Therapeutic Switching of Metformin Using Heteroleptic Cu(II) and Zn(II) Complexes: A Combined Experimental and Computational Study

Abstract

Ligands of the antidiabetic drug metformin and the natural flavonoid chrysin were used to synthesize Cu-(II) and Zn-(II) heteroleptic complexes. Metal complexation was used to repurpose metformin against the breast cancer cell line MCF-7. Structural information on the metal complexes was acquired using UV-vis absorption spectroscopy, FTIR, HRMS, TGA/DTA, XRD, SEM-EDX, molar conductance analysis, and time-dependent density functional theory (TDDFT). Accordingly, we proposed that the structure of complex <b>1</b> was [Cu-(C₄H₁₁N₅)-(C₁₅H₉O₄)-(C₂H₃O₂)], with a square pyramidal geometry, while complex <b>2</b> was [Zn-(C₄H₁₁N₅)-(C₁₅H₉O₄)]-C₂H₃O₂ and exhibited a tetrahedral geometry. The IC₅₀ values were 18.93 and 43.31 μM for complexes <b>1</b> and <b>2,</b> respectively, compared to the positive control cisplatin (IC₅₀ = 18.62 μM). The cancer cells' morphology changed from epithelial to a round shape, and the cell density decreased upon treatment, confirming the potential of the metal complexes to induce apoptosis. Computationally, the biological significance of the metal complexes was inferred from quantum chemical descriptors and molecular docking analysis. The band gap energies of the metal complexes were 2.964 and 3.648 eV for complexes <b>1</b> and <b>2</b>, respectively, compared to those of metformin (5.988 eV) and chrysin (4.403 eV). Moreover, molecular docking simulations against estrogen receptor alpha (ERα; PDB: 5GS4) revealed a binding energy of -5.69 kcal mol^-1 and an inhibition constant (<i>K</i> _i) of 51.37 μM for complex <b>1</b>, and -6.12 kcal mol^-1 and 30.12 μM, respectively, for complex <b>2</b>. This work demonstrates the therapeutic switching capability of metformin via metal complexation.