Effects of Nitrosyl Iron Complexes with Thiol, Phosphate, and Thiosulfate Ligands on Hemoglobin.

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-PO4-) 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-PO4-. 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-PO4- 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.

A nitrosyl iron complex with 3.4-dichlorothiophenolyl ligands: synthesis, structures and its reactions with targets - carriers of nitrogen oxide (NO) in vivo.

In this work, a new binuclear nitrosyl complex with 3.4-dichlorothiophenolyl ligands [Fe2(SC6H3Cl2)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 × 105 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.

Albumin as a prospective carrier of the nitrosyl iron complex with thiourea and thiosulfate ligands under aerobic conditions.

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(NH2)2)2(NO)2]2[Fe2(S2O3)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)(NO2)]+ fragment, can bind in the hydrophobic pocket of the protein. As a result of this interaction, high-molecular-weight Fe(Cys34)(His39)(NO)(NO2) is formed. The binding constant of the complex with protein measured by the quenching of intrinsic fluorescence of BSA is 7.2 × 105 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.

Influence of hemoglobin and albumin on the NO donation effect of tetranitrosyl iron complex with thiosulfate.

The effects of deoxyhemoglobin (Hb) and albumin on the NO-donor activity of the anionic tetranitrosyl iron complex with thiosulfate ligands (1) were studied for the first time. It was shown that Hb significantly stabilizes complex 1; in its presence, NO generation from the complex proceeds at a noticeably slower rate. A similar effect is observed when complex 1 is bound to albumin, in which case complex 1 decomposes 27 times slower than in the absence of albumin in the solution. The observed effects provide a prolonged action of complex 1 as NO-donor, which may enhance its potential pharmacological efficacy.