Cationic and Neutral N-Heterocyclic Carbene Gold(I) Complexes: Cytotoxicity, NCI-60 Screening, Cellular Uptake, Inhibition of Mammalian Thioredoxin Reductase, and Reactive Oxygen Species Formation

ChemMedChem. 2018 Jun 20;13(12):1218-1229. doi: 10.1002/cmdc.201800181. Epub 2018 May 23.


A structurally diverse library of 14 gold(I) cationic bis(NHC) and neutral mono(NHC) complexes (NHC: N-heterocyclic carbene) was synthesized and characterized in this work. Four of them were new cationic gold(I) complexes containing functionalized NHCs, and their X-ray crystal structures are presented herein. All of the complexes were investigated for their anticancer activities in four cancer cell lines, including a cisplatin-resistant variant, and a noncancerous cell line. Seven of the cationic gold(I) complexes were found to display high and specific cytotoxic activities toward cancer cells. Two of them were even able to overcome cisplatin resistance. Two highly potent cationic complexes (11 and 15) were also submitted to the NCI-60 cancer panel for further cytotoxicity evaluation. Complex 15 showed a surprisingly high potency toward leukemia among the nine examined cancer subtypes, particularly toward the CCRF-CEM leukemia cell line with a concentration for 50 % inhibition of growth down to 79.4 nm. In addition, cationic complex 13, which demonstrated a remarkable cytotoxicity against hepatocellular carcinoma, was selected to obtain insight into the mechanistic aspects in HepG2 cells. Cellular uptake measurements were indicative of good bioavailability. By various biochemical assays, this complex was found to effectively inhibit thioredoxin reductase and its cytotoxicity toward HepG2 cells was found to be reactive oxygen species dependent.

Keywords: antitumor agents; carbene ligands; cytotoxicity; gold; nitrogen heterocycles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / toxicity
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology*
  • Coordination Complexes / toxicity
  • Drug Resistance, Neoplasm / drug effects
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / toxicity
  • Gold / chemistry*
  • Humans
  • Molecular Structure
  • Reactive Oxygen Species / metabolism*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / toxicity
  • Thioredoxin-Disulfide Reductase / antagonists & inhibitors*


  • Antineoplastic Agents
  • Coordination Complexes
  • Enzyme Inhibitors
  • Reactive Oxygen Species
  • Small Molecule Libraries
  • Gold
  • Thioredoxin-Disulfide Reductase