Development of organometallic ruthenium-arene anticancer drugs that resist hydrolysis

Inorg Chem. 2006 Oct 30;45(22):9006-13. doi: 10.1021/ic061008y.

Abstract

With a view to develop drugs that could resist hydrolysis in aqueous media, organometallic arene-capped ruthenium(II) 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (RAPTA) complexes bearing chelating carboxylate ligands have been prepared and studied. The new complexes, Ru(eta6-cymene)(PTA)(C2O4) (1) and Ru(eta6-cymene)(PTA)(C6H6O4) (2), were found to be highly soluble and kinetically more stable than their RAPTA precursor that contains two chloride ligands in place of the carboxylate ligands. They were also able to resist hydrolysis in water and exhibited significantly lower pKa values. Importantly, they showed a similar order of activity in inhibiting cancer cell-growth proliferation (as determined by in vitro assays) and exhibited oligonucleotide binding characteristics (as evidenced by matrix-assisted laser desorption ionization mass spectrometry) similar to those of the RAPTA precursor, hence realizing a strategy for developing a new generation of stable and highly water-soluble RAPTA adducts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Benzene Derivatives / chemical synthesis
  • Benzene Derivatives / chemistry*
  • Benzene Derivatives / pharmacokinetics
  • Benzene Derivatives / pharmacology
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Drug Stability
  • Humans
  • Hydrolysis
  • Molecular Structure
  • Organometallic Compounds / chemical synthesis
  • Organometallic Compounds / chemistry*
  • Organometallic Compounds / pharmacokinetics
  • Organometallic Compounds / pharmacology
  • Ruthenium / chemistry*
  • Ruthenium / pharmacology

Substances

  • Antineoplastic Agents
  • Benzene Derivatives
  • Organometallic Compounds
  • Ruthenium