Multinuclear ruthenium(ii) complexes as anticancer agents

Abstract

A series of dinuclear ruthenium(II) complexes that contain labile chlorido ligands, [{Ru(tpy)Cl}₂{μ-bb_n}]²⁺ {designated Cl-Rubb_n; tpy = 2,2′:6′,2′′-terpyridine, bb_n = bis[4(4′-methyl-2,2′-bipyridyl)]-1,n-alkane (n = 7, 10, 12, 14 or 16)} and derivatives containing nitro substituents on the tpy ligand and/or secondary amines within the bb_n linking chain have been synthesised and their potential as anticancer agents examined. Some of the Cl-Rubb_n species showed good anticancer activity against MCF-7 and MDA-MB-231 breast cancer cell lines, with the Cl-Rubb₁₂ complex being four-times more active than cisplatin. Inclusion of nitro substituents on the tpy ligands of Cl-Rubb₁₂ resulted in significantly decreased anticancer activity. The incorporation of amine groups into the linking ligand did not increase the anticancer activity of the Cl-Rubb_n complexes. The Cl-Rubb_n complexes and those containing amine groups in the linking chain aquated at approximately the same rate, with 50% aquation within 120 minutes. By comparison, the complexes containing nitro substituents on the tpy ligand aquated extremely slowly, with 60% of the chlorido complex remaining 24 hours after they were dissolved in water. Cyclic voltammetry with the model mononuclear complex [Ru{(NO₂)₃tpy}(Me₂bpy)Cl]⁺ {(NO₂)₃tpy = 4,4′,4′′-trinitro-2,2′:6′,2′′-terpyridine} showed that the nitro substituents exerted a strong effect on the ruthenium centre, with the anodic peak corresponding to the Ru(III/II) couple shifted positively by 300 mV compared to that from the non-nitrated parent complex [Ru(tpy)(Me₂bpy)Cl]⁺. ¹H NMR studies of the reaction of the Cl-Rubb_n complexes with GMP indicated that the ruthenium complexes covalently bound the nucleotide slowly, with 33% bound in 24 hours. However, the results of this study suggest that the cytotoxicity of the dinuclear ruthenium complexes is a combination of covalent and reversible binding with DNA.