Ruthenium–arene complexes with Bis(pyrazol-1-yl)methane ligands: Structural characterization, DFT investigation, and preliminary cytotoxicity studies

Abstract

A series of four η⁶-arene ruthenium(II) half-sandwich complexes (RuL1 - RuL4) with bis(pyrazol-1-yl)methane ligands (bpzm, bdmpzm) were synthesized and characterized by FTIR, NMR, ESI-MS, elemental analysis, and single-crystal X-ray diffraction. The structures confirmed the expected piano-stool geometries, with subtle effects of arene identity (p-cymene vs. toluene) and pyrazole methylation on Ru–N bond distances and chelate angles. Density functional theory (DFT) calculations at the B3LYP/6-31G**//LanL2DZ level reproduced the experimental structural parameters within ≤ 2.7% and revealed relatively large HOMO–LUMO gaps (3.971–4.068 eV), consistent with a comparatively high degree of electronic stability across the series. Preliminary cytotoxicity studies were conducted using single-dose screening at 20 µM in 0.1% DMSO against nine human cancer cell lines, including breast, cervical, pancreatic, and rhabdomyosarcoma subtypes, revealed limited cytotoxic activity, with cell viabilities exceeding 80% in all cases. Although no direct mechanistic relationship can be established from the present data, the low cytotoxic response may be associated, in part, with the relatively high electronic and kinetic stability of the complexes, which could limit biologically relevant ligand exchange, aquation, or redox-associated activation processes.Overall, the findings highlight the importance of balancing structural stability with controlled chemical lability in the design of biologically active η⁶-arene Ru(II) complexes and provide a basis for future ligand modifications, as well as additional studies on solution stability and speciation under biologically relevant conditions, aimed at improving biological performance.