Organometallic Ruthenium(II) Arene Compounds with Antiangiogenic Activity
The antimetastatic ruthenium (II) compounds [Ru(eta(6)-p-cymene)Cl-2(PTA)] (PTA = 1,3,5-triaza-7-phosphaadamantane) (RAPTA-C) and [Ru(eta(6)-toluene)Cl-2(PTA)] (RAPTA-T), as well as their analogues [Ru(eta(6)-p-cymene)Cl-2(DAPTA)] (DAPTA = (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo [3.3.1] nonane)) (DAPTA-C) and [Ru(eta(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 mu g/mL (similar to 200 mu M). EC migration, measured 6 h after drug exposure, was also efficiently inhibited (ED50 of similar to 300 mu g/mL, similar to 500 mu M, 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.