Development of Piperazine- and Oxazine-Linked Pyrimidines as p65 Subunit Binders of NF-κB in Human Breast Cancer Cells

Nuclear factor kappa B (NF-kappa B) 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-kappa B, 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 3a and 5b inhibited breast cancer cell (MCF-7) viability with an IC50 value of 9.17 and 6.29 mu M, respectively. In silico docking studies showed that the pyrimidine ring of 3a and the 4-methoxybenzyl thiol group of 5b could strongly bind the p65 subunit of NF-kappa B, with the binding energies -9.32 and -7.32 kcal mol(-1). Furthermore, compounds 3a and 5b inhibited NF-kappa B in MCF-7 breast cancer cells. In conclusion, we herein report newer structures that target NF-kappa B in BC cells.