Zinc Thiolate Complex Research Articles

Structurally Modelling the 2-His-1-Carboxylate Facial Triad with a Bulky N,N,O Phenolate Ligand.

We present the synthesis and coordination chemistry of a bulky, tripodal N,N,O ligand, ImPh2NNO tBu (L), designed to model the 2‐His‐1‐carboxylate facial triad (2H1C) by means of two imidazole groups and an anionic 2,4‐di‐tert‐butyl‐subtituted phenolate. Reacting K‐L with MCl2 (M = Fe, Zn) affords the isostructural, tetrahedral non‐heme complexes [Fe(L)(Cl)] (1) and [Zn(L)(Cl)] (2) in high yield. The tridentate N,N,O ligand coordination observed in their X‐ray crystal structures remains intact and well‐defined in MeCN and CH2Cl2 solution. Reacting 2 with NaSPh affords a tetrahedral zinc thiolate complex, [Zn(L)(SPh)] (4), that is relevant to isopenicillin N synthase (IPNS) biomimicry. Cyclic voltammetry studies demonstrate the ligand's redox non‐innocence, where phenolate oxidation is the first electrochemical response observed in K‐L, 2 and 4. However, the first electrochemical oxidation in 1 is iron‐centred, the assignment of which is supported by DFT calculations. Overall, ImPh2NNO tBu provides access to well‐defined mononuclear, monoligated, N,N,O‐bound metal complexes, enabling more accurate structural modelling of the 2H1C to be achieved.

Synthesis and Characterization of a Thiopyridazinylmethane-Based Scorpionate Ligand: Formation of Zinc Complexes and Rearrangement Reaction

The ligand tris(6-tert-butyl-3-thiopyridazinyl)methane ([Tntm]H) was synthesized by the reaction of 6-tert-butyl-3-thiopyridazine with bromoform and reacted with zinc bis(trimethylsilylamide) (Zn(N{SiMe3}2)2) to form [Tntm]Zn(N{SiMe3}2) (1). This complex further reacts with protic and acidic substrates, generating the zinc thiolate complex [Tntm]Zn(StBu) (2) and zinc benzoate complex [Tntm]Zn(O2C-Me2C6H3) (3a). In all compounds [Tntm] was found to have tridentate coordination to the metal center in a κ3-C,N,N fashion, as established by single-crystal X-ray diffraction analyses. In solution, rapid dynamic κ3/κ4 equilibrium occurs at room temperature, while 1H NMR spectroscopy at −30 °C confirms the asymmetric solid-state structure. Furthermore, complex 3a shows a rearrangement reaction in solution where the ligand isomerizes to give a κ4-C,N,N,S (3b) and a κ4-C,N,S,S isomer (3c), respectively. Density functional theory (DFT) calculations reveal 3b and 3c to be 13.7 and 15.6 kJ/mol more stable in methylene ...

Decorating tetrathiafulvalene (TTF) with fluorinated phenyls through sulfur bridges: facile synthesis, properties, and aggregation through fluorine interactions.

Tetrathiafulvalene derivatives (TTF1-TTF9) bearing fluorinated phenyl groups attached through the sulfur bridges have been synthesized by employing a copper-mediated C-S coupling reaction of C6 H5-x Fx I (x=1, 2, 5) and a zinc-thiolate complex, (TBA)2 [Zn(DMIT)2 ] (TBA=tetrabutyl ammonium, DMIT=1,3-dithiole-2-thione-4,5-dithiolate), as the key step. Particularly, the selective synthesis of C6 F5 -substituted (TTF8) and C6 F4 -fused (TTF9) TTFs from C6 F5 I is disclosed. The physicochemical properties and crystal structures of these TTFs are fully investigated by UV/Vis absorption spectra, cyclic voltammetry, molecular orbital calculation, and single-crystal X-ray diffraction. The exchange of hydrogen versus fluorine on the peripheral phenyl groups show a notable influence on both the electronic and crystallographic natures of the resulting TTFs: 1) lowering both the HOMO and the LUMO energy levels, 2) modulating the electrochemical properties by regioselective and/or the degree of fluorination, 3) enhancing the driving forces of stacking by multiple fluorine interactions (F⋅⋅⋅S, CF⋅⋅⋅π/πF , CF⋅⋅⋅FC, and CF⋅⋅⋅H). This work indicates that the decoration with fluorinated phenyls holds promise to produce functional TTFs with novel electronic and aggregation features.

Straightforward access to aryl-substituted/fused 1,3-dithiole-2-chalcogenones by Cu-catalyzed C–S coupling between aryl iodides and zinc–thiolate complex (TBA)2[Zn(DMIT)2

The Cu-catalyzed C–S coupling between iodoaryl and a zinc–thiolate complex was achieved. This protocol provides a facile and efficient synthetic approach for aryl-substituted/fused 1,3-dithiole-2-chalcogenones, which can be converted to TTFs.

Thioester Hydrolysis Promoted by a Mononuclear Zinc Complex

The mononuclear zinc complex [(bpta)Zn](ClO(4))(2).0.5H(2)O promotes the hydrolysis of the thioester PhCH(OH)C(O)SCD(3) when dissolved in CH(3)CN:H(2)O (50:50 buffered at pH 9.0). This reaction results in the formation of a mixture of CD(3)SH and a zinc thiolate complex, the latter of which can be protonated to generate additional CD(3)SH. Kinetic studies revealed an overall second-order reaction with an activation energy that is similar to that found for aqueous OH(-) promoted thioester hydrolysis. These studies represent the first investigation of chemistry relevant to that occurring in the monozinc-containing form of human glyoxalase II.

Introduction of a high‐pressure cell for use with Raman microscopy

AbstractA high‐pressure cell for Raman spectroscopical applications has been developed. By using this cell, it is possible to investigate reactions between solids and gases, applying pressures up to 3000 bar. The cell has been successfully tested on the reaction between ferrocene and carbon monoxide. The results point towards a multi‐step reaction mechanism. Furthermore, first results are presented for the investigation of the reaction path of CO2 with a zinc thiolate complex. Copyright © 2006 John Wiley & Sons, Ltd.

Endothelial NO synthase as a source of NO and superoxide

Endothelial nitric oxide (NO) synthase (eNOS) is responsible for most of the vascular NO produced. A functional eNOS transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) via flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) in the carboxy-terminal reductase domain to the heme in the amino-terminal oxygenase domain where the substrate L-arginine is oxidized to L-citrulline and NO. This normal flow of electrons requires dimerization of the enzyme, the presence of the substrate L-arginine, and presence of the cofactor (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4), one of the most potent naturally occurring reducing agents. Cardiovascular risk factors, such as hypertension, hypercholesterolemia, diabetes mellitus, or chronic smoking, stimulate the production of reactive oxygen species (ROS) in the vascular wall. NADPH oxidases represent major sources of this ROS and have been found upregulated in animal models of hypertension, diabetes, and sedentary lifestyle. Superoxide avidly interacts with vascular NO to form peroxynitrite (ONOO−). BH4 is highly sensitive to oxidation, e.g., by ONOO−, and reduced levels of BH4 promote eNOS uncoupling. In fact, in many cases, supplementation with BH4 is capable of correcting eNOS dysfunction. Alternatively, an oxidation of the zinc-thiolate complex of eNOS by ONOO− has been proposed as a mechanism for eNOS uncoupling. Under uncoupled conditions, superoxide is generated from the oxygenase domain of eNOS. eNOS uncoupling and its change from a protective enzyme to a contributor to oxidative stress has been observed in several in vitro models and in animals with cardiovascular pathophysiology such as spontaneously hypertensive rats (SHR), angiotensin-II-induced hypertension, or diabetes. Taken together, several mechanisms seem to underlie endothelial dysfunction, but an uncoupled eNOS markedly contributes to this phenomenon.

Intramolecular NH···S Hydrogen Bonding in the Zinc Thiolate Complex [TmPh]ZnSCH2C(O)NHPh: A Mechanistic Investigation of Thiolate Alkylation as Probed by Kinetics Studies and by Kinetic Isotope Effects

The zinc thiolate complex [Tm(Ph)]ZnSCH2C(O)N(H)Ph, which features a tetrahedral [ZnS4] motif analogous to that of the Ada DNA repair protein, may be obtained by the reaction of Zn(NO3)2 with [Tm(Ph)]Li and Li[SCH2C(O)N(H)Ph] ([Tm(Ph)] = tris(2-mercapto-1-phenylimidazolyl)hydroborato ligand). Structural characterization of [Tm(Ph)]ZnSCH2C(O)N(H)Ph by X-ray diffraction demonstrates that the molecule exhibits an intramolecular N-H...S hydrogen bond between the amide N-H group and thiolate sulfur atom, a structure that is reproduced by density functional theory (DFT) calculations. The thiolate ligand of [Tm(Ph)]ZnSCH2C(O)N(H)Ph is subject to alkylation, a reaction that is analogous to the function of the Ada DNA repair protein. Specifically, [Tm(Ph)]ZnSCH2C(O)N(H)Ph reacts with MeI to yield PhN(H)C(O)CH2SMe and [Tm(Ph)]ZnI, a reaction which is characterized by second-order kinetics that is consistent with either (i) an associative mechanism or (ii) a stepwise dissociative mechanism in which the alkylation step is rate determining. Although the kinetics studies are incapable of distinguishing between these possibilities, a small normal kinetic isotope effect of kH/kD = 1.16(1) at 0 degrees C for the reaction of [Tm(Ph)]ZnSCH2C(O)N(H*)Ph (H* = H, D) with MeI is suggestive of a dissociative mechanism on the basis of DFT calculations. In particular, DFT calculations demonstrate that a normal kinetic isotope effect requires thiolate dissociation because it results in the formation of [PhN(H)C(O)CH2S]- which, as an anion, exhibits a stronger N-H...S hydrogen bonding interaction than that in [Tm(Ph)]ZnSCH2C(O)N(H)Ph. Correspondingly, mechanisms that involve direct alkylation of coordinated thiolate are predicted to be characterized by kH/kD < or = 1 because the reaction involves a reduction of the negative charge on sulfur and hence a weakening of the N-H...S hydrogen bonding interaction.

Zinc-bound thiolate-disulfide exchange: a strategy for inhibiting metallo-beta-lactamases.

The mononuclear zinc thiolate complexes [(Tp(PhMe))Zn(S-R)], where Tp(PhMe) is hydrotris((3-methyl-5-phenyl)pyrazolyl)borate and (S-R) is benzyl thiolate, 4-nitrophenylthiolate, 4-trifluoromethylphenylthiolate, 4-chlorophenylthiolate, phenylthiolate, 2-methylphenylthiolate, 4-methylphenylthiolate, 4-methoxyphenylthiolate, or 4-hydroxyphenylthiolate, were synthesized. Representative members of the class were also characterized structurally. The benzyl thiolate complex undergoes a thiolate-disulfide exchange reaction with a variety of diphenyl and dipyridyl disulfides. Kinetic studies revealed that the reaction shows saturation behavior in both complex and disulfide for most of the disulfides studied. Combined with studies of the lability of the coordinated thiolate, a mechanism is proposed where the reactive species is the zinc-coordinated thiolate. When the free benzyl thiol was allowed to react with the same disulfides, the reaction was slower by a factor of 20-200 than that for the zinc-thiolate complex, depending on the particular disulfide employed. Since most metallo-beta-lactamases contain one or more cysteine residues, the one in the active site being coordinated to zinc, the present study was extended to examine whether disulfides can be used as inhibitors of these enzymes by selective oxidation of the metal-bound cysteine. Several disulfides allowed to react with metallo-beta-lactamase CcrA from Bacteroides fragilis were moderate to potent irreversible inhibitors of the enzyme.

Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite

Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite

Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite.

Nitric oxide (NO) is produced by NO synthase (NOS) in many cells and plays important roles in the neuronal, muscular, cardiovascular, and immune systems. In various disease conditions, all three types of NOS (neuronal, inducible, and endothelial) are reported to generate oxidants through unknown mechanisms. We present here the first evidence that peroxynitrite (ONOO(-)) releases zinc from the zinc-thiolate cluster of endothelial NOS (eNOS) and presumably forms disulfide bonds between the monomers. As a result, disruption of the otherwise SDS-resistant eNOS dimers occurs under reducing conditions. eNOS catalytic activity is exquisitely sensitive to ONOO(-), which decreases NO synthesis and increases superoxide anion (O(2)(.-)) production by the enzyme. The reducing cofactor tetrahydrobiopterin is not oxidized, nor does it prevent oxidation of eNOS by the same low concentrations of OONO(-). Furthermore, eNOS derived from endothelial cells exposed to elevated glucose produces more O(2)(.-), and, like eNOS purified from diabetic LDL receptor-deficient mice, contains less zinc and fewer SDS-resistant dimers. Hence, eNOS exposure to oxidants including ONOO(-) causes increased enzymatic uncoupling and generation of O(2)(.-) in diabetes, contributing further to endothelial cell oxidant stress. Regulation of the zinc-thiolate center of NOS by ONOO(-) provides a novel mechanism for modulation of the enzyme function in disease.

Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite

Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite

Grand Larceny: Oxidant corrupts protein by filching crucial atom (Oxidative damage; Cardiovascular disease)

A new study reveals how oxidants undermine an enzyme that helps keep our blood vessels open and clear of clots. These molecular vandals steal an atom of zinc that helps hold the protein together--not only harming the enzyme in the process but also stimulating the production of more of the cell-wrecking chemicals. By gnawing on proteins and other molecules, oxidants drive heart disease, diabetes, and aging--or so the theory goes (see "The Two Faces of Oxygen" ). These hungry molecules, such as superoxide and peroxynitrite, are spawned in the normal course of metabolism. How they could wreak so much destruction is an enigma, considering that only 1 in 1000 to 1 in 10,000 amino acids in a cell show signs of oxidative wounds, says Jay Heinecke of Washington University in St. Louis, Missouri, an authority on these baneful molecules. Zou and colleagues uncovered the effects of oxidants on one of the body's key enzymes, nitric oxide synthase, which comprises two identical halves coupled by a bridge containing zinc and sulfur. True to its name, nitric oxide synthase makes nitric oxide, a versatile and vital signaling molecule that opens blood vessels and inhibits clot formation. The researchers exposed nitric oxide synthase to peroxynitrite and tracked the enzyme's response. Even small amounts of peroxynitrite broke the protein in half by swiping zinc from the bridge. The same changes occurred when the researchers treated the enzyme with a molecule that locks up zinc, confirming that the parting of the protein resulted from removing the metal. What's more, cells bathed in abnormally large amounts of glucose and cells from diabetic mice showed the same breakup of nitric oxide synthase--which suggests that damage to the enzyme might contribute to diabetes. Broken nitric oxide synthase doesn't simply fail to produce nitric oxide. Oxidation brings out the enzyme's alter ego, which instead makes superoxide. This promiscuous oxidant can react with nitric oxide to produce yet more peroxynitrite--setting off a runaway process of peroxynitrite formation. Although previous work had suggested that nitric oxide synthase might spawn peroxynitrite, this study is the first to clarify the mechanism and to show how sensitive the enzyme is, even to low concentrations of the oxidant. Both consequences of oxidation might compromise health, says biochemist Ming-Hui Zou of Boston University School of Medicine. Reduced amounts of nitric oxide narrow blood vessels and spur clotting, which worsen cardiovascular disease. Peroxynitrite also attacks a molecule that prevents constriction of blood vessels, which might explain why the arteries of diabetics expand reluctantly, Zou adds. According to Heinecke, the results also back a nontraditional view of how oxidants wreak havoc. The conventional notion--that their attack cripples proteins--is hard to square with the rarity of oxidants in the body's cells. A more plausible idea, says Heinecke, is that oxidants pervert proteins instead of wrecking them: "You are damaging a protein in a way that produces a gain in function. It's doing something bad instead of something good." --Mitch Leslie M.-H. Zou, C. Shi, R. A. Cohen, Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J. Clin. Invest. 109 , 817-826 (2002). [Abstract] [Full Text]

Catalysis by zinc ion in the reactions of carcinogenic chromium(VI) with thiols

The reactions of Cr(VI) with nine biological and nonbiological thiols (RSH) in aqueous acetate buffer (pH 5.60) have been followed by an spectrophotometric method, and a relatively stable intermediate (the thioester RSCrO 3 −) has been observed. The rate constants corresponding to the formation ( k 1), decomposition ( k −1), and redox transformation ( k 2) of that intermediate have been obtained in both the absence and presence of zinc ion. This ion acts as a true catalyst for both the formation and decomposition of the observed intermediate. The equilibrium constants for the formation of RSCrO 3 − from Cr(VI) and RSH for the different thiols have been determined. A mechanism is proposed for the formation of RSCrO 3 − in the presence of catalyst according to which the rate-determining step would be the bimolecular reaction between a zinc–thiolate complex and an acetyl–chromate ester, involving an interchange of ligands.