β-Carboline copper complex as a potential mitochondrial-targeted anticancer chemotherapeutic agent: Favorable attenuation of human breast cancer MCF7 cells via apoptosis

The development of preferentially selective cancer chemotherapeutics is a new trend in drug research. Thus, we designed and synthesized novel ternary complexes, [Cu(tryp)(Hnor)₂(DMSO)]NO₃ (1) and [Zn(tryp)(Hnor)₂(DMSO)]NO₃ (2) (tryp = DL-Tryptophane; Hnor = Norharmane, β-carboline; DMSO = Dimethyl sulfoxide), characterized with elemental analysis, FTIR, UV–vis, FL, NMR, ESI-MS, and molar conductivity. Furthermore, the TD-DFT studies with UV–vis and FTIR validated the proposed structures of 1 and 2. Moreover, we evaluated the HOMO-LUMO energy gap and found that 1 has a smaller energy gap than 2. Then, 1 and 2 were assessed for anticancer chemotherapeutic potential against cancer cell lines MCF7 (human breast cancer) and HepG2 (human liver hepatocellular carcinoma) as well as the non-tumorigenic HEK293 (human embryonic kidney) cells. The MTT assay illustrated the preferentially cytotoxic behavior of 1 when compared with that of 2 and cisplatin (standard drug) against MCF7 cells. Moreover, 1 was exposed to MCF7 cells, and the results indicated the arrest of the G2/M phases, which followed the apoptotic pathway predominantly. Generation of ROS, GSH depletion, and elevation in LPO validated the redox changes prompted by 1. These studies establish the great potential of 1 as a candidate for anticancer therapeutics.     

A thermodynamic and crystallographic study of complexes of the highly preorganized ligand 8-hydroxyquinoline-2-carboxylic acid

The metal ion complexing properties of the ligand HQC (8-hydroxyquinoline-2-carboxylic acid) are reported. The structures of [Zn(HQCH)₂] · 3H₂O (1) and [Cd(HQCH)₂] · 3H₂O (2) were determined (HQCH = HQC with phenol protonated). Both 1 and 2 are triclinic, space group , with Z = 2. For 1 a = 7.152(3), b = 9.227(4), c = 15.629(7) Å,  = 103.978(7)°, β = 94.896(7)°, γ = 108.033(8)°, R = 0.0499. For 2 a = 7.0897(5), b = 9.1674(7), c = 16.0672(11) Å,  = 105.0240(10)°, β = 93.9910(10)°, γ = 107.1270(10)°, R = 0.0330. In 1 the Zn has a distorted octahedral coordination geometry, with Zn–N of 2.00 and 2.15 Å, and Zn–O to the protonated phenolic oxygens of 2.431 and 2.220 Å. The structure of 2 is similar, with Cd–N bonds of 2.220 and 2.228 Å, with Cd–O bonds to the protonated phenolate oxygens of 2.334 and 2.463 Å. The structures of 1 and 2, and isomorphous Ni(II) and Co(II) HQC complexes reported in the literature, show very interesting short (<2.5 Å) O–O distances in H-bonds involving the protons on the coordinated phenolates and lattice water molecules. These are discussed in relation to the possible role of short low-energy H-bonds in alcohol dehydrogenase in mediating the transfer of the hydroxyl proton of the alcohol to an adjacent serine oxygen.

The formation constants for HQC are determined by UV–Visible spectroscopy at 25 °C in 0.1 M NaClO₄ with Mg(II), Ca(II), Sr(II), Ba(II), La(III), Gd(III), Zn(II), Cd(II), Ni(II), Cu(II), and Pb(II). These show greatest stabilization with metal ions with an ionic radius above 1.0 Å. This is as would be expected from the fact that HQC forms two five-membered chelate rings on complex-formation, which favors larger metal ions. The ligand design concept of using rigid aromatic backbones in ligands to achieve high levels of preorganization, and hence the high log K values (for a tridentate ligand) and strong metal ion selectivities observed for HQC, is discussed.     

Structure of Cu2(indomethacin)4 and the reaction with superoxide in aprotic systems

The copper complex of indomethacin (1-(p-chlorobenzoyl)-5-methoxy-2-methyl-indole acetate), a common anti-inflammatory drug, was prepared and characterized. Crystal structure determination revealed the dimeric form of the 1:2 complex, namely Cu₂(indomethacin)₄ · L₂, in the unit cell. Suprisingly, the copper-copper distance (263 pm) was very close to metallic copper (256 pm). The two coordination sites in the copper-copper axis can be readily replaced by superoxide. An intriguing similarity to Cu₂(acetate)₄ was seen.Due to the lipophilic nature of the indomethacin ligand, this copper complex reacted with superoxide in aprotic solvents. The superoxide dismutating activity was successfully demonstrated in Me₂SO/water and acetonitrile/water mixtures using the nitro-blue tetrazolium assay and pulse radiolysis. The second-order rate constant of 6 · 10⁹ M^?1 · s^?1 in strictly aqueous systems dropped only slightly to 1.1 · 10⁹ M^?1 · s^?1 when aprotic solvents were used. This is the fastest rate constant ever observed for a copper-dependent dismutation of superoxide. The KO₂-induced lipid peroxidation in both erythrocytes and liver microsomes was suppressed by 70% in the presence of 1 · 10^?10 mol · ml^?1 of Cu₂(indomethacin)₄. The inhibitory action dropped to 25% when Cu₂Zn₂superoxide dismutase was employed. The formation of copper · indomethacin in rat serum after administration of indomethacin was shown in vitro and in vivo.     

One-dimensional Cu(I) camphor hydrazone polymers: Structure and catalytic properties

Complexes of general formula [{CuX}₂(YNC₁₀H₁₄O)] (X = Cl; Y = NHMe, NH₂ or X = Br; Y = NH₂) were synthesised from camphor hydrazone ligands (YNC₁₀H₁₄O) by reaction with the suitable copper(I) halide. Structural analysis by X-rays performed on a red crystal of [{CuCl}₂(Me₂NNC₁₀H₁₄O)] revealed that the complex is a one-dimensional copper polymer formed by two rather different copper units bridged by chloride. One of the copper units displays a tetrahedral geometry while the other is linear. Although the geometries and neighbourhoods of the two copper units are very different the oxidation state of the metal is the same, i.e. Cu(I) as corroborated by magnetic and electrochemical measurements.The ability of [{CuCl}₂(Me₂NNC₁₀H₁₄O)] to promote the activation of 4-pentyn-1-ol towards cyclization was studied under homogeneous or heterogeneous experimental conditions. The best results were obtained under homogeneous conditions at 40 °C.     

Micronutrient availability to cereals from calcareous soils

Summary The mechanism of higher grain production of wheat (Triticum aestivum L.) by four tillage methods was explored on a sandy calcareous soil of Sahl-Al Jafara, Libya, during the year 1976–77. Tillage methods increased grain yield and dry matter weight at the boot stage in the order of no-tillage<rotovator=disc plough < subsoiler. Rotovation to 15 cm and disc ploughing to 25 cm depth enhanced grain production mainly by eliminating weed competition. In both the cases, roots penetrated < 25 cm where plough-pan existed.Further yield increases by 50 cm deep subsoiling seems to be mainly explained by N and Cu rise in plants from their marginal to optimum levels and by reduction of Mn deficiency in plant shoots. Penetration of roots beyond the 25 cm plough-pan apparently resulted in higher absorption of these nutrients from leached or native soil supplies. Subsoiling also resulted in greater Zn concentration in plant shoots which, under marginal to deficient conditions, will also increase grain production.     

A new copper(II) complex of unsymmetrical tetradentate ligand generated in situ: synthesis and molecular structure

A new copper(II) complex with tetradentate unsymmetrical ligand was prepared by one-pot condensation of methyl-2-pyrrole carboxylate, diethylenetriamine and copper(II) sulfate. The complex was characterized by elemental analysis, electronic and IR spectral, as well as X-ray crystal structure determination. The X-ray structure of the molecule reveals the copper(II) center is in a square planar environment through coordination by two nitrogen atoms of the amine, one amide nitrogen atom and one nitrogen atom of the pyrrole moieties, respectively. The copper(II) complex is neutral due to deprotonation of the amide and pyrrole groups.     

Spectrophotometric determination of formation constants for the Cu-ethylenediamine-halogen (chloride and bromide) system and their catalytic effect on the oxidative coupling of 2,6-di-tert-butyl-phenol

In order to explain the mechanism of the dimerization of 2,6-di-tert-butyl-phenol when catalyzed by the copper-ethylenediamine complexes, a spectrophotometric study of the speciation of copper(II) complexes in methanol of Cu(II), ethylendiamine and Cl⁻ or Br⁻ was carried out at 303 K. The formation constants obtained for the copper chloride system are: log β₁₀₁ = 2.90 ± 0.03, log β₁₀₂ = 6.39 ± 0.03 and log β₁₀₃ = 8.62 ± 0.04, for the copper bromide system are log β₁₀₁ = 3.01 ± 0.10, log β₁₀₂ = 5.50 ± 0.08, for the copper-ethylendiamine complexes are log β₁₁₀ = 6.13 ± 0.05 and log β₁₂₀ = 10.54 ± 0.08, and for the ternary copper-ethylenediamine chloride or bromide systems are log β₁₁₁ = 10.21 ± 0.03 and log β₁₁₁ = 10.07 ± 0.03, respectively. Knowing the speciation of the copper-ethylenediamine-halide systems, the kinetic studies can be correlated with the species in solution. Comparative studies of the oxidation reaction of 2,6-di-tert-butyl-phenol using different copper(II) complexes with chloride or bromide and ethylenediamine as catalyst are reported. Their catalytic activity in the oxidation of 2,6-di-tert-butyl-phenol was monitored in methanol solution, following the corresponding quinone formation, at 418 nm (ε = 3.95 × 10⁴ mol⁻¹ L cm⁻¹ at 303 K). The results indicate that the most active species are [Cu(en)X]⁺, where X is bromide or chloride, Both complexes have similar activity.     

Versatile nuclearity in copper complexes with ortho functionalized 1,3-bis(aryl)triazenido ligands

The synthesis, characterization and crystal structures of three new copper complexes derived from 1,3-bis(aryl)triazenido ligands bearing either a methoxycarbonyl, methylthio or a hydroxymethyl group in the ortho position of one of the aromatic rings are reported. In addition to the coordination of the triazenido fragment, the Lewis basic groups coordinate to the copper centers to form complexes with different nuclearity: {1-[2-(methoxycarbonyl)phenyl]-3-[4-methylphenyl]}triazene and {1-[2-(methylthio)phenyl]-3-[4-methylphenyl]}triazene form stable dinuclear and tetranuclear Cu(I) complexes, respectively. Reaction of {1-[2-(hydroxymethyl)phenyl]-3-[4-methylphenyl]}triazene with either Cu(I) or Cu(II) results in a novel Cu(II) hexanuclear macrocyclic complex.     

Interactions between Copper-binding Sites Determine the Redox Status and Conformation of the Regulatory N-terminal Domain of ATP7B

Copper-transporting ATPase ATP7B is essential for human copper homeostasis and normal liver function. ATP7B has six N-terminal metal-binding domains (MBDs) that sense cytosolic copper levels and regulate ATP7B. The mechanism of copper sensing and signal integration from multiple MBDs is poorly understood. We show that MBDs communicate and that this communication determines the oxidation state and conformation of the entire N-terminal domain of ATP7B (N-ATP7B). Mutations of copper-coordinating Cys to Ala in any MBD (2, 3, 4, or 6) change the N-ATP7B conformation and have distinct functional consequences. Mutating MBD2 or MBD3 causes Cys oxidation in other MBDs and loss of copper binding. In contrast, mutation of MBD4 and MBD6 does not alter the redox status and function of other sites. Our results suggest that MBD2 and MBD3 work together to regulate access to other metal-binding sites, whereas MBD4 and MBD6 receive copper independently, downstream of MBD2 and MBD3. Unlike Ala substitutions, the Cys-to-Ser mutation in MBD2 preserves the conformation and reduced state of N-ATP7B, suggesting that hydrogen bonds contribute to interdomain communications. Tight coupling between MBDs suggests a mechanism by which small changes in individual sites (induced by copper binding or mutation) result in stabilization of distinct conformations of the entire N-ATP7B and altered exposure of sites for interactions with regulatory proteins.