The first copper(I) complex of anthrahydrazone with potential ROS scavenging activity showed significant in vitro anticancer activity by inducing apoptosis and autophagy

Based on the anticancer pharmacophore of anthrahydrazone and quinoline, a new quinolylanthrahydrazone ligand, 9-AQH (anthracene-9-quinolylhydrazone), was synthesized to further afford four metal complexes, [Co-II(9-AQH)(NO3)(2)(H2O)] (1), [Ni-II(9-AQH)(2)(H2O)(2)]center dot 2NO(3) (2), [Cu-I(9-AQH)(2)]center dot NO3 (3), [Zn-II(9-AQH)(2)(NO3)]center dot NO3 (4), determined by X-ray single crystal diffraction analysis. The reaction of Cu(NO3)(2) with 9-AQH formed the stable and repeatable copper(I) complex 3. In vitro screening demonstrated only 3 showed significant and broad-spectrum anticancer activity, indicating that Cu(I) played a key role in exerting the anticancer activity. In solution, Cu(I) was not naturally oxidized to Cu(II) suggested by H-1-NMR (Nuclear Magnetic Resonance) and EPR (Electron Paramagnetic Resonance) analysis. The presence of 3 could also catalyze the H2O2 system to give hydroxyl free radicals, suggested by further EPR and electrophoresis assay. At the cellular level, although no obvious Cu(II) signals were detected and the total ROS (Reactive Oxygen Species) scavenging in the tumor cells treated with 3, the potential redox property between Cu(I)/Cu(II), as a key role, should not be denied for the significant anticancer activity of 3, considering the much complicated circumstance and other reductive substances in cells. The anticancer mechanism of 3 on the most sensitive MGC-803 cells pointed to significant cell apoptosis through mitochondrial pathway, rather than cell cycle arrest. While the autophagy observed in tumor cells treated by 3 suggested its complicated anticancer mechanism, and whether there was an intrinsic correlation still needed to be further investigated.

Automated summary

A new quinolylanthrahydrazone ligand, 9-AQH, was synthesized and used to prepare four metal complexes, among which the copper(I) complex showed significant anticancer activity and catalytic ability to generate free radicals. The potential redox property between Cu(I)/Cu(II) and the induction of cell apoptosis through mitochondrial pathway were considered as key factors in the observed anticancer activity. Further investigation is needed to explore the intrinsic correlation between autophagy and the anticancer mechanism of the copper(I) complex.