Design, synthesis and anticancer evaluation of novel half-sandwich Ru(II) complexes bearing pyrazalone moiety: Apoptosis inducers based on mitochondrial dysfunction and G0/G1 arrest

Six half-sandwich Ru(II) complexes (Ru1-Ru6), integrated with 5-phenyl-2-(pyridin-2-yl)-2,4-dihydro-3H-pyra-zol-3-one (PDPO1-PDPO6) ligands, were synthesized and spectroscopically characterized. The structure of Ru3 that crystallized as a monoclinic crystal with P21/c space group was further confirmed by X-ray single crystal diffraction. Prototropic tautomerism within the complexes transformed OH-form ligands to NH-form, forming a hydrogen bond (Cl1-H-N3). The complexes and ligands' cytotoxicity was assessed against several cancerous (HepG2, A549, MCF-7) and normal Vero cell lines. Relative to the ligands and Cisplatin, complexes (Ru2, Ru3, Ru5, Ru6) exhibited potent cytotoxicity against cancer cells, with IC50 values from 2.05 to 15.69 mu M/L, excluding Ru1 and Ru4. Specifically, Ru2, Ru3, and Ru5 demonstrated superior anti-HepG2 properties. Compared to Cisplatin, Ru2 and Ru5 were less toxic to Vero cells, highlighting their enhanced selectivity in toxicity. Structure-activity relationship (SAR) studies indicated that t-butyl substitution (in Ru2) or-Cl (in Ru5) on the benzene ring significantly improved the selective toxicity. These complexes manifested substantial lipophilicity, cellular uptake, and were quickly hydrolyzed to Ru-H2O species. Roughly positive correlations were observed between hydrolysis rate, lipophilicity, cellular uptake, and anticancer activities. Ru2, investigated specifically, induced apoptosis in HepG2 cells at concentrations of 10 and 20 mu M/L through ROS-mediated mitochondrial dysfunction and G0/G1phase arrest, associated with altered P21, cyclin D, and CDK4 expression levels.