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.
Objective:
Development of selective small molecules targeted anticancer agents
Methods:
The behavior of benzoxazinone 2 towards nitrogen nucleophiles such as hydrazine hydrate, formamide, ethanolamine, aromatic amines, and thiosemcarbazide 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.
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 p53 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 increases in the expression of p53 and caspase3 but these compounds were devoid of any significant effect on the expression of topoII and cdk1. Derivatives 10 and 13 were also similar and resulted in a ~6-fold elevation in the expression of caspase3, and more than 60% downregulation in the expression of topoII. The results of the gene expression of topoII and caspase 3 were confirmed by the measurement of the topoII concentration and caspase3 activity in the HepG2 cells.
Conclusion:
Six derivatives exerted their antiproliferative activity by arresting the cell cycle (decreasing cdk1), preventing the DNA duplication (downregulating topo II), and by inducing apoptosis (inducing p53 and caspase3). One common feature in all the six active derivatives is the presence of free amino group. These compounds have merit for further investigations.
Structure–Antioxidant–Antiproliferative Activity Relationships of Natural C7 and C7–C8 Hydroxylated Flavones and Flavanones