Organometallic Ruthenium(II) Arene Compounds with Antiangiogenic Activity

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• 作者：Patrycja Nowak-Sliwinska ; Judy R. van Beijnum ; Angela Casini ; Alexey A. Nazarov ; Georges Wagnie虁res ; Hubert van den Bergh ; Paul J. Dyson ; Arjan W. Griffioen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 9, 2011
• 年：2011
• 卷：54
• 期：11
• 页码：3895-3902
• 全文大小：1020K
• 年卷期：v.54,no.11(June 9, 2011)
• ISSN：1520-4804

文摘

The antimetastatic ruthenium(II) compounds [Ru(畏⁶-p-cymene)Cl₂(PTA)] (PTA = 1,3,5-triaza-7-phosphaadamantane) (RAPTA-C) and [Ru(畏⁶-toluene)Cl₂(PTA)] (RAPTA-T), as well as their analogues [Ru(畏⁶-p-cymene)Cl₂(DAPTA)] (DAPTA = (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane)) (DAPTA-C) and [Ru(畏⁶-toluene)Cl₂(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 鈮?00 渭g/mL (200 渭M). EC migration, measured 6 h after drug exposure, was also efficiently inhibited (ED₅₀ of 300 渭g/mL, 500 渭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.