DNA-Independent Cytotoxicity of Furan-Based Cu(II) Schiff Base Complexes: A Ligand-Controlled Mechanistic Shift

The design of Cu(II) metallodrugs has traditionally emphasized strong DNA binding as a proxy for anticancer efficacy, but this paradigm has rarely been questioned. Herein, we report two new Cu(II) aroyl-hydrazone Schiff base complexes containing either a pyrrole (Complex 1) or a furan (Complex 2) moiety, which exhibit strikingly divergent biological behaviours despite similar coordination frameworks. Multi-spectroscopic, docking, and 100 ns molecular dynamics studies revealed that Complex 1 binds strongly to CT-DNA and BSA yet shows minimal cytotoxicity, whereas Complex 2, despite weaker DNA/BSA binding, displays potent anticancer activity against MDA-MB-231 (IC₅₀ = 26.9 μM) and MCF-7 (IC₅₀ = 41.3 μM) cells. Cellular assays demonstrate that Complex 2 induces apoptosis via ROS modulation and sub-G1 cell cycle arrest in a DNA-independent pathway, challenging the conventional DNA-binding-centric model of Cu(II) metallodrug design. These findings establish that subtle heteroaryl ligand modification (furan vs. pyrrole) can rewire cytotoxic mechanisms, providing a new framework for the rational design of Cu(II)-based anticancer agents with non-canonical modes of action.