Coordination Behavior of N, N′, N″-Trisubstituted Guanidine Ligands in Their Ru-Arene Complexes: Synthetic, DNA/Protein Binding, and Cytotoxic Studies

Ruthenium complexes are fascinating for exploration as anticancer drugs after the entry of KP1019 and NAMI-A in phase II clinical trials for the treatment of metastatic tumors. The reaction of guanidine ligands with [RuCl(μ-Cl)(Ε ⁶ -p-cymene)] ₂ yielded monometallic Ru(II) complexes with N,N-type (1) and O,N-type (2 and 3) ligands, whereas both monometallic (O,N) (7) and bimetallic Ru(II) (4-6) complexes were obtained when [RuCl(μ-Cl)(Ε ⁶ -benzene)] ₂ was used as a precursor. The complexes were characterized using analytical, spectroscopic (UV-vis, FT-IR, NMR, and mass), and single-crystal X-ray crystallography techniques. The stability of the complexes was tested by UV-visible spectroscopy. The complexes were investigated for their interaction with calf thymus (CT) DNA and bovine serum albumin using various spectroscopic techniques. Spectroscopic and viscosity experiments revealed that the intrinsic DNA binding affinity of the Ru-p-cymene complexes was greater than that of the analogous Ru-benzene complexes due to the increased hydrophobicity of the p-cymene ring. The in vitro cytotoxicity of the complexes against HepG2, A549, and Vero cells was evaluated using MTT assay. The results revealed that the complexes with O,N bidentate-type ligands, 2 and 3, showed good activity against HepG2 cell lines with an IC ₅₀ value of 15.41 and 17.74 μM, respectively. The results were compared with cisplatin, and it was inferred that complexes 2 and 3 showed better activity than cisplatin. The apoptosis mode of cell death was confirmed by staining and flow cytometry methods.