Structurally related hydrazone-based metal complexes with different antitumor activities variably induce apoptotic cell death

Dalton Trans. 2017 Apr 5;46(14):4759-4767. doi: 10.1039/c6dt04613d.


Three new complexes bearing the tridentate hydrazone-based ligand 2-(2-(1-(pyridin-2-yl)ethylidene)hydrazinyl)pyridine (L) were synthesized and structurally characterized. Biological tests indicate that the Zn(ii) complex [ZnCl2(L)] is of low cytotoxicity against the hepatocellular carcinoma cell line HepG2. In contrast, the Cu(ii) and Mn(ii) complexes [CuCl2(L)] and [MnCl2(L)] are highly cytotoxic with EC50 values of 1.25 ± 0.01 μM and 20 ± 1 μM, respectively. A quantitative proteome analysis reveals that treatment of the cells with the Cu(ii) complex leads to a significantly altered abundance of 102 apoptosis-related proteins, whereas 38 proteins were up- or down-regulated by the Mn(ii) complex. A closer inspection of those proteins regulated only by the Cu(ii) complex suggests that the superior cytotoxic activity of this complex is likely to be related to an initiation of the caspase-independent cell death (CICD). In addition, an increased generation of reactive oxygen species (ROS) and a strong up-regulation of proteins responsive to oxidative stress suggest that alterations of the cellular redox metabolism likely contribute to the cytotoxicity of the Cu(ii) complex.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Caspases / metabolism
  • Cell Survival / drug effects
  • Chlorides / chemistry
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry*
  • Coordination Complexes / pharmacology*
  • Copper / chemistry
  • Dose-Response Relationship, Drug
  • Hep G2 Cells
  • Humans
  • Hydrazones / chemistry*
  • Ligands
  • Manganese Compounds / chemistry
  • Molecular Structure
  • Proteome / metabolism
  • Pyridines / chemistry
  • Reactive Oxygen Species / metabolism
  • Zinc Compounds / chemistry


  • Antineoplastic Agents
  • Chlorides
  • Coordination Complexes
  • Hydrazones
  • Ligands
  • Manganese Compounds
  • Proteome
  • Pyridines
  • Reactive Oxygen Species
  • Zinc Compounds
  • Copper
  • zinc chloride
  • Caspases
  • manganese chloride
  • cupric chloride