuranones. Rev. Roum. Chim.,  1980, 25(11-12), 1549-1560.
[32] 
Baell, J.; Walters, M.A. Chemistry: Chemical con artists foil drug discovery. Nature,  2014, 513(7519), 481-483.
[http://dx.doi.org/10.1038/513481a] [PMID: 25254460] 
[33] 
Evans, B.E.; Rittle, K.E.; Bock, M.G.; DiPardo, R.M.; Freidinger, R.M.; Whitter, W.L.; Lundell, G.F.; Veber, D.F.; Anderson, P.S.; Chang, R.S.L.; Lotti, V.J.; Cerino, D.J.; Chen, T.B.; Kling, P.J.; Kunkel, K.A.; Springer, J.P.; Hirshfield, J. Methods for drug discovery: Development of potent, selective, orally effective cholecystokinin antagonists. J. Med. Chem.,  1988, 31(12), 2235-2246.
[http://dx.doi.org/10.1021/jm00120a002] [PMID: 2848124] 
[34] 
NCI website, Available from:. http://www.dtp.nci.nih.gov
[35] 
NCI methodology, Available from:. https://dtp.cancer.gov/discovery_development/nci-60/methodology.htm
[36] 
Welsch, M.E.; Snyder, S.A.; Stockwell, B.R. Privileged scaffolds for library design and drug discovery. Curr. Opin. Chem. Biol.,  2010, 14(3), 347-361.
[http://dx.doi.org/10.1016/j.cbpa.2010.02.018] [PMID: 20303320] 
[37] 
Hübbers, A.; Hennings, J.; Lambertz, D.; Haas, U.; Trautwein, C.; Nevzorova, Y.A.; Sonntag, R.; Liedtke, C. Pharmacological inhibition of cyclin-dependent kinases triggers anti-fibrotic effects in hepatic stellate cells in vitro. Int. J. Mol. Sci.,  2020, 21(9), 3267-3288.
[http://dx.doi.org/10.3390/ijms21093267] [PMID: 32380742] 
[38] 
Sausville, E.A.; Johnson, J.I. Molecules for the millennium: how will they look? New drug discovery year 2000. Br. J. Cancer,  2000, 83(11), 1401-1404.
[http://dx.doi.org/10.1054/bjoc.2000.1473] [PMID: 11076644] 
[39] 
Shoemaker, R.H. The NCI60 human tumour cell line anticancer drug screen. Nat. Rev. Cancer,  2006, 6(10), 813-823.
[http://dx.doi.org/10.1038/nrc1951] [PMID: 16990858] 
[40] 
Hatherley, D.; Graham, S.; Turner, J.; Harlos, K.; Stuart, D.; Barclay, A.N. Paired receptor specificity explained by structures of signal regulatory proteins alone and complexed with CD47. Mol. Cell,  2008, 31, 266-277.
[http://dx.doi.org/10.1016/j.molcel.2008.05.026] 
[41] 
Baba, N.; Van, V.Q.; Wakahara, K.; Rubio, M.; Fortin, G.; Panzini, B.; Soucy, G.; Wassef, R.; Richard, C.; Tamaz, R.; Lahaie, R.; Bernard, E.J.; Caussignac, Y.; Leduc, R.; Lougnarath, R.; Bergeron, C.; Racicot, M.A.; Bergeron, F.; Panzini, M.A.; Demetter, P.; Franchimont, D.; Schäkel, K.; Weckbecker, G.; Kolbinger, F.; Heusser, C.; Huber, T.; Welzenbach, K.; Sarfati, M. CD47 fusion protein targets CD172a+ cells in Crohn’s disease and dampens the production of IL-1β and TNF. J. Exp. Med.,  2013, 210(6), 1251-1263.
[http://dx.doi.org/10.1084/jem.20122037] [PMID: 23669395] 
[42] 
Sharma, K.; Suresh, P.S.; Mullangi, R.; Srinivas, N.R. Quantitation of VEGFR2 (vascular endothelial growth factor receptor) inhibitors-review of assay methodologies and perspectives. Biomed. Chromatogr.,  2015, 29(6), 803-834.
[http://dx.doi.org/10.1002/bmc.3370] [PMID: 25424874] 
[43] 
Fontanella, C.; Ongaro, E.; Bolzonello, S.; Guardascione, M.; Fasola, G.; Aprile, G. Clinical advances in the development of novel VEGFR2 inhibitors. Ann. Transl. Med.,  2014, 2(12), 123.
[http://dx.doi.org/10.3978/j.issn.2305-5839.2014.08.14] [PMID: 25568876] 
[44] 
Hashem, A.I.; Abou-Elmagd, W.S.I.; Abd-Elaziz, A. synthesis and reactions of some 2(3H)- and 2(5H)-furanone derivatives: A comparative study. Eur. Chem. Bull.,  2014, 3(11), 1064-1068.
[http://dx.doi.org/10.17628/ecb.2014.3.1064-1068] 

Rights & Permissions Print Cite

Article Metrics

33

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1573406417666210604103135	Print ISSN 1573-4064
Publisher Name Bentham Science Publisher	Online ISSN 1875-6638

Medicinal Chemistry

Utility of Certain 2-Furanone Derivatives for Synthesis of Different Heterocyclic Compounds and Testing their Anti-Cancer Activity

Abstract

Graphical Abstract

Related Journals

Related Books

Related Articles