New substituted benzoxazine derivatives as potent inducers of membrane permeability and cell death

The search for new agents targeting different forms of cell death is an important research focus for developing
new and potent antitumor therapies. As a contribution to this endeavor, we have designed and synthesized a
series of new substituted 3,4-dihydro-2H-1,4-benzoxazine derivatives. These compounds have been evaluated for
their efficacy against MCF-7 breast cancer and HCT-116 colon cancer cell lines. Overall, substituting this heterocycle
led to improved antiproliferative activity compared to the unsubstituted derivative 1. The most active
compounds, 2b and 4b, showed IC50 values of 2.27 and 3.26 μM against MCF-7 cells and 4.44 and 7.63 μM
against HCT-116 cells, respectively. To investigate the mechanism of action of the target compounds, the inhibition
profile of 8 kinases involved in cell signaling was studied highlighting residual activity on HER2 and JNK1
kinases. 2b and 4b showed a consistent binding mode to both receptor kinases, establishing significant interactions
with known and catalytically important domains and residues. Compounds 2b and 4b exhibit potent
cytotoxic activity by disrupting cell membrane permeability, likely triggering both inflammatory and noninflammatory
cell death mechanisms. This dual capability increases their versatility in the treatment of
different stages or types of tumors, providing greater flexibility in clinical applications.