T. N. Rudneva

The structures of the dicationic tetranitrosyl iron complex with cysteamine [Fe2S2(CH2CH2NH3)2(NO)4]2+ and its decomposition products in protic media: an experimental and theoretical study

Decomposition products of [Fe2S2(CH2CH2NH3)2(NO)4]SO4·2.5H2O (1′) were studied by electrochemistry and mass spectrometry. The structures of the dicationic tetranitrosyl iron complex with cysteamine of the composition [Fe2S2(CH2CH2NH3)2(NO)4]2+ (1) and possible products of its decomposition and NO replacement by an aqua ligand were studied by quantum chemical methods at the density functional theory level. Taking into account the solvation effects, the replacement of the nitrosyl ligand in dication 1 by an aqua ligand was found to be less favorable in aqueous solution than in the gas phase. The pK value was calculated for the proton abstraction from the NH3 group of compound 1 (7.2), and the removal of NO from the deprotonated form of the complex was found to be much easier. This result is consistent with the experimental data on an increase in the rate of NO formation in aqueous solutions of 1 with increasing pH from 6 to 8 assuming that the increase in pH is accompanied by an increase in the percentage of the less stable deprotonated form of the complex and that OH− does not participate in the elementary step of NO formation. The kinetic curves of NO formation are well described by a two-step scheme of consecutive first-order reactions of the NO formation and consumption. In the gas phase, dication 1 was found to be unstable to decomposition into two mononuclear cationic dinitrosyl iron complexes with cysteamine. This result is consistent with the fact that these cations are observed in the electrospray ionization mass spectrometric experiment. The major peak in the mass spectra is associated with the [Fe2S2(CH2CH2NH3)2(NO)4 − H]+ ion. As follows from the calculations, this is due to the deprotonation of the dication as it gets rid of the hydration shell, because even the dimer of water molecules is more basic than dication 1.

Influence of ligand lipophilicity on the NO-donating ability of the binuclear tetranitrosyl iron complexes in an erythrocyte suspension

The kinetics of nitric oxide release by representatives of a new class of synthetic nitric oxide donors, binuclear tetranitrosyl iron complexes (B-TNIC) with a structure of [Fe2(SR)2(NO)4], where R is pyrimidin-2-yl, 1-methylimidazol-2-yl, benzothiazol-2-yl, cysteamine, and penicillamine, was studied under the conditions simulating the blood vessel internal environment, when an erythrocyte suspension was used as a natural trap of nitric oxide. The apparent firstorder rate constants for intraerythrocyte methemoglobin formation were determined on the basis of the kinetic data. The NO-donating ability of B-TNIC was estimated from the values of these rate constants. It is assumed that the rate for the hydrolytic decomposition of B-TNIC decreases in the presence of erythrocytes due to binding of the complexes with the cell surface, leading to the restriction of their contact with an aqueous medium. Nitric oxide donating by the complex bearing penicillamine as a ligand is stoichiometric and independent of the presence of erythrocytes. This can be due to high hydrophilicity of this complex determined from the criterion of partition coefficient in an octanol-water system. This evidently provides a high level of solvation of the complex in an aqueous medium that prevents its binding with the erythrocyte surface.

Effect of nitrosyl iron–sulfur complexes on the activity of hydrolytic enzymes

We have studied the effect of some NO donors based on new nitrosyl iron—sulfur complexes, including the anionic thiosulfate complex Na2[Fe2(S2O3)2(NO)4](4H2O (I) and neutral thiolate complexes of the general formula [Fe2(SR)2(NO)2] with R = 1-methylimidazol-2-yl (II), 3-amino-1,2,4-triazol-5-yl (III), and phenyl (IV), on the enzymatic activity of two hydrolytic enzymes, namely, cyclic guanosine monophosphate phosphodiesterase (cGMP PDEase) and Ca2+—Mg2+-dependent ATPase of sarcoplasmatic reticulum (SR Ca2+—ATPase). It has been found that all tested compounds in the concentration range 0.1 – 0.001 mM inhibit functioning of cGMP PDEase and SR Ca2+—ATPase. Compounds I and II inhibit the activity of cGMP PDEase with Ki = 1 and 5 μM, respectively. These compounds are more efficient than the reference drug nicorandil (Ki = 0.1 mM) used in clinical therapy. The inhibition of cGMP PDEase functioning favors the accumulation of cGMP, a secondary messenger in living organisms that is responsible for vasodilatory, antiaggregant, and antihypertensive properties of drugs. Inhibition of SR Ca2+—ATPase blocks active transport of Ca2+ ions, thus affecting the equilibrium of Ca ions in cells and the manifestation of the above pharmacological effects. The experimental data allow one to predict the mechanisms of action of chemical compounds under consideration as potential drugs.

Nitric oxide donation by the binuclear tetranitrosyl iron complexes in the presence of erythrocytes

The kinetic regularities of nitric oxide donation in the presence of erythrocytes by representatives of a new class of synthetic nitric oxide donors, binuclear tetranitrosyl iron complexes (B-TNIC) [Fe2(SR)2(NO)4] with thiol-containing ligands, where R is pyrimidin-2-yl, 1-methylimidazol-2-yl, benzothiazol-2-yl, and penicillamine residue, were established. The NO-donating ability of B-TNIC was estimated from the apparent rate constants of the first order for the formation of intraerythrocyte methemoglobin with the variation of the initial concentration of the complex. During the standard experimental time (15—17 min), three of the four complexes released in the solution no more than a quarter of available NO groups. Their NO-donating ability turned out to be variable increasing with an increase in the initial concentration of the complex. At the same time, the complex bearing penicillamine residues as ligands donated almost all NO groups within approximately 1 min. Features of NO donation by the B-TNIC in the presence of erythrocytes are related to the formation in the system of an additional equilibrium pool of the membrane-associated complex, which is characterized by a reduced rate of hydrolytic dissociation with NO releasing to the solution. The NO-donating ability of the B-TNIC in the presence of erythrocytes is determined by the ratio of volumes of the free and membrane-associated pools of the complex.

Revealing of the cation-binding sites on the surface of hemoglobin in its reaction with the NO donor, the nitrosyl iron complex {Fe2[S(CH2)2NH3]2(NO)4}SO4·2.5H2O

Deoxyhemoglobin (Hb) stabilizes the cationic nitrosyl iron complex with cysteamine {Fe2[S(CH2)2NH3]2(NO)4}SO4·2.5H2O (CysAm), by slowing down its hydrolysis. In the absence of Hb, the electrochemical detection of NO release in the course of the hydrolysis using a sensor electrode gave the rate constant of (5.2±0.2)·10−5 s−1. The release of NO is a reversible process, and the amount of released NO is 1.4% of the CysAm concentration. In the presence of Hb, NO is released much more slowly, and the reaction is more intense than that in the absence of Hb. The adsorption of CysAm by an Hb molecule results in NO release from the CysAm-Hb complex with a rate constant of 1·10−8 s−1. The analysis of the Hb surface revealed the possible location of the cation-binding sites, which reversibly bind the cationic CysAm complex. The kinetic parameters of NO release from CysAm in the absence and in the presence of Hb were studied by the kinetic modeling.

Magnetic properties of the tetranitrosyl-iron complex Fe2(SC3H5N2)2(NO)4

The magnetic properties of the binuclear nitrosyl-iron complexes Fe2(SC3H5N2)2(NO)4 are investigated. It is demonstrated that several types of particles, such as dimers with a pair of spins 1/2, dimers with a pair of spins 5/2, and paramagnetic particles with spin 3/2, make a contribution to the magnetic properties of the complexes. A decrease in the temperature below 25 K leads to a change in the shape of the EPR spectra corresponding to these dimers, so that Lorentzian lines (homogeneous broadening) transform into Gaussian lines (inhomogeneous broadening). This is accompanied by a stepwise change in the EPR line width and g factors. The change in the line shape indicates that complexes become asymmetric at low temperatures, possibly, due to the decrease in the spin exchange frequency below the frequency of the microwave field of the spectrometer.

Study on the decomposition of iron nitrosyl complex of μ-N–C–S type and its reaction with GSH in aqueous solution

Decomposition of binuclear neutral iron nitrosyl complex [Fe2(S2C7H4N)2(NO)4]0 (I) of μ-N–C–S structural type in aqueous solution has been studied. Effect of glutathione GSH on the decomposition of complex I has been studied.

Formation of mononuclear nitrosyl intermediates during hydrolysis of [Na2[Fe2(μ-S2O3)2(NO)4]·4H2O, a donor of nitrogen monoxide

One of the effects of endogenous NO is the formation of dinitrosyl iron complexes (DNICs), which, along with nitrosothiols, have been identified in all life forms, i.e., in the cells of bacteria, plants, and mammals [1]. Nitrosyl nonheme iron complexes have been identified by EPR as products of interaction of NO with some iron‐sulfur proteins and other iron-containing proteins [2‐5]. DNICs are intermediates in the iron-catalyzed decomposition and formation of S- nitrosothiols [6] and are considered as NO reservoirs and transporters in vivo. These results initiated the development of methods of synthesis and study of the physical and chemical properties of synthetic DNIC analogues [7] with the aim of their practical use as NO donors in medicine and biology [8, 9]. In the present paper, we report the results of the mass spectral and electrochemical studies of the products of hydrolysis of the tetranitrosyl iron thiosulfate complex Na 2 [Fe 2 ( µ -S 2 O 3 ) 2 (NO) 4 )] · 4 H 2 O (TNIC) in aqueous solutions. Study of the antimetastatic effect of the TNIC on three experimental models—melanoma B16, LL carcinoma, and AKATOL—showed that the complex inhibits metastatic growth. The combined administration of a low ineffective dose of the TNIC with cisplatin (or adriablastin) in leukemia P 388‐bearing mice leads to 100% survival among the laboratory animals [10]. Studying the TNIC decomposition products in solutions and determining the structure and properties of intermediates formed during hydrolysis are important for an understanding of molecular genetic mechanisms of action of exogenous NO donors of this class.