Aroma‐Platins: A Modular Extended‐Aromatic β‐Diketonate Platinum(II) Platform for Tunable Activation and Anticancer Activity

Platinum chemotherapy is often limited by nonspecific reactivity and variable intracellular activation. Here, we introduce Aroma-Platins, a rationally designed series of Pt(II) β-diketonate prodrug-like complexes in which the extended aromatic ring size of the β-diketonate leaving group is increased to program activation behavior and biological performance. Three congeners (Phn-Platin, Nap-Platin, and Ant-Platin) were synthesized and fully characterized, enabling a direct structure-property analysis across the series. Time-resolved studies under physiological conditions revealed ring-size-dependent activatability, with faster ligand release/complex transformation for larger π-surfaces. This reactivity was further enhanced in the presence of glutathione and dGMP, consistent with intracellular cues relevant to platinum pharmacology. Biomolecular interaction studies using ctDNA showed progressively stronger DNA association, most pronounced for Ant-Platin. In vitro evaluation across two aggressive cancer models, MDA-MB-468 and MiaPaCa2, demonstrated that Aroma-Platins are markedly more cytotoxic than their free ligands and carboplatin, with live/dead staining corroborating enhanced cell killing. Ant-Platin also exhibited enhanced DNA damage, as evidenced by immunofluorescence and cell cycle analysis studies in MDA-MB-468 cells. Collectively, this work establishes leaving-group π-engineering as a practical handle to tune Pt(II) prodrug activation, uptake, and efficacy, identifying Ant-Platin as a lead candidate for formulation-enabled translational and preclinical development.