An experimental and theoretical approach of a novel phosphoramide containing naphthoquinone with potential cytotoxic and apoptosis-inducing ability

In an attempt to synthesize a new potent cytotoxic and apoptosis-inducing agent against SK-BR-3 breast cancer cells, a new phosphoramide containing naphthoquinone (Diphenyl (1,4-dioxo-1,4-dihydronaphthalen-2-yl) phosphoramidate; A) was synthesized and characterized using some experimental techniques such as IR, 1H NMR, 13C NMR, 31P NMR, and Mass spectroscopies. The obtained data were compared with theoretical FT-IR, 1H NMR, 13C NMR and 31P NMR calculated with density functional theory (DFT), which confirmed that there is a good correlation between them. The cytotoxic activity of A against cancer cell line (SK-BR-3) and normal cell line (MCF10A) were evaluated through an MTT assay. The results showed a dose- and time-dependent anti-cancer activity with IC50 values of 10.3 mu M (24 h) and 8.1 mu M (48 h). According to the flow cytometry results, A showed great apoptosis-inducing ability at different concentrations (5 mu M) (41.88%), 20 mu M (72.6%), and 30 mu M (79.1%). Moreover, the cells inhibited through the late apoptosis pathway increased as a function of the concentration of A. In order to know the structure-activity relationship (SAR) of the synthesized compound and cyclophosphamide (Cpm), the values of HOMO and LUMO energies, hardness, softness, and electrophilicity index were investigated computationally by DFT-D correction in Material Studio 2017. Additionally, molecular docking simulation was used to compute the interactions between (A or Cpm) and transcription factor STAT3B/DNA complex (PDB ID: 1bg1), indicating A has a considerable anti-cancer potential with docking energy of -101.964 kcal.mol-1 compared with -64.281 kcal.mol-1 for Cpm.