Thiolate Site Research Articles

Synthesis and Characterization of Bridging-Diazene Diiron Half-Sandwich Complexes: The Role of Sulfur Hydrogen Bonding.

We report two bridging-diazene diiron complexes [Cp*Fe(8-quinolinethiolate)]2(μ-N2H2) (1-N2H2) and [Cp*Fe(1,2-Cy2PC6H4S)]2(μ-N2H2) (2-N2H2), synthesized by the reaction of hydrazine with the corresponding thiolate-based iron half-sandwich complex, [Cp*Fe(8-quinolinethiolate)]2 (1) and Cp*Fe(1,2-Cy2PC6H4S) (2). Crystallographic analysis reveals that the thiolate sites in 1-N2H2 and 2-N2H2 can engage in N-H···S hydrogen bonding with the diazene protons. 1-N2H2 is thermally stable in both solid and solution states, allowing for one-electron oxidation to afford a cationic diazene radical complex [1-N2H2]+ at room temperature. In contrast, 2-N2H2 tends to undergo N2H2/N2 transformation, leading to the formation of a Fe(III)-H species by the loss of N2. In addition to stabilizing HN=NH species through the hydrogen bonding, the thiolate-based ligands also seem to facilitate proton-coupled electron transfer, thereby promoting N-H cleavage.

A self-reported inhibitor of metallo-carbapenemases for reversing carbapenem resistance

Metallo-carbapenemases-mediated carbapenem-resistant Enterobacterales (CREs) has been acknowledged as “urgent threat” by the World Health Organization. The discovery of new strategies that block metallo-carbapenemases activity to reverse carbapenem resistance is an urgent need. In this study, a coumarin copper complex containing a PEG linker and glucose ligand, GluC-Cu, was used to reverse carbapenem resistance. Interestingly, it could effectively inhibit metallo-carbapenemases (NDM-1, IMP-1 and ImiS) with an IC50 value in the range of 0.23–1.21 μM, and simultaneously release the green fluorescence signal (GluC), therefore exhibiting self-reported inhibition performance. The inhibition mechanism of oxidizing Zn(II) thiolate site of NDM-1 from Cu2+ to Cu+ was verified by fluorescence assay, HR-MS, and XPS. Moreover, GluC-Cu in combination with meropenem showed excellent synergistic antibacterial effect to effectively combat E. coli expressing metallo-carbapenemases in vitro and in a mice infection model. This bifunctional metallo-carbapenemases inhibitor provides a novel chemical tool to overcome carbapenem resistance.

Porphyrin Photoabsorption and Fluorescence Variation with Adsorptive Loading on Gold Nanoparticles.

Here, we report the photophysical structure–property relationship of porphyrins adsorbed on gold nanoparticles. The number of porphyrin–alkanethiolate adsorbates per particle was adjusted by a post-synthetic thiol/thiolate exchange reaction on 1-dodecanethiolate–protected gold nanoparticles. Even with a low loading level of adsorbates (<10% of all thiolate sites on gold nanoparticles), the shoulder absorption at the Soret band was intensified, indicating the formation of aggregates of porphyrin adsorbates on the nanoparticles. Steady-state fluorescence quantum yields could be adjusted by the bulkiness of substituents at the meso-positions of the porphyrin or the methylene linker chain length, regardless of the porphyrin loading level and the nanoparticle diameter.

Dithiocarbamates combined with copper for revitalizing meropenem efficacy against NDM-1-producing Carbapenem-resistant Enterobacteriaceae

The worldwide prevalence of NDM-1-producing Gram-negative pathogens has drastically undermined the clinical efficacy of carbapenems, prompting a need to devise an effective strategy to preserve their clinical value. Here we constructed a focused compound library of dithiocarbamates and systematically evaluated their potential synergistic antibacterial activities combined with copper. SA09-Cu exhibited excellent inhibition against a series of clinical NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE) in restoring meropenem effect, and slowed down the development of carbapenem resistance. Enzymatic kinetic and isothermal titration calorimetry studies demonstrated that SA09-Cu was a noncompetitive NDM-1 inhibitor. The electron paramagnetic resonance (EPR) and X-ray photoelectron spectroscopy (XPS) revealed a novel inhibition mechanism, which is that SA09-Cu could convert NDM-1 into an inactive state by oxidizing the Zn(II)-thiolate site of the enzyme. Importantly, SA09-Cu showed a unique redox tuning ability, and avoided to be reduced by intracellular thiols of bacteria. In vivo experiments indicated that SA09 combined with CuGlu could effectively potentiate MER’s effect against NDM-1-producing E. coli (EC23) in the murine infection model. This study provides a highly promising scaffold in developing novel inhibitors to combat NDM-1-producing CREs.

Disulfiram as a potent metallo-β-lactamase inhibitor with dual functional mechanisms.

We report a promising NDM-1 inhibitor, disulfiram, which can covalently bind to NDM-1 by forming an S-S bond with the Cys208 residue. Its copper-containing metabolite in vivo, Cu(DTC)2, also inactivated NDM-1 through oxidizing the Zn(ii) thiolate site of the enzyme, therefore exhibiting dual functional inhibitory potential against B1 and B2 subclass MβLs.

Universal Anticancer Cu(DTC)2 Discriminates between Thiols and Zinc(II) Thiolates Oxidatively.

Aerobic organisms must rely on abundant intracellular thiols to reductively protect various vital functional units, especially ubiquitous zinc(II) thiolate sites of proteins, from deleterious oxidations resulting from oxidizing environments. Disclosed here is the first well-defined model study for reactions between zinc(II) thiolate complexes and copper(II) complexes. Among all the studied ligands of copper(II), diethyldithiocarbamate (DTC) displays a unique redox-tuning ability that enables copper(II) to resist the reduction by thiols while retaining its ability to oxidize zinc(II) thiolates to form disulfides. This work proves for the first time that it is possible to develop oxidants to discriminate between thiols and zinc(II) thiolates, alluding to a new chemical principle for how oxidants, especially universal anticancer Cu(DTC)2 , might circumvent the intracellular reductive defense around certain zinc(II) thiolate sites of proteins to kill malignant cells.

Universal Anticancer Cu(DTC)2 Discriminates between Thiols and Zinc(II) Thiolates Oxidatively

AbstractAerobic organisms must rely on abundant intracellular thiols to reductively protect various vital functional units, especially ubiquitous zinc(II) thiolate sites of proteins, from deleterious oxidations resulting from oxidizing environments. Disclosed here is the first well‐defined model study for reactions between zinc(II) thiolate complexes and copper(II) complexes. Among all the studied ligands of copper(II), diethyldithiocarbamate (DTC) displays a unique redox‐tuning ability that enables copper(II) to resist the reduction by thiols while retaining its ability to oxidize zinc(II) thiolates to form disulfides. This work proves for the first time that it is possible to develop oxidants to discriminate between thiols and zinc(II) thiolates, alluding to a new chemical principle for how oxidants, especially universal anticancer Cu(DTC)2, might circumvent the intracellular reductive defense around certain zinc(II) thiolate sites of proteins to kill malignant cells.

Terminal Thiolate-Dominated H/D Exchanges and H2 Release: Diiron Thiol-Hydride.

To determine the reaction pathways at a metal-ligand site in enzymes, we incorporated a terminal thiolate site into a diiron bridging hydride. Trithiolato diiron hydride, (μ-H)Fe2(pdt)(dppbz)(CO)2(SR) (1(μ-H)) [pdt2- = 1,3-(CH2)3S22-, dppbz = 1,2-C6H4(PPh2)2, RS- = 1,2-Cy2PC6H4S-)], was synthesized directly by photoassisted oxidative addition of 1,2-Cy2PC6H4SH to Fe2(pdt)(dppbz)(CO)4. The terminal thiolate in 1(μ-H) undergoes protonation, affording a thiol-hydride complex [1(μ-H)H]+. Placing an acidic SH site adjacent to the Fe-H-Fe site allows intramolecular thiol-hydride coupling and releases H2 from [1(μ-H)H]+. A diiron η2-H2 intermediate in the formation of H2 is proposed, and is evidenced by the H/D exchange reactions of [1(μ-H)H]+ with D2, D2O, and CD3OD. Isotopic exchange in [1(μ-D)H]+ is driven by an equilibrium isotope effect with 2.1 kJ/mol difference in free energy that favors [1(μ-H)D]+. [1(μ-H)H]+ catalyzes H/D scrambling between H2 and D2O or CD3OD to produce HD. The reactions based on such a "proton-hydride" model provide insights into the reversible heterolytic cleavage of H2 by H2ases.

Activation of Epoxides by a Cooperative Iron–Thiolate Catalyst: Intermediacy of Ferrous Alkoxides in Catalytic Hydroboration

This paper describes a cooperative iron–thiolate catalyst Cp*Fe(1,2-Ph2PC6H4S)(NCMe) (Cp*– = C5Me5–, [1(NCMe)]) for regioselective hydroboration of aryl epoxide by pinacolborane (HBpin). The critical catalytic step involves the direct addition of epoxide to the catalyst rather than activation of the B–H bond of HBpin. Through iron–thiolate cooperation, [1(NCMe)] opens the aryl epoxide rings affording ferrous–alkoxide compounds. Notably, the ferrous–alkoxide intermediate (4) was structurally characterized after its isolation from the reaction of [1(NCMe)] with trans-2,3-diphenyloxirane. The more Lewis acidic hydroboranes such as H3B·THF and 9-BBN (BBN = borabicyclononane) can also be captured by [1(NCMe)]. The resulting iron–borane adducts [1H(BH2)] and [1H(BBN)] feature an agnostic Fe···B–H interaction. DFT calculations indicate that the addition of HBpin across the iron–thiolate sites is endergonic by 12.9 kcal/mol, whereas it is exergonic by 20.2 kcal/mol with BH3 and 4.6 kcal/mol with 9-BBN. Combining ...

Zinc Thiolate Reactivity toward Nitrogen Oxides: Insights into the Interaction of Zn2+ with S-Nitrosothiols and Implications for Nitric Oxide Synthase

Zinc thiolate complexes containing N(2)S tridentate ligands were prepared to investigate their reactivity toward reactive nitrogen species, chemistry proposed to occur at the zinc tetracysteine thiolate site of nitric oxide synthase (NOS). The complexes are unreactive toward nitric oxide (NO) in the absence of dioxygen, strongly indicating that NO cannot be the species directly responsible for S-nitrosothiol formation and loss of Zn(2+) at the NOS dimer interface in vivo. S-Nitrosothiol formation does occur upon exposure of zinc thiolate solutions to NO in the presence of air, however, or to NO(2) or NOBF(4), indicating that these reactive nitrogen/oxygen species are capable of liberating zinc from the enzyme, possibly through generation of the S-nitrosothiol. Interaction between simple Zn(2+) salts and preformed S-nitrosothiols leads to decomposition of the -SNO moiety, resulting in release of gaseous NO and N(2)O. The potential biological relevance of this chemistry is discussed.

Application of structural analogs of dimercaptosuccinic acid-functionalized silica nanoparticles (DMSA-[silica]) to adsorption of mercury, cadmium, and lead

In order to gain additional insight into mercury selectivity with nano-sized DMSA-[silica], we investigated a series of ligands related to DMSA, these are: monomercaptosuccinic acid; MMSA, 2-mercapto-4-methyl-5-thiazoleacetic acid; MCT, ortho-thiosalicylic acid; o-TSA and para-thiosalicylic acid; p-TSA. The MMSA chelate is structurally similar to DMSA except that it has only one thiol group. The chelates o-TSA and p-TSA each have one thiol and one carboxylic acid group. MCT includes neutral S and N atoms in close proximity to the thiolate binding site. MCT, o-TSA and p-TSA resemble each other in having equal numbers of carboxylic acid and thiol groups and formation of amide bonds with the linker on silica is expected to eliminate the carboxylate binding sites, making thiolates the only binding sites for Hg(II), Cd(II), and Pb(II) metals ions in the nano-sized; MMSA-[silica], MCT-[silica], o-TSA-[silica], and p-TSA-[silica]. Each of the nano-sized MMSA-[silica], MCT-[silica], o-TSA-[silica], and p-TSA-[silica], show a higher preference for Hg(II) over Cd(II) and Pb(II) compared to the same free chelates in solution, respectively. In addition, there are differences in the level of metal ion chelation for each functionalized silica nanoparticle. These differences in the degree of metal chelation for each functionalized silica nanoparticles surface are explained by the difference in thiolate/carboxylate ratio upon attachment to the surface and on steric reasons based on the orientation of the thiol groups on the surface. When attached via amide bond formation, the thiolate site in o-TSA-[silica] will face towards the silica surface, while for p-TSA-[silica], the thiolate site is expected to be pointed outwards and away from the silica surface. In comparing MMSA-[silica] to DMSA-[silica], the thiolate/carboxylate ratio decreases from 2/1 in DMSA-[silica] to 1/1 in MMSA-[silica] (assuming attachment via one amide bond in each case). This effect of increasing the ratio of thiolate to carboxylate upon attachment to the surface is believed to play a role in the selectivity enhancement towards Hg(II) over Cd(II) and Pb(II).

Synthesis and Characterization of Thiolate-Oxo Ligated Zinc Alkyl Derivatives for Production of Zn-Based Nanoparticles.

A series of mercapto-oxo containing reagents [3-mercaptopropionic acid (H2-3MPA), 4-mercaptophenol (H2-4MP), 2-mercaptopyridine-N-oxide (H-2MPO)] was reacted with diethyl zinc (ZnEt2) in hexanes/pyridine (py) to yield {(μ4-3MPA)[Zn(Et)(py)]4}∞ (1), [(py)2(Et)Zn(μ3-4MP)Zn(Et)(py)]2 (2), and (2MPO)Zn(Et)py (3). For polymeric 1, each of the functional sites of the 3MPA was bound to four tetrahedral (Td) coordinated Zn(Et)(py) subunits. The sulfur of the 3MPA bridges two of the 'Zn(Et)(py)' subunits, which are also bridged by the two carboxylate oxygens of another 3MPA to propagate the chain. In contrast, 2 forms a discrete tetranuclear species consisting of two Zn(Et)(py) moieties bridged by the oxygens of two 4MP ligands with the thiolate sites of each terminated by Zn(Et)(py)2 moieties. Compound 3 adopts a monomeric species using a chelating 2MPO, a terminal Et, and a bound py to fill the Td coordination of the Zn metal center. Compounds 1 - 3 were then used to generate nanoparticles via solution precipitation and solvothermal routes to determine the effect these precursors have on the morphology and composition of the final materials produced. Compounds 1 - 3 were found to form zincite, zinc metal, or mixed zincite/wurtzite phases from solution precipitation or solvothermal routes; however, no routes yielded the mixed anion (i.e., ZnO x S y ) materials.

Nucleophilicities of amino acids and peptides

The kinetics of the reactions of amino acids with stabilized diarylcarbenium ions (Ar(2)CH(+)) have been studied photometrically in aqueous solution at variable pH. In the range of 10.5 < pH < 12, the amino acids react much faster than the competing nucleophiles hydroxide and water. Though the pK(aH) values of the amino acids vary by almost four units, the nucleophilic reactivities of all primary amino groups differ by less than a factor of 4. The secondary amino group of proline is 10(2) times more reactive, and the thiolate site in cysteine exceeds the reactivities of the primary amino groups by a factor of 10(4). Nucleophilicity parameters N as defined by the correlation log k(20 degrees C) = s(N + E) have been determined in order to include amino acids into the most comprehensive nucleophilicity scales presently available, which provide a direct comparison of n-, pi-, and sigma-nucleophiles.

Structural investigation of thiophene thiol adsorption on Au nanoclusters: Influence of back bonds

The adsorption of thiolate radicals on the Au24 nanocluster truncated from the Au (111) surface is investigated using first principles electronic structure calculations under the density functional theory formalism. Particular emphasis is given to understanding the chemical interactions at the gold-sulfur interface. In order to describe the influence of the back bonds at the thiolate sites we have carried out adsorption studies with thiophene 2-thiolate (-ST) and thiophen–2-yl-methanethiolate (-SCH2T) along with atomic sulfur (S), mercapto (-SH), and methylthiolate (-SCH3). The results suggest that the adsorption geometry at the gold-sulfur interface is strongly dependent on the local environment of the terminal sulfur atom. The interfacial charge transfer is found to be localized along the Au-S bonds and does not influence the molecular structure of the thiophene ring.

Folding pathway of apo-metallothionein induced by Zn 2+, Cd 2+ and Co 2+

Metal ion binding to the sulfhydryl groups of apometallothionein (apo-MT) causes both the formation of native metal–thiolate clusters and the folding of the polypeptide chain of each domain. Cd 2+ and Zn 2+ react with apo-MT to form metal–thiolate bonds in reactions that are complete within milliseconds and which are pH-dependent. Dual mixing experiments were conducted that involve the initial reaction of metal ion and apo-MT followed by mixing with 5,5′- N-dithio-bis(2-nitrobenzoate) or EDTA after 26 ms. They showed that structures had formed within the brief reaction period which were resistant to rapid reaction with reagents that interact with sulfhydryl groups or metal ions, respectively. It was concluded that native metallothionein domains had been constituted within this brief period. Apo-MT was also titrated with Co 2+ to yield Co n–MT ( n=1–7). Initially, Co 2+ bound to independent, tetrahedral thiolate sites. Spectrophotometric analysis of the titration suggested that the independent Co(II) sites began to coalesce into clusters at n=4 (pH 7.2) or n=5 (pH 8.4). Back titration of free sulfhydryl groups (S) in Co n–MT ( n=1–7) with iodoacetamide at pH 7.2 confirmed that clustering began at n=4. Upon conversion of these alkylated structures to the corresponding 113Cd 2+ species 113Cd NMR spectroscopy established that the location of Co(II) in Co n–MT ( n=1–3) was non-specific and that at n=4, the only observable structure was Co(II) 4S 11. The results suggest possible kinetic pathways of folding that are conceptually similar to those hypothesized for other small proteins.

Electrochemical Reduction of a Bridging Imide: Generation of Ammonia at a Dimolybdenum Tris(-thiolate) Site

Electrochemical Reduction of a Bridging Imide: Generation of Ammonia at a Dimolybdenum Tris(-thiolate) Site

Cytochrome P-450 Model (Porphinato)(thiolato)iron(III) Complexes with Single and Double NH···S Hydrogen Bonds at the Thiolate Site

Cytochrome P-450 Model (Porphinato)(thiolato)iron(III) Complexes with Single and Double NH···S Hydrogen Bonds at the Thiolate Site

A model for the interaction of alcohol with the zinc thiolate site of alcohol dehydrogenase

A model for the interaction of alcohol with the zinc thiolate site of alcohol dehydrogenase

Synthesis and structure of [Ph4P]2[Cu6(S4)3S5],a polycyclic hexanuclear copper (I)cluster with complete sulphur co-ordination

The reaction of a methanolic CuI–thiolate solution with elemental sulphur yields deep-red[CU6(S4)3S5]2–which is the first hexanuclear CuIcluster with the complete sulphur co-ordination; the polycyclic anion can be regarded as an inorganic analogue of a corresponding mixed thiolate-sulphide complex and thus can serve as a possible model for cuI–thiolate sites in biological systems.