Bidentate ligands on osmium(VI) nitrido complexes control intracellular targeting and cell death pathways

J Am Chem Soc. 2013 Sep 25;135(38):14060-3. doi: 10.1021/ja4075375. Epub 2013 Sep 16.

Abstract

The cellular response evoked by antiproliferating osmium(VI) nitrido compounds of general formula OsN(N^N)Cl3 (N^N = 2,2'-bipyridine 1, 1,10-phenanthroline 2, 3,4,7,8-tetramethyl-1,10-phenanthroline 3, or 4,7-diphenyl-1,10-phenanthroline 4) can be tuned by subtle ligand modifications. Complex 2 induces DNA damage, resulting in activation of the p53 pathway, cell cycle arrest at the G2/M phase, and caspase-dependent apoptotic cell death. In contrast, 4 evokes endoplasmic reticulum (ER) stress leading to the upregulation of proteins of the unfolded protein response pathway, increase in ER size, and p53-independent apoptotic cell death. To the best of our knowledge, 4 is the first osmium compound to induce ER stress in cancer cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2,2'-Dipyridyl / chemistry*
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Cell Line, Tumor
  • Coordination Complexes / chemical synthesis*
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology
  • DNA Damage
  • Drug Screening Assays, Antitumor
  • Endoplasmic Reticulum Stress
  • G2 Phase Cell Cycle Checkpoints
  • Humans
  • Ligands
  • M Phase Cell Cycle Checkpoints
  • Osmium*
  • Phenanthrolines / chemistry*
  • Signal Transduction
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Antineoplastic Agents
  • Coordination Complexes
  • Ligands
  • Phenanthrolines
  • Tumor Suppressor Protein p53
  • Osmium
  • 2,2'-Dipyridyl