Exploring the DNA-binding and anticancer potential of polypyridyl ruthenium(II) complexes

Organometallic medicines based on ruthenium (Ru) have attracted interest as chemotherapeutic and bioimaging agents due to their low toxicity and superior physical optical characteristics. However, there are still no ideal candidates in clinical trials due to the lack of understanding of the structure-activity relationships (SARs) of polypyrodyl Ru(II) complexes. Though increasing the electron-donating ability of the ligands has been proven to benefit bioactivity due to the fast hydroxylation rate between chlorine and DNA, the total electronic effects are much more important, especially for the binding modes between Ru(II)-polypyridyl complexes and DNA. By evaluating the electron-donating ability of the ligand complexes 1 - 4 through density functional theory (DFT) calculations, bioactivities tests, and docking studies, we investigated the relationship between the structures of Ru(II) complexes and cytotoxicity. Our findings showed that it was insufficient to merely consider the impact of electron-donating effects on biological activities in place of interaction modes. Furthermore, the cellular imaging study investigated the complex with phenyl substituents (1) and confirmed that the main target was DNA. Besides, the "off-on" emission phenomena of complex 1 indicated that there is also covalent interaction with DNA. These findings offer valuable insight into the development of SARs of polypyrodyl Ru(II) complexes.