Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis and Reactivity of 6,8-Dibromo-2-ethyl-4H-benzo[d][1,3]oxazin-4-one Towards Nucleophiles and Electrophiles and Their Anticancer Activity

Author(s): Maher A. El-hashash, Amira T. Ali, Rasha A. Hussein and Wael M. El-Sayed*

Volume 19, Issue 4, 2019

Page: [538 - 545] Pages: 8

DOI: 10.2174/1871520619666190201145221

Price: $65

Abstract

Background: The genetic heterogeneity of tumor cells and the development of therapy-resistant cancer cells in addition to the high cost necessitate the continuous development of novel targeted therapies.

Methods: In this regard, 14 novel benzoxazinone derivatives were synthesized and examined for anticancer activity against two human epithelial cancer cell lines; breast MCF-7 and liver HepG2 cells. 6,8-Dibromo-2- ethyl-4H-benzo[d][1,3]oxazin-4-one was subjected to react with nitrogen nucleophiles to afford quinazolinone derivatives and other related moieties (3-12). Benzoxazinone 2 responds to attack with oxygen nucleophile such as ethanol to give ethyl benzoate derivative 13. The reaction of benzoxazinone 2 with carbon electrophile such as benzaldehyde derivatives afforded benzoxazinone derivatives 14a and 14b.The structure of the prepared compounds was confirmed with spectroscopic tools including IR, 1H-NMR, and 13C-NMR.

Results: Derivatives 3, 9, 12, 13, and 14b exhibited high antiproliferative activity and were selective against cancer cells showing no toxicity in normal fibroblasts. Derivative 3 with NH-CO group in quinazolinone ring was effective only against breast cells, while derivative 12 with NH-CO group in imidazole moiety was only effective against liver cells probably through arresting cell cycle and enabling repair mechanisms. The other derivatives (9, 13, and 14b) had broader antiproliferative activity against both cell lines. These derivatives enhance the expression of the p53 and caspases 9 and 3 to varying degrees in both cell lines. Derivative 14b caused the highest induction in the investigated genes and was the only derivative to inhibit the EGFR activity.

Conclusions: The unique features about derivative 14b could be attributed to its high lipophilicity, high carbon content, or its extended conjugation through planar aromatic system. More investigations are required to identify the lead compound(s) in animal models.

Keywords: Benzoxazinone derivatives, nitrogen nucleophiles, anticancer, p53, apoptosis, chemotherapeutic agents.

« Previous Next »
Graphical Abstract

[1]
Elledge, S.J. Cell cycle checkpoints: Preventing an identity crisis. Science, 1996, 274, 1664-1672.
[2]
Boffetta, P.; Kaldor, J.M. Secondary malignancies following cancer chemotherapy. Acta Oncol., 1994, 33, 1-9.
[3]
Curtis, A.E.; Courtney, C.A. Synthesis of chromone, quinolone and benzoxazinone sulfonamide nucleosides as conformationally constrained inhibitors of adenylating enzymes required for siderophore biosynthesis. J. Org. Chem., 2013, 78(15), 7470-7481.
[4]
El-Mekabaty, A. Chemistry of 4H-3,1-benzoxazin-4-ones. Int. J. Mod. Org. Chem., 2013, 2, 81-121.
[5]
Ozden, S.; Ozturk, A.M.; Goker, H.; Altanlar, N. Synthesis and antimicrobial activity of some new 4-hydroxy-2H-1,4-benzoxazin-3(4H)-ones. ILFarmaco, 2000, 55, 715-718.
[6]
Mhaske, S.; Argade, N. The chemistry of recently isolated naturally occurring quiazolinone alkaloids. Tetrahedron, 2006, 62, 9787-9826.
[7]
Chandrika, M.P.; Yakaiah, T.; Raghuramaraa, A.; Narasaiah, B.; Chakrareddy, N.; Shridhar, V. Synthesis of novel 4,6-disubstituted quinazoline derivatives, their anti-inflammatory and anti-cancer activity (cytotoxic) against U 937 leukemia cell lines. Eur. J. Med. Chem., 2008, 43, 846-852.
[8]
Arora, A.; Scholar, E.M. Role of tyrosine kinase inhibitors in cancer therapy. J. Pharmacol. Exp. Ther., 2005, 315(3), 971-979.
[9]
Sionov, R.V.; Haupt, Y. The cellular response to p53: The decision between life and death. Oncogene, 1999, 18, 6145-6157.
[10]
Lacroix, M.; Toillon, R.A.; Leclercq, G. p53 and breast cancer, an update. Endocr. Relat. Cancer, 2006, 13, 293-325.
[11]
Hollstein, M.; Sidransky, D.; Vogelstein, B.; Harris, C.C. p53 mutations in human cancers. Science, 1991, 253, 49-53.
[12]
Vogan, K.; Bernstein, M.; Leclerc, J.M.; Brisson, L.; Brossard, J.; Brodeur, G.M.; Pelletier, J.; Gros, P. Absence of p53 gene mutations in primary neuroblastomas. Cancer Res., 1993, 53, 5269-5273.
[13]
George, P. P53 How crucial is its role in cancer. Int. J. Curr. Pharmaceut. Res., 2011, 3(2), 19-25.
[14]
Goldar, S.; Khaniani, M.S.; Derakhshan, S.M.; Baradaran, B. Molecular mechanisms of apoptosis and roles in cancer development and treatment. Asian Pac. J. Cancer Prev., 2015, 16(6), 2129-2144.
[15]
Walsh, J.G.; Cullen, S.P.; Sheridan, C.; Lüthi, A.U.; Gerner, C.; Martin, S.J. Executioner caspase-3 and caspase-7 are functionally distinct proteases. Proc. Natl. Acad. Sci., 2008, 105, 12815-12819.
[16]
Manash, K.P.; Anup, K.M. Tyrosine kinase -Role and significance in cancer. Int. J. Med. Sci., 2004, 1(2), 101-115.
[17]
Bhullar, K.S.; Lagarón, N.O.; McGowan, E.M.; Parmar, I.; Jha, A.; Hubbard, B.P.; Rupasinghe, H.P.V. Kinase-targeted cancer therapies: Progress, challenges and future directions. Mol. Cancer, 2018, 17(1), 48-67.
[18]
Nitiss, J.L. Targeting DNA topoisomerase II in cancer chemotherapy. Nat. Rev. Cancer, 2009, 9(5), 338-350.
[19]
Bishayee, A.; Block, K. A broad-spectrum integrative design for cancer prevention and therapy: The challenge ahead. Semin. Cancer Biol., 2015, 35, S1-S4.
[20]
Denizot, F.; Lang, R. Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J. Immunol. Methods, 1986, 89, 271-277.
[21]
Hussein, R.A.; El-Husseiny, E.A.; Hassanin, L.A.; El-Sayed, W.M. The prophylactic and therapeutic effects of safranal and selenite on liver damage induced by thyrotoxicosis in adult male albino rats. Int. J. Clin. Pharmacol. Toxicol., 2017, 6, 270-279.
[22]
El-Metwally, S.A.; Khalil, A.K.; El-Naggar, A.M.; El-Sayed, W.M. Novel Tetrahydrobenzo [b] Thiophene analogues exhibit anticancer activity through enhancing apoptosis and inhibiting tyrosine kinase. Anticancer. Agents Med. Chem., 2018, 18(12), 1761-1769.
[23]
Ismail, M.A.; Youssef, M.M.; Arafa, R.K.; Al-Shihry, S.S.; El-Sayed, W.M. Synthesis and antiproliferative activity of monocationic arylthiophene derivatives. Eur. J. Med. Chem., 2017, 126, 789-798.
[24]
El-hashash, M.A.; El-Shahawi, M.M.; Ragab, E.A.; Nagdy, S. Synthesis and antifunal activity of novel quinazolin-4(3H)-one derivatives. Synth. Commun., 2015, 45, 2240-2250.
[25]
Ozaki, T.; Nakagawara, A. Role of p53 in cell death and human cancers. Cancers, 2011, 3, 994-1013.
[26]
Sun, J.; Wei, Q.; Zhou, Y.; Wang, J.; Lui, Q.; Hua, X. A systemic analysis of FDA-approved anticancer drugs. BMC Syst. Biol., 2017, 11, 87-102.
[27]
Wang, S.; Konorev, E.A.; Kotamraju, S.; Joseph, J.; Kalivendi, S.; Kalyanaraman, B. Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms intermediacy of H2O2- And p53-dependent pathways. J. Biol. Chem., 2004, 279(24), 25535-25543.
[28]
Sonntag, R.; Gassler, N.; Bangen, J.M.; Trautwein, C.; Liedtke, C. Pro-apoptotic Sorafenib signaling in murine hepatocytes depends on malignancy and is associated with PUMA expression in vitro and in vivo. Cell Death Dis., 2014, 5, 1-12.
[29]
Jänicke, R.U. MCF-7 breast carcinoma cells do not express caspase-3. Breast Cancer Res. Treat., 2009, 117(1), 219-221.
[30]
Hartmann, J.T.; Haap, M.; Kopp, H.G.; Lipp, H.P. Tyrosine kinase inhibitor - A review on pharmacology, metabolism and side effects. Curr. Drug Metab., 2009, 10(5), 470-481.

Rights & Permissions Print Cite
Article Metrics
34
5
© 2024 Bentham Science Publishers | Privacy Policy