Ruthenium(ii) polypyridyl complexes and the DNA damage response: mechanisms and therapeutic implications

Ruthenium(ii) polypyridyl complexes (RPCs) have generated substantial interest due to their biomolecular binding capabilities, favourable photophysical properties, and anticancer activity. DNA is widely reported as a target for RPCs, and their recent development as photosensitisers for photodynamic therapy further emphasises DNA damage as a key biological outcome. The aim of this review is to highlight recent studies in the design of RPCs as pharmacological DNA-targeting agents and describe what is known about their impact on the DNA damage response (DDR). This, in turn, provides insight into the nature of the DNA lesions induced by these complexes. The relationship between binding mode, activation of specific DDR pathways, and resultant cell fate in human cancer cell lines is examined and, where appropriate, placed in a therapeutic context. Implications for enhancing cancer selectivity, including the use of RPCs alongside DDR inhibitors in combination strategies, as well as associated safety considerations, are discussed.