Probing the drug-DNA interactions of new cytotoxic fluorinated platinum(II) complexes

In this work we report a new series of fluorinated 8-aminoquinoline and 8-aminoquinaldine platinum dichloride complexes (1-5) and investigate their anticancer potential and in vitro interactions with DNA. Initially, agarose gel electrophoresis experiments demonstrated crosslinking interactions with DNA, with complexes 2 and 3 displaying comparable activity to the cisplatin control. We then combined microscale thermophoresis (MST) and fluorescent intercalator displacement (FID) assays to characterise both their affinity and interaction mode towards DNA binding prior to performing cellular pharmacological tests. The results follow a general trend associated with DNA recognition whereby the more active agents displayed modest apparent binding constants (K_app) in the same range as Pt-8AQ (aromatic Pt control) and pronounced intercalator displacement during FID analyses. Interestingly, a fluorescence quenching effect was observed during MST investigations for the fluorinated complexes but not for cisplatin, suggesting a possible additional π-π interaction between the aromatic group of the ligand and the DNA-bound fluorophore. This dual mode of interaction may also contribute to the relatively higher DNA-binding affinity observed for complexes 2 and 3 and could be associated with their enhanced cytotoxic behaviour. Finally, inductively coupled plasma mass spectrometry (ICP-MS) analysis revealed that although 2 and 3 presented a lower percentage of total intracellular platinum associated with DNA compared to proteins, the relative amount of platinum per microgram of DNA was markedly higher than that of cisplatin. This finding suggests that, once localised inside the nucleus, the complexes may interact more efficiently with DNA, which appears linked to their heightened recognition properties.