A gold(I) phosphine complex containing a naphthalimide ligand functions as a TrxR inhibiting antiproliferative agent and angiogenesis inhibitor

J Med Chem. 2009 Feb 12;52(3):763-70. doi: 10.1021/jm8012135.

Abstract

The novel luminescent gold(I) complex [N-(N',N'-dimethylaminoethyl)-1,8-naphthalimide-4-sulfide](triethylphosphine)gold(I) was prepared and investigated for its primary biological properties. Cell culture experiments revealed strong antiproliferative effects and induction of apoptosis via mitochondrial pathways. Biodistribution studies by fluorescence microscopy and atomic absorption spectroscopy showed the uptake into cell organelles, an accumulation in the nuclei of tumor cells, and a homogeneous distribution in zebrafish embryos. In vivo monitoring of vascularisation in developing zebrafish embryos revealed a significant anti-angiogenic potency of the complex. Mechanistic experiments indicated that the inhibition of thioredoxin reductase (based on the covalent binding of a gold triethylphosphine fragment) might be involved in the pharmacodynamic behavior of this novel gold species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis*
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Embryo, Nonmammalian / drug effects
  • HT29 Cells
  • Humans
  • Maximum Tolerated Dose
  • Microscopy, Confocal
  • Organogold Compounds / chemical synthesis*
  • Organogold Compounds / pharmacology*
  • Tandem Mass Spectrometry
  • Thioredoxin-Disulfide Reductase / antagonists & inhibitors*
  • Zebrafish

Substances

  • (N-(N',N'-dimethylaminoethyl)-1,8-naphthalimide-4-sulfide)(triethylphosphine)gold(I)
  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Organogold Compounds
  • Thioredoxin-Disulfide Reductase