Ru(II)‐arene complexes with phenolic acid ligands: Synthesis, density function theoretical calculations, anti‐cancer studies, and cell death mechanisms

Abstract

Six new complexes (1–6), [Ru(η6‐p‐cymene)(FA)Cl] (1), [Ru(η6‐p‐cymene)(PA)Cl] (2), [Ru(η6‐p‐cymene)(SA)Cl] (3), [Ru(η6‐p‐cymene)(FA)PPh3]Cl (4), [Ru(η6‐p‐cymene)(PA)PPh3]Cl (5), [Ru(η6‐p‐cymene)(SA)PPh3]Cl(6), [HFA = ferulic acid, HPA = p‐coumaric acid, HSA = sinapinic acid], were synthesized and well characterized by various spectroscopic, analytical techniques and computational studies. Amongst these six complexes, complexes 4, 5, and 6 were found to be selectively cytotoxic toward melanoma (A375) cell lines and were non‐cytotoxic toward non‐cancerous cell lines (HEK 293 T). Further investigation on the probable bio‐molecular interaction mechanisms revealed that all the complexes show strong groove binding interactions with the DNA, however, complexes 3, 4 and 3, 6 show strong interaction with BSA and HSA, respectively. Through Hoechst staining it can be elucidated that complexes 4–6 cause characteristic apoptotic nuclear changes in the cells indicating apoptosis as the cell death mechanism caused by complexes 4–6. To further confirm the cell death mechanism, protein expression analysis was done through western blotting, which showed a decrease in anti‐apoptotic protein (Bcl‐xL) expression and increased pro‐apoptotic protein (PARP) expression, which confirms the cell death by apoptosis. Using DCFDA staining, we observed that complexes 4, 5, and 6 produced more ROS in the cells, which also might be the cause of cell death by the complexes. Along with that the complexes show enhanced anti‐migratory abilities depicted through wound healing assay.