Synthesis, crystal structure and antimelanoma activity of a novel copper (I) thiocyanate tris (4-methoxyphenyl) phosphine complex

• Cu(I) thiocyanate phosphine complex synthesized and fully characterized. • Exhibits strong cytotoxicity in A375 cells (IC 50 = 16.59 µM). • Shows low cytotoxic effect toward normal HEK293 cells. • Induces apoptosis via chromatin condensation and caspase-3/7 activation. • Mitochondrial stress in galactose medium confirms intrinsic apoptosis. Metal-based complexes have gained considerable attention in cancer research owing to their promising cytotoxic activity. Melanoma is an aggressive skin cancer with high metastatic potential, significantly limiting treatment efficacy and survival outcomes. In this study, a novel copper (I) thiocyanate tris(4-methoxyphenyl) phosphine complex ( VK2 ) was synthesized and structurally characterized using nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), elemental analysis, single-crystal X-ray diffraction and Ultraviolet-visible spectroscopy (UV–Vis). The antiproliferative effect of VK2 was evaluated against malignant A375 melanoma cells and non-cancerous HEK293 cells using the Alamar Blue assay. Apoptotic induction was assessed via light and fluorescence microscopy, caspase-3/7 activity, and Muse Annexin V/7-aminoactinomycin D (7-AAD) staining. Mitochondrial involvement in cell death was further confirmed using the Mitochondrial Tox-Glo™ assay. VK2, a phosphine-stabilized Cu(I) complex, was confirmed to have adopted a tetrahedral structure. Unlike Cu(II) analogues that readily generate reactive oxygen species (ROS), Cu(I) complexes are stabilized by soft-donor ligands and display distinct structure activity relationships such as increased lipophilicity. Preliminary UV–Vis studies suggest that VK2 can undergo Cu(I)/Cu(II) interconversion under oxidative conditions, potentially relevant to its bioactivity. The complex further exhibited selective cytotoxicity against A375 cells with an IC 50 of 16.59 ± 6.00 µM, compared to 35.24 ± 3.56 µM in HEK293 cells. VK2 induced classical apoptotic features, including chromatin condensation, nuclear fragmentation, and caspase activation. Importantly, mitochondrial toxicity was enhanced under galactose-supplemented conditions, indicating apoptosis via the intrinsic (mitochondrial) pathway. These findings suggest that VK2 is a promising copper-based anticancer agent against melanoma cells.