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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

[ Vol. 19 , Issue. 4 ]

Author(s):

Maher A. El-hashash, Amira T. Ali, Rasha A. Hussein and Wael M. El-Sayed*   Pages 538 - 545 ( 8 )

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.

Affiliation:

University of Ain Shams, Faculty of Science, Department of Chemistry, Abbassia 11566, Cairo, University of Ain Shams, Faculty of Science, Department of Chemistry, Abbassia 11566, Cairo, Hormonal Evaluation Department, National Organization for Drug Control & Research (NODCAR), Cairo, University of Ain Shams, Faculty of Science, Department of Zoology, Abbassia 11566, Cairo

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