Synthesis and characterization of a diruthenium-ibuprofenato complex comparing its anti-inflammatory activity with that of a copper(II)-ibuprofenato complex

The ibuprofen complex of diruthenium(II,III) was prepared and characterized by electronic (UV-Vis) and vibrational (FTIR) spectroscopies and thermogravimetry. The copper(II)-ibuprofenato complex was prepared by a different route from that described in the literature. Both complexes were tested in vivo for anti-inflammatory activity. Oral administration of the two complexes inhibited development of carrageenin-induced edema in rats, this inhibition being similar to that observed for oral administration of the parent drug (free ibuprofen). However, gastric irritation was lower as compared to that of ibuprofen. Diruthenium-ibuprofenato exhibited a protective effect at light intensity ulceration while the copper-ibuprofenato complex was more effective in the protection of severe intensity ulceration.     

Synthesis, structural characterization and biological activity of p-fluorobenzaldehyde thiosemicarbazones and of a nickel complex

New thiosemicarbazones (1-7), derived from p-fluorobenzaldehyde and differently substituted thiosemicarbazides, were synthetized and characterized by means of NMR and IR techniques. The p-fluorobenzaldehyde thiosemicarbazone Hfbt (1), the p-fluorobenzaldehyde 4-phenylthiosemicarbazone Ph-Hfbt (4) and complex [Ni(fbt)2] (8) were also characterized by X-ray diffractometry. Molecules 1 and 4 consist of two units: the p-fluorobenzaldehyde residue and the thiosemicarbazonic chain. In the reaction of 1 with NiAc2.4H2O, complex 8 was afforded. The molecular structure of 8 consists of the neutral molecules [Ni(fbt)2] with the metal placed on a symmetry centre. The coordination results in a square planar configuration and involves the sulphur atom and the hydrazine nitrogen atom of the two ligands in a trans configuration. Moreover, for compounds 1, 2, 4, and 8, assays of proliferation inhibition and apoptosis tests in vitro on human leukemia cell line U937 were carried out.     

Synthesis, structural characterization and antitumor activity evaluations of copper complex with tetraazamacrocyclic ligand.

Cu (II) complex with 1,4,7,10-tetrakis(2-cyanoethyl-)-1,4,7,10-tetraazacyclododecane was prepared and characterized by X-ray diffraction. Four nitrogen atoms of macrocyclic ligand and oxygen atom of water molecule defined a tetragonal pyramidal polyhedron surrounding the central copper atom. Preliminary pharmacological tests showed that it had antitumor activity against P388 and BEL-7404 cell lines in vitro. Also it exhibited perturbation effects to K562 tumor cell lines at G0-G1 stage and further studies showed that it can cleave supercoiled DNA (pBR 322) to nicked and linear DNA in aerobic condition.     

Synthesis, characterization and crystal structure of copper(II) ternary complex with cinoxacin and histamine

In order to enhance the knowledge of how quinolones may exert their antibacterial action, the synthesis of a new copper(II) mixed ligand, containing histamine complex was carried out. Crystal structure of [Cu(hsm)(cnx)NO₃]H₂O shows that Cu(II) cation displays a distorted square pyramidal geometry. Cinoxacinate (cnx) acts as bidentate ligand bonded to the Cu(II) ion through the oxygen atoms of the 3-carboxylate and 4-keto groups and histamine (hsm) is coordinated by the aliphatic amino group and the non protonated nitrogen of imidazole. Molar conductivity, elemental analysis, infrared and electronic spectroscopy have been used to characterize the complex. The results here reported indicate that cnx coordination mode is similar to that found in other complexes reported previously, being only found that metal-ligand distances are slightly different because the asymmetry of the coordination environment. This result also, may support the hypothesis that the mechanism of action of quinolones could be through a copper(II) complex carrier with imidazole ligands in their coordination environment.     

Synthesis and characterization of a binuclear coumarin-3-carboxylate copper(II) complex

The copper(II) complex of coumarin-3-carboxylic acid (CcaH) has been prepared and characterized on the basis of elemental and thermal analysis, IR, Raman, EPR, UV-Vis reflectance and 1H-NMR spectra. A detail analysis of all spectra data is presented with particular emphasis on the elucidation of the coordination mode of the ligand and the structure of the complex. All data are consistent with a binuclear structure for the complex with four coumarin-3-carboxylates as bridges and one water ligand per copper ion. The significantly lower than the spin-only value magnetic moment of the complex and the EPR spectra at various temperature are indicative of a magnetic interaction between the two copper atoms.     

Synthesis, isomer characterization, and anti-inflammatory properties of nitroarachidonate

Nitrated fatty acids (nitroalkenes) have been recently detected and quantified in cell membranes and human plasma. However, nitration of arachidonate (AA), that could redirect AA-dependent cell signaling pathways, has not been studied in detail. Herein, we synthesized and determined for the first time the isomer distribution of nitroarachidonate (AANO2) and demonstrate its ability to modulate inflammation. Synthesis of AANO2 was achieved by AA treatment with sodium nitrite in acidic conditions following HPLC separation. Mass spectrometry (MS) analysis showed the characteristic MS/MS transition of AANO2 (m/z 348/301). Moreover, the IR signal at 1378.3 cm(-1) and NMR studies confirmed the presence of mononitrated nitroalkenes. Positional isomer distribution was determined by NMR and MS fragmentation with lithium; four major isomers (9-, 12-, 14-, and 15-AANO2) were identified, which exhibited key anti-inflammatory properties. These include their ability to release biologically relevant amounts of nitric oxide, induce cGMP-dependent vasorelaxation, and down-regulate inducible nitric oxide synthase (NOS2) expression during macrophage activation, providing unique structural evidence and novel regulatory signaling properties of AANO2.     

Synthesis,biological characterization and evaluation of molecular mechanisms of novel copper complexes as anticancer agents

BackgroundTo overcome the hurdles of cisplatin, majorly its toxicity and resistance, there has been extensive search for alternative anti-cancer metal-based compounds. Here, three Cu(II)-complexes, Cu(Sal-Gly)(phen), Cu(Sal-Gly)(pheamine), Cu(Sal-Gly)(phepoxy) are characterized for their interaction with DNA, cytotoxicity and mechanism of action.MethodsThe binding ability of the complexes to Calf-Thymus DNA was evaluated by competition fluorescence studies with thiazole-orange, UV–Vis and circular dichroism spectroscopic titrations. Cytotoxicity was evaluated by MTT analysis. The DNA damage was analyzed through cleavage of supercoiled DNA via agarose gel-electrophoresis, and 8-oxo-guanidine and ɣH2AX staining in cells. Apoptosis was detected via DNA condensation/fragmentation, mitochondrial membrane potential, Annexin V staining and caspase 3/7 activity. Formation of reactive oxygen species was determined by DCFDA- and GSSG/GSH-analysis.ResultsBinding constants to DNA were evaluated as 1.7 × 10⁶ (Cu(Sal-Gly)(phen)), 2.5 × 10⁶ (Cu(Sal-Gly)(pheamine)) and 3.2 × 10⁵ (Cu(Sal-Gly)(phepoxy)). All compounds induced DNA damage. Apoptosis was the main form of cell death. There was an increase in ROS, which is most likely responsible for the observed DNA-damage. Although the compounds were cytotoxic to all tested cancer cell lines, only Cu(Sal-Gly)(pheamine) displayed significantly lower toxicity towards non-cancer cells, its associated phenotypes differing from the other two Cu-complexes. Thus, Cu(Sal-Gly)(pheamine) was further assayed for molecular changes in response to drug treatment using a custom designed RT-qPCR array. Results showed that Harakiri was significantly upregulated. Presence of p53 was not required for apoptosis in response to Cu-complexes.Conclusions and general significanceThese Cu-complexes, namely Cu(Sal-Gly)(pheamine), may be considered promising anticancer agents with activity in cancer cells even with deficient p53 status.     

Synthesis, characterization and crystal structure of a monomeric and a macrocyclic copper (II) complex with a large cavity using benzylacetylacetone ligand

The bidentate ligand benzylacetylacetone was used to synthesize the Cu(II) complexes 1 and 2 without and with 4,4^′-bipyridine ligand, respectively. The complexes were characterized by analytical and spectroscopic studies. The mononuclear complex [Cu(C₁₀H₉O₂)₂] (1) has been synthesized by the reaction of copper acetate with the ligand whereas the tetranuclear complex [Cu₄(4,4^′-bpy)₄(C₁₀H₉O₂)₄(C₂H₃O₂)₄] (2) has been synthesized by the reaction of copper acetate with the ligand followed by the addition of 4,4^′-bipyridine. The X-ray analysis shows that the complex 1 has square planar geometry and the complex 2 has square pyramidal geometry around the metal centers. The thermogravimetric studies showed that the complexes undergo decomposition in multiple steps.     

Synthesis, characterization and deepening in the comprehension of the biological action mechanisms of a new nickel complex with antiproliferative activity

Thiosemicarbazones are versatile organic compounds that present considerable pharmaceutical interest because of a wide range of properties. In our laboratory we synthesised some new metal-complexes with thiosemicarbazones derived from natural aldehydes which showed peculiar biological activities. In particular, a nickel complex [Ni(S-tcitr)₂] (S-tcitr = S-citronellalthiosemicarbazonate) was observed to induce an antiproliferative effect on U937, a human histiocytic lymphoma cell line, at low concentrations (IC₅₀ = 14.4 μM). Therefore, we decided to study the interactions of this molecule with various cellular components and to characterise the induced apoptotic pathway. Results showed that [Ni(S-tcitr)₂] causes programmed cell death via down-regulation of Bcl-2, alteration of mitochondrial membrane potential and caspase-3 activity, regardless of p53 function. The metal complex is not active on G₀ cells (i.e. fresh leukocytes) but is able to induce perturbation of the cell cycle on stimulated lymphocytes and U937 cells, in which a G₂/M block was detected. It reaches the nucleus where it induces, at low concentrations (2.5-5.0 μM), DNA damage, which could be partially ascribed to oxidative stress. [Ni(S-tcitr)₂] is moreover able to strongly reduce the telomerase activity. Although the biological target of this metal complex is still unknown, the reported data suggest that [Ni(S-tcitr)₂] could be a good model for the synthesis of new metal thiosemicarbazones with specific biological activity.     

Synthesis and characterization of a topologically constrained tetraaza macropolycycle and its copper(II) complex

A new macropolycycle, 2,13-dimethyl-1,5,12,16-tetraazapentacyclo[14.6.2.2^5.12.0^6.11.0^17.22]hexacosane (L³), has been prepared by the reaction of 3,14-dimethyl-2,6,13,17-tetraazatricyclo[16.4.0.0^7.12]docosane (L¹) with 1-bromo-2-chloroethane. The macropolycycle readily reacts with anhydrous copper(II) ion to yield [CuL³]²⁺ in dry methanol but does not with nickel(II) ion, showing a high copper(II) ion selectivity. Crystal structure of [CuL³](ClO₄)₂ shows that the complex has a distorted square-planar coordination polyhedron with a trans-IV type N-conformation. The Cu-N distances [1.989(3) and 2.015(3) Å] of [CuL³](ClO₄)₂ are distinctly shorter than those of [CuL¹](ClO₄)₂ and other related macrocyclic copper(II) complexes. The d-d transition band for [CuL³](ClO₄)₂ is observed at 447 nm, which is ca. 40 nm shorter than that for [CuL¹](ClO₄)₂.     

Mononuclear copper(II) complexes with quinolones and nitrogen-donor heterocyclic ligands: Synthesis, characterization, biological activity and interaction with DNA

The neutral mononuclear copper(II) complexes with the quinolone antibacterial drugs, pipemidic acid and N-propyl-norfloxacin, in the presence or absence of nitrogen-donor heterocyclic ligands, 2,2′-bipyridine, 1,10-phenanthroline or 2,2′-dipyridylamine, have been prepared and characterized spectroscopically. The interaction of copper(II) with the deprotonated quinolone ligand leads to the formation of the neutral mononuclear complexes of the type [Cu(quinolone)₂(H₂O)] (1)–(2) while the presence of the N-donor ligand leads to the formation of the neutral mononuclear complexes of the type [Cu(quinolone)(N-donor)Cl] (3)–(8). In all the complexes, copper(II) is pentacoordinate having a distorted square pyramidal geometry. The electron paramagnetic resonance spectra of 1 and 2 are typical of mononuclear Cu(II) complexes, while for the mixed-ligands complexes 3–8 a mixture of dimeric and monomeric species is indicated. The interaction of the complexes with calf-thymus DNA has been investigated with diverse spectroscopic techniques and has shown that the complexes can be bound to calf-thymus DNA by the intercalative mode. The antimicrobial activity of the complexes has been tested on three different microorganisms. All the complexes show an increased biological activity in comparison to the corresponding free quinolone ligand.     

Synthesis and biological comparison of enantiomers of mepenzolate bromide,a muscarinic receptor antagonist with bronchodilatory and anti-inflammatory activities

Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and airflow limitations. We recently proposed that the muscarinic antagonist mepenzolate bromide (mepenzolate) would be therapeutically effective against COPD due to its muscarinic receptor-dependent bronchodilatory activity as well as anti-inflammatory properties. Mepenzolate has an asymmetric carbon atom, thus providing us with the opportunity to synthesize both of its enantiomers ((R)- and (S)-mepenzolate) and to examine their biochemical and pharmacological activities. (R)- or (S)-mepenzolate was synthesized by condensation of benzilic acid with (R)- or (S)-alcohol, respectively, followed by quaternization of the tertiary amine. As predicted by computational simulation, a filter-binding assay in vitro revealed that (R)-mepenzolate showed a higher affinity for the muscarinic M3 receptor than (S)-mepenzolate. In vivo, the bronchodilatory activity of (R)-mepenzolate was superior to that of (S)-mepenzolate, whereas anti-inflammatory activity was indistinguishable between the two enantiomers. We confirmed that each mepenzolate maintained its original stereochemistry in the lung when administered intratracheally. These results suggest that (R)-mepenzolate may have superior properties to (S)-mepenzolate as a drug to treat COPD patients given that the former has more potent bronchodilatory activity than the latter.     

Synthesis, characterization and biological activity of copper complexes with pyridoxal thiosemicarbazone derivatives. X-ray crystal structure of three dimeric complexes

A dimeric copper complex of the unsubstituted pyridoxal thiosemicarbazone (H(2)L), [[Cu(HL)(OH(2))](2)]Cl(2).2H(2)O, previously tested on Friend murine cell lines has been recently resynthesized to evaluate its behavior on different murine and human leukemic cell lines and has been compared, in vitro and in vivo, with its monomeric counterpart [Cu(H(2)L)(OH(2))Cl]Cl. On TS/A murine adenocarcinoma cell line in vitro, both compounds significantly inhibit cell proliferation at micromolar concentrations, although the dimeric compound is more active. Despite this cytotoxicity they lack in vivo activity on TLX5 lymphoma. The unsubstituted dimeric [[Cu(HL)(OH(2))](2)]Cl(2).2H(2)O induces apoptosis on CEM and U937 human cell lines, with IC(50) concentrations of 1.2 x 10(-5) and 6.7 x 10(-6) M, respectively, but it is inactive on K562. Moreover, it alters significantly the cell cycle of U937 and CEM lines and decreases the telomerase activity of U937. To verify if other dimeric copper complexes show relevant biological activity new complexes with N-substituted pyridoxal thiosemicarbazones have been synthesized and characterized using spectroscopic techniques. Three of them, namely [Cu(Me(2)-HL)Cl](2).6H(2)O (Me(2)-H(2)L=pyridoxal N1,N1-dimethylthiosemicarbazone) (1), [Cu(MeMe-HL)Cl](2)Cl(2).4H(2)O (MeMe-HL=pyridoxal N1,N2-dimethylthiosemicarbazone) (2), [Cu(Et-H(2)L)Cl](2)Cl(2).2H(2)O (Et-H(2)L=pyridoxal N1-ethylthiosemicarbazone) (3), were also characterized by X-ray diffractometry. These complexes are dimeric and all three present a square pyramidal coordinative geometry with the ligand showing an SNO tridentate behavior. Their biological activities have been tested in vitro on U937, CEM and K562 cell lines to ascertain their effectiveness in comparison to the corresponding unsubstituted complex [[Cu(HL)(OH(2))](2)]Cl(2).2H(2)O. Compound 1 shows weak proliferation inhibition on all three cell lines, but it does not induce apoptosis and it does not inhibit telomerase activity, compound 2 is not effective at low concentration and is toxic at higher doses; compound 3 inhibits CEM cell growth better than complex 1 but it does not exert any other biological effect.     

Synthesis and characterization of a dinuclear ferric complex with redox-active ligands

A dinuclear ferric complex with the redox-active ligand (L^Cl₂)^2- (H₂L^Cl₂ = N,N′-dimethyl-bis(3,5-dichloro-2-hydroxybenzyl)-1,2-diaminoethane), was synthesized and characterized. The two iron(III) ions are six-coordinate in a distorted octahedral environment of the donor set of one (L^Cl₂)²⁻ and one amine and one phenolate donor of a second (L^Cl₂)²⁻, which bridges the two complex halves. The relatively low-symmetric complex 1 crystallizes in the space group R. The crystal structure contains hexagonal, one-dimensional channels parallel to the c axis with diameters of ∼13 Å. The absorption spectrum of 1 exhibits strong characteristic features of p_π → d_π^∗, p_π → d_σ^∗, phenolate-to-metal CTs, and π → π^∗ ligand transitions. Electrochemical studies on 1 reveal the redox-activity of the coordinated ligand (L^Cl₂)²⁻ by showing irreversible oxidative electron-transfer waves. The reductive electron transfers at negative potentials seem to originate from metal-centered processes. A detailed comparison to complexes with similar donor sets provides new insights into the electrochemical properties of these kinds of complexes.     

Synthesis,characterization and biological studies of diosgenyl analogues

A series of optical amino acid diosgenyl esters and diosgenyl salicylate conjugates were designed and synthesized to develop new anticancer and anti-inflammatory agents. The analogue 9c that contains an 6-aminohexanoic acid residue at C-3 of diosgenin exhibits higher potency against all three tumor cell lines with IC₅₀ values ranging from 4.7 μM in C26 cells to 14.6 μM in Hep G2 cells. In addition, seven of newly synthesized compounds significantly inhibit xylene-induced ear edema and exhibit comparable or better anti-inflammatory activities than those of diosgenin and aspirin. Furthermore, preliminary structure–activity relationship studies demonstrate that diosgenyl salicylate conjugates have stronger anti-inflammatory activities than amino acid diosgenyl esters.     

Synthesis, solid-state characterization and antimicrobial activities of three different polymorphs of a copper(II) complex with 4-isopropyltropolone (hinokitiol)

There exist at least three different polymorphs in the copper(II) complex [Cu(hino)₂] with a hinokitiol ligand (Hhino; 4-isopropyltropolone¹). In addition to deep-green plate crystals 1a and deep-green rod crystals 1b, whose crystal structures have been recently reported, novel green needle crystals 1c of [Cu(hino)₂] were found, the crystal structure of which was here determined by single-crystal X-ray analysis. Since only one crystal structure has been reported for the copper(II) complex [Cu(trop)₂] with a tropolone ligand (Htrop), the polymorphism found in the crystals of [Cu(hino)₂] would be due to the presence of the isopropyl group on the tropolone ring. The synthetic conditions giving the three polymorphs in good yields were found and the crystals were characterized with elemental analysis, FT-IR, TG/DTA and X-ray powder diffraction (XPD) measurements, as well as solution molecular weight measurements for 1a. The solid-state magnetic behaviors or the temperature-dependent magnetic susceptibilities were measured with Superconductivity Quantum Interference Devices (SQUID): 1a showed a weak ferromagnetic interaction, 1b showed a paramagnetic nature with S=1/2, while 1c showed a weak antiferromagnetic interaction. The antimicrobial activities for selected bacteria, yeasts and molds were also measured in the water-suspension system: 1a and 1b showed no activity, while 1c showed modest activities, and these activities were compared with those of the neutral Hino and the anionic hino⁻ ligands.     

Synthesis and characterization of the atropisomeric relationships of a substituted N-phenyl-bipyrazole derivative with anti-inflammatory properties

This work describes the atropisomeric relationships of 3-methyl-5-(3-methyl-5-phenyl-1H-pyrazol-1-yl)-1-phenyl-1H-pyrazol-4-amine (2d), which belongs to series 4-aminobipyrazole derivatives designed as anti-inflammatory agents. The (1)H nuclear magnetic resonance spectra obtained in the presence of a chiral lanthanide shift salt associated to chiral high-performance liquid chromatography analysis, X-ray diffraction, and molecular modeling tools confirmed that ortho bis-functionalized bipyrazole 2d exists as a mixture of aR,aS-atropisomers. These results provide useful information to understand the pharmacological profile of this derivative and of other 4-aminobipyrazole analogs.     

A novel 1,2,4-triazole-based copper(II) complex: Synthesis, characterization, magnetic property and nuclease activity

A novel binuclear copper(II) complex [Cu₂L(μ-SO₄)](PF₆)₂ (1) (L = 3,5-bis (bis(pyridine-2-ylmethyl)amino)methyl)-4H-1,2,4-triazol-4-amine) has been synthesized and structurally characterized. X-ray structure shows that the two copper(II) atoms are bridged by one bidentate sulfate ion and the 1,2,4-triazole ring of L with Cu1?Cu2 distance of 4.404 Å. Each copper(II) center has a distorted trigonal-bipyramidal configuration. Variable-temperature magnetic susceptibility studies (2-300 K) indicate the existence of weak antiferromagnetic coupling between the copper(II) ions in complex 1. The interaction of complex 1 with calf thymus DNA (CT-DNA) has been studied by UV absorption, fluorescence spectroscopy, circular dichroism spectroscopy, viscosity and cyclic voltammetry. Furthermore, complex 1 was able to promote single and double strand DNA cleavage in both aerobic and anaerobic conditions, the pseudo-Michaelis-Menten kinetic parameters k_cat = 2.58 h⁻¹ and K_m = 1.2 × 10⁻⁴ M were obtained for 1. The hydrolytic cleavage of DNA by the complex was supported by the evidence from free radical quenching, anaerobic experiment, thiobarbituric acid-reactive substances (TBARS) assay.