Metal copper complexes have attracted extensive attention as potential alternatives to
platinum-based anticancer drugs due to their possible different modes of action. Herein, a new
copper(II)
gluconate complex, namely [Cu(DPQ)(Gluc)]·2H2O (CuGluc, DPQ = pyrazino[2,3-f][1,10]
phenanthroline), with good water-solubility and high anticancer activity was synthesized by using
D-gluconic acid (Gluc-2H) as an auxiliary
ligand. The complex was well characterized by single-crystal X-ray diffraction analysis, elemental analysis, molar conductivity, and Fourier transform infrared spectroscopy (FTIR). The
DNA-binding experiments revealed that CuGluc was bound to
DNA by intercalation with end-stacking binding. CuGluc could oxidatively cleave
DNA, in which 1O2 and H2O2 were involved. In addition, CuGluc was bound to the IIA subdomain of
human serum albumin (HSA) through hydrophobic interaction and hydrogen bonding, showing a good affinity for HSA. The complex showed superior anticancer activity toward several
cancer cells than
cisplatin in vitro. Further studies indicated that CuGluc caused apoptotic cell death in human
liver cancer (HepG2) cells through elevated intracellular
reactive oxygen species (ROS) levels,
mitochondrial dysfunction, cell cycle arrest, and
caspase activation. Interestingly, CuGluc also triggered the ferroptosis mechanism through
lipid peroxide accumulation and inhibition of
glutathione peroxidase 4 (GPX4) activity. More importantly, CuGluc significantly inhibited
tumor growth in vivo, which may benefit from the combined effects of apoptosis and ferroptosis. This work provides a promising strategy to develop highly effective antitumor
copper complexes by coordinating with the
glucose metabolite
D-gluconic acid and exploiting the synergistic effects of apoptosis and ferroptosis mechanisms.