Platinum(II) complexes with 4,5-diazafluorene ligands: Synthesis, structural features, and in vitro antiproliferative evaluation

A series of platinum(II) complexes bearing 9,9-diaryl-4,5-diazafluorene bidentate ligands (N-N) has been synthesized, and their structural and antiproliferative properties were evaluated. The aryl substituents on the diazafluorene core feature representative variations in electronic and steric properties. Two families of complexes were prepared: type a [PtCl₂(N-N)] and type b [Pt(C₆F₅)₂(N-N)]. All compounds were characterized by NMR and MS, and single-crystal X-ray diffraction of selected examples confirmed the expected square-planar geometry. Stability studies in DMSO‑d₆ revealed contrasting behaviour: type b complexes remained intact over 48 h, whereas type a compounds underwent solvolysis to form [PtCl₂(κ¹-N-N)(DMSO)] species. Under high DMSO excess, the process results in partial conversion to fully substituted species. The solvolysis of complex 2a was examined at varying DMSO concentrations for equilibrium constants estimation, and ¹H NMR monitoring over time, followed by microkinetic modelling, supported a stepwise associative substitution mechanism. Antiproliferative activity of the complexes was analyzed in lung carcinoma (A-549), cervical carcinoma (HeLa), and ovarian adenocarcinoma (SK-OV-3) cell lines as well as non-malignant lung fibroblasts (MRC-5). Several complexes of both families exhibited cytotoxicity comparable or superior to cisplatin in lung, cervical, and ovarian cancer cell lines. Notably, complex 9a emerged as a remarkably promising candidate, combining high potency with the best selectivity index against lung cancer cells. EMSA experiments revealed supercoiled DNA interaction only for type a compounds, suggesting distinct mechanisms of action for the two families. The Pt cellular uptake was estimated, revealing no correlation between cellular uptake and IC₅₀ values.