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

Redox‐active metal complexes of bioessential 3 d 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)]ClO 4 ( F1 ), [Cu(Ph‐tpy)(Ph‐acac)]ClO 4 ( F2 ), and [Cu(Ph‐tpy)(Ph 2 ‐acac)]ClO 4 ( F3 ). In these compounds, acac, Ph‐acac, and Ph 2 ‐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 (IC 50 : 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.