Transferring the concept of multinuclearity to ruthenium complexes for improvement of anticancer activity

J Med Chem. 2009 Feb 26;52(4):916-25. doi: 10.1021/jm8013234.

Abstract

Multinuclear platinum anticancer complexes are a proven option to overcome resistance of established anticancer compounds. Transferring this concept to ruthenium complexes led to the synthesis of dinuclear Ru(II)-arene compounds containing a bis(pyridinone)alkane ligand linker. A pronounced influence of the spacer length on the in vitro anticancer activity was found, which is correlated to the lipophilicity of the complexes. IC(50) values in the same dimension as for established platinum drugs were found in human tumor cell lines. No cross-resistance to oxoplatin, a cisplatin prodrug, was observed for the most active complex in three resistant cell lines; in fact, a 10-fold reversal of sensitivity in two of the oxoplatin-resistant lines was found. (Bio)analytical characterization of the representative examples showed that the ruthenium complexes hydrolyze rapidly, forming predominantly diaqua species that exhibit affinity toward transferrin and DNA, indicating that both proteins and nucleobases are potential targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • DNA / metabolism
  • Drug Resistance, Neoplasm
  • Humans
  • Hydrolysis
  • Hydrophobic and Hydrophilic Interactions
  • Inhibitory Concentration 50
  • Ligands
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / metabolism
  • Organometallic Compounds / pharmacology*
  • Platinum Compounds / pharmacology
  • Ruthenium / chemistry
  • Ruthenium / metabolism
  • Ruthenium / pharmacology*
  • Structure-Activity Relationship
  • Transferrin / metabolism

Substances

  • Antineoplastic Agents
  • Ligands
  • Organometallic Compounds
  • Platinum Compounds
  • Transferrin
  • Ruthenium
  • DNA