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

[Display omitted] • Synthesis and characterisation of twelve new substituted 3,4-dihydro-2 H -1,4-benzoxazine derivatives. • Compounds 2b and 4b showed promising antiproliferative activity against MCF-7 breast cancer and HCT-116 colon cancer cell lines. • 2b and 4b displayed a consistent binding mode to hHER2 and hJNK1 kinases. • 2b and 4b exhibited potent cytotoxic activity by disrupting cell membrane permeability, likely triggering both inflammatory and non-inflammatory cell death mechanisms. • In the HCT-116 cell line, 2b and 4b arrest the cell cycle in the S phase. 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-2 H -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 IC 50 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 non-inflammatory 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. [ABSTRACT FROM AUTHOR]