Pt(iv) scaffold effects on nucleolar stress and DNA damage response pathways

The platinum compounds cisplatin and oxaliplatin are widely used anticancer agents. Although platinum compounds have long been thought to induce cell death through the DNA damage response (DDR), subsequent work has shown that oxaliplatin instead engages a nucleolar stress pathway characterized by disruptions to ribosome biogenesis. Importantly, tuning platinum compounds' non-labile ligand identity, particularly incorporation of the diaminocyclohexane (DACH) ligand, influences nucleolar stress induction. While effective, Pt(ii) drugs are limited by severe side effects arising, in part, from multiple targets as well as a lack of selectivity between malignant and non-malignant cells. The axial ligands of Pt(iv) compounds afford tunable properties that may improve selectivity. Here, we investigate how platinum compound ligand identity and oxidation state together dictate engagement of either the DDR or nucleolar stress pathway. Using a series of dicarboxylate Pt(iv) complexes derived from cisplatin and DACH-Pt scaffolds, we find that Pt(iv) compounds bearing aliphatic dicarboxylate axial ligands preserve the pathway specificity encoded by their Pt(ii) cores: cisplatin analogs primarily activate the DDR, whereas DACH-Pt analogs preferentially induce nucleolar stress. Increasing compound lipophilicity enhances antiproliferative activity and cellular accumulation, and accelerates pathway activation. However, analysis of uptake, response onset, and IC₅₀ values reveals that lipophilicity alone does not fully account for biological activity. Notably, we identify the most potent nucleolar stress inducer reported, a Pt(iv) compound requiring ∼1000-fold lower concentrations to trigger nucleolar stress than the DACH-Pt(ii) analogue. Together, these findings establish Pt(iv) ligand design as a strategy to optimize antiproliferative activity while selectively intensifying DDR or nucleolar stress.