Aim: Using cytotoxic agents with apoptosis induction may represent one of new strategies for cancer treatment to overcome the increased resistance of the disease.
Methodology: Two series of benzo[f][1,4]oxazepine-3,5(2H,4H)-diones (compounds 5, 6a-f) and 3-phenylbenzo[f][1,4]oxazepin-5(4H)-ones (compounds 10, 11a-f) were synthesized and screened for their cytotoxicity against leukemia K-562 and breast T-47D cancer cell lines as well as normal fibroblasts WI-38.
Results: The tested compounds revealed good cytotoxicity and selectivity toward cancer cell lines relative to the normal cells, especially compounds 6f, 10 and 11e, f. These compounds were screened for cell cycle disturbance and apoptosis induction. They were found to cause PreG1 apoptosis and complete cell growth arrest at G2/M. They induce apoptosis via caspase-3 and Bax activation and downregulation of Bcl2.
Conclusion: benzo[f][1,4]oxazepine represents a scaffold for further optimization to obtain promising anticancer agents.
Keywords: Bax; Bcl2; apoptosis inducer; benzoxazepines; caspase-3; cell cycle analysis.