DNA Noncovalent Interactions of Dinuclear η6-Arene Ru(II) Complexes: Influence of Complex Charge and Bridging Ligand Length on DNA Binding Mode and Cytotoxic Activity.

A series of dinuclear η⁶-arene Ru(II) complexes with the general formulae {[(η⁶-p-cym)Ru(L1)]2(μ-BL-i)}2+ (1)-(3) and {[(η⁶-p-cym)2Ru2(L1)(L2)](μ-BL-i)}3+ (4)-(6), [L1 = benzo[h]quinoline (bq), L2 = 1,10-phenanthroline (phe) and BL-i the bridging ligands with i = 1 -3, 4,4'-bipyridine (BL-1), 1,2-bis(4-pyridyl)ethane (BL-2) and 1,3-bis(4-pyridyl)propane (BL-3)] were synthesized and fully characterized by high-resolution mass spectrometry and NMR spectroscopy. The crystal structures of the complexes (1)-(3) were determined by single-crystal X-ray diffraction. DNA binding interactions of the water-soluble chloride salts of the complexes (4)-(6) were investigated by NMR spectroscopy using the B-type DNA model oligonucleotide duplex d(5'-CGCGAATTCGCG-3')2. 1H NMR chemical shift changes revealed that the chelating ligands (phe or bq) partially intercalate and/or bind in the helix minor groove. Among these, complex {[(η⁶-p-cym)2Ru2(phe)(bq)](μ-BL-1)}3+, (4), induced the most pronounced perturbations, including partial helix unwinding. Fluorescence quenching experiments yielded the Stern-Volmer constants (Ksv) and the binding constants (Kb) in the moderate-to-high affinity range, consistent with the NMR observations. Preliminary cytotoxicity studies showed that the chloride salts of the complexes (1)-(6) exhibit low-micromolar IC50 values against MCF-7, A2780, and cisplatin-resistant A2780cis-resistant cell lines, while showing moderate selectivity for cancer cells over normal fibroblasts.