Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Research Article

Synthesis and Apoptotic Activities of New 2(3H)-benzoxazolone Derivatives in Breast Cancer Cells

Author(s): Emine Erdag, Eda Becer, Yusuf Mulazim, Hafize Seda Vatansever, Hilal Kabadayı and Banu Kesanli*

Volume 21 , Issue 1 , 2021

Published on: 21 July, 2020

Page: [84 - 90] Pages: 7

DOI: 10.2174/1871520620666200721125820

Price: $65

Abstract

Background: 2(3H)-Benzoxazolone derivatives are preferential structural blocks in pharmacological probe designing with the possibility of modifications at various positions on the core structure. Benzoxazolones showed various biological activities such as analgesics, anti-inflammatory and anti-cancer.

Objective: In the present work, we have prepared new Mannich bases of 2(3H)-benzoxazolone derivatives and evaluated their cytotoxicities and proapoptotic properties in MCF-7 breast cancer cell line.

Methods: The structures of these compounds were characterized by FT-IR, elemental analysis, 1H and 13C NMR. Cytotoxicities of all the target compounds were investigated by MTT assay. Apoptotic properties of compounds were evaluated by immunocytochemistry using antibodies against caspase-3, cytochrome-c, FasL, and also TUNEL assay.

Results: These two novel compounds, 1 and 2, both have the same piperazine substituent on the nitrogen atom of benzoxazolone and the main difference in the structures of these compounds is the presence of Cl substituent at the 5- position of the benzoxazolone ring. MTT results showed that compounds 1 and 2 were effective in terms of reduction of cell viability at 100μM and 50μM concentration for 48h, respectively. As a result of immunohistochemical staining, Fas L and caspase-3 immunoreactivities were significantly increased in MCF-7 cells after treatment with compound 1. Additionally, caspase-3 and cytochrome-c immunoreactivities were also increased significantly in MCF-7 cells after treatment with compound 2. The number of TUNEL positive cells was significantly higher in MCF-7 cells when compared with the control group after treatment with both compounds 1 and 2.

Conclusion: It could be concluded that N-substituted benzoxazolone derivatives increase potential anti-cancer effects and they could be promising novel therapeutic agents for chemotherapy.

Keywords: 2(3H)-benzoxazolone, mannich reaction, cytotoxicity, apoptosis, breast cancer, MCF-7.

Graphical Abstract
[1]
Poupaert, J.; Carato, P.; Colacino, E.; Yous, S. 2(3H)-benzoxazolone and bioisosters as “privileged scaffold” in the design of pharmacological probes. Curr. Med. Chem., 2005, 12(7), 877-885.
[http://dx.doi.org/10.2174/0929867053507388] [PMID: 15853716]
[2]
Erol, D.D.; Aytemir, M.D.; Yulug, N. Synthesis and antimicrobial activity of thiazolinomethyl-2(3H)-benzoxazolone derivatives I. Eur. J. Med. Chem., 1995, 30(6), 521-524.
[http://dx.doi.org/10.1016/0223-5234(96)88264-X]
[3]
Deng, B.L.; Cullen, M.D.; Zhou, Z.; Hartman, T.L.; Buckheit, R.W., Jr; Pannecouque, C.; De Clercq, E.; Fanwick, P.E.; Cushman, M. Synthesis and anti-HIV activity of new Alkenyldiarylmethane (ADAM) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) incorporating benzoxazolone and benzisoxazole rings. Bioorg. Med. Chem., 2006, 14(7), 2366-2374.
[http://dx.doi.org/10.1016/j.bmc.2005.11.014] [PMID: 16321539]
[4]
Mulazim, Y.; Berber, C.; Erdogan, H.; Ozkan, M.H.; Kesanli, B. Synthesis and analgesic activities of some new 5-chloro-2(3H)-benzoxazolone derivatives. EuroBiotech J., 2017, 1(3), 235-240.
[http://dx.doi.org/10.24190/ISSN2564-615X/2017/03.07]
[5]
Yang, L.; Liu, Y.; Fan, M.; Zhu, G.; Jin, H.; Liang, J.; Liu, Z.; Huang, Z.; Zhang, L. Identification and characterization of benzo[d]oxazol-2(3H)-one derivatives as the first potent and selective small-molecule inhibitors of chromodomain protein CDYL. Eur. J. Med. Chem., 2019, 182, 111656-111665.
[http://dx.doi.org/10.1016/j.ejmech.2019.111656] [PMID: 31494467]
[6]
Loreto, C.; La Rocca, G.; Anzalone, R.; Caltabiano, R.; Vespasiani, G.; Castorina, S.; Ralph, D.J.; Cellek, S.; Musumeci, G.; Giunta, S.; Djinovic, R.; Basic, D.; Sansalone, S. The role of intrinsic pathway in apoptosis activation and progression in Peyronie’s disease. BioMed Res. Int., 2014, 2014616149
[http://dx.doi.org/10.1155/2014/616149]] [PMID: 25197653]
[7]
Salvesen, G.S.; Duckett, C.S. IAP proteins: Blocking the road to death’s door. Nat. Rev. Mol. Cell Biol., 2002, 3(6), 401-410.
[http://dx.doi.org/10.1038/nrm830] [PMID: 12042762]
[8]
Plati, J.; Bucur, O.; Khosravi-Far, R. Apoptotic cell signaling in cancer progression and therapy. Integr. Biol., 2011, 3(4), 279-296.
[http://dx.doi.org/10.1039/c0ib00144a] [PMID: 21340093]
[9]
Ivanova, Y.; Momekov, G.; Petrov, O.; Karaivanova, M.; Kalcheva, V. Cytotoxic Mannich bases of 6-(3-aryl-2-propenoyl)-2(3H)-benzoxazolones. Eur. J. Med. Chem., 2007, 42(11-12), 1382-1387.
[http://dx.doi.org/10.1016/j.ejmech.2007.02.019] [PMID: 17459529]
[10]
Petrov, O.; Ivanova, Y.; Momekov, G.; Kalcheva, V. New synthetic chalcones: Cytotoxic Mannich bases of 6-(4-chlorocinnamoyl)-2(3H)-benzoxazolone. Lett. Drug Des. Discov., 2008, 5, 358-361.
[http://dx.doi.org/10.2174/157018008785777342]
[11]
Bilginer, S.; Gul, H.I.; Erdal, F.S.; Sakagami, H.; Levent, S.; Gulcin, I.; Supuran, C.T. Synthesis, cytotoxicities, and carbonic anhydrase inhibition potential of 6-(3-aryl-2-propenoyl)-2(3H)-benzoxazolones. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 1722-1729.
[http://dx.doi.org/10.1080/14756366.2019.1670657] [PMID: 31576761]
[12]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell, 2011, 144(5), 646-674.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[13]
Ivanova, Y.B.; Momekov, G.T.; Petrov, O.I. New heterocyclic chalcones. Part 6. Synthesis and cytotoxic activities of 5- or 6-(3-aryl-2-propenoyl)-2(3 H)-benzoxazolones. Heterocycl. Commun., 2013, 19(1), 23-28.
[http://dx.doi.org/10.1515/hc-2012-0081]
[14]
El-Helby, A.A.; Sakr, H.; Eissa, I.H.; Abulkhair, H.; Al-Karmalawy, A.A.; El-Adl, K. Design, synthesis, molecular docking, and anticancer activity of benzoxazole derivatives as VEGFR-2 inhibitors. Arch. Pharm. (Weinheim), 2019, 352(10)e1900113
[http://dx.doi.org/10.1002/ardp.201900113] [PMID: 31448458]
[15]
Omar, A.M.E. AboulWafa, O.M.; El-Shoukrofy, M.S.; Amr, M.E. Benzoxazole derivatives as new generation of anti-breast cancer agents. Bioorg. Chem., 2020, 96103593
[http://dx.doi.org/10.1016/j.bioorg.2020.103593] [PMID: 32004897]
[16]
Romeo, G.; Prezzavento, O.; Intagliata, S.; Pittalà, V.; Modica, M.N.; Marrazzo, A.; Turnaturi, R.; Parenti, C.; Chiechio, S.; Arena, E.; Campisi, A.; Sposito, G.; Salerno, L. Synthesis, in vitro and in vivo characterization of new benzoxazole and benzothiazole-based sigma receptor ligands. Eur. J. Med. Chem., 2019, 174, 226-235.
[http://dx.doi.org/10.1016/j.ejmech.2019.04.056] [PMID: 31042618]
[17]
Schneider, P.; Bodmer, J.L.; Holler, N.; Mattmann, C.; Scuderi, P.; Terskikh, A.; Peitsch, M.C.; Tschopp, J. Characterization of Fas (Apo-1, CD95)-fas ligand interaction. J. Biol. Chem., 1997, 272(30), 18827-18833.
[http://dx.doi.org/10.1074/jbc.272.30.18827] [PMID: 9228058]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy