Synthesis, in vitro cytotoxic and apoptotic effects, and molecular docking study of novel adamantane derivatives

[4‐(Adamantane‐1‐carboxamido)‐3‐oxo‐1‐thia‐4‐azaspiro[4.4]nonan‐2‐yl]acetic acid (4a) and [4‐(adamantane‐1‐carboxamido)‐8‐nonsubstituted/substituted‐3‐oxo‐1‐thia‐4‐azas‐piro[4.5]decane‐2‐yl]acetic acid (4b–g) derivatives were synthesized; their structures were verified by elemental analysis, infrared spectroscopy, 1H nuclear magnetic resonance (NMR), 13C NMR, and mass spectroscopy data; and their in vitro cytotoxicity activities were investigated against human hepatocellular carcinoma, human prostate adenocarcinoma, and human lung carcinoma cell lines (HepG2, PC‐3, and A549, respectively), and a mouse fibroblast cell line (NIH/3T3). All compounds, except compound 4e, were found as cytotoxic, especially on A549 cells as compared with the other cells (selectivity index = 2.01–11.6). As a further step, the effects of compounds 4a–c on apoptosis induction were tested and the expression of selected apoptosis genes was analyzed. Among the selected compounds, compound 4a induced apoptosis remarkably. Moreover, computational calculations of the binding of compounds 4a–c to the BIR3 domain of the human inhibitor of apoptosis protein revealed ligand–protein interactions at the atomistic level and emphasized the importance of a hydrophobic moiety on the ligands for better binding. Novel adamantane derivatives (4a–g) were synthesized and investigated for their in vitro cytotoxicity against three human carcinoma cell lines. All compounds, except compound 4e, showed cytotoxicity. Apoptosis induction by compounds 4a–c and the expression of selected apoptosis genes were analyzed. Ligands 4a–c bound to similar binding pockets of the human inhibitor of apoptosis protein, with similar binding affinities.