Necroptosis-inducing rhenium(V) oxo complexes

J Am Chem Soc. 2015 Mar 4;137(8):2967-74. doi: 10.1021/ja511978y. Epub 2015 Feb 20.

Abstract

Rhenium(V) oxo complexes of general formula [ReO(OMe)(N^N)Cl2], where N^N = 4,7-diphenyl-1,10-phenanthroline, 1, or 3,4,7,8-tetramethyl-1,10-phenanthroline, 2, effectively kill cancer cells by triggering necroptosis, a non-apoptotic form of cell death. Both complexes evoke necrosome (RIP1-RIP3)-dependent intracellular reactive oxygen species (ROS) production and propidium iodide uptake. The complexes also induce mitochondrial membrane potential depletion, a possible downstream effect of ROS production. Apparently, 1 and 2 are the first rhenium complexes to evoke cellular events consistent with programmed necrosis in cancer cells. Furthermore, 1 and 2 display low acute toxicity in C57BL/6 mice and reasonable stability in fresh human blood.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / toxicity
  • Apoptosis / drug effects*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Drug Stability
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Necrosis / chemically induced
  • Organometallic Compounds / chemical synthesis
  • Organometallic Compounds / chemistry*
  • Organometallic Compounds / pharmacology*
  • Organometallic Compounds / toxicity
  • Phenanthrolines / chemistry*
  • Receptor, PAR-1 / metabolism
  • Rhenium / chemistry*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • Organometallic Compounds
  • Phenanthrolines
  • Receptor, PAR-1
  • Tumor Suppressor Protein p53
  • Rhenium
  • 1,10-phenanthroline