Antitumor trans-N-heterocyclic carbene-amine-Pt(II) complexes: synthesis of dinuclear species and exploratory investigations of DNA binding and cytotoxicity mechanisms

J Med Chem. 2013 Mar 14;56(5):2074-86. doi: 10.1021/jm301780s. Epub 2013 Feb 20.

Abstract

A series of bimetallic [(NHC)PtX2]2(diamine) complexes have been prepared as a new chemotype for potential anticancer agents. These complexes display an uncommon set of structural features as far as they combine two bifunctional, trans-configured platinum centers. They display cytotoxic activities in the micromolar range on many cancerous cell lines and do not cross-react with cisplatin in A2780/DDP cell lines. They bind slowly to double-stranded DNAs, giving monoadducts as the major products. Pathways for cellular toxicity have been investigated for both mono- and bimetallic trans-(NHC)PtX2(amine) complexes. It has been highlighted that, unlike cisplatin, these complexes do not induce cell cycle arrest. They trigger apoptosis in A2780 cells by a pathway involving translocation of apoptosis-inducing factor and caspase 12 to the nucleus. Moreover, bimetallic complexes may induce necrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis Inducing Factor / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cisplatin / pharmacology
  • DNA / metabolism*
  • DNA Fragmentation
  • Diamines / chemical synthesis
  • Diamines / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Organoplatinum Compounds / chemical synthesis
  • Organoplatinum Compounds / pharmacology*

Substances

  • Antineoplastic Agents
  • Apoptosis Inducing Factor
  • Diamines
  • Organoplatinum Compounds
  • DNA
  • Cisplatin