Cu(II) complexes with heterocyclic substituted thiosemicarbazones: the case of 5-formyluracil. Synthesis,characterization, x-ray structures,DNA interaction studies,and biological activity

Two new 5-formyluracil thiosemicarbazone (H(3)ut) derivatives, Me-H(3)ut (1) and Me(2)-H(3)ut (2), were synthesized by reacting thiosemicarbazides, mono- and dimethylated on the aminic nitrogen, with 5-formyluracil and were subsequently characterized. These ligands, treated with copper chloride and nitrate, afforded three complexes: [Cu(Me-H(3)ut)Cl(2)].H(2)O (3), [Cu(Me(2)-H(3)ut)Cl(2)].H(2)O (4), and [Cu(Me-H(3)ut)(NO(3))(OH(2))(2)]NO(3) (5). The crystal structures of these complexes have been determined by single-crystal X-ray diffraction. In 3 and 4, a similar pentacoordination is present; the copper atom is surrounded by the ligand SNO donor atoms and by two chloride ions. The structure of 5 consists of [Cu(Me-H(3)ut)(NO(3))(OH(2))(2)](+) cations and nitrate anions. The copper coordination (4 + 2) involves the SNO ligand atoms and a water oxygen in the basal plane; the apical positions are occupied by a second water oxygen and by an oxygen of a monodentate nitrate group. Two biochemical techniques, namely DNA titration in the UV-vis region and thermal denaturation, have been employed to probe the details of DNA binding of these compounds. Analysis of the results suggests that our compounds are able to interact with DNA by electrostatic and groove binding but not by intercalation. The compounds have been also tested in vitro on human leukemic cell line U937, but they are not able to inhibit significantly cell proliferation.     

二十四元六氮大环双核铜(I)配合物的氧化去甲基作用: 单加氧酶的模拟

以5-溴-2-甲氧基-1, 3-苯二甲醛与二乙烯三胺通过[2+2]缩合,合成了一个新的六氮杂二十四元大环配体, 并在[Cu(CH3CN)4]ClO4存在下生成Cu(I)大环配合物, 然后在空气(或氧气)中氧化, 得到了新的大环双核Cu(II)配合物, 用多种方法对其进行了表征, 用1H NMR谱等方法鉴定了氧化产物。实验结果表明: 在Cu(I)配合物氧化过程中,能使配体环上的一个甲氧基发生断裂, 形成苯氧桥和水桥联的Cu(II)配合物。在木质素酶等单加氧酶的氧化过程中也伴随着氧化去甲基作用。本文首次用大环配合物对这一过程进行了模拟, 并测定了氧化反应中的吸氧量和吸氧速率常数。     

New dioxadiaza- and trioxadiaza-macrocycles containing one dibenzofuran unit with two amino pendant arms: synthesis, protonation and complexation studies

New dioxadiaza- and trioxadiaza-macrocycles containing one rigid dibenzofuran unit (DBF) and N-(2-aminoethyl) pendant arms were synthesized, N,N'-bis(2-aminoethyl)-[17](DBF)N(2)O(2) (L(1)) and N,N'-bis(2-aminoethyl)-[22](DBF)N(2)O(3) (L(2)), respectively. The binding properties of both macrocycles to metal ions and structural studies of their metal complexes were carried out. The protonation constants of both compounds and the stability constants of their complexes with Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), and Pb(2+) were determined at 298.2 K, in aqueous solutions, and at ionic strength 0.10 mol dm(-3) in KNO(3). Mononuclear complexes with both ligands were formed, and dinuclear complexes were only found for L(2). The thermodynamic binding affinities of the metal complexes of L(2) are lower than those of L(1) as expected, but the Pb(2+) complexes of both macrocycles exhibit close stability constant values. On the other hand, the binding affinities of Cd(2+) and Pb(2+) for L(1) are very high, when compared to those of Co(2+), Ni(2+) and Zn(2+). These interesting properties were explained by the presence of the rigid DBF moiety in the backbone of the macrocycle and to the special match between the macrocyclic cavity size and the studied larger metal ions. To elucidate the adopted structures of complexes in solution, the nickel(II) and copper(II) complexes with both ligands were further studied by UV-vis-NIR spectroscopy in DMSO-H(2)O 1 : 1 (v/v) solution. The copper(II) complexes were also studied by EPR spectroscopy in the same mixture of solvents. The crystal structure of the copper complex of L(1) was also determined. The copper(II) displays an octahedral geometry, the four nitrogen atoms forming the equatorial plane and two oxygen atoms, one from the DBF unit and the other one from the ether oxygen, in axial positions. One of the ether oxygens of the macrocycle is out of the coordination sphere. Our results led us to suggest that this geometry is also adopted by the Co(2+) to Zn(2+) complexes, and only the larger Cd(2+) and Pb(2+) manage to form complexes with the involvement of all the oxygen atoms of the macrocyclic backbone.     

A study on the coordinative versatility of new N,S-donor macrocyclic ligands: XAFS, and Cu2+ complexation thermodynamics in solution

We investigated, both in the solid state and in aqueous solution, the coordination environment and stability behavior of four macrocyclic ligands (three N(2)S(2) and one N(3)S(2)) and of the corresponding Cu(II) complexes. The structural characterization in the solid state of the copper derivatives was performed by X-Ray Absorption Spectroscopy. Copper is found to be 4-fold coordinated with a CuN(2)S(2) environment with different Cu-S distances depending on the size of the macrocyclic ring. The EXAFS technique has indicated that nitrogen and sulfur atoms are more preferable to oxygen atoms as donor systems, without the evidence of coordination of the carboxylic moieties to copper in the first shell. The joint EXAFS and XANES study of the copper(II) complex with the N(3)S(2) ligand confirms the 4-fold coordination with an additional, long Cu-N interaction. The Cu(2+) complexation constants for one ligand were determined in aqueous solution. The results indicate that the species [CuL], although isolated in the solid state, is not the most abundant at the pH of blood serum. Instead, at pH 7.4 the protonated [Cu(HL)](+) species was found to be the most relevant. The behaviour of the copper complexes in the presence of the strong copper chelating bioagent human serum albumin was also examined in order to gain information on the stability of these compounds in biological fluids.     

Modeling the mononuclear, dinuclear, and trinuclear copper(I) reaction centers of copper proteins using pyridylalkylamine ligands connected to 1,3,5-triethylbenzene spacer

The structure and O2-reactivity of copper(I) complexes supported by novel ligands, Pye2 (1,3,5-triethyl-2,4-bis((N-benzyl-N-(2-(pyridin-2-yl)ethyl)-)aminomethyl)benzene), Pye3 (1,3,5-triethyl-2,4,6-tris((N-benzyl-N-(2-(pyridin-2-yl)ethyl))aminomethyl)benzene), MePym2 (1,3,5-triethyl-2,4-bis((N-benzyl-N-(6-methylpyridin-2-ylmethyl))aminomethyl)benzene), and MePym3 (1,3,5-triethyl-2,4,6-tris((N-benzyl-N-(6-methylpyridin-2-ylmethyl))aminomethyl)benzene) have been examined. The ligands are designed to construct mono-, di-, and trinuclear copper(I) complexes by connecting two or three pyridylalkylamine metal-binding sites to a 1,3,5-triethylbenzene spacer. Thus, the reaction of the ligands with [CuI(CH3CN)4]X (X = PF6, CF3SO3) or CuICl gave the expected mononuclear copper(I) complexes [CuI(Pye2)(CF3SO3)] (1) and [CuI(Pye3)](CF3SO3) (2), dinuclear copper(I) complex [CuI2(MePym2)(Cl)]CuICl2 (3), and trinuclear copper(I) complex [CuI3(MePym3)(CH3CN)3](CF3SO3)3 (4), the structures of which were determined by X-ray crystallographic analysis. The mononuclear copper(I) complexes, 1 and 2, exhibit a distorted three-coordinate T-shape structure and a trigonal planar structure, respectively, which are very close to the coordination geometry of the CuA site of PHM (peptidylglycine alpha-hydroxylating monooxygenase) and the CuB site of CcO (cytochrome c oxidase). Notably, 1 and 2 showed a significantly high oxidation potential (990 mV vs SCE), thus showing virtually no reactivity toward O2. On the other hand, the metal centers of the dinuclear and trinuclear copper(I) complexes, 3 and 4, exhibit a distorted trigonal planar geometry and a trigonal pyramidal geometry, respectively. In contrast to the mononuclear copper(I) complexes, these dinuclear and trinuclear copper(I) complexes reacted with O2 to induce an aromatic ligand hydroxylation reaction involving an NIH-shift of one of the ethyl substituents on the benzene spacer. The NIH-shift of the alkyl substituent on the aromatic ring is strong evidence of the electrophilic aromatic substitution mechanism, although the active oxygen intermediate could not be directly detected during the course of the reaction. The biological relevance of the copper(I) complexes is also discussed on the basis of structure and O2-reactivity.     

铜锌异双核配合物[CuZn(fsan)(H_2O)]·H_2O的合成、晶体结构和电化学性质

合成了标题化合物[CuZn(fsan)(H2O)]H2O [H4(fsan)为N, N?- 二(3-羧基水杨醛叉)缩乙撑二胺],用单晶X-ray衍射法测定了它的晶体结构,该晶体属单斜晶系,空间群P21/n,a = 11.695(2), b = 14.646(3), c = 12.265(3) ? ?= 118.46(3)°, V = 1847.0(6) ?,C18H12CuN2O8Zn, Mr = 513.21, Z = 4, Dc = 1.846 g/cm3, (MoK? = 2.502mm-1,F(000) = 1028,R = 0.0478,wR = 0.0902 (I>2(I)), 2951个可观测衍射点。该分子结构为双核单元,铜原子位于“内部”由2个氮原子和2个酚氧原子构成的平面正方场中。“外部”锌原子与2个酚氧原子、2个端基羧氧原子及轴向水分子中的氧原子配位,锌原子处于变形四方锥几何构型之中。金属原子通过2个酚氧原子桥联在一起。结合晶体结构对配合物做了电化学研究。     

Kupfer(II)-Komplexe von N-Benzoyl-O-methyl-N′-phenyl-isoharnstoffen

Copper(II) Complexes of N-Benzoyl-O-methyl-N′-phenyl-isoureas By reaction of N-benzoyl-N′-(p-nitro/p-bromphenyl)thioureas with copper(II)acetate-monohydrate in methanole insoluble copper(I)precipitates have been obtained, from which filtrates bis[N-benzoyl-O-methyl-N′-(p-nitrophenyl)-isoureato]copper(II) 1 and bis[N-benzoyl-O-methyl-(p-bromphenyl)-isoureato]copper(II) 2 were isolated. The moleculare structure of 1 with planar trans coordination has been determined by single crystal X-ray diffraction methods. The N-benzoyl-O-methyl- N′-(o-nitrophenyl)-isourea 3 and N-benzoyl-O-methyl-N′-(p-bromphenyl)-isourea 4 have been prepared by reaction of the corresponding N-benzoyl-N′-phenyl-thioureas with mercury(II)acetate in methanolic solution. The molecular structure of 3 has been determined by single crystal X-ray diffraction methods. The NH-tautomeric form is stabilized by a bifurcated intramolecular hydrogen bond to an oxygen atom of the o-nitro group and the benzoyl oxygen atom. XPS, NMR and mass-spectrometric investigations also confirm the structures.     

Synthesis,characterization, crystal structure,and biological activity of the copper complex

This work reports the synthesis and biological activity of the copper complex with 2–thenoyltrif-luoroacetone (HTTA). The complex was characterized by elemental analysis, infrared spectroscopy, and thermogravimetric analysis. The crystal structure was determined by single-crystal X-ray diffraction. The complex exists as a parallelogram with four coordination sites occupied by the carbonyl oxygen atoms from HTTA. The antibacterial activity test shows that the complex exhibits better antibacterial ability against Escherichia coli and Staphylociccus aureus (MIC were about 180, 150 μg/ml, respectively) and can be considered as broad-spectral antimicrobial. The antitumor activity of the copper(II) complex is tested by methyl thiazolyl tetrazolium assays against human Leukemia cells K562. The copper(II) complex exhibits potent antitumor effects against K562 cell lines. The IC₅₀ value of the complex is about 0.01 μg/ml. The research shows that the complex can inhibit K562 tumor cell growth and generation and induce apoptosis. The inhibition ratio is accele by increasing the dosage and has a significant positive correlation with medication dosage.     

One-pot synthesis, photoluminescence, and electrocatalytic properties of subnanometer-sized copper clusters

Subnanometer-sized copper nanoclusters were prepared by a one-pot procedure based on wet chemical reduction. The structural characteristics of the 2-mercapto-5-n-propylpyrimidine-protected nanoclusters, Cu(n) (n ≤ 8), were determined by mass spectrometry. The Cu nanoclusters displayed apparent luminescence, with dual emissions at 425 and 593 nm, with quantum yields of 3.5 and 0.9%, respectively, and high electrocatalytic activity in the electoreduction of oxygen.     

Sorption of heavy metals in cationic and anionic forms by SKS synthetic carbons modified with nitrogen and sulfur

Data on the sorbability of ions of heavy metals (lead, cobalt, cadmium, zinc, copper, nickel) from Ringer’s solution with complex composition by untreated SKS synthetic carbons and those modified with nitrogen and sulfur were obtained. Exploratory studies of the sorption of complex anions of copper and iron with complexing ligands (Cl and CN) were performed. Selectivity series of toxic metals were determined on the basis of their calculated distribution coefficients. It was shown that the best sorption effect is due to the presence of nitrogen atoms and strongly acidic SO₃H groups in the carbon structure.     

[Cu（L-Ⅱe）（Phen）（H2O）（ClO4）]的合成、结构及稳定性研究

合成了三元混配配合物[Cu(L-Ile)(Phen)(H_2O)(ClO_4)](L-Ile=L=异亮氨酸,phen=1,10-邻菲咯啉),通过红外光谱、紫外-可见光谱、摩尔电导率、X射线单晶结构分析,对配合物进行了表征。该晶体属单斜晶系,P2_1空间群,晶胞参数:a=1.1704(5)nm,b=0.8090(5)nm,c=2.1822(5)nm,β=98.061(5)°,Z=2,D_x=1.60Mg·m~(-3),R_1=0.0462,wR_2=0.1225。每个配合物分子中Cu(Ⅱ)离子与一个L-Ile(N,O)配体、一个Phen(N,N)配体、一个H_2O(O)配体及一个Cl_O~-(O)形成六配位的畸变八面体构型。本文还用电位滴定法测定了配合物的稳定常数,结果表明,配合物具有高的稳定性。     

乙二胺双缩3-醛基水杨酸Schiff碱铜镍异双核配合物的晶体结构

合成了乙二胺双缩3-醛基水杨酸Sch iff碱铜镍异双核配合物CuN i(ES)(H2O)2.H2O[H4ES为N,N′-二(3-醛基水杨酸)缩乙撑二胺],用单晶X-ray衍射法测定了晶体结构,该晶体属六方晶系,空间群P322I,晶胞参数a=1.283 90(18)nm,b=1.283 90(18)nm,c=0.995 7(2)nm,α=90°,β=90°,γ=120°,V=1.421 4(4)nm3,C18H18CuN iN2O9,Mr=528.59,Z=3,ρ=1.853 g/cm3.在配合物中,Cu处于由两个氮原子和两个酚氧原子所形成的平面四方场中,N i处于由两个酚氧原子、两个羧基氧原子和两个轴向水分子氧所形成的六配位变形八面体场中,且内部铜原子和外部镍原子通过两个酚氧原子桥联起来.     

铜电极表面硅烷膜的自组装及其性能研究

应用自组装技术在铜电极表面上制备3巯基丙基三甲氧基硅烷自组装膜.红外光谱研究该自组装膜结构,电化学方法考察3-巯基丙基三甲氧基硅烷膜在5%NaCl溶液中对铜电极的缓蚀性能.结果表明,于不同浓度的3-巯基丙基三甲氧基硅烷乙醇溶液中自组装的硅烷膜表现出较好的抗腐蚀性.     

Effect of terminal N-substitution in 2-oxo-1,2-dihydroquinoline-3-carbaldehyde thiosemicarbazones on the mode of coordination, structure, interaction with protein, radical scavenging and cytotoxic activity of copper(II) complexes

Four 2-oxo-1,2-dihydroquinoline-3-carbaldehyde N-substituted thiosemicarbazone ligands (H(2)-OQtsc-R, where R = H, Me, Et or Ph) and their corresponding new copper(II) complexes [CuCl(2)(H(2)-OQtsc-H)]·2H(2)O (1), [CuCl(2)(H(2)-OQtsc-Me)]·2H(2)O (2), [CuCl(2)(H(2)-OQtsc-Et)(CH(3)OH)]Cl (3) and [CuCl(H-OQtsc-Ph)]·CH(3)OH (4) have been synthesized in order to correlate the effect of terminal N-substitution on coordination behaviour, structure and biological activity. Single crystal X-ray diffraction studies revealed that the complexes 1, 2 and 3 have square pyramidal geometry around the central metal ion. In the complexes 1 and 2, the copper ion is coordinated by the ligand with ONS donor atoms, one chloride ion in apical position and the other chloride in the basal plane. Complex 3 consists of [CuCl(2)(H(2)-OQtsc-Et)(CH(3)OH)](+) cation and a chloride as counter ion. The copper ion is coordinated by the ligand with ONS donor atoms and by one chloride ion in the basal plane. One methanol molecule is bonded through its neutral oxygen in the apical position. Complex 4 is square planar with the ligand coordinating through uni-negative tridentate ONS(-) and by one chloride ion in the basal plane. The binding of complexes with lysozyme protein was carried out by fluorescence spectroscopy. Investigations of antioxidation properties showed that all the copper(II) complexes have strong radical scavenging properties. The cytotoxicity of the complexes 3 and 4 against NIH 3T3 and HeLa cell lines showed that synergy between the metal and ligands results in a significant enhancement in the cell death with IC(50) of ~10-40 μM. A size dependence of substitution at terminal N in the thiosemicarbazones on the biological activities of the complexes has been observed.     

Cytotoxicity and photocytotoxicity of a dendritic C(60) mono-adduct and a malonic acid C(60) tris-adduct on Jurkat cells

The cytotoxic and photocytotoxic effects of two water-soluble fullerene derivatives, a dendritic C(60) mono-adduct and the malonic acid C(60) tris-adduct were tested on Jurkat cells. Cell growth and vitality were determined by a cell counting and staining technique. After 2 weeks cultivation in the presence of the fullerene derivatives, it was found that only the dendritic mono-adduct inhibits cell growth (within 2 weeks the cell number decreased to 19%), whereas the tris-malonic acid adduct has little effect. The growth inhibition is reversible; cultivating the same cells further in the absence of fullerene, the cell number increased to 106.4%. Other experiments showed that these fullerene derivatives become toxic when irradiated with UVA or UVB light. The cell death is mainly caused by membrane damage and it is UV dose-dependent. Tris-malonic acid fullerene was found to be more phototoxic than the dendritic derivative. This result is in contrast to the singlet oxygen quantum yields determined for the two compounds. We propose that the two fullerene derivatives may interact with the cell membrane in different ways thus causing the observed effects. Further experiments will be done to determine the location and concentration of the two compounds in and on the cells.     

配合物Cu_2（C_（21）H_（20）N_2O_3）（CH_3COO）_2的EXAFS研究

用延伸Ｘ射线吸收精细结构（ＥＸＡＦＳ），测定了标题化合物中两个铜原子的配位结构。两个铜原子有相同的配位，确认每个铜原子均与一个氮原子，三个氧原子形成四配位结构。一氧一氮源于ＨＳＢ，而另两个氧由乙酸提供。     

Crystal structure of copper sulfate and thiocyanate complexes with 5-bromo-and 5-nitrosalicylaldehyde thiosemicarbazones

The crystal structures of (5-bromosalicylidenethiosemicarbazido)aquacopper(II) sulfato(5-bromosalicylidenethiosemicarbazido)aquacuprate(II) tetrahydrate (I), (5-nitrosalicylidenethiosemicarbazido)dimethylsulfoxide(methanol)copper(II) sulfate (II), and catena(μ-thiocyanato)(5-nitrosalicylidenethiosemicarbazido)copper(II) (III) were determined. In structure I, the independent part of the unit cell contains four water molecules of crystallization and the cation-anion complex [Cu(H₂O)(L)][Cu(H₂O)(L)(SO₄)] containing two nonequivalent copper complexes (A and B). In these, the metal atom coordinates monodeprotonated 5-bromosalicylaldehyde thiosemicarbazone (HL) and water molecules, and in anion B also a sulfate ion. In complex ions A and B, sulfur, azomethine nitrogen, and phenolic oxygen of the salicylidene thiosemicarbazone fragment, and also water molecule form a distorted planar square around the metal atom. The axial vertex of the pyramid in anion B is occupied by the oxygen atom of the monodentate sulfate anion. In structure II, the independent part of the unit cell contains the (5-nitrosalicylidenethiosemicarbazido)dimethylsulfoxide(methanol)copper(II) complex cation and the sulfate anion. The coordination polyhedron of the central atom is a slightly distorted tetragonal pyramid whose base is formed by sulfur, azomethine nitrogen, phenolic oxygen of thiosemicarbazone, and dimethyl sulfoxide oxygen. The axial position is occupied by the methanol oxygen atom. In structure III, the copper atom coordinates 5-nitrosalicylaldehyde thiosemicarbazone and the thiocyanate ion, which combines complexes into infinite polymer chains along the [010] direction. The copper coordination polyhedron in III is a slightly distorted tetragonal pyramid whose base is formed by sulfur, azomethine nitrogen, phenolic oxygen of thiosemicarbazone, and nitrogen of thiocyanate ion, the axial vertex is occupied by sulfur of thiocyanate ion of the neighboring complex.     

Tetraalkoxyaluminates of nickel(II), copper(II), and copper(I)

The syntheses and structural details of tetraisopropoxyaluminates and tetra-tert-butoxyaluminates of nickel(II), copper(I), and copper(II) are reported. Within the nickel series, either Ni[Al(OiPr)4]2.2HOiPr, with nickel(II) in a distorted octahedral oxygen environment, or Ni[Al(OiPr)4]2.py, with nickel(II) in a square-pyramidal O4N coordination sphere, or Ni[(iPrO)(tBuO)3Al]2, with Ni(II) in a quasi-tetrahedral oxygen coordination, has been obtained. Another isolated complex is Ni[(iPrO)3AlOAl(OiPr)3].3py (with nickel(II) being sixfold-coordinated), which may also be described as a "NiO" species trapped by two Al(OiPr)3 Lewis acid-base systems stabilized at nickel by three pyridine donors. Copper(I) compounds have been isolated in three forms: [(iPrO)4Al]Cu.2py, [(tBuO)4Al]Cu.2py, and Cu2[(tBuO)4Al]2. In all of these compounds, the aluminate moiety behaves as a bidentate unit, creating a tetrahedrally distorted N2O2 copper environment in the pyridine adducts. In the base-free copper(I) tert-butoxyaluminate, a dicopper dumbbell [Cu-Cu 2.687(1) A] is present with two oxygen contacts on each of the copper atoms. Copper(II) alkoxyaluminates have been characterized either as Cu[(tBuO)4Al]2, {Cu(iPrO)[(iPrO)4Al]}2, and Cu[(tBuO)3(iPrO)Al]2 (copper being tetracoordinated by oxygen) or as [(iPrO)4Al]2Cu.py (pentacoordinated copper similar to the nickel derivative). Finally, a copper(II) hydroxyaluminate has been isolated, displaying pentacoordinate copper (O4N coordination sphere) by dimerization, with the formula {[(tBuO)4Al]Cu(OH).py}2. The formation of all of these isolated products is not always straightforward because some of these compounds in solution are subject to decomposition or are involved in equilibria. Besides NMR [copper(I) compounds], UV absorptions and magnetic moments are used to characterize the compounds.     

Dioxadiaza- and trioxadiaza-macrocycles containing one dibenzofuran unit selective for cadmium

The binding properties of dioxadiaza- ([17](DBF)N2O2) and trioxadiaza- ([22](DBF)N2O3), macrocyclic ligands containing a rigid dibenzofuran group (DBF), to metal cations and structural studies of their metal complexes have been carried out. The protonation constants of these two ligands and the stability constants of their complexes with Ca2+, Ba2+, and Mn2+, Co2+, Ni2+, Cu2+, Zn2+ and Cd2+, were determined at 298.2 K in methanol-water (1:1, v/v), and at ionic strength 0.10 mol dm-3 in KNO3. The values of the protonation constants of both ligands are similar, indicating that no cavity size effect is observed. Only mononuclear complexes of these ligands with the divalent metal ions studied were found, and their stability constants are lower than expected, especially for the complexes of the macrocycle with smaller cavity size. However, the Cd2+ complex with [17](DBF)N2O2 exhibits the highest value of stability constant for the whole series of metal ions studied, indicating that this ligand reveals a remarkable selectivity for cadmium(II) in the presence of all the metal ions studied, except copper(II), indicating that this ligand reveals a remarkable selectivity for cadmium(II) in the presence of the mentioned metal ions. The crystal structures of H2[17](DBF)N2O3(2+) (diprotonated form of the ligand) and of its cadmium complex were determined by X-ray diffraction. The Cd2+ ion fits exactly inside the macrocyclic cavity exhibiting coordination number eight by coordination to all the donor atoms of the ligand, and additionally to two oxygen atoms from one nitrate anion and one oxygen atom from a water molecule. The nickel(II) and copper(II) complexes with the two ligands were further studied by UV-vis-NIR and the copper(II) complexes also by EPR spectroscopic techniques in solution indicating square-pyramidal structures and suggesting that only one nitrogen and oxygen donors of the ligands are bound to the metal. However an additional weak interaction of the second nitrogen cannot be ruled out.     

A Tri‐copper(II) Complex Displaying DNA‐Cleaving Properties and Antiproliferative Activity against Cancer Cells

A new disubstituted terpyridine ligand and the corresponding tri‐copper(II) complex have been prepared and characterised. The binding affinity and binding mode of this tri‐copper complex (as well as the previously reported mono‐ and di‐copper analogues) towards duplex DNA were determined by using UV/Vis spectroscopic titrations and fluorescent indicator displacement (FID) assays. These studies showed the three complexes to bind moderately (in the order of 10⁴ M ^?1) to duplex DNA (ct‐DNA and a 26‐mer sequence). Furthermore, the number of copper centres and the nature of the substituents were found to play a significant role in defining the binding mode (intercalative or groove binding). The nuclease potential of the three complexes was investigated by using circular plasmid DNA as a substrate and analysing the products by agarose‐gel electrophoresis. The cleaving activity was found to be dependent on the number of copper centres present (cleaving potency was in the order: tri‐copper>di‐copper>mono‐copper). Interestingly, the tri‐copper complex was able to cleave DNA without the need of external co‐reductants. As this complex displayed the most promising nuclease properties, cell‐based studies were carried out to establish if there was a direct link between DNA cleavage and cellular toxicity. The tri‐copper complex displayed high cytotoxicity against four cancer cell lines. Of particular interest was that it displayed high cytotoxicity against the cisplatin‐resistant MOLT‐4 leukaemia cell line. Cellular uptake studies showed that the tri‐copper complex was able to enter the cell and more importantly localise in the nucleus. Immunoblotting analysis (used to monitor changes in protein levels related to the DNA damage response pathway) and DNA‐flow cytometric studies suggested that this tri‐copper(II) complex is able to induce cellular DNA damage.