This paper reports on the synthesis and characterization of two new ternary copper(II) complexes: Cu(doxycycline)(1,10-phenanthroline)(H2O)(ClO4)(ClO4) (1) and ...Cu(tetracycline)(1,10-phenanthroline)(H2O)(ClO4)(ClO4) (2). These compounds exhibit a distorted tetragonal geometry around copper, which is coordinated to two bidentate ligands, 1,10-phenanthroline and tetracycline or doxycyline, a water molecule, and a perchlorate ion weakly bonded in the axial positions. In both compounds, copper(II) binds to tetracyclines via the oxygen of the hydroxyl group and oxygen of the amide group at ring A and to 1,10-phenanthroline via its two heterocyclic nitrogens. We have evaluated the binding of the new complexes to DNA, their capacity to cleave it, their cytotoxic activity, and uptake in tumoral cells. The complexes bind to DNA preferentially by the major groove, and then cleave its strands by an oxidative mechanism involving the generation of ROS. The cleavage of DNA was inhibited by radical inhibitors and/or trappers such as superoxide dismutase, DMSO, and the copper(I) chelator bathocuproine. The enzyme T4 DNA ligase was not able to relegate the products of DNA cleavage, which indicates that the cleavage does not occur via a hydrolytic mechanism. Both complexes present an expressive plasmid DNA cleavage activity generating single- and double-strand breaks, under mild reaction conditions, and even in the absence of any additional oxidant or reducing agent. In the same experimental conditions, Cu(phen)22+ is approximately 100-fold less active than our complexes. These complexes are among the most potent DNA cleavage agents reported so far. Both complexes inhibit the growth of K562 cells with the IC50 values of 1.93 and 2.59 μmol L–1 for compounds 1 and 2, respectively. The complexes are more active than the free ligands, and their cytotoxic activity correlates with intracellular copper concentration and the number of Cu-DNA adducts formed inside cells.
Four new ternary complexes of copper(II) were synthesized and characterized: Cu(hyd)(bpy)(acn)(ClO4)(ClO4) (1), Cu(hyd)(phen)(acn)(ClO4)(ClO4) (2), Cu(Shyd)(bpy)(acn)(ClO4)(ClO4) (3) and ...Cu(Shyd)(phen)(acn)(ClO4)(ClO4) (4), in which acn=acetonitrile; hyd=2-furoic acid hydrazide, bpy=2,2-bipyridine; phen=1,10-phenanthroline and Shyd=2-thiophenecarboxylic acid hydrazide. The cytotoxic activity of the complexes in a chronic myelogenous leukemia cell line was investigated. All complexes are able to enter cells and inhibit cellular growth in a concentration-dependent manner, with an activity higher than that of the corresponding free ligands. The substitution of Shyd for hyd increases the activity, while the substitution of bpy for phen renders the complex less active. Therefore, the most potent complex is 4 with an IC50 value of 1.5±0.2μM. The intracellular copper concentration needed to inhibit 50% of cell growth is approximately 7×10−15mol/cell. It is worth notifying that a correlation between cytotoxic activity, DNA binding affinity and DNA cleavage was found: 1<3<2<4.
The synthesis, characterization, DNA interactions, cellular uptake and cytotoxic effect of four copper(II) complexes containing 2-furoic acid hydrazide derivatives and N-donor heterocyclic ligands are reported. The complexes enter tumoral cells, bind and cleave DNA molecule, and inhibit cellular growth. A good correlation between cytotoxicity and DNA cleavage activity was found. Display omitted
•Four new complexes of CuII with mixed ligands were synthesized and characterized.•The complexes enter cells, bind and cleave DNA molecule, and inhibit cellular growth.•The higher the DNA binding constant, the greater is the cytotoxic effect.•A good correlation between cytotoxicity and DNA cleavage activity was found.
Five ternary copper(II) complexes, Cu2(phen)2(L1)(ClO4)2 (1), Cu2(phen)2(L1)(DMSO)2(PF6)2 (2), Cu2(bpy)2(L1)(ClO4)2(H2O)2 (3), Cu2(dmp)2(L1)(ClO4)2(H2O)2 (4), and Cu(phen)(L2)2(ClO4)2 (5), in which ...phen = 1,10-phenanthroline, bpy = 2,2′-bipyridine, dmp = 2,9-dimethyl-1,10-phenanthroline, H2L1 = 1,4-dihydroxyanthracene-9,10-dione and HL2 = 1-hydroxyanthracene-9,10-dione, DMSO = dimethylsulfoxide, were synthesized and fully characterized. Complex 2 was obtained through the substitution of perchlorate for DMSO. When two hydroxyquinone groups are present, L1 makes a bridge between two Cu(II) ions, which also bind two nitrogens of the respective diimine ligand. The compounds bind to calf thymus DNA and oxidatively cleave pUC19 DNA according to the following order of activity 1 > 4–5 > 3. Furthermore, complexes 1, 3, 4 and 5 inhibit topoisomerase-I activity and the growth of myelogenous leukemia cells with the IC50 values of 1.13, 10.60, 0.078, and 1.84 μmol L−1, respectively. Complexes 1 and 4 are the most active in cancer cells and in DNA cleavage.
Five ternary copper(II) complexes with hydroxyanthraquinones and N,Nheterocyclic ligands interact with DNA, inhibit topoisomerase activity and are highly cytotoxic to chronic myelogenous leukemia cells, with IC50 values in the range 0.08–10 μmol L−1. Display omitted
•Cu(II) complexes with hydroxyanthraquinones and diimines oxidatively cleave DNA.•Dihydroxyquinones bridge two Cu(II) ions also bound to two diimine nitrogens.•The complexes inhibit topoisomerase I activity at low concentrations.•Cytotoxicity to myelogenous leukemia cells is in the range 0.08–10 μM.
A new cis-dihalo copper(II) complex, CuII(HLbz)(Cl)2.CH3CN (1), where HLbz = (S)-2-(((2-(2-(pyridin-2-yl)-2H-benzoe1,3oxazin-3(4H)-yl)ethyl)amino)methyl)phenol), was isolated by reacting copper(II) ...chloride dihydrate and the H2L ligand (H2L = 2,2′-((2-(pyridin-2-yl)imidazolidine-1,3-diyl)bis(methylene))diphenol) in a MeOH/CH3CN (1:3 v/v) mixture. The complex formation occurred via the ligand modification during complexation, producing a unique structure containing 2H-benzoe1,3oxazin, as observed from the single crystal X-ray structure determination. The complex was characterized by elemental analysis, potentiometric titration, spectroscopic techniques (UV–Vis, FT-IR) and conductance measurements. Complex 1 inhibits the growth of myelogenous leukemia cells with an IC50 of 17.3 μmol L−1.
The copper (II) complex results from the coordination of the imidazolidine ligand that undergoes an intramolecular reaction forming a six-membered 2H-benzo e 1, 3 oxazin heterocycle during complexation reaction. The metallic ion shows a distorted square pyramidal coordination geometry. Cytotoxic activity of the copper (II) complex against myelogenous leukemia cell line (K562) was investigated. Display omitted
•Intramolecular reaction during complexation leads to benzoxazine ring formation.•cis-dichloro copper complex presents a distorted square pyramidal geometry.•Copper(II) complex showed activity against myelogenous leukemia cells.
Two new bismuth(III) complexes, BiL1Cl2 (1) and BiL2Cl2 (2), in which L1 is (2-hydroxy-4-6-di-tert-butylbenzyl-2-pyridylmethyl)amine and L2 is 2,4-diiodo-6-((pyridine-2-ylmethylamino)methyl)phenol, ...were synthesized and characterized by elemental and conductivity analyses, atomic absorption spectrometry, infrared and 1H NMR spectroscopies. The molecular structure of 1 reveals that the NN'O ligand forms a 1:1 complex with bismuth through coordination via the nitrogen of the aliphatic amine, the nitrogen of the pyridine ring and the oxygen of the phenolate. The coordination sphere is completed with two chloride anions in a distorted square pyramidal geometry. Bismuth exhibits the same coordination mode in compound 2. The cytotoxic activity of 1 and 2 was investigated in a chronic myelogenous leukemia cell line. The complexes are approximately three times more potent than the corresponding free ligands, with the IC50 values 0.30 and 0.38 μM for complex 1 and 2, respectively. To address the cellular mechanisms underlying cell demise, apoptosis was quantified by flow cytometry analysis. From 0.1 μM, both complexes induce apoptosis and there is a remarkable concentration-dependent increase in the population of cells in apoptosis. The complexes were also evaluated against Gram-positive and Gram-negative bacteria. Both inhibited the bacterial growth in a concentration-dependent way, with remarkable activity in some of the tested strains, for example, complex 2 was more active than its free ligand against all bacterial strains and approximately fourteen times more potent against S. dysenteriae and S. typhimurium.
Two new Bi(III) complexes with asymmetric NN'O ligands were highly cytotoxic to chronic myelogenous leukemia cells, with IC50 values in the range 0.3–0.4 μmol L−1. Both complexes induce a remarkable concentration-dependent increase in the population of cells in apoptosis. Display omitted
•Bismuth compounds with asymmetric NN'O ligands are cytotoxic to leukemia cells.•Bi(III) binds to an amine N, a pyridine N, a phenolate oxygen, and two chlorides.•Bismuth complexes induce apoptosis in K562 cells at significant low concentrations.•BiCl2(2-hydroxy-4-6-di-tert-butylbenzyl-2-pyridylmethyl)amine is active vs. S. aureus.•Complex 2 is 14 times as potent as the ligand in S. dysenteriae and S. typhimurium.
Purple acid phosphatases (PAPs) are a group of metallohydrolases that contain a dinuclear FeIIIMII center (MII = Fe, Mn, Zn) in the active site and are able to catalyze the hydrolysis of a variety of ...phosphoric acid esters. The dinuclear complex (H2O)FeIII(μ-OH)ZnII(L-H)(ClO4)2 (2) with the ligand 2-N-bis(2-pyridylmethyl)aminomethyl-4-methyl-6-N′-(2-pyridylmethyl)(2-hydroxybenzyl) aminomethylphenol (H2 L-H) has recently been prepared and is found to closely mimic the coordination environment of the FeIIIZnII active site found in red kidney bean PAP (Neves et al. J. Am. Chem. Soc. 2007, 129, 7486). The biomimetic shows significant catalytic activity in hydrolytic reactions. By using a variety of structural, spectroscopic, and computational techniques the electronic structure of the FeIII center of this biomimetic complex was determined. In the solid state the electronic ground state reflects the rhombically distorted FeIIIN2O4 octahedron with a dominant tetragonal compression aligned along the μ-OH−Fe−Ophenolate direction. To probe the role of the Fe−Ophenolate bond, the phenolate moiety was modified to contain electron-donating or -withdrawing groups (−CH3, −H, −Br, −NO2) in the 5-position. The effects of the substituents on the electronic properties of the biomimetic complexes were studied with a range of experimental and computational techniques. This study establishes benchmarks against accurate crystallographic structural information using spectroscopic techniques that are not restricted to single crystals. Kinetic studies on the hydrolysis reaction revealed that the phosphodiesterase activity increases in the order −NO2 ←Br ←H ←CH3 when 2,4-bis(dinitrophenyl)phosphate (2,4-bdnpp) was used as substrate, and a linear free energy relationship is found when log(k cat/k 0) is plotted against the Hammett parameter σ. However, nuclease activity measurements in the cleavage of double stranded DNA showed that the complexes containing the electron-withdrawing −NO2 and electron-donating −CH3 groups are the most active while the cytotoxic activity of the biomimetics on leukemia and lung tumoral cells is highest for complexes with electron-donating groups.
Two new complexes of Ru(II) with mixed ligands were prepared: Ru(bpy)
smp(PF
) (
) and Ru(phen)
smp(PF
) (
), in which smp = sulfamethoxypyridazine; bpy = 2,2'-bipyridine; phen = 1,10-phenanthroline. ...The complexes have been characterized by elemental and conductivity analyses; infrared, NMR, and electrospray ionization mass spectroscopies; and X-ray diffraction of single crystal. Structural analyses reveal a distorted octahedral geometry around Ru(II) that is bound to two bpy (in
) or two phen (in
) via their two heterocyclic nitrogens and to two nitrogen atoms from sulfamethoxypyridazine-one of the methoxypyridazine ring and the sulfonamidic nitrogen, which is deprotonated. Both complexes inhibit the growth of chronic myelogenous leukemia cells. The interaction of the complexes with bovine serum albumin and DNA is described. DNA footprinting using an oligonucleotide as substrate showed the complexes' preference for thymine base rich sites. It is worth notifying that the complexes interact with the Src homology SH3 domain of the Abl tyrosine kinase protein. Abl protein is involved in signal transduction and implicated in the development of chronic myelogenous leukemia. Nuclear magnetic resonance (NMR) studies of the interaction of complex
with the Abl-SH3 domain showed that the most affected residues were T79, G97, W99, and Y115.
Five new copper(II) complexes of the type Cu(NO)(NN)(ClO4)2, in which NO=4-fluorophenoxyacetic acid hydrazide (4-FH) or 4-nitrobenzoic hydrazide (4-NH) and NN=1,10-phenanthroline (phen), ...4–4′-dimethoxy-2-2′-bipyridine (dmb) or 2,2-bipyridine (bipy) were synthesized and characterized using various spectroscopic methods. The X-ray structural analysis of one representative compound indicates that the geometry around the copper ion is distorted octahedron, in which the ion is coordinated to hydrazide via the terminal nitrogen and the carbonyl oxygen, and to heterocyclic bases via their two nitrogen atoms. Two perchlorate anions occupy the apical positions, completing the coordination sphere. The cytotoxic activity of compounds was investigated in three tumor cell lines (K562, MDA-MB-231 and MCF-7). Concerning K562 cell line, the complexes with 1,10-phenanthroline exhibit high cytotoxic activity and are more active than carboplatin, free ligands and Cu(phen)22+. Considering the cytotoxicity results, further investigations for the compounds Cu(4-FH)(phen)(ClO4)2 I and Cu(4-NH)(phen)(ClO4)2∙H2O III were performed. Flow cytometric analysis revealed that these complexes induce apoptotic cell death in MDA-MB-231 cell line and bind to DNA with K values of 4.38×104 and 2.62×104, respectively. These compounds were also evaluated against wild type Mycobacterium tuberculosis (ATCC 27294) and exhibited antimycobacterial activity, displayed MIC values lower than those of the corresponding free ligands.
•Five new copper(II) complexes with hydrazides and heterocyclic bases were synthesized.•The X-ray structural analysis of one representative compound has been performed.•The complexes showed cytotoxic properties toward three tumor cell lines.•Two complexes induce apoptotic death and exhibited antimycobacterial activity.
New copper(II) complexes with hydrazides and heterocyclic bases have been synthesized and characterized. Some complexes exhibited high cytotoxic activity and have been more active than carboplatin. Two selected compounds induce apoptotic cell death in MDA-MB-231 cell line and bind to DNA with K values of 4.38×104 and 2.62×104, respectively. Display omitted
This paper describes the synthesis, structural analysis, as well as the magnetic and spectroscopic characterizations of three new dicopper(II) complexes with dinucleating phenol-based ligands ...containing different thioether donor substituents: aromatic (1), aliphatic (2) or thiophene (3). Temperature-dependent magnetometry reveals the presence of antiferromagnetic coupling for 1 and 3 (J = −2.27 cm−1 and -5.01 cm−1, respectively, H = -2JS1S2) and ferromagnetic coupling for 2 (J = 5.72 cm−1). Broken symmetry DFT calculations attribute this behavior to a major contribution from the dz2 orbitals for 1 and 3, and from the dx2-y2 orbitals for 2, along with the p orbitals of the oxygens. The bioinspired catalytic activities of these complexes related to catechol oxidase were studied using 3,5-di-tert-butylcatechol as substrate. The order of catalytic rates for the substrate oxidation follows the trend 1 > 2 > 3 with kcat of (90.79 ± 2.90) × 10−3 for 1, (64.21 ± 0.99) × 10−3 for 2 and (14.20 ± 0.32) × 10−3 s−1 for 3. The complexes also cleave DNA through an oxidative mechanism with minor-groove preference, as indicated by experimental and molecular docking assays. Antimicrobial potential of these highly active complexes has shown that 3 inhibits both Staphylococcus aureus bacterium and Epidermophyton floccosum fungus. Notably, the complexes were found to be nontoxic to normal cells but exhibited cytotoxicity against epidermoid carcinoma cells, surpassing the activity of the metallodrug cisplatin. This research shows the multifaceted properties of these complexes, making them promising candidates for various applications in catalysis, nucleic acids research, and antimicrobial activities.
The paper reports three dicopper(II) complexes with ligands containing different thioether donor groups. These complexes demonstrate catalytic activities related to catechol oxidation, also DNA oxidative cleavage (minor-groove preference), and antimicrobial effects. Remarkably, they exhibit potent cytotoxicity against cancer cells, surpassing cisplatin, while non-toxicity was found in normal cells. Display omitted
•Synthesis, X-ray structure, magnetic and solution studies of dicopper(II) complexes with thioether-substituted ligands.•Ability of the complexes to catalyze the oxidation of the catechol substrate as metalloenzyme mimics•DNase activity though an oxidative mechanism•The complexes revealed potent cytotoxic activity against tumoral cells and antimicrobial properties.
This work describes the synthesis, characterization and in vitro anticancer activity of two platinum(II) complexes of the type Pt(L1)2(1,10-phen) 1 and Pt(L2)2(1,10-phen) 2, where ...L1 = 5-heptyl-1,3,4-oxadiazole-2-(3H)-thione, L2 = 5-nonyl-1,3,4-oxadiazole-2-(3H)-thione and 1,10-phen = 1,10-phenanthroline. As to the structure of these complexes, the X-ray structural analysis of 1 indicates that the geometry around the platinum(II) ion is distorted square-planar, where two 5-alkyl-1,3,4-oxadiazol-2-thione derivatives coordinate a platinum(II) ion through the sulfur atom. A chelating bidentate phenanthroline molecule completes the coordination sphere. We tested these complexes in two breast cancer cell lines, namely, MCF-7 (a hormone responsive cancer cell) and MDA-MB-231 (triple negative breast cancer cell). In both cells, the most lipophilic platinum compound, complex 2, was more active than cisplatin, one of the most widely used anticancer drugs nowadays. DNA binding studies indicated that such complexes are able to bind to ct-DNA with Kb values of 104 M−1. According to data from dichroism circular and fluorescence spectroscopy, these complexes appear to bind to the DNA in a non-intercalative, probably via minor groove. Molecular docking followed by semiempirical simulations indicated that these complexes showed favorable interactions with the minor groove of the double helix of ct-DNA in an A-T rich region. Thereafter, flow cytometry analysis showed that complex 2 induced apoptosis and necrosis in MCF-7 cells.
Two platinum(II) complexes with 5-alkyl-1,3,4-oxadiazol-2(3H)-thione derivatives were active against two tumor cell lines and induced apoptosis and necrosis in MCF-7 cells. Display omitted
•New Pt(II) complexes with 5-alkyl-1,3,4-oxadiazol-2(3H)-thione derivatives were prepared.•They were active against two tumor cell lines.•\Both complexes bind to ct-DNA with Kb values in the range of 104 M−1.•Molecular docking studies suggest that these complexes bind to the minor groove of DNA.•The most active complex induced apoptosis and necrosis in MCF-7 cells.
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