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Nuclear factor kappa B (NF–κB) is a potential therapeutic target in breast cancer. In the current study, a new class of oxazine– and piperazine–linked pyrimidines was developed as inhibitors of NF–κB, overcoming the complexity of the oxazine structure found in nature and enabling synthesis under laboratory conditions. Among the series of synthesized and tested oxazine–pyrimidine and piperazine–pyrimidine derivatives, compounds <b>3a</b> and <b>5b</b> inhibited breast cancer cell (MCF–7) viability with an IC₅₀ value of 9.17 and 6.29 µM, respectively. <i>In silico</i> docking studies showed that the pyrimidine ring of <b>3a</b> and the 4–methoxybenzyl thiol group of <b>5b</b> could strongly bind the p65 subunit of NF–κB, with the binding energies −9.32 and −7.32 kcal mol⁻¹. Furthermore, compounds <b>3a</b> and <b>5b</b> inhibited NF–κB in MCF–7 breast cancer cells. In conclusion, we herein report newer structures that target NF–κB in BC cells.