Biomolecular Interactions and Anticancer Mechanisms of Ru(II)-Arene Complexes of Cinnamaldehyde-Derived Thiosemicarbazone Ligands: Analysis Combining In Silico and In Vitro Approaches

Our
study focuses on synthesizing and exploring the potential of
three N-(4) substituted thiosemicarbazones derived from cinnamic aldehyde,
alongside their Ru(II)-(η6 -p-cymene)/(η6-benzene) complexes. The synthesized compounds were comprehensively
characterized using a range of analytical techniques, including FT-IR,
UV–visible spectroscopy, NMR (1H, 13C),
and HRMS. We investigated their electronic and physicochemical properties
via density functional theory (DFT). X-ray crystal structures validated
structural differences identified by DFT. Molecular docking predicted
promising bioactivities, supported by experimental observations. Notably,
docking with EGFR suggested an inhibitory potential against this cancer-related
protein. Spectroscopic titrations revealed significant DNA/BSA binding
affinities, particularly with DNA intercalation and BSA hydrophobic
interactions. RuPCAM displayed the strongest binding
affinity with DNA (Kb = 6.23 × 107 M–1) and BSA (Kb = 9.75 × 105 M–1). Assessed the cytotoxicity of the complexes
on cervical cancer cells (HeLa), and breast cancer cells (MCF-7 and
MDA-MB 231), revealing remarkable potency. Additionally, selectivity
was assessed by examining MCF-10a normal cell lines. The active complexes
were found to trigger apoptosis, a vital cellular process crucial
for evaluating their potential as anticancer agents utilizing staining
assays and flow cytometry analysis. Intriguingly, complexation with
Ru(II)-arene precursors significantly amplified the bioactivity of
thiosemicarbazones, unveiling promising avenues toward the creation
of powerful anticancer agents.