Ruthenium(II) arene complexes bearing 1,10-phenanthroline substituted with an imidazolium salt: Synthesis, and cytotoxic activities

Researchers are increasingly focusing on developing target-specific, highly cytoselective, lipophilic, water-soluble Ru(II) arene complexes to mitigate the side effects of commercially available platinum-based anticancer drugs. In this context, we present novel Ru(II) arene complexes, (Ru1 and Ru1a-f), which are based on a 1,10-phenanthroline-substituted imidazolium core derivatized with alkyl (butyl(a), octyl(b), dodecyl(c)) or benzyl ((benzyl(d), 2,4,6-trimethylbenzyl(e), pentamethylbenzyl(f)) groups. The structures of these complexes were characterized using ¹H, ¹³C, ¹⁹F and, ³¹P nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared spectroscopy, mass spectrometry and elemental analysis. The cytotoxic activities of Ru1 and Ru1a-f complexes were tested against the cancer cell lines MCF-7 and MDA-MB-231 and normal cell lines, such as MCF-10 A. The cell cycle distribution in the MCF-7 and MDA-MB-231 breast cancer cell lines after 72 h of incubation with IC₅₀ concentration of the complex Ru1c can validly inhibit cell growth in the G2/M phase. Flow cytometry analysis showed that the complex Ru1c induced apoptosis in MCF-7 and MDA-MB-231 breast cancer cells. Additionally, the binding mode of the complex Ru1c with Fish-Salmon DNA was examined using ultraviolet-visible spectroscopy. Interaction of Ru1c complex with bovine serum albumin was analyzed by absorption study. The stability of all complexes in the solvent was assessed using ¹H NMR spectroscopy. Additionally, quantitative determination of the total ruthenium level within the cells was performed by inductively coupled plasma mass spectrometry (ICP-MS). Molecular docking was performed to evaluate the interaction residues and docking scores of Ru1c and the reference drug cis‑platinum against CDK1, cyclin B1, Bcl-xL and Bcl-2 proteins.