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.

Banerjee M.

Karri R.

Rawat K.S.

Muthuvel K.

Pathak B.

Roy G.

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Shiv Nadar University

Angewandte Chemie - International Edition

Synthetic organic molecules, which can selectively convert excess intracellular copper (Cu) ions to nanozymes with an ability to protect cells from oxidative stress, are highly significant in developing therapeutic agents against Cu-related disorder like Wilson's disease. Here, we report 1,3-bis(2-hydroxyethyl)-1H-benzoimidazole-2-selenone (1), which shows a remarkable ability to remove Cu ion from glutathione, a major cytosolic Cu-binding ligand, and thereafter converts it into copper selenide (CuSe) nanozyme that exhibits remarkable glutathione peroxidase-like activity, at cellular level of H 2 O 2 concentration, with excellent cytoprotective effect against oxidative stress in hepatocyte. Cu-driven deselenization of 1, under physiologically relevant conditions, occurred in two steps. The activation of C=Se bond by metal ion is the crucial first step, followed by cleavage of the metal-activated C=Se bond, initiated by the OH group of N-(CH 2 ) 2 OH substituent through neighboring group participation (deselenization step), resulted in the controlled synthesis of various types of Cu 2-x Se nanocrystals (NCs) (nanodisks, nanocubes, and nanosheets) and tetragonal Cu 3 Se 2 NCs, depending upon the oxidation state of the Cu ion used to activate the C=Se bond. Deselenization of 1 is highly metal-selective. Except Cu, other essential metal ions, including Mn 2+ , Fe 2+ , Co 2+ , Ni 2+ , or Zn 2+ , failed to produce metal selenide under identical reaction conditions. Moreover, no significant change in the expression level of Cu-metabolism-related genes, including metallothioneines MT1A, is observed in liver cells co-treated with Cu and 1, as opposed to the large increase in the concentrations of these genes observed in cells treated with Cu alone, suggesting the participation of 1 in Cu homeostasis in hepatocyte. © 2019 American Chemical Society.

ACS Applied Materials and Interfaces

Copper-Driven Deselenization: A Strategy for Selective Conversion of Copper Ion to Nanozyme and Its Implication for Copper-Related Disorders

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

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

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.

Inorganic Chemistry

Cleavage of Hg-C Bonds of Organomercurials Induced by ImOHSe via Two Distinct Pathways

Here we report that [S2]-donor ligands BmmOH, BmmMe, and BmeMe bind rapidly and reversibly to the mercury centers of organomercurials, RHgX, and facilitate the cleavage of Hg-C bonds of RHgX to produce stable tetracoordinated Hg(II) complexes and R2Hg. Significantly, the rate of cleavage of Hg-C bonds depends critically on the X group of RHgX (X = BF4-, Cl-, I-) and the [S2]-donor ligands used to induce the Hg-C bonds. For instance, the initial rate of cleavage of the Hg-C bond of MeHgI induced by BmeMe is almost 2-fold higher than the initial rate obtained by BmmOH or BmmMe, indicating that the spacer between the two imidazole rings of [S2]-donor ligands plays a significant role here in the cleavage of Hg-C bonds. Surprisingly, we noticed that the initial rate of cleavage of the Hg-C bond of MeHgI induced by BmeMe (or BmmMe) is almost 10-fold and 100-fold faster than the cleavage of Hg-C bonds of MeHgCl and [MeHg]BF4 respectively, under identical reaction conditions, suggesting that the Hg-C bond of [MeHg]BF4 is highly inert at room temperature (21 °C). We also show here that the nature of the final stable cleaved products, i.e. Hg(II) complexes, depends on the X group of RHgX and the [S2]-donor ligands. For instance, the reaction of BmmMe with MeHgCl (1:1 molar ratio) afforded the formation of the 16-membered metallacyclic dinuclear mercury compound (BmmMe)2Hg2Cl4, in which the two Cl atoms are located inside the ring, whereas due to the large size of the I atom, a similar reaction with MeHgI yielded polymeric [(BmmMe)2HgI2]m·(MeHgI)n. However, the treatment of BmmMe with ionic [RHg]BF4 led to the formation of the tetrathione-coordinated mononuclear mercury compound [(BmmMe)2Hg](BF4)2, where BF4- serves as a counteranion. © 2017 American Chemical Society.

Activation of the Hg-C Bond of Methylmercury by [S2]-Donor Ligands

Journal of the American Chemical Society

Protolytic Cleavage of Hg–C Bonds Induced by 1-Methyl-1,3-dihydro-2H-benzimidazole-2-selone: Synthesis and Structural Characterization of Mercury Complexes