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Synthesis, Antiproliferative Activity, and Apoptotic Profile of New Derivatives from the Meta Stable Benzoxazinone Scaffold

[ Vol. 22 , Issue. 6 ]

Author(s):

Amira A. El-Sayed, Maher A. El-Hashash and Wael M. El-Sayed*   Pages 1226 - 1237 ( 12 )

Abstract:


Background: Cancer exerts a huge strain on the health system. The emerging resistance to the current chemotherapies demands the continuous development of new anticancer agents with lower cost, higher efficacy, and greater specificity. <P> Objective: This study aimed at developing selective small molecules as targeted anticancer agents. <P> Methods: The behavior of benzoxazinone 2 towards nitrogen nucleophiles, such as hydrazine hydrate, formamide, ethanolamine, aromatic amines, and thiosemicarbazide, was described. The behavior of the amino quinazolinone 3 towards carbon electrophiles and P2S5 was also investigated. The antiproliferative activity of 17 new benzoxazinone derivatives was examined against the growth of three human cancer cell lines; liver HepG2, breast MCF-7, and colon HCT-29, in addition to the normal human fibroblasts WI-38, and the selectivity index was calculated. The possible molecular pathways, such as the cell cycle and apoptosis, were investigated. <P> Results: Derivatives 3, 7, 8, 10, 13, and 15 had a significant (less than 10 μM) antiproliferative activity against the three cancer cell lines investigated. Derivative 7 showed the best antiproliferative profile comparable to that of doxorubicin. The selectivity index for all the effective derivatives ranged from ~5-12 folds, indicating high selectivity against the cancer cells. Derivative 15 caused ~ 7-fold and 8-fold inductions in the expression of <i>p53</i> and caspase3, respectively. It also caused a ~ 60% reduction in the expression of both topoisomerase II (topoII) and cyclin-dependent kinase 1 (cdk1). Derivatives 3, 7, and 8 had a similar profile; ~ 6-8-fold increased in the expression of <i>p53</i> and <i>caspase3</i> but these compounds were devoid of any significant effect on the expression of <i>topoII</i> and <i>cdk1</i>. Derivatives 10 and 13 were also similar and resulted in a ~6-fold elevation in the expression of<i>caspase3</i>, and more than 60% downregulation in the expression of <i>topoII</i>. The results of the gene expression of <i>topoII</i> and <i>caspase3</i> were confirmed by the measurement of the <i>topoII</i> concentration and caspase3 activity in the HepG2 cells. <P> Conclusion: Six derivatives exerted their antiproliferative activity by arresting the cell cycle (decreasing <i>cdk1</i>), preventing the DNA duplication (downregulating topo II), and inducing apoptosis (inducing <i>p53</i> and caspase3). One common feature in all the six active derivatives is the presence of a free amino group. These compounds have merit for further investigations.

Keywords:

Quinazolinone, regiospecificity, cell cycle, p53, apoptosis, caspase, topoisomerase.

Affiliation:

Laboratory of Synthetic Organic Chemistry, Department of Chemistry, Faculty of Science, University of Ain Shams, Abbassia 11566, Cairo, Laboratory of Synthetic Organic Chemistry, Department of Chemistry, Faculty of Science, University of Ain Shams, Abbassia 11566, Cairo, Department of Zoology, Faculty of Science, University of Ain Shams, Abbassia 11566, Cairo

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