Synthesis of a tetranitrosyl iron complex with unique structure and properties as an inhibitor of phosphodiesterases.

A novel neutral tetranitrosyl iron complex {[Fe(H2O)4]2+[FeR2(NO)2]22-}·4H2O (1) with R = 5-(3-pyridyl)-4H-1,2,4-triazole-3-thiolyls (C7H5N4S), which is a supramolecular ensemble, has been synthesized and studied. As follows from X-ray diffraction analysis, this is an octahedral Fe2+complex (Lewis acid) with two monoanionic dinitrosyl groups [FeR2(NO)2]- (Lewis base) and 4 water molecules as the ligands. As follows from Mössbauer spectra, the coordinating Fe2+ ion is in a low-spin state S = 0, and the dinitrosyl Fe+ ion is in a low-spin state S = 1/2. According to the data of EPR spectroscopy, mass-spectrometry and amperometry, complex 1 in solution forms dinitrosyl particles of [Fe(C7H6N4S-H)2(NO)2]- composition, which are responsible for NO generation. In addition, complex 1 was shown to be a 5-6 times more efficient phosphodiesterase (PDE) inhibitor at 5 × 10-5 M and 10-4 M concentrations than its thioligand. Probable binding sites of the [FeR2(NO)2]- ligand for the bovine PDE1B model have been determined by molecular docking and quantum-chemical calculations.

Effects of albumin-bound nitrosyl iron complex with thiosulfate ligands on lipid peroxidation and activities of mitochondrial enzymes in vitro.

Nitric oxide (NO) mediates diverse physiological processes in living organisms. Small molecular NO donors usually lack stability and have a short half-life in human tissues, limiting the therapeutic application. The anionic tetranitrosyl iron complex with thiosulfate ligands (TNIC) is one of the most promising NO donors. This study shows that bovine serum albumin (BSA) can effectively stabilize the TNIC complex under aerobic (physiological) conditions, which contributes to its prolonged action as NO donor. Our results demonstrated that TNIC-BSA inhibits formation of TBARS - standard biomarker for the lipid peroxidation induced oxidative stress. Also, it was found that TNIC-BSA inhibits the catalytic activity of mitochondrial membrane-bound enzymes: cytochrome c oxidase and monoamine oxidase A. Together, these results demonstrate that, stabilization of TNIC with BSA opens up the possibility of its practical application in chemotherapy of socially significant diseases.

Effects of Covalent Conjugates of Fullerene Derivatives with Xanthene Dyes on Activity of Ca2+-ATPase of the Sarcoplasmic Reticulum.

The effects of the newly synthesized covalent conjugates of water-soluble fullerene derivatives (WSFD) with xanthene dyes: polyanionic WSFD-fluorescein (1), polycationic WSFD-fluorescein (2), polyanionic WSFD-eosin (3), and polyanionic WSFD (4), polycationic WSFD (5), fluorescein (6) and eosin (7), on activity of the membrane-bound Ca2+-ATPase of the sarcoplasmic reticulum (SR Ca2+-ATPase) were studied. Compounds 1, 3, 4, 6, and 7 inhibit the hydrolytic function of the enzyme, the inhibition constants for these compounds are Ki=1.3×10-5 M (1), Ki=4.7×10-6 M (3), Ki=2.5×10-6 M (4), Ki=6.1×10-5 M (6), and Ki=5.8×10-6 M (7). The effects of compounds 3, 6, and 7 on the hydrolytic function of the enzyme is competitive; compounds 1 and 4 are noncompetitive. Polycationic WSFD fluorescein (2) and polycationic WSFD (5) do not affect ATP hydrolysis, but inhibit active Ca2+ transport in a concentration of 0.01 mM by 100±10 and 40±4%, respectively. Conjugates 1 and 3 completely inhibit the hydrolytic and transport functions of the enzyme in a concentration of 0.01 mM, and in a concentration of 0.001 mM inhibit active Ca2+ transport by 60±6 and 55±6% uncoupling the hydrolytic and transport functions of SR Ca2+-ATPases. The obtained results demonstrate a significant effect of the studied compounds on the active transmembrane transfer of Ca2+ and make it possible to predict the presence of antimetastatic and antiaggregatory activities of the studied compounds.

Antioxidant Activity of Tetranitrosyl Iron Complex with Thiosulfate Ligands and Its Effect on Catalytic Activity of Mitochondrial Enzymes In vitro.

The antioxidant and antiradical properties of the tetra nitrosyl iron complex with thiosulfate ligands (TNIC) were studied in vitro in mouse brain homogenates. It was found for the first time that TNIC is an effective antioxidant. The effect of TNIC on the catalytic activity of mitochondrial enzymes cytochrome c oxidase and monoamine oxidase A was studied. It was shown for the first time that TNIC is an inhibitor of the catalytic activity of cytochrome c oxidase and monoamine oxidase A in animal brain mitochondria in vitro.