Pharmacomodulation on Gold-NHC complexes for anticancer applications - is lipophilicity the key point?

Eur J Med Chem. 2018 Sep 5;157:320-332. doi: 10.1016/j.ejmech.2018.07.070. Epub 2018 Aug 2.


A series of four new mononuclear cationic gold(I) complexes containing nitrogen functionalized N-heterocyclic carbenes (NHCs) was synthesized and fully characterized by spectroscopic methods. The X-ray structures of three complexes are presented. These lipophilic gold(I) complexes originate from a pharmacomodulation of previously described gold(I)-NHC complexes, by replacing an aliphatic spacer with an aromatic one. The Log P values of the resulting complexes increased by 0.7-1.5, depending on the substituents in comparison to the aliphatic-linker systems. The new series of complexes has been investigated in vitro for their anti-cancer activities in PC-3 (prostate cancer) and T24 (bladder cancer) cell lines and in the non-cancerous MC3T3 (osteoblast) cell line. All tested complexes show high activities against the cancer cell lines with GI50 values lower than 500 nM. One complex (11) has been selected for further investigations. It has been tested in vitro in six cancer cell lines from different origins (prostate, bladder, lung, bone, liver and breast) and two non-cancerous cell lines (osteoblasts, fibroblasts). Moreover, cellular uptake measurements were indicative of a good bioavailability. By various biochemical assays, this complex was found to effectively inhibit the thioredoxin reductase (TrxR) and its cytotoxicity towards prostate PC-3, bladder T24 and liver HepG2 cells was found to be ROS-dependent.

Keywords: Cancer; Glutathione; Gold; Lipophilicity; N-heterocyclic carbene; ROS; Thioredoxin reductase.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Gold / chemistry
  • Gold / pharmacology*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Hydrophobic and Hydrophilic Interactions*
  • Methane / analogs & derivatives*
  • Methane / chemistry
  • Methane / pharmacology
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Heterocyclic Compounds
  • carbene
  • Gold
  • Methane