α-Aminophosphonate and oxazaphosphinane compounds as potential cancer inhibitors: in vitro evaluation and computational studies

In this study, α-aminophosphonates and oxazaphosphinanes were synthesized and evaluated for their potential anticancer activity. The objective was to assess their cytotoxic effects against various cancer cell lines and to investigate their molecular interactions with cancer-related targets. The synthesized compounds were tested in vitro against four human cancer cell lines: HCT116 (colon), A549 (lung), PC3 (prostate), and MCF-7 (breast). Cytotoxicity was assessed through IC50 determination. Molecular docking was performed on cyclin-dependent kinase 2 (CDK2) and anaplastic lymphoma kinase (ALK), followed by 300 ns molecular dynamics (MD) simulations for the most active compounds. Density functional theory (DFT) calculations were conducted to analyze electronic properties and reactive functional sites. Most compounds showed moderate to good anticancer activity, with IC50 values ranging from 28.8 to 242.0 µM. Docking studies revealed strong binding affinities toward ALK (−6.23 to −8.46 kcal/mol) and CDK2 (−6.60 to −8.14 kcal/mol). Compounds 9b and 10c demonstrated the most favorable activity, exhibiting stable interactions in MD simulations and distinct electronic profiles in DFT analyses. The integrated experimental and computational results identify compounds 9b and 10c as promising lead candidates for further development as potential anticancer agents.