Phenyl‐Substituted Mixed‐Ligand Cu(II) <i>β</i> ‐Diketonates: Synthesis, Cytotoxicity, and Mechanistic Evaluation in Lung, Liver, and Ovarian Cancer Cells

Redox-active metal complexes of bioessential 3d metal ions, such as Cu(II), offer promising, potentially safer alternatives to Pt(II)-based chemotherapy. We report the synthesis, characterization, and biological evaluation of three phenyl-substituted Cu(II) β-diketonate complexes bearing a fixed 4'-phenyl-2,2':6',2″-terpyridine (Ph-tpy) ligand: [Cu(Ph-tpy)(acac)]ClO₄ (F1), [Cu(Ph-tpy)(Ph-acac)]ClO₄ (F2), and [Cu(Ph-tpy)(Ph₂-acac)]ClO₄ (F3). In these compounds, acac, Ph-acac, and Ph₂-acac represent the O,O-donor monoanionic β-diketonate ligands derived from 2,4-pentanedione, 1-phenyl-1,3-butanedione, and 1,4-diphenyl-1,4-butanedione, respectively. The 1:1 electrolytic, one-electron paramagnetic complexes were stable in solution for 48 h, with increasing lipophilicity (log P: 1.22-1.89). In vitro, F1-F3 showed potent cytotoxicity against A549, HepG2, and SKOV-3 cells (IC₅₀: 1.2-4.2 µM, 24 h) and minimal toxicity toward Vero cells (∼90 µM), demonstrating promising potency and selectivity. AO/PI staining, DNA laddering, and clonogenic assays confirmed apoptosis induction and proliferation inhibition, with qRT-PCR revealing upregulation of p53, p21, and BAX, and downregulation of BCL-2 in cancer cells. Flow cytometry indicated G1-phase arrest. Docking studies suggested favorable binding to EGFR, ALK, and HSA, while molecular dynamics simulations suggested the formation of stable protein-ligand complexes. Collectively, these mixed-ligand Cu(II) complexes exhibit high anticancer efficacy, low toxicity to normal cells, and multi-target interactions, underscoring their potential as next-generation chemotherapeutic agents.