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

Abstract

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 3a and 5b inhibited breast cancer cell (MCF–7) viability with an IC50 value of 9.17 and 6.29 µM, 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–κB, with the binding energies −9.32 and −7.32 kcal mol−1. Furthermore, compounds 3a and 5b inhibited NF–κB in MCF–7 breast cancer cells. In conclusion, we herein report newer structures that target NF–κB in BC cells.

Targeting NF-κB signaling cascades of glioblastoma by a natural benzophenone, garcinol, via in vitro and molecular docking approaches

“…Thus, treatment with garcinol can significantly inhibit NF-κB signaling and, critically, modulate its associated target genes that are involved in cellular proliferation and resistance to apoptosis in C6 cells. Furthermore, molecular docking analysis of garcinol with NF-κB confirmed the involvement of important amino acid residues such as Pro 275 , Trp 258 , Glu 225 , and Gly 259 (Huxford et al, 2002;Cai et al, 2021;Ravish et al, 2023). Cai et al (2021) Huxford et al (2002) documented the crucial role of Trp 258 in the binding and specificity of NF-κB to Iκ-Bα.…”

Synthesis of novel triazoles as anticancer agents targeting pJNK in human breast cancer cells

“…23 Similarly, the linker –S-CH 2 – serves as an active structural motif in various reported anticancer lead molecules, such as compounds E and F , which demonstrated remarkable anticancer activity against various BC cells. 24 Another report was made on ibuprofen-tethered oxadiazole-S-CH 2 -triazole ( G ) and –S–CH 2 -containing benzotriazole-tethered oxadiazole ( H ) derivatives demonstrating anticancer activity against BC cells by targeting various biological pathways. 25,26…”