Structural, Quantum Chemical, and Cytotoxicity Analysis of Acetylplatinum(II) Complexes with PASO2 and DAPTA Ligands

Abstract

The development of novel platinum-based anticancer agents remains a critical objective in medicinal inorganic chemistry, particularly in light of resistance and toxicity limitations associated with cisplatin. In this study, the synthesis, structural characterization, quantum chemical analysis, and cytotoxic evaluation of four new acetylplatinum(II) complexes (cis-[Pt(COMe)2(PASO2)2], cis-[Pt(COMe)2(DAPTA)2], trans-[Pt(COMe)Cl(DAPTA)2], and trans-[Pt(COMe)Cl(PASO2)]: 1–4, respectively) bearing cage phosphine ligands PASO2 (2-thia-1,3,5-triaza-phosphaadamantane 2,2-dioxide) and DAPTA (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) are presented. The coordination geometries and NMR spectral features of the cis/trans isomers were elucidated through multinuclear NMR and DFT calculations at the B3LYP/6-311++G(d,p)/LanL2DZ level, with strong agreement between experimental and theoretical data. Quantum Theory of Atoms in Molecules (QTAIM) analysis was applied to investigate bonding interactions and assess the covalent character of Pt–ligand bonds. Cytotoxicity was evaluated against five human cancer cell lines. The PASO2-containing complex in cis-configuration, 1, demonstrated superior activity against thyroid (8505C) and head and neck (A253) cancer cells, with potency surpassing that of cisplatin. The DAPTA complex 2 showed enhanced activity toward ovarian (A2780) cancer cells. These findings highlight the influence of ligand structure and isomerism on biological activity, supporting the rational design of phosphine-based Pt(II) anticancer drugs.