Nitric oxide release from half-sandwich Ru(II)-p-cymene acylthiourea nitrite complexes: antiproliferative activities and vasorelaxant properties.

Abstract

In half-sandwich Ru(II)-p-cymene frameworks, the labile chlorido ligand can readily undergo substitution by various donor groups such as triphenylphosphine, azide, or a nitro group. In the present study, we report for the first time the incorporation of a nitrito (NO₂^-) ligand into an acylthiourea-based Ru(II)-p-cymene system. The six Ru(II)-p-cymene complexes comprising chlorido derivatives L₁RuCl-L₃RuCl (1a-3a) and nitrite-bound analogues L₁RuNO₂-L₃RuNO₂ (1b-3b) were synthesized under distinct reaction conditions and fully characterized. The molecular structures of complexes 1b and 2b were established by single-crystal X-ray diffraction analysis, while FT-IR, UV-Vis, and ¹H/¹³C NMR spectroscopic studies clearly differentiated the coordination of the two co-ligands. A nitric oxide release study was performed chemically using (TPP)Co as an NO trapping agent, showing >70% NO release in an acidic environment for 1b and 2b. The antiproliferative activity of Ru-nitro complexes was greater than that of precursor Ru-chloride complexes in both TNBC (HCC1937) and non-TNBC (SKBR-3) cells. In the TNBC line, complexes 1b and 2b showed the lowest IC₅₀ values (8.55 ± 1.00 and 7.47 ± 0.95 μM) and induced higher caspase-3/7 apoptotic activity than L1 and L2, which themselves produced greater activity than 1a and 2a. In vasorelaxation studies, 1b and 2b showed pronounced relaxation, achieving 85.48 ± 7.47% and 77.18 ± 4.97%, which are significantly greater than their chlorido complexes. DFT-D3 calculations were also performed to evaluate NO and OH release for all complexes, revealing that complex 2b exhibited higher NO-release, consistent with its observed anticancer activity.