Authors
Megha Biswas, Kanishka Chaudhary, Kajol, Rakesh Kumar Pathak
Published in
Chemistry (Weinheim an der Bergstrasse, Germany). Pages e71473. Aug 14, 2026. Epub Aug 14, 2026.
Abstract
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.
PMID:
42596861
Bibliographic data and abstract were imported from PubMed on 14 Aug 2026.
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