Role of copper chelating agents: between old applications and new perspectives in neuroscience

The role of copper element has been an increasingly relevant topic in recent years in the fields of human and animal health, for both the study of new drugs and innovative food and feed supplements. This metal plays an important role in the central nervous system, where it is associated with glutamatergic signaling, and it is widely involved in inflammatory processes. Thus, diseases involving copper(Ⅱ) dyshomeostasis often have neurological symptoms, as exemplified by Alzheimer's and other diseases(such as Parkinson's and Wilson's diseases). Moreover, imbalanced copper ion concentrations have also been associated with diabetes and certain types of cancer, including glioma. In this paper, we propose a comprehensive overview of recent results that show the importance of these metal ions in several pathologies, mainly Alzheimer's disease, through the lens of the development and use of copper chelators as research compounds and potential therapeutics if included in multi-target hybrid drugs. Seeing how copper homeostasis is important for the well-being of animals as well as humans, we shortly describe the state of the art regarding the effects of copper and its chelators in agriculture, livestock rearing, and aquaculture, as ingredients for the formulation of feed supplements as well as to prevent the effects of pollution on animal productions.

Role of copper in central nervous system physiology and pathology

Copper is a transition metal and an essential element for the organism,as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs,including the central nervous system.Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B,Menkes disease and Wilson’s disease,respectively,and also in multifactorial neurological disorders such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and multiple sclerosis.This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology,reports about unbalances in copper levels and/or distribution under disease,describes relevant animal models for human disorders where copper metabolism genes are dysregulated,and discusses relevant therapeutic approaches modulating copper availability.Overall,alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.

Synthesis,Crystal Structure and Antibacterial Activity of a New Ternary Copper(Ⅱ) Complex with 2,6-Pyridinedicarboxylic Acid and 1,10-Phenanthroline

A new ternary copper（Ⅱ） complex, [C43H27Cu2N7O5][C14H6CuN2O8]＇6.5H2O, has been synthesized by the reaction of copper sulfate, 2,6-pyridinedicarboxylic acid and 1,10- phenanthroline （phen）, and characterized by elemental analysis, IR, UV and X-ray single-crystal diffraction. It crystallizes in triclinic, space group P1, with a = 14.379（5）, b = 15.510（5）, c = 15.835（6） A, a = 78.567（6）, β = 63.594（6）, y = 81.287（6）°, V= 3092.1（19） A3, C57H46Cn3N9O19.5, Mr = 1359.54, Z = 2, Dc = 1.446 Mg/m3, λ（MoKa） = 0.71073 A,μ = 1.101 mm^-1, F（000） = 1362, S = 1.071, the final R = 0.0718 and wR = 0.11960 for 10705 observer reflections （I 〉 2σ（I））. The structure unit of the title complex consisfs of a mononuclear part and a di-nuclear part, and the three copper ions show three coordination modes. Each 6-coordinated geometry of the Cu atom is a distorted octahedral coordination geometry. The 3D supramolecular system is formed by the hydrogen bond O-H-O and π-π stacking interaction between neighboring single cells. The antibacterial activity of the title complex is also studied.

Synthesis and Crystal Structure of a Copper(II) Complex with Benzilic Acid and 1,10-Phenanthroline

A new complex [Cu（phen）3][（C6H4）2C（OH）COO]2·6H2O was prepared by selfassembly of benzilic acid, 1,10-phenanthroline （phen）, and copper perchlorate. It crystallizes in triclinic, space group P1-, with a = 1.14661（17）, b = 1.6455（2）, c = 1.6457（2） nm, α= 74.779（2）, β = 74.904（3）, γ = 84.424（3）°, V = 2.8914（7） nm^3, Dc = 1.340 g/cm^3, Z = 2, F（000） = 1218, GOOF = 1.018, the final R = 0.0643 and wR= 0.1633. The crystal structure shows that the copper ion is coordinated with six nitrogen atoms from six 1,10-phenanthroline molecules, forming a distorted octahedral coordination geometry.

Crystal Structure of 〔Aqua(oxalato)(1,10-phenanthroline)(H_2O)〕copper(Ⅱ) Monohydrate

The title compound FCu (C2O4) (phen ) H2O)] H2O (phen=1, 10-phenanthroline) crystallizes in monoclinic system, space group P21/n with a = 8. 453 1639 observed reflections. The Cu(Ⅱ) atom is coordinated bytwo N atoms of phen, two O atoms of oxalate and one O atom of water, and in square-pyramidal environment. The molecules of the structure are joined to each other in thecrystal lattice by hydrogen bonds to yield a one-dimensional chain structure.

Synthesis and Crystal Structure of[Copper(1,10-phenanthroline)_2(pyridine)]perchlorates

The complex [Cu(phen)2py](ClO4)2 was obtained by the reaction of 1,10-phenanthroline with Cu(ClO4)2·6H2O in water and by recrystallization from pyridine. A single-crystal X-ray study shows that the complex is a square pyramidal arrangement of five nitrogen atoms from the two 1,10-phenanthroline ligands and one pyridine ligand, respectively. The compound is orthorhombic, C29H21N5Cl2O8Cu, Mr = 701.958, with space group Pbcn, a = 29.9593(3), b = 16.1240(3), c = 11.9183(6) ?, V = 5757.3(3) ?3, Z = 8, Dc = 1.409g/cm3, μ =1.121 mm-1, F(000) = 2465, R = 0.0539, Rw = 0.1380 for 4293 reflections with I >2σ(I). The bond lengths of Cu(1)－N(1), Cu(1)－N(2), Cu(1)－N(3) and Cu(1)－N(4) are 2.223(3), 2.017(3), 2.013(3) and 2.038(3) ?, respectively. The distance from copper to pyridine N(5) is 2.012(3) ?. The angles N(2)－Cu(1)－N(3) and N(4)－Cu(1)－N(5) are 176.1(1) ° and 160.9(1)°, respectively. The angles between axial position nitrogen atom N (1) and four square position nitrogen atoms N(2), N(3), N(4), N(5) are 79.3(1), 98.3(1), 90.7(1), 108.4(1)°, respectively.

Copper Metabolism and Cuproptosis:Molecular Mechanisms and Therapeutic Perspectives in Neurodegenerative Diseases

Copper is an essential trace element,and plays a vital role in numerous physiological processes within the human body.During normal metabolism,the human body maintains copper homeostasis.Copper deficiency or excess can adversely affect cellular function.Therefore,copper homeostasis is stringently regulated.Recent studies suggest that copper can trigger a specific form of cell death,namely,cuproptosis,which is triggered by excessive levels of intracellular copper.Cuproptosis induces the aggregation of mitochondrial lipoylated proteins,and the loss of iron-sulfur cluster proteins.In neurodegenerative diseases,the pathogenesis and progression of neurological disorders are linked to copper homeostasis.This review summarizes the advances in copper homeostasis and cuproptosis in the nervous system and neurodegenerative diseases.This offers research perspectives that provide new insights into the targeted treatment of neurodegenerative diseases based on cuproptosis.

Crystal Structure of the Addition Compound of N,N′-Bi(2-pyridylmethyl)-Oxamide and the Complex of Copper with 1,10-Phenanthroline

The structure of addition compound Cu(phen)3(PMoxdH)(CO4)2 was establish ed by means of X-ray crystallography,where PMoxdH is N,N-Bi(2-pyridyl-methyl)-oxamide,in which six nitrogen atoms of the three 1,10,-phen-anthroline bind to the copper ion and the oxygen atom of PMoxdH is uncoordinated.

Solid-liquid Extraction Spectrophotometric Determination of Copper with 2,9-dimethyl-1,10-phenanthroline

Solid liquid extraction of copper ion (I) with 2, 9-dimethyl-1, 10-phenanthroline (neo-cuproine, DMP) into molten naphthalene followed by chloroform spectrophotometric determination has been studied experimentally. The ternary complex Cu(I)-DMP-ClO4 was extracted quantitatively into molten naphthalene in the range of pH from 5 to 6 at 85 C-. Absorbance was spectrophotometrically determined at 459 nm against the reagent blank after the solid naphthalene layer was anhydrously dissolved in chloroform. Beer's law is obeyed over a concentration range of 0.5-70 mug/mL. The molar absorptivity and Sandell's sensitivity are 1.0x10(4) L/(mol(.)cm) and 0.0099 mug(.)cm(2) respectively. In addition, the various conditions on determination and the interference of coexisted ions were discussed, and the method was applied to the determination of copper ion both in tea samples and cadmium sulfate reagents. The results are in good agreement with those obtained by ICP AES method.

Synthesis and Structure of Dimeric Copper (I) Complex from Bis[(2,2’)-dimethyl 2,2’-(1,10-phenanthroline-2,9-diyl) bis(methan-1-yl-1-ylidene)-bis(hydrazinecarbo dithioate)]

Metal complex, bis[(2,2’)-dimethyl 2,2’-(1,10-phenanthrline-2,9-diyl)bis(methan-1-yl-1-ylidene)-bis(hydrazinecarrbo dithioate)copper(I)], was synthesized from the reaction of Schiff base, (2,2’)-dimethyl 2,2’-(1,10-phenanthroline-2,9-diyl)bis(methan-1-yl-1-ylidene)-bis(hydrazinecarbo dithioate) and CuCl2 at reflux condition in methanol. The copper centers of the complex appear to be reduced. This probably was facilitated by in situ oxidative formation of disulfide bond at the uncomplexed ligand moieties. Single crystal X-ray diffraction analysis reveals the distorted tetrahedral geometry around the copper centers. This compound crystallizes in the triclinic space group, P-1 with crystallographic parameters: a = 10.006(3) ?, b = 13.272(3) ?, c = 22.123(6) ?, α = 85.656(6)°, β = 81.656(6)°, γ = 73.097(5)°, μ = 1.223 mm-1 , V = 2779.5(13) ?3, Z = 2, Dc = 1.437 Mg/m3, T = 293 (2) K.

Synthesis and Supramolecular Structure of Chloro(1,10-phenanthroline)copper(I) Hexahydrate

The title compound, C24H28ClCuN4O6 （Mr = 567.49）, has been prepared and its crystal structure has been determined by X-ray diffraction method. The crystal belongs to monoclinic, space group C2/c with a = 23.1905（14）, b = 30.1877（12）, c = 7.4881 （3） A, β = 97.631 （2）°, V = 5195.8（4） A^3, Z = 8, Dc = 1.451 g/cm^3,μ = 0.989 mm^-1, F（000） = 2352, S = 1.030, R = 0.0694, wR = 0.2120 （I 〉 2σ（I））, R = 0.0950 and wR = 0.2322 （all data）. The crystal consists of the Cu（Ⅰ） complex and lattice water molecules. The Cu（Ⅰ） atom is coordinated by two phenanthroline （phen） molecules and one chlorine anion with a distortetl trigonal dipyramidal coordination geometry. By the aid of aromatic π-π stacking, the Cu（Ⅰ） complex molecules form two-dimensional supramolecular layers. Lattice water molecules locate between the adjacent layers to form a three-dimensional sandwich-like supramolecular structure.

Effects of Copper-phenanthroline on Pentachlorophenol-induced Adaptation and Cell Death of Escherichia coli

Objective To evaluate the effects of copper-phenanthroline （CuOP） on pentachlomphenol （PCP）-induced adaptation and cell death of Escherichia coli. Methods Bacterial growth and adaptation to PCP were monitored spectrophotometrically at 600 nm. Inactivation of bacterial cells was determined from colony count on agar dishes. Cellular ATP content and accumulation of PCP were assessed by chemiluminescence and HPLC analysis respectively. The formation of PCP-Cu-OP complex was shown by UV-visible spectra. Results Escherichia coli （E. coli） could adapt to PCP, a wood preservative and insecticide used in agriculture. The adaptation of E. coli to PCP prevented its death to the synergistic cytotoxicity of CuOP plus PCP and declined cellular accumulation and uncoupling of oxidative phosphorylation of PCP. Furthermore, CuOP and PCP neither produced reactive oxygen species （ROS） nor had a synergistic effect on uncoupling of oxidative phosphorylation in E. coli. The synergistic cytotoxicity of CuOP and PCP in E. coli might be due to the formation of lipophilic PCP-Cu-OP complex. Conclusion Our data suggested that adaptation of E. coli to PCP decreased the synergistic effects of CuOP and PCP on prokaryotic cell death due to the formation of lipophilic PCP-Cu-OP complex, but it had no effect on the uncoupling of oxidative phosphorylation and production of reactive oxygen species in E. coli.

Crystal Structure of a Ternary Copper(Ⅱ) Complex of N,N'-(p-Xylylene)dialanine Acid and 1,10-Phenanthroline

The compound [Cu2（bpy）2（PDIAla）（H2O）2]（ClO4）2·H2O（H2PDIAla = N,N＇-（p-xylylene）dialanine,bipy = 2,2＇-bipyridine） 1 has been synthesized and structurally determined by single-crystal X-ray diffraction,elemental analyses and IR spectroscopy.The crystal belongs to the monoclinic system,space group P21 with a = 10.9772（6）,b = 18.5464（9）,c = 11.0790（6） ,β = 116.3110o,V = 2021.87（18） 3,Z = 2,Dc = 1.594 Mg/m3,Mr = 970.70,μ = 1.260 mm-1,F（000） = 996,λ（MoKα） = 0.71073 ,the final R = 0.0400 and wR = 0.1050 for all observed reflections.In the structure,the O（5）-H（52）…O（4） hydrogen bonding between aqua ligand and carbonyl oxygen of the H2PDIAla ligand along the c axis produce hydrogen-bonded helices which are assembled along the b axis through O（61）-H（61）…O（2） and N（6）-H（6N）…O（2） interactions to form 2-D layers that are further linked by π···π interactions between bpy ligands to yield a three-dimensional supramolecular network.

Design of low-alloying and high-performance solid solution-strengthened copper alloys with element substitution for sustainable development

Solid solution-strengthened copper alloys have the advantages of a simple composition and manufacturing process,high mechanical and electrical comprehensive performances,and low cost;thus,they are widely used in high-speed rail contact wires,electronic component connectors,and other devices.Overcoming the contradiction between low alloying and high performance is an important challenge in the development of solid solution-strengthened copper alloys.Taking the typical solid solution-strengthened alloy Cu-4Zn-1Sn as the research object,we proposed using the element In to replace Zn and Sn to achieve low alloying in this work.Two new alloys,Cu-1.5Zn-1Sn-0.4In and Cu-1.5Zn-0.9Sn-0.6In,were designed and prepared.The total weight percentage content of alloying elements decreased by 43%and 41%,respectively,while the product of ultimate tensile strength(UTS)and electrical conductivity(EC)of the annealed state increased by 14%and 15%.After cold rolling with a 90%reduction,the UTS of the two new alloys reached 576 and 627MPa,respectively,the EC was 44.9%IACS and 42.0%IACS,and the product of UTS and EC(UTS×EC)was 97%and 99%higher than that of the annealed state alloy.The dislocations proliferated greatly in cold-rolled alloys,and the strengthening effects of dislocations reached 332 and 356 MPa,respectively,which is the main reason for the considerable improvement in mechanical properties.

Synthesis and Crystal Structure of the Copper(Ⅱ) Complex with 1,10-Phenanthroline-5,6-dione

The complex Cu(phon)(NO3)2(CH3CN) (phon = 1,10-phenanthroline-5,6-dione) has been synthesized and characterized by elemental analysis, infrared and UV-Vis spectra. X-ray diffraction analysis at room temperature indicates that the complex crystallizes in orthorhombic system, space group P212121 with a = 8.353(1), b = 11.299(2), c = 17.764(2) A, V= 1676.5(4) A3, Z = 4, C14H9CuN5O8, Mr = 438.8, Dc = 1.739 g/cm3, F(000) = 884 and μ(MoKα) = 1.361 mm-1. The final R and wR factors for the observed reflections with I > 2σ(I) are 0.0353 and 0.0855, respectively. R = 0.0432 and wR = 0.0899 for all data. The structure of the title complex consists of a neutral mononuclear entity. The central Cu (II) atom is five-coordinated by two nitrogen donors of one ligand, two unidentate NO3- ions and one CH3CN molecule. The coordination geometry of Cu (II) can be considered as a distorted trigonal bipyramidal configuration. The complex ability of the NO3-ion has more effect than that of the ClO4- ion on the structure of the complex.

Synthesis and Crystal Structure of the Copper(II) Complex with Tris-(1,10-phenanthroline-5,6-dione)

The title complex [CuL3]（ClO4）2·2H2O·2CH3CN （L = 1,10-phenanthroline-5,6-dione） has been synthesized and characterized by elemental analysis, conductivity, infrared and UV-Vis spectra. X-ray diffraction analysis at room temperature indicates that the complex （C40H28Cl2CuN8O16, Mr = 1011.14） crystallizes in orthorhombic system, space group P212121 with a=13.983（1）, b=14.310（1）, c= 20\^890（2） , V = 4179.7（6） 3, Z = 4, Dc = 1.607 g/cm3, F（000） = 2026,μ（MoKα） = 0.736 mm-1. The final R and wR factors are 0.0446 and 0.1212 respectively with 8545 independent reflections. The title complex is composed of a discrete [CuL3]2+ cation, uncoordinated ClO4- anions, H2O and CH3CN molecules. The central Cu（II） atom is six-coordinated by six nitrogen donors of three ligands. The coordination geometry of Cu（II） could be considered as an approximately ideal octahedral configuration with little static Jahn-Teller distortion （the longest and shortest Cu-N bonds are 2.102 vs 2.139 with the mean length of 2.122 ）, which is very rare for a six-coordinated Cu（II） complex.

Recombinogenic Effect of the Ternary Complex of Copper（II） with Doxycycline and 1,10-Phenanthroline on Somatic Cells of Drosophila melanogaster

In the search for new anti-tumor agents, exploiting features such as the flexibility of coordination modes of metals have become an alternative strategy for synthesizing pharmaceuticals. It has been shown that the CuDP （copper（II）, doxycycline, and 1,10-phenanthroline） complex cleaves DNA strands by an oxidative mechanism and by intercalating the major groove, resulting in a cytotoxic action. The objective of this study was to assess the mutageinc/recombinogenic effects of the CuDP complex in vivo using the SMART （Somatic Mutation and Recombination Test） in Drosophila melanogaster. Treatments were carried out with third instar larvae at the standard cross and high bioactivation cross using three concentrations of CuDP （6.92, 13.84 or 27.67 mM）. The mutagenic doxorubicin （0.4 mM） was used as a positive control and reverse osmosis water as a negative control. For each compound, marked trans-heterozygous and balanced heterozygous individuals were analyzed to determine the mutational and recombinogenic events occurring in the cells, We found that CuDP significantly increased the frequencies of mutant cells in both standard and high bioactivation crosses, mostly by induction of recombination. These data show that CuDP is a direct recombinogenic agent that is independent of bioactivation,

Editorial Commentary:Copper Homeostasis in Neurodegenerative Diseases

Copper,as an essential trace nutrient,plays a crucial role in biological processes such as mitochondrial respiration,antioxidant stress response,and the synthesis of biomolecules.Typically,cellular copper concentrations are maintained at very low levels,a pattern also observed in cancer cells to prevent adverse consequences of copper overload,such as cuproptosis.This involves copper dependency,accumulation of lipidated proteins,and a reduction in Fe-S cluster proteins[1].Various neurodegenerative diseases are associated with imbalances in copper homeostasis.

Detection of Al, Mg, Ca, and Zn in copper slag by LIBS combined with calibration curve and PLSR methods

The precise measurement of Al, Mg, Ca, and Zn composition in copper slag is crucial for effective process control of copper pyrometallurgy. In this study, a remote laser-induced breakdown spectroscopy(LIBS) system was utilized for the spectral analysis of copper slag samples at a distance of 2.5 m. The composition of copper slag was then analyzed using both the calibration curve(CC) method and the partial least squares regression(PLSR) analysis method based on the characteristic spectral intensity ratio. The performance of the two analysis methods was gauged through the determination coefficient(R^(2)), average relative error(ARE), root mean square error of calibration(RMSEC), and root mean square error of prediction(RMSEP). The results demonstrate that the PLSR method significantly improved both R^(2) for the calibration and test sets while reducing ARE, RMSEC, and RMSEP by 50% compared to the CC method. The results suggest that the combination of LIBS and PLSR is a viable approach for effectively detecting the elemental concentration in copper slag and holds potential for online detection of the elemental composition of high-temperature molten copper slag.

Interphase migration and enrichment of lead and zinc during copper slag depletion

An interphase migration and enrichment model of lead and zinc during molten copper slag depletion was established.The occurrence of various components in copper slag was predicted using sulfur-oxygen potential calculations and confirmed through high-temperature experiments.The recovery rate of copper can reach 90.13%under the optimal conditions of 1200°C,an iron to silicon mass ratio of 1.0,3 wt.%ferrous sulfide,and a duration of 45 min.Lead(54.07 wt.%)and zinc(17.42 wt.%)are found in the flue dust as lead sulfate,lead sulfide,and zinc oxide,while copper matte contains lead(14.44 wt.%)and zinc sulfide(1.29 wt.%).The remaining lead and zinc are encapsulated as oxides within the fayalite phase.