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Medicinal Chemistry


ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

Design, Synthesis and Antitumor Assessment of Phenylureas Bearing 5-Fluoroindolin-2-one Moiety

Author(s): Yunrui Cai, Tong Chen, Huajian Zhu and Hongbin Zou*

Volume 16 , Issue 7 , 2020

Page: [958 - 968] Pages: 11

DOI: 10.2174/1573406416666200206123319

Price: $65


Background: The development of novel antineoplastic agents remains highly desirable.

Objective: This study focuses on the design, synthesis, and antitumor evaluation of phenyl ureas bearing 5-fluoroindolin-2-one moiety.

Methods: Three sets of phenylureas were designed and synthesized and their antiproliferative ability was measured against four human carcinoma cell lines (Hela, Eca-109, A549, and MCF-7) via MTT assay. In vivo anticancer activity was further evaluated in xenograft models of human breast cancer (MCF-7).

Results: A total of twenty-one new compounds were synthesized and characterized by means of 1H and 13C NMR as well as HR-MS. Three sets of compounds (1a‒1c, 2a‒2c, and 3a‒3c) were initially constructed, and preliminary antiproliferative activities of these molecules were evaluated against Hela, Eca-109, A549 and MCF-7, highlighting the meta-substituted phenylureas (1a‒1c) as the most cytotoxic set. A series of meta-substituted phenylureas derivatives (1d‒1o) were then designed and synthesized for structure-activity relationship study. Most of the new compounds showed desirable cytotoxicity, among which compound 1g exhibited the most remarkable cytotoxic effects against the tested human cancer cells with IC50 values ranging from 1.47 to 6.79 μM. Further studies showed that compound 1g suppressed tumor growth in human breast cancer (MCF- 7) xenograft models without affecting the body weight of its recipients.

Conclusion: In this study, twenty-one new compounds, containing the privileged structures of phenylurea and 5-fluoroindolin-2-one, were designed and synthesized. Subsequent structureactivity studies showed that 1g was the most bioactive antitumor agent among all tested compounds, hence a potentially promising lead compound once given further optimization.

Keywords: Phenylurea, 5-fluoroindolin-2-one, rational design, antiproliferative activity, structure activity relationship, in vivo antitumor activity.

Graphical Abstract
Bagi, C.M. Summary - Cancer cell metastases session. J. Musculoskelet. Neuronal Interact., 2002, 2, 579-580.
Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. CA Cancer J. Clin., 2011, 61(2), 69-90.
[] [PMID: 21296855]
Aravapalli, S.; Lai, H.; Teramoto, T.; Alliston, K.R.; Lushington, G.H.; Ferguson, E.L.; Padmanabhan, R.; Groutas, W.C. Inhibitors of Dengue virus and West Nile virus proteases based on the aminobenzamide scaffold. Bioorg. Med. Chem., 2012, 20(13), 4140-4148.
[] [PMID: 22632792]
Hwang, S.H.; Wagner, K.M.; Morisseau, C.; Liu, J.Y.; Dong, H.; Wecksler, A.T.; Hammock, B.D. Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase. J. Med. Chem., 2011, 54(8), 3037-3050.
[] [PMID: 21434686]
Eissa, I.H.; Mohammad, H.; Qassem, O.A.; Younis, W.; Abdelghany, T.M.; Elshafeey, A.; Abd Rabo Moustafa, M.M.; Seleem, M.N.; Mayhoub, A.S. Diphenylurea derivatives for combating methicillin- and vancomycin-resistant Staphylococcus aureus. Eur. J. Med. Chem., 2017, 130, 73-85.
[] [PMID: 28249208]
Dorosti, N.; Delfan, B.; Gholivand, K.; Valmoozi, A.A.E. Synthesis, crystal structure, biological evaluation, electronic aspects of hydrogen bonds, and QSAR studies of some new N-(substituted phenylurea) diazaphosphore derivatives as anticancer agents. Med. Chem. Res., 2016, 25, 769-789.
Jagtap, A.D.; Kondekar, N.B.; Sadani, A.A.; Chern, J.W. Ureas: Applications in Drug Design. Curr. Med. Chem., 2017, 24(6), 622-651.
[] [PMID: 27897114]
Motzer, R.J.; Nosov, D.; Eisen, T.; Bondarenko, I.; Lesovoy, V.; Lipatov, O.; Tomczak, P.; Lyulko, O.; Alyasova, A.; Harza, M.; Kogan, M.; Alekseev, B.Y.; Sternberg, C.N.; Szczylik, C.; Cella, D.; Ivanescu, C.; Krivoshik, A.; Strahs, A.; Esteves, B.; Berkenblit, A.; Hutson, T.E. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J. Clin. Oncol., 2013, 31(30), 3791-3799.
[] [PMID: 24019545]
King, J.; Palmer, D.H.; Johnson, P.; Ross, P.; Hubner, R.A.; Sumpter, K.; Darby, S.; Braconi, C.; Iwuji, C.; Swinson, D.; Collins, P.; Patel, K.; Nobes, J.; Muazzam, I.; Blesing, C.; Kirkwood, A.; Nash, S.; Meyer, T. Sorafenib for the treatment of advanced hepatocellular cancer–a UK audit. Clin. Oncol. (R. Coll. Radiol.), 2017, 29(4), 256-262.
[] [PMID: 27964898]
Wilhelm, S.; Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R.A.; Schwartz, B.; Simantov, R.; Kelley, S. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat. Rev. Drug Discov., 2006, 5(10), 835-844.
[] [PMID: 17016424]
Zask, A.; Verheijen, J.C.; Curran, K.; Kaplan, J.; Richard, D.J.; Nowak, P.; Malwitz, D.J.; Brooijmans, N.; Bard, J.; Svenson, K.; Lucas, J.; Toral-Barza, L.; Zhang, W.G.; Hollander, I.; Gibbons, J.J.; Abraham, R.T.; Ayral-Kaloustian, S.; Mansour, T.S.; Yu, K. ATP-competitive inhibitors of the mammalian target of rapamycin: design and synthesis of highly potent and selective pyrazolopyrimidines. J. Med. Chem., 2009, 52(16), 5013-5016.
[] [PMID: 19645448]
Lum, R.T.; Cheng, M.; Cristobal, C.P.; Goldfine, I.D.; Evans, J.L.; Keck, J.G.; Macsata, R.W.; Manchem, V.P.; Matsumoto, Y.; Park, S.J.; Rao, S.S.; Robinson, L.; Shi, S.; Spevak, W.R.; Schow, S.R. Design, synthesis, and structure-activity relationships of novel insulin receptor tyrosine kinase activators. J. Med. Chem., 2008, 51(19), 6173-6187.
[] [PMID: 18788731]
Christensen, M.K.; Erichsen, K.D.; Olesen, U.H.; Tjørnelund, J.; Fristrup, P.; Thougaard, A.; Nielsen, S.J.; Sehested, M.; Jensen, P.B.; Loza, E.; Kalvinsh, I.; Garten, A.; Kiess, W.; Björkling, F. Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship. J. Med. Chem., 2013, 56(22), 9071-9088.
[] [PMID: 24164086]
Kumar, A.; Ito, A.; Hirohama, M.; Yoshida, M.; Zhang, K.Y. Identification of new SUMO activating enzyme 1 inhibitors using virtual screening and scaffold hopping. Bioorg. Med. Chem. Lett., 2016, 26(4), 1218-1223.
[] [PMID: 26810265]
Prakash, C.R.; Raja, S.; Saravanan, G. Synthesis and anti-epileptic activity of some novel 3-(4-(4-(substituted benzylideneamino)-5-mercapto-4-1,2,4-triazole-3-yl)phenylimino)-1-((dimethyl amino) methyl)-5-fluoroindolin-2-one derivatives. Int. J. Pharm. Pharm. Sci., 2014, 6, 539-544.
Zou, H.; Zhang, L.; Ouyang, J.; Giulianotti, M.A.; Yu, Y. Synthesis and biological evaluation of 2-indolinone derivatives as potential antitumor agents. Eur. J. Med. Chem., 2011, 46(12), 5970-5977.
[] [PMID: 22019188]
Furuta, K.; Kawai, Y.; Mizuno, Y.; Hattori, Y.; Koyama, H.; Hirata, Y. Synthesis of 3-[4-(dimethylamino)phenyl]alkyl-2-oxindole derivatives and their effects on neuronal cell death. Bioorg. Med. Chem. Lett., 2017, 27(18), 4457-4461.
[] [PMID: 28807440]
Chow, L.Q.; Eckhardt, S.G. Sunitinib: from rational design to clinical efficacy. J. Clin. Oncol., 2007, 25(7), 884-896.
[] [PMID: 17327610]
La, D.S.; Belzile, J.; Bready, J.V.; Coxon, A.; DeMelfi, T.; Doerr, N.; Estrada, J.; Flynn, J.C.; Flynn, S.R.; Graceffa, R.F.; Harriman, S.P.; Larrow, J.F.; Long, A.M.; Martin, M.W.; Morrison, M.J.; Patel, V.F.; Roveto, P.M.; Wang, L.; Weiss, M.M.; Whittington, D.A.; Teffera, Y.; Zhao, Z.; Polverino, A.J.; Harmange, J.C. Novel 2,3-dihydro-1,4-benzoxazines as potent and orally bioavailable inhibitors of tumor-driven angiogenesis. J. Med. Chem., 2008, 51(6), 1695-1705.
[] [PMID: 18311900]

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