Organometallic ruthenium(II) arene compounds with antiangiogenic activity

J Med Chem. 2011 Jun 9;54(11):3895-902. doi: 10.1021/jm2002074. Epub 2011 May 16.

Abstract

The antimetastatic ruthenium(II) compounds [Ru(η(6)-p-cymene)Cl(2)(PTA)] (PTA = 1,3,5-triaza-7-phosphaadamantane) (RAPTA-C) and [Ru(η(6)-toluene)Cl(2)(PTA)] (RAPTA-T), as well as their analogues [Ru(η(6)-p-cymene)Cl(2)(DAPTA)] (DAPTA = (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane)) (DAPTA-C) and [Ru(η(6)-toluene)Cl(2)(DAPTA)] (DAPTA-T), respectively, were tested in in vitro bioassays for endothelial cell function. All compounds showed low toxicity profiles and similar dose-dependent antiproliferative effects in endothelial cells at ≥100 μg/mL (∼200 μM). EC migration, measured 6 h after drug exposure, was also efficiently inhibited (ED(50) of ∼300 μg/mL, ∼500 μM, for all compounds). Since no cytostatic effect was noted, the inhibition of proliferation was considered mainly to consist of antiangiogenic activity. RAPTA-T and DAPTA-C were also tested in vivo in the chicken chorioallantoic membrane (CAM) assay and found to inhibit CAM development. Importantly, effective prevention of revascularization of the CAM after vaso-occlusive photodynamic therapy was observed. The reported ruthenium complexes show promising antimetastatic activity involving inhibition of angiogenesis and therefore are attractive agents for development of anticancer therapies based on combination of chemo- and angiostatic treatments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis*
  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chick Embryo
  • Chorioallantoic Membrane / drug effects
  • Cymenes
  • Dose-Response Relationship, Drug
  • Endothelial Cells / drug effects
  • Endothelial Cells / physiology
  • Humans
  • Organometallic Compounds / chemical synthesis*
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / pharmacology
  • Photochemotherapy
  • Ruthenium* / toxicity

Substances

  • Angiogenesis Inhibitors
  • Cymenes
  • Organometallic Compounds
  • RAPTA-T
  • dichloro(4-cymene)(1,3,5-triaza-7-phosphatricyclo(3.3.1.1)decane)ruthenium(II)
  • Ruthenium