ABSTRACT
This study evaluates the action of the new ruthenium complexes trans-RuCl(2)(nic)(4)] (I) and trans-[RuCl(2)(i-nic)(4)] (II) as free radical scavengers. In our experiments, both compounds acted as scavengers of superoxide anion (O(2)*(-)), hydroxyl radicals (HO*) and nitrogen monoxide (formally known as 'nitric oxide'; NO*). In addition, complexes I and II potentiated the release of NO* from S-nitroso-N-acetyl-DL-penicilamine (SNAP), a NO* donor. Complex II, but not I, also decreased the nitrite levels in culture media of activated macrophages. A hypsochromic shift of lambda(max) and a significant change in half-wave potential (E(1/2)) was observed when NO* was added to the Complex II. Thiobarbituric reactive substance (TBARS) levels were significantly reduced in rats treated for 1 week with Complex II plus tert-butylhydroperoxide, when compared to rats treated only with tert-butylhydroperoxide. None of the complexes showed cytotoxicity. These findings support the suggestion that the new ruthenium complexes, especially trans-[RuCl(2)(i-nic)(4)] or its derivatives, might provide potential therapeutic benefits in disorders where reactive nitrogen (RNS) or oxygen (ROS) species are involved.
Subject(s)
Free Radical Scavengers/chemistry , Free Radical Scavengers/pharmacology , Isonicotinic Acids/chemistry , Isonicotinic Acids/pharmacology , Nicotinic Acids/chemistry , Nicotinic Acids/pharmacology , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Ruthenium/chemistry , Animals , Hydroxyl Radical/metabolism , In Vitro Techniques , Lipid Peroxidation/drug effects , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/metabolism , Male , Mice , Nitric Oxide/metabolism , Nitric Oxide Donors/pharmacology , Rats , Rats, Wistar , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/metabolism , S-Nitroso-N-Acetylpenicillamine/pharmacology , Superoxides/metabolism , Thiobarbituric Acid Reactive Substances/metabolismABSTRACT
This work discusses both the synthesis of trans-[RuCl2(dinic)4], dinic = 3,5-pyridinecarboxylic acid, and its main characteristics including potentiometric titration, spectroscopic and electrochemical properties, and some biological properties. The complex was synthesized using ruthenium blue solution as the precursor in a synthetic route. The complex was characterized using electronic spectroscopy, vibrational FT-IR spectroscopy, and Raman spectroscopy, as well as 1H and 13C NMR. The results indicated that the complex exhibits a trans-geometry. Cyclic voltammetry carried out in water:acetone 1:1 solution revealed a quasi-reversible process centered on the Ru(II) atom, as well as a dependence of the redox potential, E1/2, on pH. An analysis of the electronic spectra revealed that the MLCT (metal ligand charge transfer) band underwent a hypsochromic shift as the pH increased. Spectroelectrochemical analysis indicated that the visible region band progressively faded out upon oxidation. The equilibrium constants for the eight protons of the complex were determined by potentiometric titration. The complex neither inhibits the activity of nitrogen monoxide synthase nor acts as a scavenger for nitrogen monoxide. Nevertheless, the complex shows antinociceptive properties and acts as a scavenger for hydroxyl radicals.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Free Radical Scavengers/chemical synthesis , Free Radical Scavengers/pharmacology , Nicotinic Acids/chemical synthesis , Nicotinic Acids/pharmacology , Organometallic Compounds/chemical synthesis , Organometallic Compounds/pharmacology , Analgesics/chemistry , Animals , Electrochemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Free Radical Scavengers/chemistry , Magnetic Resonance Spectroscopy , Male , Mice , Nicotinic Acids/chemistry , Nitric Oxide Synthase/antagonists & inhibitors , Organometallic Compounds/chemistry , Potentiometry , Spectrophotometry , Spectroscopy, Fourier Transform Infrared , Spectrum Analysis, RamanABSTRACT
This study evaluates the actions of the new ruthenium complexes trans-[RuCl2(nic)4] (Complex I) and trans-[RuCl2(i-nic)4] (Complex II) as antinociceptives, and their interaction with nitric oxide isoenzymes and with acetylcholine-induced relaxation of rat and rabbit aorta. Complex II inhibited, in a graded manner, neuronal and inducible nitric oxide (NO) synthase, and was about two fold more effective in inhibiting the neuronal NO synthase than the inducible form of the enzyme. Complex I was inactive. Both complexes failed to interfere with constitutive endothelial nitric oxide synthase because they did not change the mean arterial blood pressure of rats. The vasorelaxant effect of acetylcholine was markedly antagonised by the Complexes I and II in rings of both rat and rabbit aorta. Complexes I and II, given intraperitoneally, like N(omega)-nitro-L-arginine methyl ester (L-NAME) and N(G)-nitro-L-arginine (L-NOARG), inhibited, in a graded manner, both phases of the pain response induced by formalin. The actions of L-NAME, L-NOARG and Complex II, but not that of Complex I, were largely reversed by L-arginine. Both complexes failed to affect the motor response of animals in the rota-rod test and had no effect in the hot-plate assay. Together, these findings provide indications that the new ruthenium complexes, especially Complex II and its derivatives, might be of potential therapeutic benefit in the management of pain disorders.
