ABSTRACT
Ruthenium(II) complexes bearing a tridentate bis(N-heterocyclic carbene) ligand reacted with iminoiodanes (PhI=NR) resulting in the formation of isolable ruthenium(III)-amido intermediates, which underwent cleavage of a C-N bond of the tridentate ligand and formation of an N-substituted imine group. The RuIII -amido intermediates have been characterized by 1 Hâ NMR, UV/Vis, ESI-MS, and X-ray crystallography. DFT calculations were performed to provide insight into the reaction mechanism.
ABSTRACT
A macrocyclic ruthenium(III) complex [RuIII (N2 O2 )Cl2 ]Cl (Ru-1) is reported as an inhibitor of angiogenesis and an anti-tumor compound. The complex is relatively non-cytotoxic towards endothelial and cancer cell lines inâ vitro, but specifically inhibited the processes of angiogenic endothelial cell tube formation and cancer cell invasion. Moreover, compared with known anti-cancer ruthenium complexes, Ru-1 is distinct in that it suppressed the expression of vascular endothelial growth factor receptor-2 (VEGFR2), and the associated downstream signaling that is crucial to tumor angiogenesis. In addition, inâ vivo studies showed that Ru-1 inhibited angiogenesis in a zebrafish model and suppressed tumor growth in nude mice bearing cancer xenografts.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Macrocyclic Compounds/pharmacology , Neovascularization, Pathologic/drug therapy , Ruthenium/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Angiogenesis Inhibitors/chemistry , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Coordination Complexes/chemistry , Dose-Response Relationship, Drug , Down-Regulation/drug effects , Drug Screening Assays, Antitumor , Female , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Macrocyclic Compounds/chemistry , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Nude , Neovascularization, Pathologic/pathology , Ruthenium/chemistry , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/metabolism , ZebrafishABSTRACT
This study investigated the effect of fosinopril (Fos), valsartan (Val), and combination of both drugs (Fos + Val) on the cardiac and renal expression of aquaporin-1 (AQP1) and aquaporin-2 (AQP2) in congestive heart failure (CHF). A rat model of CHF was created by ligating the left anterior descending coronary artery to induce acute myocardial infarction (AMI). Rats were treated by Fos, Val, or Fos + Val for 4 weeks. In renal medulla and cortex, AMI was associated with 2.2- and 1.8-fold increase in AQP2 mRNA expression when compared with Sham-operated rats (medulla: 23.6 +/- 2.8 vs. 52.3 +/- 8.7%; P<0.001; cortex: 19.4 +/- 3.9 vs. 35.5 +/- 7.1%; P<0.05). All the treatment regimens were able to normalize AQP2 transcription in the renal medulla (Fos, 19.9 +/- 4.9%; Val, 22.8 +/- 4.9%; Fos + Val, 20.1 +/- 5.1%; P=NS vs. Sham) and in the cortex (Fos, 21.2 +/- 6.7%; Val, 20.4 +/- 6.0%; Fos + Val, 18.9 +/- 7.5%; P=NS vs. Sham). Similarly, the AQP2 protein expression increased by 2.1-fold after CHF (P<0.05), and was normalized by the treatment regimens (Sham, 0.57 +/- 0.19%; CHF, 1.22 +/- 0.45%; Fos, 0.39 +/- 0.36%; Val, 0.46 +/- 0.34%; Fos + Val, 0.36 +/- 0.15%; all P<0.05 vs. CHF). These treatment regimens also prevented the increase in body weight as found in untreated CHF rats (analysis of variance P<0.05). The renal and cardiac AQP1 gene and protein expressions were unaltered in CHF or by medical therapy. There was no observed cardiac AQP2 expression in all the study groups. Treatment with Fos, Val, or combination therapy was effective in preventing the upregulation of renal AQP2 gene and protein expressions in CHF rats caused by AMI.
