Effect of solvents and glutathione on the decomposition of the nitrosyl iron complex with N-ethylthiourea ligands: An experimental and theoretical study.

Dinitrosyl iron complexes (DNICs) are a depot and potential source of free NO in organisms. Their synthetic analog, N-ethylthiourea DNIC [Fe(SC(NH2)(NHC2H5))2(NO)2]+Cl-∙[Fe(SC(NH2)(NHC2H5))Cl(NO)2]0 (complex 1), as cardioprotective and cytostatic agent is a promising prodrug for the treatment of socially relevant diseases. In this work, transformation mechanism of complex 1 has been studied in anaerobic aqueous solution (pH = 7.0), DMSO, and ethanol. It was shown that the solvent has a significant effect on the decomposition of complex. According to EPR-spectroscopy, only cationic part of complex is found upon its dissolution in water; only neutral part is retained in DMSO, and both fragments are present in ethanol. Effective generation of NO occurs in an aqueous solution. The structures of the decomposition products were proposed for all solvents, their UV-spectra and rate constants were calculated. From the experimental and theoretical data obtained, it follows that complex 1 is most stable in DMSO. Solutions of complex in a DMSO-water mixture can be used to improve its bioavailability in further in vitro and in vivo studies. Also, we have analyzed its interaction with glutathione (GSH), which can participate in the metabolism of this compound. This study shows that complex 1 reacts with GSH to form a new binuclear DNIC with two GS--ligands. It was found that the resulting complex is a more prolonged NO-donor than the initial one: k = 6.1∙10-3·s-1 in buffer, k = 6.4∙10-5 s-1 with GSH. This reaction may prevent S-glutathionylation of the essential enzyme systems and is important for metabolism of complex, associated with its antitumor activity.

Reversible dissociation and ligand-glutathione exchange reaction in binuclear cationic tetranitrosyl iron complex with penicillamine.

This paper describes a comparative study of the decomposition of two nitrosyl iron complexes (NICs) with penicillamine thiolic ligands [Fe2(SC5H11NO2)2(NO)4]SO4 ·5H2O (I) and glutathione- (GSH-) ligands [Fe2(SC10H17N3O6)2(NO)4]SO4 ·2H2O (II), which spontaneously evolve to NO in aqueous medium. NO formation was measured by a sensor electrode and by spectrophotometric methods by measuring the formation of a hemoglobin- (Hb-) NO complex. The NO evolution reaction rate from (I) k 1 = (4.6 ± 0.1)·10(-3) s(-1) and the elimination rate constant of the penicillamine ligand k 2 = (1.8 ± 0.2)·10(-3) s(-1) at 25°C in 0.05 M phosphate buffer, pH 7.0, was calculated using kinetic modeling based on the experimental data. Both reactions are reversible. Spectrophotometry and mass-spectrometry methods have firmly shown that the penicillamine ligand is exchanged for GS(-) during decomposition of 1.5·10(-4) M (I) in the presence of 10(-3) M GSH, with 76% yield in 24 h. As has been established, such behaviour is caused by the resistance of (II) to decomposition due to the higher affinity of iron to GSH in the complex. The discovered reaction may impede S-glutathionylation of the essential enzyme systems in the presence of (I) and is important for metabolism of NIC, connected with its antitumor activity.