Terpyridine Glycoconjugates and Their Metal Complexes: Antiproliferative Activity and Proteasome Inhibition

Metal terpyridine complexes have gained substantial interest in many application fields, such as catalysis and supramolecular chemistry. In recent years, the biological activity of terpyridine and its metal complexes has aroused considerable regard. On this basis, we synthesised new terpyridine derivatives of trehalose and glucose to improve the water solubility of terpyridine ligands and target them in cancer cells through glucose transporters. Glucose derivative and its copper(II) and iron(II) complexes showed antiproliferative activity. Interestingly, trehalose residue reduced the cytotoxicity of terpyridine. Moreover, we tested the ability of parent terpyridine ligands and their copper complexes to inhibit proteasome activity as an antineoplastic mechanism.     

1,10-菲咯啉及其衍生物铜配合物的合成、表征及其抗肿瘤作用

设计合成了多吡啶铜配合物并通过质谱和元素分析进行了结构表征,对两种配合物体外抑制MCF-7乳腺癌细胞的作用与机理进行初步探讨。结果表明多吡啶铜配合物2具有一定的抗肿瘤活性,能够诱导乳腺癌细胞凋亡,作用机制与下调Bcl-2和上调Bax有关,其抗肿瘤活性与铜配合物的分子结构相关。     

The Cytotoxic Effect of Copper (II) Complexes with Halogenated 1,3-Disubstituted Arylthioureas on Cancer and Bacterial Cells

A series of eight copper (II) complexes with 3-(4-chloro-3-nitrophenyl)thiourea were designed and synthesized. The cytotoxic activity of all compounds was assessed in three human cancer cell lines (SW480, SW620, PC3) and human normal keratinocytes (HaCaT). The complexes 1, 3, 5, 7 and 8 were cytotoxic to the studied tumor cells in the low micromolar range, without affecting the normal cells. The complexes 1, 3, 7 and 8 induced lactate dehydrogenase (LDH) release in all cancer cell lines, but not in the HaCaT cells. They provoked early apoptosis in pathological cells, especially in SW480 and PC3 cells. The ability of compounds 1, 3, 7 and 8 to diminish interleukin-6 (IL-6) concentration in a cell was established. For the first time, the influence of the most promising Cu (II) complexes on intensities of detoxifying and reactive oxygen species (ROS) scavenging the enzymes of tumor cells was studied. The cytotoxic effect of all copper (II) conjugates against standard and hospital bacterial strains was also proved.     

Synthesis,characterization and antitumour studies of metal chelates of N1-isonicotinoyl-3-methyl-4-(p-hydroxybenzilidene)-2-pyrazolin-5-one

The cobalt(II), nickel(II) and copper(II) complexes of N-Isonicotinoyl-3-methyl-4-(p-hydroxybenzilidene)-2-pyrazolin-5-one (IMHBP) with different counter anions have been prepared and characterized. An octahedral geometry has been assigned to the cobalt(II) and nickel(II) complexes and a square-planar structure to the copper(II) complexes. IMHBP acts as a neutral bidentate ligand in all these complexes by coordinating through the oxygen atoms of the amide group and carbonyl at position-5. The other coordination sites are satisfied by anions alone or anions and water molecules. The ligand and the complexes were screened for their possible antitumour activity. The copper(II) complexes are appreciably active in reducing mice tumours.     

Reactivity of Intermediates in the Photochemistry of Copper(II) Macrocyclic Complexes

The reactivity of unstable copper macrocycles which act as intermediates in photochemical transformations of copper(II) complexes with synthetic macrocyclic ligands has been reviewed. Although most of these species were investigated by flash photolysis, a number of pulse radiolytic investigations of related species were also incorporated in this review.     

Tetranuclear Thioureacopper(II) Complexes

By replacement of methanol in the Cu₄OX₆(MeOH)₄ (X  Cl, Br) complexes with thiourea (tu), N,N′-diphenylthiourea (diftu), N,N′-dimethlthiourea (dimtu), tetramethylthiourea (tmtu) and acetylthiourea (actu), the complexes Cu₄OCl₆L₄ where L  tu, tu(0.3 Et₂O), diftu, dimtu, tmtu, actu (0.5Et₂O) and the complexes Cu₄OBr₆L₄, where L  tu, diftu, dimtu, tmtu have been prepared. Their infrared and electronic spectra indicate the presence of Cu₄O grouping and the trigonal bipyramidal coordination of copper(II). These complexes exhibit e.p.r. signals in the temperature range 100–260 K, in contrast to other known complexes of this structural type, which showed the e.p.r. signals at significantly lower temperatures. Thiourea and its derivatives are not able to reduce copper(II) in reaction with the tetranuclear Cu₄OX₆(MeOH)₄ complexes in methanol-ether solution due to the redox stabilizing effect of the tetranuclear structure.     

钴(Ⅱ)、镍(Ⅱ)、铜(Ⅱ)与2,4-二羟基二苯甲酮配合物的合成与表征

以2,4-二羟基二苯甲酮(BP)为配体与M2+(M=Co,Ni,Cu)合成了几种新的配合物,研究了配合物的热稳定性。通过元素分析、IR、UV、TG-DTA和电导分析对配合物进行了表征。结果表明配合物的组成为M(BP)2.nH2O,配体中羰基氧和邻位羟基氧与中心离子配位构成平面正方形结构,三种配合物的热稳定性为:Co(Ⅱ)>Ni(Ⅱ)>Cu(Ⅱ)。     

Pharmacological Role of Anions (Sulphate, Nitrate, Oxalate and Acetate) on the Antibacterial Activity of Cobalt(II), Copper(II) and Nickel(II) Complexes With Nicotinoylhydrazine-Derived ONO, NNO and SNO Ligands

Mixed ligands biologically active complexes of cobalt(II), copper(II) and nickel(II) with nicotinoylhydrazine-derived ONO, NNO and SNO donor schiff-base ligands having the same metal ion but different anions such as sulphate, nitrate, oxalate and acetate have been synthesised and characterised on the basis of their physical, analytical and spectral data. In order to evaluate the role of anions on their bioability, these ligands and their synthesised metal complexes with various anions have been screened against bacterial species such as Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus and the title studies have proved a definative role of anions in increasing the biological activity.     

Copper(II) Complexes of Pyridazine-Based Azo-azomethine Ligands: Synthesis, Characterization Thermal and Absorption Properties

New copper(II) complexes with blue–violet light wavelength absorption were synthesized using direct reaction of acyclic azo-azomethine pyridazine-based ligands with copper ion. The prepared complexes were characterized using elemental analysis, spectroscopic methods and thermal analyses. The absorption properties of the prepared complexes in the region 200–800 nm and also the influence on the difference of absorption maximum of complexes were investigated. The thermogravimetric results show that the framework of all complexes is stable up to 270–320 °C.     

Tuning Anti-Biofilm Activity of Manganese(II) Complexes: Linking Biological Effectiveness of Heteroaromatic Complexes of Alcohol,Aldehyde, Ketone,and Carboxylic Acid with Structural Effects and Redox Activity

The constantly growing resistance of bacteria to antibiotics and other antibacterial substances has led us to an era in which alternative antimicrobial therapies are urgently required. One promising approach is to target bacterial pathogens using metal complexes. Therefore, we investigated the possibility of utilizing series of manganese(II) complexes with heteroaromatic ligands: Alcohol, aldehyde, ketone, and carboxylic acid as inhibitors for biofilm formation of Pseudomonas aeruginosa. To complete the series mentioned above, Mn-dipyCO-NO₃ with dipyridin-2-ylmethanone (dipyCO) was isolated, and then structurally (single-crystal X-ray analysis) and physicochemically characterized (FT-IR, TG, CV, magnetic susceptibility). The antibacterial activity of the compounds against representative Gram-negative and Gram-positive bacteria was also evaluated. It is worth highlighting that the results of the cytotoxicity assays performed (MTT, DHI HoloMonitorM4) indicate high cell viability of the human fibroblast (VH10) in the presence of the Mn(II) complexes. Additionally, the inhibition effect of catalase activity by the complexes was studied. This paper focused on such aspects as studying different types of intermolecular interactions in the crystals of the Mn(II) complexes as well as their possible effect on anti-biofilm activity, the structure–activity relationship of the Mn(II) complexes, and regularity between the electrochemical properties of the Mn(II) complexes and anti-biofilm activity.     

Synthesis, Characterisation and Antifungal Activities of Some New Copper(II) Complexes of Isomeric 3,5,7,7,10,12,14,14-Octamethyl-1,4,8,11-Tetraazacyclotetradecanes

Three isomeric Me(8)[14]anes, L(A), L(B) and L(C), undergo complexation with copper(II) salts to form a series of [CuLX(n)(H(2)O)(x)]X(y).(H(2)O)(z) complexes where L = L(A), L(B) and L(C); X = Cl, Br, NO(3); n, x, y and z may have values of 0, 1 or 2. The complexes have been characterised on the basis of analytical, spectroscopic, magnetic and conductance data. Further, the X-ray crystal structure of one complex, [CuL(B)(OH(2))(2)](NO(3))(2), has been determined. The antifungal activity of all three isomeric ligands and their complexes has been investigated against a range of phytopathogenic fungi.     

Metral54-100萃取分离铜、镍的密度泛函研究

采用密度泛函理论DFT/B3LYP/6-31G+(d, p)方法计算不同配位形态的铜、镍萃合物的结合能、全局活性指数、局部活性指数和红外光谱,探讨了1-苯基-1,3癸二酮(Mextral54-100)萃取Cu(II), Ni(II)的行为及机理。结果表明,Mextral54-100对Cu(II)的萃取能力大于Ni(II)。在反萃过程中,铜的萃合物更易被反萃。萃合物羰基表现出最高的反应活性,为活性中心。萃合物中氨分子的取代数越多,萃合物构型近似于稳定的八面体结构。配体氨逐一被萃取剂的羰基取代,有效避免共萃氨。Mextral54-100从铜、镍氨混合溶液中萃取–反萃Cu(II)和Ni(II)的实验结果与理论预测结果吻合,进一步通过FT-IR证实了理论计算结果的准确性,密度泛函理论有望成为一种研究萃取分离性能的新方法。     

Interpretation of the sod-like activity of a series of copper(II) complexes with thiosemicarbazones

In the present paper we report the SOD-like activity of a series of copper(II) complexes with acetaldehyde, acetophenone, 2-oxo-glutaric acid, methyl-furfural, piruvic acid, salicylaldehyde, 2-acetylpyridine thiosemicarbazones and ribose bis(thiosemicarbazone). The complexes were studied by EPR spectroscopy. A linear correlation between f=g₆/A₆ and the SOD-like activity was observed. The higher f values correspond to copper(II) complexes with enhanced tetrahedral distortion.     

Pyrazole Derived Cationic Surfactants and their Tin and Copper Complexes: Synthesis,Surface Activity,Antibacterial and Antifungal Efficacy

Five membered heterocyclic cationic 3-pyrazolium surfactants namely: 2-[2-(alkyloxy)-2-oxoethyl]-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-3-pyrazolium bromide (decyl-; dodecyl-) and their copper and tin complexes were synthesized, their structures were confirmed using different spectroscopic tools. The IR spectra of the metal complexes showed that these compounds exhibit a tetrahedron structure with the transition metal ion (M²⁺) at the center and the cationic ligands arranged in the apexes, while the halide ions in the center. The synthesized compounds were evaluated as biocides against different types of bacteria and fungi. The biological activity data showed that the cationic surfactants exhibit moderate to high efficacy against the tested microorganisms (either bacteria or fungi). While, complexation of these cationic surfactants with Cu (II) and Sn (II) ions the antimicrobial activity was strongly increased. The surface activity of these compounds were discussed and correlated to their chemical structure and the type of substituents on the heterocyclic moiety. Meanwhile, the antimicrobial assay was correlated to the surface activities of the synthesized compounds.     

CuII Pyrazolyl-Benzimidazole Dinuclear Complexes with Remarkable Antioxidant Activity

Three dinuclear coordination complexes generated from 1-n-butyl-2-((5-methyl-1H-pyrazole-3-yl)methyl)-1H-benzimidazole ( L ), have been synthesized and characterized spectroscopically and structurally by single crystal X-ray diffraction analysis. Reaction with iron(II) chloride and then copper(II) nitrate led to a co-crystal containing 78 % of [Cu(NO₃)(μ-Cl)( L’ )]₂ ( C₁ ) and 22 % of [Cu(NO₃)(μ-NO₃)( L’ )]₂ ( C₂ ), where L was oxidized to a new ligand L^’ . A mechanism is provided. Reaction with copper chloride led to the dinuclear complex [Cu(Cl)(μ-Cl)( L) ]₂ ( C₃ ). The presence of N−H⋅⋅⋅O and C−H⋅⋅⋅O intermolecular interactions in the crystal structure of C₁ and C₂ , and C−H⋅⋅⋅N and C−H⋅⋅⋅Cl hydrogen bonding in the crystal structure of C₃ led to supramolecular structures that were confirmed by Hirshfeld surface analysis. The ligands and their complexes were tested for free radical scavenging activity and ferric reducing antioxidant power. The complex C₁ / C₂ shows remarkable antioxidant activities as compared to the ligand L and reference compounds.     

Copper Complexes Obtained from the Schiff Base of Quinoline-2-Aldehyde and Aliphatic Diamines

Schiff base bis (2— quinolidene)- diamine gives a purple-red complex with copper ions with a λ_max at 530 mμ. The optimum pH for production of this complex is approximately 9.5. None of the metallic ions of the analytical groups II and III give rise to red complexes with the above Schiff base. Manganous (Mn²⁺) and stannous (Sn²⁺)ions as well as reducing agents such as hydrazine or hydroxylamine exert a catalytic effect on the rate of formation of these copper complexes. The thermal stability of the copper complex formed from the Schiff bases (2-quinoline-aldehyde with NH₂-(CH₂)_n-NH₂) is greater for diamine for which n = 4–6 than for n = 2–3.     

Synthesis and Characterization of Coordinatively Unsaturated Copper (II) Complexes of 1,3-Bis(2'-Pyridyl)-1,2-Diaza-2-Butene and Their Antityrosinase Activity

The coordinatively unsaturated copper (II) complexes of 1,3-bis(2'-pyridyl)-1,2-diaza-2- butene with different ancillary anions were synthesized which can bind to copper centers of tyrosinase enzyme. The compounds were found to exhibit inhibitory activities against mushroom tyrosinase and the nature and extent of inhibition is modulated according to the type of ancillary anions.     

Synthesis, Characterization and Antiproliferative Activity of the Co(II), Ni(II), Cu(II), Pd(II) and Pt(II) Complexes of 2-(4-Thiazolyl)Benzimidazole (Thiabendazole)

Complexes of 2-(4-thiazolyi)benzimidazole (thiabendazole, THBD) with Co(II), Ni(II), Cu(ll) of general formula ML(2)(NO(3))(2) H(2)O and complexes of Pd(II) and Pt(II) of general formula ML2Cl(2) H(2)O have been obtained and characterized by elemental analyses, IR and far IR spectroscopy and magnetic measurements. The X-ray crystal structure of the copper(II) complex has been determined. The in vitro cell proliferation inhibitory activity of these compounds was examined against human cancer cell lines A 549 (lung carcinoma), HCV-29 T (urinary bladder carcinoma), MCF-7 (breast cancer), T47D (breast cancer), MES-SA (uterine carcinoma) and HL-60 (promyelocytic leukemia). Pt-THBD has been found to exhibit an antileukemic activity of the HL-60 line cells matching that of an arbitrary criterion.     

2,2-(2,2'-4(S)-苯基-4,5-二氢(噁)唑啉基)丙烷金属络合物对硝酮环加成反应的催化作用

研究了手性双噁唑啉配体2,2-（2,2’-4（S）-苯基-4,5-二氢噁唑啉基）丙烷（5）与铜或锌的配合物对二苯基硝酮（8）与3-（（E）-2-丁烯酰基）-1,3-噁唑烷-2-酮（6）和2,3-二氢呋喃（7）两种烯烃的环加成反应的催化效果。研究结果表明,双噁唑啉金属络合物对硝酮的环加成反应有较好的催化作用,表现在反应速度的提高和立体选择性的改变。比较而言,（5）与铜的配合物具有更好的催化作用。使用二氯亚砜作为氯化试剂对双噁唑啉（5）的合成方法进行了合理的改进,使产率由69．7％提高到89％。     

Copper(II) Complexes Containing Natural Flavonoid Pomiferin Show Considerable In Vitro Cytotoxicity and Anti-inflammatory Effects

A series of new heteroleptic copper(II) complexes of the composition [Cu(L)(bpy)]NO₃·2MeOH (1), [Cu(L)(dimebpy)]NO₃·2H₂O (2), [Cu(L)(phen)]NO₃·2MeOH (3), [Cu(L)(bphen)]NO₃·MeOH (4), [Cu(L)(dppz)]NO₃·MeOH (5) was prepared, where HL = 3-(3,4-dihydroxyphenyl)-5-hydroxy-8,8-dimethyl-6-(3-methylbut-2-ene-1-yl)-4H,8H-benzo[1,2-b:3,4-b′]dipyran-4-one, (pomiferin) and bpy = 2,2′-bipyridine, dimebpy = 4,4′-dimethyl-2,2′-bipyridine, phen = 1,10-phenanthroline, bphen = 4,7-diphenyl-1,10-phenanthroline, and dppz = dipyrido[3,2-a:2′,3′-c]phenazine. The complexes were characterized using elemental analysis, infrared and UV/Vis spectroscopies, mass spectrometry, thermal analysis and conductivity measurements. The in vitro cytotoxicity, screened against eight human cancer cell lines (breast adenocarcinoma (MCF-7), osteosarcoma (HOS), lung adenocarcinoma (A549), prostate adenocarcinoma (PC-3), ovarian carcinoma (A2780), cisplatin-resistant ovarian carcinoma (A2780R), colorectal adenocarcinoma (Caco-2) and monocytic leukemia (THP-1), revealed the complexes as effective antiproliferative agents, with the IC₅₀ values of 2.2–13.0 μM for the best performing complexes 3 and 5. All the complexes 1–5 showed the best activity against the A2780R cells (IC₅₀ = 2.2–6.6 μM), and moreover, the complexes demonstrated relatively low toxicity on healthy human hepatocytes, with IC₅₀ > 100 μM. The complexes were evaluated by the Annexin V/propidium iodide apoptosis assay, induction of cell cycle modifications in A2780 cells, production of reactive oxygen species (ROS), perturbation of mitochondrial membrane potential, inhibition of apoptosis and inflammation-related signaling pathways (NF-κB/AP-1 activity, NF-κB translocation, TNF-α secretion), and tested for nuclease mimicking activity. The obtained results revealed the corresponding complexes to be effective antiproliferative and anti-inflammatory agents.