Inorganics, Volume 7, Issue 7 (July 2019) – 12 articles

3,1,2-Ruthenadicarbadodecaborane complexes bearing the [C₂B₉H₁₁]²⁻ (dicarbollide) ligand are robust scaffolds, with exceptional thermal and chemical stability. Our previous work has shown that these complexes possess promising anti-tumor activities in vitro, and tend to form aggregates (or self-assemblies) in aqueous solutions. Here, we report on the synthesis and characterization of four ruthenium(II) complexes of the type [3-(η⁶-arene)-1,2-R₂-3,1,2-RuC₂B₉H₉], bearing either non-polar (R = Me (2–4)) or polar (R = CO₂Me (7)) substituents at the cluster carbon atoms. The behavior in aqueous solution of complexes 2, 7 and the parent unsubstituted [3-(η⁶-p-cymene)-3,1,2-RuC₂B₉H₁₁] (8) was investigated via UV-Vis spectroscopy, mass spectrometry and nanoparticle tracking analysis (NTA). All complexes showed spontaneous formation of self-assemblies (10⁸–10⁹ particles mL⁻¹), at low micromolar concentration, with high polydispersity. For perspective applications in medicine, there is thus a strong need for further characterization of the spontaneous self-assembly behavior in aqueous solutions for the class of neutral metallacarboranes, with the ultimate scope of finding the optimal conditions for exploiting this self-assembling behavior for improved biological performance. Full article

A disulfide-bridged peptide containing two Ni²⁺ binding sites based on the nickel superoxide dismutase protein, {Ni₂(SOD^mds)} has been prepared. At physiological pH (7.4), it was found that the metal sites are mononuclear with a square planar NOS₂ coordination environment with the two sulfur-based ligands derived from cysteinate residues, the nitrogen ligand derived from the amide backbone, and a water ligand. Furthermore, S K-edge X-ray absorption spectroscopy indicated that the two cysteinate sulfur atoms ligated to nickel are each protonated. Elevation of the pH to 9.6 results in the deprotonation of the cysteinate sulfur atoms, and yields a binuclear, cysteinate bridged Ni₂²⁺ center with each nickel contained in a distorted square planar geometry. At both pH = 7.4 and 9.6, the nickel sites are moderately air sensitive, yielding intractable oxidation products. However, at pH = 9.6, {Ni₂(SOD^mds)} reacts with O₂ at an ~3.5-fold faster rate than at pH = 7.4. Electronic structure calculations indicate that the reduced reactivity at pH = 7.4 is a result of a reduction in S(3p) character and deactivation of the nucleophilic frontier molecular orbitals upon cysteinate sulfur protonation. Full article

Nickel (Ni) metal and Ni compounds are widely used in applications like stainless steel, alloys, and batteries. Nickel is a naturally occurring element in water, soil, air, and living organisms, and is essential to microorganisms and plants. Thus, human and environmental nickel exposures are ubiquitous. Production and use of nickel and its compounds can, however, result in additional exposures to humans and the environment. Notable human health toxicity effects identified from human and/or animal studies include respiratory cancer, non-cancer toxicity effects following inhalation, dermatitis, and reproductive effects. These effects have thresholds, with indirect genotoxic and epigenetic events underlying the threshold mode of action for nickel carcinogenicity. Differences in human toxicity potencies/potentials of different nickel chemical forms are correlated with the bioavailability of the Ni²⁺ ion at target sites. Likewise, Ni²⁺ has been demonstrated to be the toxic chemical species in the environment, and models have been developed that account for the influence of abiotic factors on the bioavailability and toxicity of Ni²⁺ in different habitats. Emerging issues regarding the toxicity of nickel nanoforms and metal mixtures are briefly discussed. This review is unique in its covering of both human and environmental nickel toxicity data. Full article

Reactions of 4,5-dicyano-1-methylimidazole with CuX₂ (X = Cl, Br) in alcohol solvents (ethanol and methanol) resulted in the formation of Cu(II) carboximidate complexes [CuCl₂(5- cyano-4-C(OEt)N-1-methylimidazole)(EtOH)] (1), [Cu₂(µ-Cl)₂Cl₂(5-cyano-4-C(OMe)N-1-methylimidazole)₂] (2), [Cu₂(µ-Br)₂Br₂(5-cyano-4-C(OMe)N-1-methylimidazole)₂] (3), and [Cu₂(µ-Br)₂Br₂(5-cyano-4-C(OEt)N-1-methylimidazole)₂] (4). The structures were determined by the X-ray crystallographic method, and further spectroscopic and computational methods were employed to explain the structural features. The solvent contributed to the alcoholysis reaction of the cyano group, as the result of which the ligand coordinated to the metal center in bidentate mode forming a five-membered chelating ring. In 1, the solvent also acts as an additional ligand, which coordinates to the metal center of a monomeric complex. In compounds 2–4, two halogen ligands link the metal atoms forming dihalo-bridged copper dimers. The infrared absorption characteristics were verified by simulation of the infrared spectra at the density functional theory level. In addition, the electronic absorption characteristics were explained by simulation of the UV–Vis spectra using the TD-DFT method. Molecular modelling at the DFT level was performed to study the effects of halogen type and steric hindrance of the alkoxy groups in forming the copper(II) complexes. Full article

The natural copper isotopic compositions of superoxide dismutase and metallothionein from six post-mortem human frontal cortices were determined using a combination of size exclusion protein liquid chromatography, followed by anion exchange chromatography and multiple collector inductively-coupled plasma mass spectrometry. Superoxide dismutase was enriched in the heavier ⁶⁵Cu relative to the metallothionein fraction in all specimen pairs. The isotopic compositions were independent of copper content. This finding provides evidence that nitrogen ligands in protein copper binding sites will be enriched in heavy metal isotopes, and sulphur ligands will preferentially incorporate lighter isotopes in vivo. This in turn has implications for understanding isotopic distributions within different components in the body and the dominant ligands in different tissues. Differences in Cu isotope distributions between the two proteins were seen between Alzheimer’s disease and healthy control samples, when normalised for sex. Full article

Maturation of urease involves post-translational insertion of nickel ions to form an active site with a carbamylated lysine ligand and is assisted by urease accessory proteins UreD, UreE, UreF and UreG. Here, we review our current understandings on how these urease accessory proteins facilitate the urease maturation. The urease maturation pathway involves the transfer of Ni²⁺ from UreE → UreG → UreF/UreD → urease. To avoid the release of the toxic metal to the cytoplasm, Ni²⁺ is transferred from one urease accessory protein to another through specific protein–protein interactions. One central theme depicts the role of guanosine triphosphate (GTP) binding/hydrolysis in regulating the binding/release of nickel ions and the formation of the protein complexes. The urease and [NiFe]-hydrogenase maturation pathways cross-talk with each other as UreE receives Ni²⁺ from hydrogenase maturation factor HypA. Finally, the druggability of the urease maturation pathway is reviewed. Full article

[NiFe]-carbon monoxide dehydrogenase reversibly catalyzes the oxidation of CO to CO₂. Its active site is a unique NiFe₄S₄ cluster, known as C-cluster. In Rhodospirillum rubrum, three nickel-dependent proteins, CooC, CooT and CooJ are required for Ni insertion into the active site. Among them, CooJ is a histidine-rich protein, containing two distinct and spatially separated Ni(II)-binding sites: a strictly conserved N-terminal site and a variable histidine tail at the C-terminus. Here, using biophysical techniques, we study the behavior of the protein upon Ni(II) addition. Using circular dichroism and chemical denaturation, we show that the binding of Ni(II) to the protein increases its stability. Moreover, high-order oligomers are formed through nickel–histidine tail interactions, both in vitro and in cellulo, via a dynamical and reversible process. Full article

The catalytic effects of 1,1,3,3-Tetramethylguanidine (TMG), 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD), 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) in the reaction with glycidyl phenyl ether (GPE) at 40 °C were investigated. For the reaction, the %conversion of GPE was only 11%, carried out at 40 °C over 14 days in the presence of TBD.Additionally, there was little catalytic activity for the same reaction performed under typical storage conditions at 25 °C. The effect of TBD with 2-methylimidazole-intercalated α-zirconium phosphate (α-ZrP∙2MIm), as a latent thermal initiating system in the reaction with GPE, was then examined. The reaction did not proceed within 1 h at 80 °C. On increasing the temperature to 120 °C, the %conversion reached 75% for reaction at 1 h. Under typical storage conditions (7 days at 25 °C), the %conversion of GPE was only 7%. With addition of TBD to α-ZrP∙2MIm, reagent stability was maintained, and the polymerization reaction proceeded rapidly with the application of heat. Full article

The mononuclear copper complexes [Cu{NH=C(OR)NC(OR)=NH}₂] with alkoxy-1,3,5-triazapentadiene ligands that have different substituents (R = Me (1), Et (2), ⁿPr (3), ⁱPr (4), CH₂CH₂OCH₃ (5)) were prepared, characterized (including the single crystal X-ray analysis of 3) and studied as catalysts in the mild oxidation of alkanes with H₂O₂ as an oxidant, pyridine as a promoting agent and cyclohexane as a main model substrate. The complex 4 showed the highest activity with a yield of products up to 18.5% and turnover frequency (TOF) up to 41 h⁻¹. Cyclohexyl hydroperoxide was the main reaction product in all cases. Selectivity parameters in the oxidation of substituted cyclohexanes and adamantane disclosed a dominant free radical reaction mechanism with hydroxyl radicals as C–H-attacking species. The main overoxidation product was 6-hydroxyhexanoic acid, suggesting the presence of a secondary reaction mechanism of a different type. All complexes undergo gradual alteration of their structures in acetonitrile solutions to produce catalytically-active intermediates, as evidenced by UV/Vis spectroscopy and kinetic studies. Complex 4, having tertiary C–H bonds in its ⁱPr substituents, showed the fastest alteration rate, which can be significantly suppressed by using the CD₃CN solvent instead of CH₃CN one. The observed process was associated to an autocatalytic oxidation of the alkoxy-1,3,5-triazapentadiene ligand. The deuterated complex 4-d₃₂ was prepared and showed higher stability under the same conditions. The complexes 1 and 4 showed different reactivity in the formation of H₂¹⁸O from ¹⁸O₂ in acetonitrile solutions. Full article

Nickel is a naturally occurring element found in the Earth’s crust and an International Agency for Research on Cancer (IARC)-classified human carcinogen. While low levels found in the natural environment pose a minor concern, the extensive use of nickel in industrial settings such as in the production of stainless steel and various alloys complicate human exposure and health effects. Notably, interactions with nickel macromolecules, primarily through inhalation, have been demonstrated to promote lung cancer. Mechanisms of nickel-carcinogenesis range from oxidative stress, DNA damage, and hypoxia-inducible pathways to epigenetic mechanisms. Recently, non-coding RNAs have drawn increased attention in cancer mechanistic studies. Specifically, nickel has been found to disrupt expression and functions of micro-RNAs and long-non-coding RNAs, resulting in subsequent changes in target gene expression levels, some of which include key cancer genes such as p53, MDM2, c-myc, and AP-1. Non-coding RNAs are also involved in well-studied mechanisms of nickel-induced lung carcinogenesis, such as the hypoxia-inducible factor (HIF) pathway, oxidative stress, DNA damage and repair, DNA hypermethylation, and alterations in tumor suppressors and oncogenes. This review provides a summary of the currently known epigenetic mechanisms involved in nickel-induced lung carcinogenesis, with a particular focus on non-coding RNAs. Full article

Nickel is an essential cofactor for some pathogen virulence factors. Due to its low availability in hosts, pathogens must efficiently transport the metal and then balance its ready intracellular availability for enzyme maturation with metal toxicity concerns. The most notable virulence-associated components are the Ni-enzymes hydrogenase and urease. Both enzymes, along with their associated nickel transporters, storage reservoirs, and maturation enzymes have been best-studied in the gastric pathogen Helicobacter pylori, a bacterium which depends heavily on nickel. Molecular hydrogen utilization is associated with efficient host colonization by the Helicobacters, which include both gastric and liver pathogens. Translocation of a H. pylori carcinogenic toxin into host epithelial cells is powered by H₂ use. The multiple [NiFe] hydrogenases of Salmonella enterica Typhimurium are important in host colonization, while ureases play important roles in both prokaryotic (Proteus mirabilis and Staphylococcus spp.) and eukaryotic (Cryptoccoccus genus) pathogens associated with urinary tract infections. Other Ni-requiring enzymes, such as Ni-acireductone dioxygenase (ARD), Ni-superoxide dismutase (SOD), and Ni-glyoxalase I (GloI) play important metabolic or detoxifying roles in other pathogens. Nickel-requiring enzymes are likely important for virulence of at least 40 prokaryotic and nine eukaryotic pathogenic species, as described herein. The potential for pathogenic roles of many new Ni-binding components exists, based on recent experimental data and on the key roles that Ni enzymes play in a diverse array of pathogens. Full article