Anticancer Agents: Does a Phosphonium Behave Like a Gold(I) Phosphine Complex? Let a "Smart" Probe Answer!

J Med Chem. 2015 Jun 11;58(11):4521-8. doi: 10.1021/acs.jmedchem.5b00480. Epub 2015 May 27.

Abstract

Gold phosphine complexes, such as auranofin, have been recognized for decades as antirheumatic agents. Clinical trials are now underway to validate their use in anticancer or anti-HIV treatments. However, their mechanisms of action remain unclear. A challenging question is whether the gold phosphine complex is a prodrug that is administered in an inactive precursor form or rather that the gold atom remains attached to the phosphine ligand during treatment. In this study, we present two novel gold complexes, which we compared to auranofin and to their phosphonium analogue. The chosen ligand is a phosphine-based smart probe, whose strong fluorescence depends on the presence of the gold atom. The in vitro biological action of the gold complexes and the phosphonium derivative were investigated, and a preliminary in vivo study in healthy zebrafish larvae allowed us to evaluate gold complex biodistribution and toxicity. The different analyses carried out showed that these gold complexes were stable and behaved differently from phosphonium and auranofin, both in vitro and in vivo. Two-photon microscopy experiments demonstrated that the cellular targets of these gold complexes are not the same as those of the phosphonium analogue. Moreover, despite similar IC50 values in some cancer cell lines, gold complexes displayed a low toxicity in vivo, in contrast to the phosphonium salt. They are therefore suitable for future in vivo investigations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Antirheumatic Agents / chemistry
  • Antirheumatic Agents / pharmacokinetics
  • Antirheumatic Agents / pharmacology
  • Auranofin / chemistry
  • Auranofin / pharmacology*
  • Cell Proliferation / drug effects*
  • Gold / chemistry*
  • Humans
  • Larva / drug effects*
  • Larva / growth & development
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Phosphines / chemistry*
  • Structure-Activity Relationship
  • Tissue Distribution
  • Tumor Cells, Cultured
  • Zebrafish / growth & development

Substances

  • Antineoplastic Agents
  • Antirheumatic Agents
  • Ligands
  • Phosphines
  • Auranofin
  • Gold
  • phosphine