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

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.