Journal of Biological Inorganic Chemistry最新文献

Infections caused by the airborne fungal pathogen, Aspergillus fumigatus, are increasing in severity due to growing numbers of immunocompromised individuals and the increasing incidence of antifungal drug resistance, exacerbating treatment challenges. Gallium has proven to be a strong candidate in the fight against microbial pathogens due to its iron-mimicking capability and substitution of Ga(III) in place of Fe(III), disrupting iron-dependent pathways. Since the antimicrobial properties of 2,2′-bipyridine and derivatives have been previously reported, we assessed the in vitro activity and proteomic effects of a recently reported heteroleptic Ga(III) polypyridyl catecholate compound against A. fumigatus. This compound has demonstrated promising growth-inhibition and impact on the A. fumigatus proteome compared to untreated controls. Proteins associated with DNA replication and repair mechanisms along with lipid metabolism and the oxidative stress responses were elevated in abundance compared to control. Crucially, a large number of mitochondrial proteins were reduced in abundance. Respiration is an important source of energy to fuel metabolic processes required for growth, survival and virulence, the disruption of which may be a viable strategy for the treatment of microbial infections.

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A series of biotin-functionalized transition metal complexes was prepared by iClick reaction from the corresponding azido complexes with a novel alkyne-functionalized biotin derivative ([Au(triazolato^R,R′)(PPh₃)], [Pt(dpb)(triazolato^R,R′)], [Pt(triazolato^R,R′)(terpy)]PF₆, and [Ir(ppy)(triazolato^R,R′)(terpy)]PF₆ with dpb = 1,3-di(2-pyridyl)benzene, ppy = 2-phenylpyridine, and terpy = 2,2′:6′,2′′-terpyridine and R = C₆H₅, R′ = biotin). The complexes were compared to reference compounds lacking the biotin moiety. The binding affinity toward avidin and streptavidin was evaluated with the HABA assay as well as isothermal titration calorimetry (ITC). All compounds exhibit the same binding stoichiometry of complex-to-avidin of 4:1, but the ITC results show that the octahedral Ir(III) compound exhibits a higher binding affinity than the square-planar Pt(II) complex. The antibacterial activity of the compounds was evaluated on a series of Gram-negative and Gram-positive bacterial strains. In particular, the neutral Au(I) and Pt(II) complexes showed significant antibacterial activity against Staphylococcus aureus and Enterococcus faecium at very low micromolar concentrations. The cytotoxicity against a range of eukaryotic cell lines was studied and revealed that the octahedral Ir(III) complex was non-toxic, while the square-planar Pt(II) and linear Au(I) complexes displayed non-selective micromolar activity.

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We have approached the construction of an artificial enzyme by employing a robust protein scaffold, lactococcal multidrug resistance regulator, LmrR, providing a structured secondary and outer coordination spheres around a molecular rhodium complex, [Rh^I(P^Et2N^glyP^Et2)₂]⁻. Previously, we demonstrated a 2–3 fold increase in activity for one Rh-LmrR construct by introducing positive charge in the secondary coordination sphere. In this study, a series of variants was made through site-directed mutagenesis where the negative charge is located in the secondary sphere or outer coordination sphere, with additional variants made with increasingly negative charge in the outer coordination sphere while keeping a positive charge in the secondary sphere. Placing a negative charge in the secondary or outer coordination sphere demonstrates decreased activity by a factor of two compared to the wild-type Rh-LmrR. Interestingly, addition of positive charge in the secondary sphere, with the negatively charged outer coordination sphere restores activity. Vibrational and NMR spectroscopy suggest minimal changes to the electronic density at the rhodium center, regardless of inclusion of a negative or positive charge in the secondary sphere, suggesting another mechanism is impacting catalytic activity, explored in the discussion.

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Nitric oxide synthases (NOSs), a family of flavo-hemoproteins with relatively rigid domains linked by flexible regions, require optimal FMN domain docking to the heme domain for efficient interdomain electron transfer (IET). To probe the FMN-heme interdomain docking, the magnetic dipole interactions between the FMN semiquinone radical (FMNH^•) and the low-spin ferric heme centers in oxygenase/FMN (oxyFMN) constructs of neuronal and inducible NOS (nNOS and iNOS, respectively) were measured using the relaxation-induced dipolar modulation enhancement (RIDME) technique. The FMNH^• RIDME data were analyzed using the mesoscale Monte Carlo calculations of conformational distributions of NOS, which were improved to account for the native degrees of freedom of the amino acid residues constituting the flexible interdomain tethers. This combined computational and experimental analysis allowed for the estimation of the stabilization energies and populations of the docking complexes of calmodulin (CaM) and the FMN domain with the heme domain. Moreover, combining the five-pulse and scaled four-pulse RIDME data into a single trace has significantly reduced the uncertainty in the estimated docking probabilities. The obtained FMN—heme domain docking energies for nNOS and iNOS were similar (-3.8 kcal/mol), in agreement with the high degree of conservation of the FMN—heme domain docking interface between the NOS isoforms. In spite of the similar energetics, the FMN—heme domain docking probabilities in nNOS and iNOS oxyFMN were noticeably different (~ 0.19 and 0.23, respectively), likely due to differences in the lengths of the FMN—heme interdomain tethers and the docking interface topographies. The analysis based on the IET theory and RIDME experiments indicates that the variations in conformational dynamics may account for half of the difference in the FMN—heme IET rates between the two NOS isoforms.

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Iron(III) complexes based on N,N´-bis(salicylidene)ethylenediamine (salene) scaffolds have demonstrated promising anticancer features like induction of ferroptosis, an iron dependent cell death. Since poor cellular uptake limits their therapeutical potential, this study aimed to enhance the lipophilic character of chlorido[N,N′-bis(salicylidene)-1,2-bis(3-methoxyphenyl)ethylenediamine]iron(III) complexes by introducing lipophilicity improving ligands such as fluorine (X1), chlorine (X2) and bromine (X3) in 5-position in the salicylidene moieties. After detailed characterization the binding to nucleophiles, logP values and cellular uptake were determined. The complexes were further evaluated regarding their biological activity on MDA-MB 231 mammary carcinoma, the non-tumorous SV-80 fibroblast, HS-5 stroma and MCF-10A mammary gland cell lines. Stability of the complexes in aqueous and biological environments was proven by the lack of interactions with amino acids and glutathione. Cellular uptake was positively correlated with the logP values, indicating that higher lipophilicity enhanced cellular uptake. The complexes induced strong antiproliferative and antimetabolic effects on MDA-MB 231 cells, but were inactive on all non-malignant cells tested. Generation of mitochondrial reactive oxygen species, increase of lipid peroxidation and induction of both ferroptosis and necroptosis were identified as mechanisms of action. In conclusion, halogenation of chlorido[N,N′-bis(salicylidene)-1,2-bis(3-methoxyphenyl)ethylenediamine]iron(III) complexes raises their lipophilic character resulting in improved cellular uptake.

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The effect of binding of divalent metal cations (Ca²⁺, Cu²⁺, Mg²⁺, Mn²⁺, Zn²⁺) on the kinetics of fibril formation of bovine α-lactalbumin at acidic conditions is considered. The kinetic parameters of the process were determined using a thioflavin T fluorescence assay. The DSC thermograms of bovine α-lactalbumin in the presence and absence of cations were recorded. The duration of the lag period correlates with the changes in the thermal stability of the molten globule of the protein in the presence of cations. The final thioflavin T fluorescence intensity after formation of the mature fibrils decreases under the influence of calcium ions which strongly bind to the monomeric protein, and increases in solutions containing copper and especially zinc. These ions seem to accelerate secondary nucleation processes and change the fibril morphology, which was confirmed by atomic force microscopy imaging.

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In order to discover a new antibiotic drug with better or similar activity of the already existing drugs, a series of novel cobalt(II) complexes with β-diketonate as ligands is synthesized and tested on four strains of bacteria and four species of fungi. All compounds showed notable antimicrobial activity against all tested strains. More importantly, some cobalt(II) complexes displayed greater activity than ketoconazole. It is important to notice that on the tested strains Mucor mucedo and Penicillium italicum complex 2B showed five times better activity compared to ketoconazole, while complex 2D had two times better activity on Penicillium italicum strain compared to ketoconazole. Moreover, investigations with bovine serum albumin were performed. Investigations showed that the tested complexes have an appropriate affinity for binding to bovine serum albumin. In addition, the molecular docking study was performed to investigate more specifically the sites and binding mode of the tested cobalt(II) complexes with β-diketonate as ligands to bovine serum albumin, tyrosyl-tRNA synthetase, topoisomerase II DNA gyrase, and cytochrome P450 14 alpha-sterol demethylase. In conclusion, all the results indicated the great prospective of the novel cobalt complexes for some potential clinical applications in the future.

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The medicinal properties of transition metal complexes are greatly influenced by the nature and physico-chemical features of the ligand present in the complex structure. Due to the unique biological properties of the organoselenium compounds reflected in the variety of pharmacological activities (such as antioxidative, antiviral, antimicrobial and anticancer), the last years have brought increased interest for their use as a ligands compounds in the design and syntheses of range of transition metal-based coordination compounds that have been explored as antitumor and antimicrobial agents. Our aim in this review is to provide the overview of an recent development of the transition metal complexes bearing organoselenium ligands in the structure that could be promising choice for the treatment of various diseases, particularly cancer and infective diseases. For this purpose, the complexes of Co, Ni, Cu, Zn, Ru, Pd, Pt, Au and Sn as the most explored examples will be included and discussed.

The elucidation of metal-dependent biological processes requires selective reagents for manipulating metal ion levels within biological solutions such as growth media or cell lysates. To this end, we immobilized a phosphine sulfide-stabilized phosphine (PSP) ligand on agarose to create a resin for the selective removal of copper from chemically complex biological media through simple filtration or centrifugation. Comprised of a conformationally preorganized phenylene-bridged backbone, the PSP-ligand binds Cu(I) with a 1:1 stoichiometry and exhibits a pH-independent Cu(I) dissociation constant in the low zeptomolar range. Neither Zn(II), Fe(II), nor Mn(II) interact with the ligand at millimolar concentrations, thus offering a much-improved selectivity towards copper over other commonly employed solid-supported chelators such as Chelex 100. As revealed by X-ray fluorescence elemental analysis, the immobilized chelator effectively removes copper from cell culture growth media and cell lysate isolated from mouse fibroblasts. In addition to preparing copper-depleted media or cell lysates for biological studies, PSP-immobilized ligands might prove equally useful for applications in radiochemistry, materials science, and environmental science.

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Lapachol (2-hydroxy-3-(3-methylbut-2-en-1-yl)naphthalene-1,4-dione) is a 1,4-naphthoquinone-derived natural product that presents numerous bioactivities and was shown to have cytotoxic effects against several human tumor cells. Indium(III) complexes with a variety of ligands also exhibit antineoplastic activity. Indium(III) complexes [In(lap)Cl₂].4H₂O (1), [In(lap)₂Cl(Et₃N)] (2), [In(lap)₃]·2H₂O (3) [In(lap)(bipy)Cl₂] bipy = 2,2′-bipyridine (4) and [In(lap)(phen)Cl₂] phen = 1,10-phenanthroline (5) were obtained with 2-hydroxy-3-(3-methylbut-2-en-1-yl)naphthalene-1,4-dione (lapachol). Crystal structure determinations for (4) and (5) revealed that the indium(III) center is coordinated to two O atoms from lapachol, two N atoms from 1,10-phenanthroline or 2,2′-bipyridine, and two chloride anions, in a distorted octahedral geometry. Although both complexes (4) and (5) interacted with CT-DNA in vitro by an intercalative mode, only 5 exhibited cytotoxicity against MCF-7 and MDA-MB breast tumor cells. 1,10-phenanthroline and complex (5) presented cytotoxic effects against MCF-7 and MDA-MB cells, with complex (5) being threefold more active than 1,10-phenanthroline on MCF-7 cells. In addition, complex (5) significantly reduced the formation of MDA-MB-231 colonies in a clonogenicity assay. The foregoing results suggest that further studies on the cytotoxic effects and cellular targets of complex (5) are of utmost relevance.

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