DFT and TD-DFT Study of the Structure-Cytotoxic Activity Relationship of Ruthenium Polypyridine Complexes Derived from RuCl2(azpy)2

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Ruthenium polypyridine complexes are of interest because of their cytotoxic activity and their lower toxicity relative to cisplatin. This study applies density functional theory and time-dependent density functional theory to examine structure–cytotoxic activity relationships in five ruthenium azopyridine complexes derived through ligand substitution. Ground-state geometries and vibrational frequencies were evaluated at the B3LYP/LanL2DZ level in the gas phase, followed by analyses of global and local reactivity, frontier molecular orbitals, natural bond orbitals and electronic absorption. The calculations indicate that molecular geometry influences the proposed mode of interaction between the complexes and DNA bases. The α-RuCl₂(azpy)₂ complex has the smallest HOMO–LUMO energy gap among the studied compounds, while substitution of the chlorine atoms by polypyridine ligands increases stability and decreases chemical reactivity relative to the reference complex. NBO analysis identifies donor–acceptor interactions involving ruthenium and the coordinated nitrogen atoms and reveals an LP(Ru)→π*(N1=N2) interaction associated with metal-to-ligand charge transfer. The calculated local-reactivity descriptors identify distinct reactive sites at the ruthenium centre and the azo-nitrogen atoms. TD-DFT calculations further show absorption in the visible region and metal-to-ligand charge-transfer features. Collectively, the results provide a computational structure–activity interpretation of the reported cytotoxicity trends and indicate spectroscopic properties relevant to the proposed photodynamic-therapy application.