Synthesis, nucleic acid binding and cytotoxicity of oligonuclear ruthenium complexes containing labile ligands

Abstract

We report the synthesis, nucleic acid binding and cytotoxicity of the complexes [Ru(terpy)(Me2bpy)Cl]+, [Ru(terpy)(phen)Cl]+ and dinuclear [{Ru(terpy)Cl}2(mu-bbn)]2+ {where Me2bpy = 4,4'-dimethyl-2,2'-bipyridine; phen = 1,10-phenanthroline; and bbn = bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane, with n = 7, 10, 12, 14}. The complexes were isolated from the reaction of the [Ru(terpy)Cl3] precursor with the respective bidentate and di-bidentate bridging ligands. The time-course UV-Visible spectroscopy of the reaction of the mono- and dinuclear complexes with guanosine 5-monophosphate (GMP) showed the movement of the metal-to-ligand charge transfer (MLCT) band to lower wavelengths, accompanied by a hypochromism effect. The formation of the aqua complex and phosphate-bound intermediates in the reaction were detected by the time-course 1H NMR and 31P NMR experiments, which also demonstrated that the complex bound to the N7 guanine was the major product. The UV-Visible and 1H NMR studies showed no evidence of the interaction of the complexes with both adenosine 5-monophosphate (AMP) and cytidine 5-monophosphate (CMP). Cytotoxicity studies of these complexes against a murine leukemia L1210 cell line revealed that the dinuclear [{Ru(terpy)Cl}2(mu-bbn)]2+ complexes were significantly more cytotoxic than mononuclear [Ru(terpy)(Me2bpy)Cl]+. The [{Ru(terpy)Cl}2(mu-bb14)]2+ complex appeared to be the most active (IC50 = 4.2 muM).