Targeting non-canonical DNA with π-extended Schiff Base complexes of Zinc(II), Copper(II), and Nickel(II): Insights into G-Quadruplex binding modes

The selective recognition of G-quadruplex (G4) DNA structures by metal complexes holds considerable promise for anticancer drug development, particularly for targeting oncogene promoters and telomeric regions. Herein, we report the synthesis, structural characterization, and DNA-binding strength evaluation of a new series of transition metal complexes derived from a N₄ tetradentate naphthalene-bridged Schiff base ligand (Naphthim). The zinc(II), copper(II) and nickel(II) complexes were obtained via in situ or transmetallation protocols and characterized by NMR, HR-ESI-MS, and elemental analysis. Among them, the copper(II) complex, 2, [CuNaphthim]²⁺, exhibited the highest DNA-binding affinity and G4-stabilizing ability, as assessed by FRET-based DNA melting assays, UV-Vis absorption, and circular dichroism (CD) spectroscopy. Despite lacking cationic side chain substituents, 2 showed moderate stabilization of several G4 structures, with a preferential effect on the cMyc quadruplex. Comparative studies with the benchmark [CuPhenim]²⁺ complex revealed that π-extension of the ligand framework substantially enhances DNA-binding affinity and modulates selectivity. UV-Vis and CD spectroscopy revealed clear differences in DNA-binding behavior between 2 and [CuPhenim]²⁺, with compound 2 exhibiting stronger and more defined interactions across both G4 and duplex targets. These trends found support by molecular docking, which uncovered distinct binding modes depending on G4 topology and echoed the observed affinity profiles. These findings highlight the Naphthim scaffold as a promising modular platform for the design of G4-targeting metal complexes.