Thiol-containing Ligands Research Articles

The influence of exogenous and endogenous nitric oxide on the human and animal body

It has been shown that the inhalation of gaseous NO (exogenous nitric oxide) leads to the formation of nitrosonium cations (NO+) in the circulating blood of humans and animals during the oxidation of NO, which can have a detrimental effect on pathogenic viruses and bacteria. When thiols enter the blood simultaneously with NO inhalation, they form S-nitrosothiols with NO+ and cause hypotensive effect in animals. The biological effect of endogenous NO, which is produced in cells and tissues with the participation of NO synthases in animals and humans, is mediated by the dinitrosyl iron complexes (DNIC) formed with thiol-containing ligands. As NO and NO+ donors, these complexes have a variety of regulatory and cytotoxic effects on the animal and human body. In particular, the NO+ released by DNIC was shown to suppress SARS-CoV-2 infection in Syrian hamsters.

Spectroscopic, electrochemical, and kinetic trends in Fe(III)–thiolate disproportionation near physiologic pH

In addition to its primary oxygen-atom-transfer function, cysteamine dioxygenase (ADO) exhibits a relatively understudied anaerobic disproportionation reaction (ADO-Fe(III)-SR → ADO-Fe(II) + ½ RSSR) with its native substrates. Inspired by ADO disproportionation reactivity, we employ [Fe(tacn)Cl3] (tacn = 1,4,7-triazacyclononane) as a precursor for generating Fe(III)–thiolate model complexes in buffered aqueous media. A series of Fe(III)–thiolate model complexes are generated in situ using aqueous [Fe(tacn)Cl3] and thiol-containing ligands cysteamine, penicillamine, mercaptopropionate, cysteine, cysteine methyl ester, N-acetylcysteine, and N-acetylcysteine methyl ester. We observe trends in UV–Vis and electron paramagnetic resonance (EPR) spectra, disproportionation rate constants, and cathodic peak potentials as a function of thiol ligand. These trends will be useful in rationalizing substrate-dependent Fe(III)–thiolate disproportionation reactions in metalloenzymes.Graphical abstract

Ca-oxalate crystals are involved in cadmium storage in a high Cd accumulating cultivar of cacao

Cadmium (Cd) concentrations in cacao often exceed food limits. A better understanding of the molecular mechanisms of Cd accumulation in cacao trees is necessary to advance Cd mitigation strategies. This study explores Cd distribution and speciation (i.e., chemical form) within the vegetative organs of a high Cd accumulating cacao cultivar growing in soil with background Cd concentrations (0.28 mg Cd kg−1) by synchrotron radiation-based micro- and nano-X-ray fluorescence imaging and X-ray absorption spectroscopy on duplicate samples of roots, young branches, mature branches, and leaves. In both the roots and branches, the incorporation of Cd in Ca-oxalate crystals with binding to oxygen-ligands was identified as a major mechanism of Cd regulation. The Ca-oxalate crystals were more abundant in the branches than in the roots. We suggest that the incorporation of Cd into the Ca-oxalate crystals may limit the transfer of Cd to other organs like the leaves and beans. The roots also featured Cd-sulfur species in dilated cells of the wood, probably for the retention of Cd in the roots by strong binding with Cd to thiol-containing ligands. A Cd hotspot in large, secreting channels of the branches suggested that mucilage may play a role in the transport of Cd within cacao trees. The leaves had local Cd enrichments in the parenchymatous tissues and displayed a higher Cd concentration in the mesophyll compared to the epidermis. These insights in Cd distribution and speciation underscore that Theobroma cacao L. develops original Cd detoxification strategies, strongly different from non-tolerant species such as cereals.

Why gaseous nitric oxide inhalation does not influence on systemic arterial pressure in human and animal organisms?

The reason has been elucidated why gaseous nitric oxide inhalation does not produce hypotensive effect in human and animal organisms. The defect was completely removed when low molecular thiol solutions were added by intravenous pathway simultaneously with gaseous NO inhalation into the animals (rats). The proposition was made that gaseous NO molecules including through the lungs into the circulation of the blood are transformed as a result of one-electron mechanism oxidation into nitosonium cation (NO+) which are not capable of vasodilating and thereby hypotensive action on men and animals. NO+ cation binding with low molecular thiols results in the S-nitrosothiol (RS-NO) formation with following release of the nitrosyl component from the RS-NO in the form of neutral NO molecule characterized with hypotensive activity. The formation of another NO donor - dinitrosyl iron complexes with thiol-containing ligands did not occur in the animals. Hypotensive action observed in lungs could be determined by gaseous NO penetration trough external vascular wall followed by the activation of vasodilation and hypotensia inductor - guanylate cyclase enzyme immediately inside of vascular walls.

Dinityrosyl Iron Complexes with Thiol-Containing Ligands as a Functionally Active “Working Form” of Nitric Oxide System in Living Organisms: A Review

Experimental data were summarized to assume that dinitrosyl iron complexes (DNICs) with thiol-containing ligands are an endogenous “working form” of the nitric oxide (NO) system in living organisms. DNICs can function as donors of both neutral NO molecules, which are responsible for positive regulatory effects of the NO system on various physiological and biochemical processes in humans and animals, and nitrosonium cations (NO+), which are responsible mostly for negative cytotoxic activity of the system. Special attention is paid to the finding that DNICs, especially in combination with dithiocarbamate derivatives, suppress SARS-CoV-2 infection in Syrian hamsters.

Dinityrosyl Iron Complexes with Thiol-Containg Ligands as a Funcionally Active “Working Form” of Nitric Oxide System in Living Organisms

The experimental data are summarized which allow to suggest that dinitrosyl iron complexes (DNIC) with thiol-containing ligands can be considered as an endogenous “working form” of nitric oxide (NO) system in living organisms. The complexes can function as donors of both neutral NO molecules as well as nitrosonium cations (NO+) which exert respectively positive (regulatory) or negative (cytotoxic) effect on human and animal organisms. A special attention is paid to DNIC capacity to block (especially in combination with dithiocarbamate derivatives) coronavirus SARS-CoV-2 infection in Syrian hamsters.

Effect of Peroxynitrite and <i>tert</i>-Butyl Hydroperoxide on Thiol Ligands of Dinitrosyl Iron Complexes

Low molecular weight dinitrosyl iron complexes (DNICs) with thiol-containing ligands are a physiological form for deposit and transport of nitric oxide (NO) in the organism, herewith DNICs can exhibit antioxidant and antiradical properties. It was that DNICs containing cysteine, glutathione and lipoic acid as ligands, decreased the rate of dihydrodamine oxidation by peroxynitrite formed during 3-morpholinononymine decomposition. Thiol (sulfhydryl) ligands are present in DNICs in the form of thiolate anions (R-S−), which protects these groups from oxidation by peroxynitrite. When tert-butyl peroxide was used as an oxidizer at low concentration, the protective effect of DNICs on their SH-groups was observed for complexes with lipoic acid (LA-DNIC) and with glutathione (GS-DNIC). LA-DNIC was more resistant to oxidizing agents and more effective peroxynitrite trap than other DNICs. DNICs associated with bovine serum albumin had a negligible protective effect on cysteine residue during oxidation by peroxynitrite and tert-butyl hydroperoxide. The obtained results allow us to consider low molecular weight DNICs with thiol ligands as peroxynitrite traps and thiol residues protectors in proteins.

Dinitrosyl iron complexes with thiol-containing ligands as sources of universal cytotoxins - nitrosonium cations

It was shown that the release of a half of nitrosyl ligands from dinitrosyl iron units in the form of nitrosonium cation (NO+) from binuclear dinitrosyl iron complexes with thiol-containing ligands (B-DNIC) during DNIC decomposition in acid solutions is increased with the decrease of the stability of these complexes and completely blocked with the increase of the concentrations of free thiols (non-included into B-DNIC) up to the level that was two times and more than that of dinitrosyl iron units. It was demonstrated that the less stable B-DNIC with mercaptosuccinate degrade in an acidic environment at ambient temperature, while the decomposition of more stable B-DNIC with glutathione was only marked when the solution was heated at 80°C. The inhibition of NO+ release from B-DNIC in the presence of elevated free thiol level in the solution was due to the ability of free thiols to induce the reduction of NO+ to NO.

Dinitrosyl Iron Complexes with Thiol-Containing Ligands as Sources of Universal Cytotoxins, Nitrosonium Cations

Dinitrosyl Iron Complexes with Thiol-Containing Ligands as Sources of Universal Cytotoxins, Nitrosonium Cations

Ligand-Mediated Revival of Degraded α-CsPbI3 to Stable Highly Luminescent Perovskite.

Although α-CsPbI3 is regarded as an attractive optical luminophore, it is readily degraded to the optically inactive δ-phase under ambient conditions. Here, we present a simple approach to revive degraded ("optically sick") α-CsPbI3 through "medication" with thiol-containing ligands. The effect of different types of thiols is systematically studied through optical spectroscopy. The structural reconstruction of degraded α-CsPbI3 nanocrystals to cubic crystals in the presence of thiol-containing ligands is visualized through high-resolution transmission electron microscopy and supported by X-ray diffraction analysis. We found that 1-dodecanethiol (DSH) effectively revives degraded CsPbI3 and results in high immunity towards moisture and oxygen, hitherto unreported. DSH facilitates the passivation of surface defects and etching of degraded Cs4 PbI6 phase, thus reverting them back to the cubic CsPbI3 phase, leading to enhanced PL and environmental stability.

Exploration of surface chemistry effects on the biodistribution and pharmacokinetics of dual-ligand luminescent gold nanoparticles

Understanding how surface chemistry influences gold nanoparticle (AuNP) biodistribution and pharmacokinetics is critical for the design of Au-based nanoprobes for in vivo sensing and imaging. AuNPs prepared using a single surface ligand have been widely studied; however, limited work has been reported for luminescent AuNPs decorated with multiple surface ligands. Herein, we describe the synthesis and characterization of four dual-ligand luminescent AuNPs prepared using a combination of four thiol-containing ligands (GSH, MUA, tDK, tDY). The impact of surface chemistry on in vivo biodistribution and pharmacokinetics was then investigated for each dual-ligand AuNP type using a mouse model. Our results indicate that variation of one of the two surface ligands can exert a significant influence on the pharmacokinetics and biodistribution of the AuNPs. Interestingly, we observed changes in biodistribution in the lung and digestive organs, as well as blood circulation time. These results are expected to inform the future de novo design of dual-ligand luminescent AuNPs for in vivo applications.

High Dose Inhalation with Gaseous Nitric Oxide in COVID-19 Treatment

A method of treatment of a new coronavirus infection COVID-19 in patients undergoing high flow oxygenation is proposed and technically implemented; the method is based on high-dose inhalation of gaseous nitric oxide (NO) with the patient’s spontaneous breathing. The results of the treatment of this disease demonstrating the high efficiency of the new method are presented. A possible mechanism of the blocking effect of high doses of inhaled nitric oxide on the replication of the SARS-CoV-2 virus is discussed; it is based on the formation of dinitrosyl iron complexes in the respiratory tract and lungs of COVID-19 patients with thiol-containing ligands acting as donors of NO and nitrosonium NO+ cations in a living organism that have a cytotoxic effect on the SARS CoV-2 virus.

Positive (Regulatory) and Negative (Cytotoxic) Effects of Dinitrosyl Iron Complexes on Living Organisms.

The proposed in our studies mechanism of dinitrosyl iron complex (DNIC) formation through the main step of disproportionation of two NO molecules in complex with Fe2+ ion leads to emergence of the resonance structure of dinitrosyl-iron fragment of DNIC, [Fe2+(NO)(NO+)]. The latter allowed suggesting capacity of these complexes to function as donor of both neutral NO molecules as well as nitrosonium cations (NO+), which has been demonstrated in experiments. Analysis of biological activity of DNICs with thiol-containing ligands presented in this review demonstrates that NO molecules and nitrosonium cations released from the complexes exert respectively positive (regulatory) and negative (cytotoxic) effects on living organisms. It has been suggested to use dithiocarbamate derivatives to enhance selective release of nitrosonium cations from DNIC in living organisms followed by simultaneous incorporation of the released NO molecules into the biologically non-active mononitrosyl iron complexes with dithiocarbamate derivatives.

Isolipoic acid-linked gold nanoparticles bearing the thomsen friedenreich tumor-associated carbohydrate antigen: Stability and in vitro studies.

We have previously prepared gold nanoparticles (AuNPs) bearing the Thomsen-Friedenreich antigen disaccharide (TFag), a pan-carcinoma, Tumor-Associated Carbohydrate Antigen (TACA), as tools for various assays and biological applications. Conjugation to AuNPs typically involves the use of thiols due to the affinity of sulfur for the gold surface of the nanoparticle. While a use of a single thiol-containing ligand bound to the gold surface is standard practice, several studies have shown that ligands bearing multiple thiols can enhance the strength of the conjugation in a nearly linear fashion. (R)-(+)-α-Lipoic acid (LA), a naturally occurring disulfide-containing organic acid that is used as a cofactor in many enzymatic reactions, has been used as a linker to conjugate various molecules to AuNPs through its branched di-thiol system to enhance nanoparticle stability. We sought to use a similar system to increase nanoparticle stability that was devoid of the chiral center in (R)-(+)-α-lipoic acid. Isolipoic acid, an isomer of LA, where the exocyclic pentanoic acid chain is shifted by one carbon on the dithiolane ring to produce an achiral acid, was thought to act similarly as LA without the risk of any contaminating (L)-(−) isomer. We synthesized AuNPs with ligands of both serine and threonine glycoamino acids bearing the TFag linked to isolipoic acid and examined their stability under various conditions. In addition, these particles were shown to bind to Galectin-3 and inhibit the interaction of Galectin-3 with a protein displaying copies of the TFag. These agents should prove useful in the design of potential antimetastatic therapeutics that would benefit from achiral linkers that are geometrically linear and achiral.

Ligand-Tuned Energetics for the Selective Synthesis of Ni2P and Ni12P5 Possessing Bifunctional Electrocatalytic Activity toward Hydrogen Evolution and Hydrazine Oxidation Reactions.

The occurrence of many phases and stoichiometries of nickel phosphides calls for the development of synthetic levers to selectively produce phases with purity. Herein, thiol (-SH) and carboxylate (-COO-) functional groups in ligands were found to effectively tune the energetics of nickel phosphide phases during hydrothermal synthesis. The initial kinetic product Ni2P transforms into thermodynamically stable Ni12P5 at longer reaction times. The binding of carboxylate onto Ni2P promotes this phase transformation to produce pure-phase Ni12P5 within 5 h compared to previous reports (∼48 h). Thiol-containing ligands inhibit this transformation process by providing higher stability to the Ni2P phase. Cysteine-capped Ni2P showed excellent geometric and intrinsic electrocatalytic activity toward both hydrogen evolution and hydrazine oxidation reactions under alkaline conditions. This bifunctional electrocatalytic nature enables cysteine-capped Ni2P to promote hydrazine-assisted hydrogen generation that requires lower energy (0.46 V to achieve 10 mA/cmgeo2) compared to the conventional overall water splitting (1.81 V to achieve 10 mA/cmgeo2) for hydrogen generation.

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

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.

CdS Nanoplates Modification as a Platform for Synthesis of Blue-Emitting Nanoparticles.

In this paper, the study of surface modification of two-dimensional (2D), non-luminescent CdS nanoplates (NPLs) by thiol-containing ligands is presented. We show that a process of twophase transfers with appropriate ligand exchange transforms non-luminescent NPLs into spherical CdS nanoparticles (NPs) exhibiting a blue photoluminescence with exceptionally high quantum yield ~90%. In the process, transfer from inorganic solvent to water is performed, with appropriately selected ligand molecules and pH values (forward phase transfer), which produces NPs with modified size and shape. Then, in reverse phase transfer, NPs are transferred back to toluene due to surface modification by combined Cd (OL)2 and Cd (Ac)2. As a result, spherical NPs are formed (average diameter between 4 and 6 nm) with PL QY as high as 90%. This is unique for core only CdS NPs without inorganic shell.

Nitrosonium Cation as a Cytotoxic Component of Dinitrosyl Iron Complexes with Thiol-containing Ligands (based on the Experimental Work on MCF7 Human Breast Cancer Cell Culture).

Here we demonstrate that binuclear dinitrosyl iron complexes with thiol-containing ligands (glutathione and mercaptosuccinate, B-DNIC-GSH and B-DNIC-MS, respectively) exert cytotoxic effects on MCF7 human breast cancer cells. We showed that they are mediated by nitrosonium cations released from these complexes (NO+). This finding is supported by the cytotoxic effect of both B-DNICs on MCF7 cells evidenced to retain or was even promoted in the presence of N-Methyl-D-glucamine dithiocarbamate (MGD). MGD recruits an iron nitrosyl group [Fe(NO)] from the iron-dinitrosyl fragment [Fe(NO)2] of B-DNIC-MS forming stable mononitrosyl complexes of iron with MGD and releasing NO+ cations from a [Fe(NO)2] fragment.

Gaseous Nitric Oxide and Dinitrosyl Iron Complexes with Thiol-Containing Ligands as Potential Medicines that Can Relieve COVID-19.

It is shown that the inhalation of gaseous nitric oxide (gNO) or sprayed aqueous solutions of binuclear dinitrosyl iron complexes with glutathione or N-acetyl-L-cysteine by animals or humans provokes no perceptible hypotensive effects. Potentially, these procedures may be useful in COVID-19 treatment. The NO level in complexes with hemoglobin in blood decreases as the gNO concentration in the gas flow produced by the Plazon system increases from 100 to 2100 ppm, so that at 2000 ppm more than one-half of the gas can be incorporated into dinitrosyl complexes formed in tissues of the lungs and respiratory tract. Thus, the effect of gNO inhalation may be similar to that observed after administration of solutions of dinitrosyl iron complexes, namely, to the presence of dinitrosyl iron complexes with thiol-containing ligands in lung and airway tissues. With regard to the hypothesis posited earlier that these complexes can suppress coronavirus replication as donors of nitrosonium cations (Biophysics 65, 818, 2020), it is not inconceivable that administration of gNO or chemically synthesized dinitrosyl iron complexes with thiol-containing ligands may help treat COVID-19. In tests on the authors of this paper as volunteers, the tolerance concentration of gNO inhaled within 15 min was approximately 2000 ppm. In tests on rats that inhaled sprayed aqueous solutions of dinitrosyl iron complexes, their tolerance dose was approximately 0.4 mmol/kg body weight.

The Autowave Mode of the Formation of Dinitrosyl Iron Complexes with Thiol-Containing Ligands

Addition of a 20-μL drop of a mixture containing 1 mM Fe2+ + 0.5 M glutathione to the surface of 0.5 M S-nitrosoglutathione solution, which is expected to form dinitrosyl iron complexes with glutathione, generated short-lived (0.2 s) concentric ring-shaped structures in the S-nitrosoglutathione solution. The number of the ring-like structures exceeded the number of concentric circles spread across the water surface (mechanical waves) when droplets of water fall into a body of an aqueous solution. It appears likely that the ring-shaped structures observed in the S-nitrosoglutathione solution are associated with an autowave distribution of products generated during the formation of dinitrosyl iron complexes with glutathione.