Effect of ancillary ligands on the topoisomerases II and transcription inhibition activity of polypyridyl ruthenium(II) complexes.

To explore the structure-activity relationship of polypyridyl ruthenium(II) complexes as topoisomerase II and T7 RNA polymerase inhibitors, four new complexes, [Ru(4dmb)(2)(ppd)](2+) (4dmb=4,4'-dimethyl-2,2'-bipyridine, ppd=pteridino[6,7-f][1,10] phenanthroline-1,13(10H,12H)-dione), [Ru(5dmb)(2)(ppd)](2+) (5dmb=5,5'-dimethyl-2,2'-bipyridine), [Ru(dip)(2)(ppd)](2+) (dip=4,7-diphenyl-1,10-phenanthroline), and [Ru(ip)(2)(ppd)](2+) (ip=imidazole[4,5-f][1,10]phenanthroline) have been synthesized and characterized in detail by (1)H NMR spectroscopy, mass spectrometry and elemental analysis. Their interaction with calf thymus DNA and the inhibitory activity towards topoisomerase II and T7 RNA polymerase were investigated. The results suggest that although all of these four Ru(II) complexes are potent DNA intercalators, topoisomerase II inhibitors and DNA transcription inhibitors, their DNA binding strength and inhibitory activities are quite different. The activity of ip- and dip-complexes are significantly higher than the dmb-complexes. To explain the experimental regularity and reveal the underlying quantum chemistry mechanism of the biological activity, the properties of energy levels and population of frontier molecular orbitals and excited state transitions of these complexes have been studied by density functional theory (DFT) and time-depended DFT (TDDFT) calculations. The results suggest that ancillary ligands bearing lower energy of the lowest unoccupied molecular orbitals (LUMOs), better hydrophobicity and less steric hindrance of are beneficial to the DNA intercalation and topoisomerase II and DNA transcription inhibition of their complexes.