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Nitrosyl iron complexes are remarkably multifactorial pharmacological agents. These compounds have been proven to be particularly effective in treating cardiovascular and oncological diseases. We evaluated and compared the antioxidant activity of tetranitrosyl iron complexes (TNICs) with thiosulfate ligands and dinitrosyl iron complexes (DNICs) with glutathione (DNIC-GS) or phosphate (DNIC-PO 4 - ) ligands in hemoglobin-containing systems. The studied effects included the production of free radical intermediates during hemoglobin (Hb) oxidation by tert -butyl hydroperoxide, oxidative modification of Hb, and antioxidant properties of nitrosyl iron complexes. Measuring luminol chemiluminescence revealed that the antioxidant effect of TNICs was higher compared to DNIC-PO 4 - . DNIC-GS either did not exhibit antioxidant activity or exerted prooxidant effects at certain concentrations, which might have resulted from thiyl radical formation. TNICs and DNIC-PO 4 - efficiently protected the Hb heme group from decomposition by organic hydroperoxides. DNIC-GS did not exert any protective effects on the heme group; however, it abolished oxoferrylHb generation. TNICs inhibited the formation of Hb multimeric forms more efficiently than DNICs. Thus, TNICs had more pronounced antioxidant activity than DNICs in Hb-containing systems.

The effect of a promising NO donor, a binuclear nitrosyl iron complex (NIC) with 3,4-dichlorothiophenolyls [Fe 2 (SC 6 H 3 Cl 2 ) 2 (NO) 4 ], on the adenylate cyclase and soluble guanylate cyclase enzymatic systems was studied. In in vitro experiments, this complex increased the concentration of important secondary messengers, such as cAMP and cGMP. An increase of their level by 2.4 and 4.5 times, respectively, was detected at NIC concentration of 0.1 mM. The ligand of the complex, 3,4-dichlorothiophenol, produced a less pronounced effect on adenylate cyclase. It was shown that the effect of this complex on the activity of soluble guanylate cyclase was comparable to the effect of anionic nitrosyl complex with thiosulfate ligands that exhibits vasodilating and cardioprotective properties., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

A novel neutral tetranitrosyl iron complex {[Fe(H 2 O) 4 ] 2+ [FeR 2 (NO) 2 ] 2 2- }·4H 2 O (1) with R = 5-(3-pyridyl)-4 H -1,2,4-triazole-3-thiolyls (C 7 H 5 N 4 S), which is a supramolecular ensemble, has been synthesized and studied. As follows from X-ray diffraction analysis, this is an octahedral Fe 2+ complex (Lewis acid) with two monoanionic dinitrosyl groups [FeR 2 (NO) 2 ] - (Lewis base) and 4 water molecules as the ligands. As follows from Mössbauer spectra, the coordinating Fe 2+ 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(C 7 H 6 N 4 S-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 [FeR 2 (NO) 2 ] - ligand for the bovine PDE1B model have been determined by molecular docking and quantum-chemical calculations.

In this work, a new binuclear nitrosyl complex with 3.4-dichlorothiophenolyl ligands [Fe 2 (SC 6 H 3 Cl 2 ) 2 (NO) 4 ] has been synthesized. Nitrosyl iron complexes (NICs) are systems for the storage and delivery of NO in the body. There is a dynamic equilibrium between dinitrosyl iron units bound to low molecular weight ligands and high molecular weight (protein) ligands in vivo . From this point of view, the transformation of the studied complex in DMSO and buffer, as well as in biological systems, has been analyzed. In DMSO, it decomposes into mononuclear NICs, which quickly decay in buffer solutions with NO release. The high molecular weight product is formed as a result of the binding of the complex to bovine serum albumin (the Stern-Volmer constant is 2.1 × 10 5 M -1 ). In this case, the complex becomes a prolonged NO-donor. Such a long-term effect has been observed for the first time. Similarly, in a system with oxyhemoglobin, NO generation is slower; the UV-vis spectra show a gradual formation of methemoglobin. On the other hand, reduced glutathione has little effect on the NO-donor properties of the complex despite the fact that ligand substitution is observed in the system and a binuclear product is formed. Mucin binds the complex, and the decomposition mechanism is different from that for buffer solutions. Thus, these proteins and glutathione are able to participate in the transformation of the complex and modulate its properties as a potential drug.

High-molecular-weight dinitrosyl iron complexes (DNICs) are formed in living systems and are a stable depot of nitrogen monoxide (NO). In this work, using experimental and theoretical methods, we investigated the interaction of their synthetic analog, a promising cardiotropic complex of the composition [Fe(SC(NH 2 ) 2 ) 2 (NO) 2 ] 2 [Fe 2 (S 2 O 3 ) 2 (NO) 4 ], with bovine serum albumin (BSA) in aqueous aerobic solutions. We suggested that, under these conditions, the decomposition product of the initial complex with oxygen, the [Fe(NO)(NO 2 )] + fragment, can bind in the hydrophobic pocket of the protein. As a result of this interaction, high-molecular-weight Fe(Cys34)(His39)(NO)(NO 2 ) is formed. The binding constant of the complex with protein measured by the quenching of intrinsic fluorescence of BSA is 7.2 × 10 5 M -1 . According to EPR and UV-spectroscopy data, the interaction of the complex with the protein leads to its significant stabilization. In addition to coordination binding, the studied complex can be adsorbed onto the protein surface due to weak intermolecular interactions, resulting in the prolonged generation of NO.

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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 Ca 2+ -ATPase of the sarcoplasmic reticulum (SR Ca 2+ -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 Ca 2+ 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 Ca 2+ transport by 60±6 and 55±6% uncoupling the hydrolytic and transport functions of SR Ca 2+ -ATPases. The obtained results demonstrate a significant effect of the studied compounds on the active transmembrane transfer of Ca 2+ and make it possible to predict the presence of antimetastatic and antiaggregatory activities of the studied compounds.

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.