We show that the N-methylimidazole-based selone ImOHSe having an N-CH2CH2OH substituent has the remarkable ability to degrade methylmercury by two distinct pathways. Under basic conditions, ImOHSe converts MeHgCl into biologically inert HgSe nanoparticles and Me2Hg via the formation of an unstable intermediate (MeHg)2Se (pathway I). However, under neutral conditions, in the absence of any base, ImOHSe facilitates the cleavage of the Hg-C bond of MeHgCl at room temperature (23 °C), leading to the formation of a stable cleaved product, the tetracoordinated mononuclear mercury compound (ImOHSe)2HgCl2 and Me2Hg (pathway II). The initial rate of Hg-C bond cleavage of MeHgCl induced by ImOHSe is almost 2-fold higher than the initial rate observed by ImMeSe. Moreover, we show that ImYSe (Y = OH, Me) has an excellent ability to dealkylate Me2Hg at room temperature. Under acidic conditions, in the presence of excess ImYSe, the volatile and toxic Me2Hg further decomposes to the tetracoordinated mononuclear mercury compound [(ImYSe)4Hg]2+. In addition, the treatment of ImOHSe with MeHgCys or MeHgSG in phosphate buffer (pH 8.5) afforded water-soluble Hg(SeS) nanoparticles via unusual ligand exchange reactions, whereas its derivative ImOMeSe or ImMeSe, lacking the N-CH2CH2OH substituent, failed to produce Hg(SeS) nanoparticles under identical reaction conditions. © 2017 American Chemical Society.

Banerjee M.

Roy G.

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Shiv Nadar University

Inorganic Chemistry

Here we report the coordination behaviour of an imidazole-based [S 1 ]-donor ligand, 1,3-dimethyl-imidazole-2(3H)-thione (L1), and [S 2 ]-donor ligand, 3,3′-methylenebis(1-methyl-imidazole-2(3H)-thione) (L2) or 4,4′-(3,3′-methylenebis-(2-thioxo-2,3-dihydro-imidazole-3,1-diyl))dibutanoic acid (L3), with HgX 2 (X = Cl, Br or I) in solution and the solid state. NMR, UV-Vis spectroscopic, and single crystal X-ray studies demonstrated that L1 or L2 coordinated rapidly and reversibly to the mercury center of HgX 2 through the thione moiety. Treatment of L2 with HgCl 2 or HgBr 2 afforded 16-membered metallacycle k 1 -(L2) 2 Hg 2 Cl 4 or k 1 -(L2) 2 Hg 2 Br 4 where two Cl or Br atoms are located inside the ring. In contrast, treatment of L2 with HgI 2 afforded a chain-like structure of k 1 -[L2Hgl 2 ] n , possibly due to the large size of the iodine atom. Interestingly, [S 1 ] and [S 2 ]-donor ligands (L1, L2, and L3) showed an excellent efficacy to protect liver cells against HgCl 2 induced toxicity and the strength of their efficacy is in the order of L3 &gt; L2 &gt; L1. 30\% decrease of ROS production was observed when liver cells were co-treated with HgCl 2 and L1 in comparison to those cells treated with HgCl 2 only. In contrast, 45\% and 60\% decrease of ROS production was observed in the case of cells co-treated with HgCl 2 and thiones L2 and L3, respectively, indicating that [S 2 ]-donor ligands L2 and L3 have better cytoprotective effects against oxidative stress induced by HgCl 2 than [S 1 ]-donor ligand L1. Water-soluble ligand L3 with N-(CH 2 ) 3 CO 2 H substituents showed a better cytoprotective effect against HgCl 2 toxicity than L2 in liver cells. © 2019 The Royal Society of Chemistry.

Fulltext

Metallomics

Cytoprotective effects of imidazole-based [S 1 ] and [S 2 ]-donor ligands against mercury toxicity: A bioinorganic approach

The Hg−C bond of MeHgCl, a ubiquitous environmental toxicant, is notoriously inert and exceedingly difficult to cleave. The cleavage of the Hg−C bond of MeHgCl at low temperature, therefore, is of significant importance for human health. Among various bis(imidazole)-2-selones LnSe (n=1–4, or 6), the three-spacer L3Se shows extraordinarily high reactivity in the degradation of various mercury alkyls including MeHgCl because of its unique ability to coordinate through κ2-fashion, in which both the Se atoms simultaneously attack the Hg center of mercury alkyls for facile Hg−C bond cleavage. It has the highest softness (σ) parameter and the lowest HOMO(LnSe)-LUMO(MeHgX) energy gap and, thus, L3Se is the most reactive among LnSe towards MeHgX (X=Cl or I). L3Se is highly efficient, more than L1Se, in restoring the activity of antioxidant enzyme glutathione reductase (GR) that is completely inhibited by MeHgCl; 80 \% GR activity is recovered by L3Se relative to 50 \% by L1Se. It shows an excellent cytoprotective effect in liver cells against MeHgCl-induced oxidative stress by protecting vital antioxidant enzymes from inhibition caused by MeHgCl and, thus, does not allow to increase the intracellular reactive oxygen species (ROS) levels. Furthermore, it protects the mitochondrial membrane potential (ΔΨm) from perturbation by MeHgCl. Major Hg-responsive genes analyses demonstrate that L3Se plays a significant role in MeHg+ detoxification in liver cells. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chemistry - A European Journal

Exploiting the κ2-Fashioned Coordination of [Se2]-Donor Ligand L3Se for Facile Hg−C Bond Cleavage of Mercury Alkyls and Cytoprotection against Methylmercury-Induced Toxicity

Methylation and demethylation of mercury compounds are two important competing processes that control the net production of highly toxic mercury alkyls, methylmercury (MeHg+) and dimethylmercury (Me2Hg), in environment. Although the microbial and the photochemical methylation and demethylation processes are well studied in recent years but the chemical methylation and demethylation processes have not been studied well. Herein, we report for the first time that the CuSe nanosheet has remarkable ability to activate the highly inert Hg−C bonds of various MeHg+ and Me2Hg compounds at room temperature (21 °C). It facilitates the conversion of MeHg+ into Me2Hg in the absence of any proton donors. Whereas, in the presence of any proton source, it has unique ability to degrade MeHg+ into CH4 and inorganic mercury (Hg2+). Detailed studies revealed that the relatively fast Hg−C bond cleavage was observed in case of MeHgSPh or MeHgI in comparison to MeHgCl, indicating that the Hg−C bond in MeHgCl is relatively inert in nature. On the other hand, the Hg−C bond in Me2Hg is considered to be exceedingly inert and, thus, difficult to cleave at room temperature. However, CuSe nanosheets showed unique ability to degrade Me2Hg into CH4 and Hg2+, via the formation of MeHg+, under acidic conditions at room temperature. DFT calculations revealed that the Hg−C bond activation occurs through adsorption on the surface of (100)-faceted CuSe nanosheets. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chemistry - An Asian Journal

Chemical Degradation of Mercury Alkyls Mediated by Copper Selenide Nanosheets

Organomercurials, such as methylmercury (MeHg+), are among the most toxic materials to humans. Apart from inhibiting proteins, MeHg+ exerts its cytotoxicity through strong binding with endogenous thiols cysteine (CysH) and glutathione (GSH) to form MeHgCys and MeHgSG complexes. Herein, it is reported that the N,N-disubstituted benzimidazole-based thione 1 containing a N−CH2CH2OH substituent converts MeHgCys and MeHgSG complexes to less toxic water-soluble HgS nanoparticles (NPs) and releases the corresponding free thiols CysH and GSH from MeHgCys and MeHgSG, respectively, in solution by unusual ligand-exchange reactions in phosphate buffer at 37 °C. However, the corresponding N-substituted benzimidazole-based thione 7 and N,N-disubstituted imidazole-based thione 3, in spite of containing a N−CH2CH2OH substituent, failed to convert MeHgX (X=Cys, and SG) to HgS NPs under identical reaction conditions, which suggests that not only the N−CH2CH2OH moiety but the benzimidazole ring and N,N-disubstitution in 1, which leads to the generation of a partial positive charge at the C2 atom of the benzimidazole ring in 1:1 MeHg-conjugated complex of 1, are crucial to convert MeHgX to HgS NPs under physiologically relevant conditions. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Protection of Endogenous Thiols against Methylmercury with Benzimidazole-Based Thione by Unusual Ligand-Exchange Reactions

Organomercurials including methylmercury are ubiquitous environmental pollutants and highly toxic to humans. Now it could be shown that N-methylimidazole based thiones/selones having an N-CH2CH2OH substituent are remarkably effective in detoxifying various organomercurials to produce less toxic HgE (E=S, Se) nanoparticles. Compounds lacking the N-CH2CH2OH substituent failed to produce HgE nanoparticles upon treatment with organomercurials, suggesting that this moiety plays a crucial role in the detoxification by facilitating the desulfurization and deselenization processes. This novel way of detoxifying organomercurials may lead to the discovery of new compounds to treat patients suffering from methylmercury poisoning. Getting rid of mercury: Insoluble HgE (E=S, Se) nanoparticles (NPs) are formed under physiologically relevant conditions when organomercurials are treated with N-methylimidazole-based thiones/selones having an N-CH2CH2OH substituent. Compounds lacking the N-CH2CH2OH substituent failed to produce HgE NPs upon treatment with organomercurials under identical reaction conditions. A novel pathway of detoxifying various organomercurials is described. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Angewandte Chemie - International Edition

Chemical Detoxification of Organomercurials

Herein, we describe the synthesis and biomimetic activity of a series of N,N-disubstituted thiones and selones that contain an imidazole pharmacophore. The N,N-disubstituted thiones do not show any inhibitory activity towards LPO-catalyzed oxidation reactions, but their corresponding N,N-disubstituted selones exhibit inhibitory activity towards LPO-catalyzed oxidation reactions. Substituents on the N atom of the imidazole ring appear to have a significant effect on the inhibition of LPO-catalyzed oxidation and iodination reactions. Selones 16, 17, and 19, which contain methyl, ethyl, and benzyl substituents, exhibit similar inhibition activities towards LPO-catalyzed oxidation reactions with IC50 values of 24.4, 22.5, and 22.5 μM, respectively. However, their activities are almost three-fold lower than that of the commonly used anti-thyroid drug methimazole (MMI). In contrast, selone 21, which contains a N-CH2CH2OH substituent, exhibits high inhibitory activity, with an IC50 value of 7.2 μM, which is similar to that of MMI. The inhibitory activity of these selones towards LPO-catalyzed oxidation/iodination reactions is due to their ability to decrease the concentrations of the co-substrates (H2O2 and I 2), either by catalytically reducing H2O2 (anti-oxidant activity) or by forming stable charge-transfer complexes with oxidized iodide species. The inhibition of LPO-catalyzed oxidation/iodination reactions by N,N-disubstituted selones can be reversed by increasing the concentration of H2O2. Interestingly, all of the N,N-disubstituted selones exhibit high anti-oxidant activities and their glutathione peroxidase (GPx)-like activity is 4-12-fold higher than that of the well-known GPx-mimic ebselen. These experimental and theoretical studies suggest that the selones exist as zwitterions, in which the imidazole ring contains a positive charge and the selenium atom carries a large negative charge. Therefore, the selenium moieties of these selones possess highly nucleophilic character. The 77Se NMR chemical shifts for the selones show large upfield shift, thus confirming the zwitterionic structure in solution. Stop, in the name of love: The inhibition of lactoperoxidase (LPO)-catalyzed reactions by a series of N,N-disubstituted thiones and selones that contain an imidazole pharmacophore is described. The inhibitory activity not only depends on the substituent that is attached to the nitrogen atom, but also on the nature of the chalcogen atom. The inhibition of LPO activity by selones is due to their ability to scavenge the substrate, hydrogen peroxide. Copyright © 2013 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim.