StructureActivity Relationship of Polypyridyl Ruthenium(II) Complexes as DNA Intercalators, DNA Photocleavage Reagents, and DNA Topoisomerase and RNA Polymerase Inhibitors

Abstract

To investigate the relationship between the molecular structure and biological activity of polypyridyl Ru(II) complexes, such as DNA binding, photocleavage ability, and DNA topoisomerase and RNA polymerase inhibition, six new [Ru(bpy)(2)(dppz)](2+) (bpy=2,2'-bipyridine; dppz=dipyrido[3,2-a:2,',3'-c]phenazine) analogs have been synthesized and characterized by means of (1)H-NMR spectroscopy, mass spectrometry, and elemental analysis. Interestingly, the biological properties of these complexes have been identified to be quite different via a series of experimental methods, such as spectral titration, DNA thermal denaturation, viscosity, and gel electrophoresis. To explain the experimental regularity and reveal the underlying mechanism of 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 DNA intercalative ligands with better planarity, greater hydrophobicity, and less steric hindrance are beneficial to the DNA intercalation and enzymatic inhibition of their complexes.

Synthesis, characterization and DNA-binding properties of Ru(II) complexes coordinated by ofloxacin as potential antitumor agents

“…Viscosity changes were measured using CT DNA with increasing concentrations of the complexes as shown in figure 5. The effects of ofloxacin, 1, 2, and 3 versus [Ru(bpy) 3 ] 2+ and EB (ethidium bromide) on the relative viscosity of rod-like DNA are shown in figure 5. [Ru(bpy) 3 ] 2+ interacts with DNA in a classical electrostatic effect with little changes in the viscosity of CT DNA and EB interacts with DNA in a classical intercalating mode showing increasing viscosity [35,36]. The relative viscosity of the DNA does not change as the amounts of ofloxacin, 1, 2, and 3 increase, which is similar with [Ru(bpy) 3 ] 2+ .…”

Photoinduced DNA Cleavage and Photocytotoxic of Phenanthroline-Based Ligand Ruthenium Compounds

“…The amount of Form I (the intact supercoil form) decreased and the amount of Form II (the nicked circular form) increased. Many polypyridyl ruthenium complexes have been reported to be DNA photocleavers [ 30 , 43 , 49 , 50 ]. For example, [Ru(bpy) 2 dppn] 2+ (dppn = 4,5,9,16-tetraaza-dibenzo[a,c]naphthacene) can completely cleave Form I into Form II at 5 μM [ 49 ].…”

The 1,10-Phenanthroline Ligand Enhances the Antiproliferative Activity of DNA-Intercalating Thiourea-Pd(II) and -Pt(II) Complexes Against Cisplatin-Sensitive and -Resistant Human Ovarian Cancer Cell Lines

“…We confirmed here that metal phenanthroline complexes were active TOPO-II inhibitors, and showed again that Pd(phen) were the most active TOPO-II inhibitors among the tested metal planar complexes, even at the smallest concentration tested. Although a mechanism of action cannot be exactly proposed [8,32], their interaction with DNA and TOPO-II may result in cell death via apoptosis [33].…”