Physico-Chemistry of Dinitrosyl Iron Complexes as a Determinant of Their Biological Activity

Abstract

In this article we minutely discuss the so-called “oxidative” mechanism of mononuclear form of dinitrosyl iron complexes (M-DNICs) formations proposed by the author. M-DNICs are proposed to be formed from their building material—neutral NO molecules, Fe2+ ions and anionic non-thiol (L−) and thiol (RS−) ligands based on the disproportionation reaction of NO molecules binding with divalent ion irons in pairs. Then a protonated form of nitroxyl anion (NO−) appearing in the reaction is released from this group and a neutral NO molecule is included instead. As a result, M-DNICs are produced. Their resonance structure is described as [(L−)2Fe2+(NO)(NO+)], in which nitrosyl ligands are represented by NO molecules and nitrosonium cations in equal proportions. Binding of hydroxyl ions with the latter causes conversion of these cations into nitrite anions at neutral pH values and therefore transformation of DNICs into the corresponding high-spin mononitrosyl iron complexes (MNICs) with the resonance structure described as [(L−)2Fe2+(NO)]. In case of replacing L− by thiol-containing ligands, which are characterized by high π-donor activity, electron density transferred from sulfur atoms to iron-dinitrosyl groups neutralizes the positive charge on nitrosonium cations, which prevents their hydrolysis, ensuring relatively a high stability of the corresponding M-DNICs with the resonance structure [(RS−)2Fe2+ (NO, NO+)]. Therefore, M-DNICs with thiol-containing ligands, as well as their binuclear analogs (B-DNICs, respective resonance structure [(RS−)2Fe2+2 (NO, NO+)2]), can serve donors of both NO and NO+. Experiments with solutions of B-DNICs with glutathione or N-acetyl-L-cysteine (B-DNIC-GSH or B-DNIC-NAC) showed that these complexes release both NO and NO+ in case of decomposition in the presence of acid or after oxidation of thiol-containing ligands in them. The level of released NO was measured via optical absorption intensity of NO in the gaseous phase, while the number of released nitrosonium cations was determined based on their inclusion in S-nitrosothiols or their conversion into nitrite anions. Biomedical research showed the ability of DNICs with thiol-containing ligands to be donors of NO and NO+ and produce various biological effects on living organisms. At the same time, NO molecules released from DNICs usually have a positive and regulatory effect on organisms, while nitrosonium cations have a negative and cytotoxic effect.

Electronic Structure and Transformation of Dinitrosyl Iron Complexes (DNICs) Regulated by Redox Non-Innocent Imino-Substituted Phenoxide Ligand

“…The advanced spectroscopic methods including ENDOR, EPR, IR, UV–vis, Mössbauer, and NRVS unveil the concomitant formation of {Fe­(NO) 2 } 9 DNIC and Roussin’s red ester (RRE) via nitrosylation of nonheme Fe proteins/model compounds. ,,− In a model study, biomimetic {Fe­(NO) 2 } 9 DNIC derived from nitrosylation of [Fe–S] clusters or nitrosylation of iron in the presence of cysteine/reduced glutathione was validated as [(RS) 2 Fe­(NO) 2 ] − by the distinctive EPR signal at g = 2.03 . Over the past decades, the in-depth biomimetic studies provide unprecedented molecular insights resulting from the developments of synthetic strategies and structural characterizations on a series of mononuclear classic four-coordinate DNICs, nonclassic five-coordinate DNICs, and binuclear DNICs coordinated/bridged with biologically relevant ligands. , Specifically, the study concludes that both mononuclear and binuclear DNICs containing S/N/O donor sets dictate the thermodynamic stability/kinetic robustness of [Fe­(NO) 2 ] 9/10 electronic configurations as well as modulate the oxidation states of coordinated NO moiety for the designated chemical reactivity. ,− In translating molecular insights obtained from this fundamental research into real-world applications, significant progress has been made on [Fe­(NO) 2 ] motif serving as a functional building block for promoting electrochemical H 2 evolution from water, CO 2 valorization via C–C bond coupling under ambient condition, and controlled/targeted delivery of NO for biomedical treatments associated with versatile diseases. − ,,− ,,,− …”

“… 29 , 31 − 44 In translating molecular insights obtained from this fundamental research into real-world applications, significant progress has been made on [Fe(NO) 2 ] motif serving as a functional building block for promoting electrochemical H 2 evolution from water, 45 CO 2 valorization via C–C bond coupling under ambient condition, 46 and controlled/targeted delivery of NO for biomedical treatments associated with versatile diseases. 2 − 8 , 10 , 17 − 19 , 26 , 30 , 47 − 54 …”

Molecular Hydrogen: From Molecular Effects to Stem Cells Management and Tissue Regeneration

“…The prospect of using endogenously formed low-molecular-weight gaseous compounds as regulators began to arise only after the establishment of the biological activity of nitrogen monoxide (i.e., nitric oxide; NO • ), for which the Nobel Prize in Medicine and Physiology was awarded [ 4 ]. Later, the ability of other substances—previously considered exclusively as toxic—to act as endogenous gaso-transmitters was discovered.…”

Novel Type of Tetranitrosyl Iron Salt: Synthesis, Structure and Antibacterial Activity of Complex [FeL’2(NO)2][FeL’L”(NO)2] with L’-thiobenzamide and L”-thiosulfate

“…Being effective low-toxic exogenous nitric oxide (NO) donors complementary to a human organism, low-molecular dinitrosyl complexes of tetrahedral iron involving two nitrosyl and two sulfur-containing ligands, as structural analogs of the active sites of dinitrosyl [1Fe-2S] proteins, are promising for practical application in medicine, which is the reason for the increasing interest in fundamental studies of their structural features [ 3 , 4 , 5 ]. As follows from our investigations, the activity of dinitrosyl complexes of tetrahedral iron (DNICs) and their dimers ( Figure 1 A,B) as antibacterial agents is comparable and/or higher than that of antibiotics used in clinics [ 6 , 7 , 8 , 9 , 10 ].…”