Naphthyl-Substituted Ruthenium(II)-Arene Complexes: Exploring the Impact of Binding Modes on Cytotoxicity in Cancer and Normal Cell Lines.

Abstract

This study investigated the cytotoxic properties of three naphthyl-substituted ruthenium(II)-arene complexes (Ru1, Ru2, and Ru3) against various cancer cell lines (MCF-7, Caco-2, and HepG2) and a healthy cell line (Vero). Herein, we report the novel synthesis and characterization of Ru3 for the first time. The complexes were fully characterized by ¹H, ¹³C, and 2D NMR spectroscopies, and their interactions with DNA and bovine serum albumin (BSA) were evaluated. Binding constant (Kb) determinations revealed values of 2.95 × 10⁴ M^-1, 2.27 × 10⁴ M^-1, and 3.70 × 10⁴ M^-1 for Ru1, Ru2, and Ru3 with FS-DNA, respectively, while Ru2 exhibited a significantly higher binding constant of 0.86 × 10⁵ M^-1 with BSA, indicating a favorable binding interaction. Molecular docking of Ru3 was performed against BSA, EGFR wild type (EGFRWT), and mutant EGFRT790M. Ru3 exhibited docking scores of -178.827, -204.437, and -176.946 kJ/mol with BSA, EGFRWT, and EGFRT790M, respectively. Cytotoxicity assays revealed that Ru1-3 exhibited superior activity against MCF-7 and Caco-2 cells compared to HepG2 cells. Following a 24-h exposure, Ru2 exhibited an IC₅₀ of 1.39 μg/mL against the Caco-2 cell line. Morphological analysis suggested that all complexes induced apoptosis in cancer cells. Notably, Ru2 demonstrated minimal activity against Vero cells, indicating selectivity. Hirshfeld surface analysis was employed to investigate intermolecular interactions within the crystal structures of the complexes, providing insights into their molecular shapes and potential for interactions with other molecules. In conclusion, this study highlights the promising potential of naphthyl-substituted ruthenium(II) complexes as anticancer agents. Their selective cytotoxicity and ability to induce apoptosis warrant further investigation for the development of novel cancer therapies.