Assessment of a novel Cu (II) complex as a potential anticancer agent

Widely used in cancer treatment, chemotherapy still faces hindering challenges, ranging from severe induced toxicity to drug resistance acquisition. As means to overcome these setbacks, newly synthetized compounds have recently come into play with the basis of improved pharmacokinetic/pharmacodynamic properties. With this mind-set, this project aimed towards the antiproliferative potential characterization of a group of metallic compounds. Additionally the incorporation of the compounds within a nanoformulation and within new combination strategies with commercial chemotherapeutic drugs was also envisaged. Cell viability assays presented copper (II) compound (K4) as the most promising, presenting an IC50 of 6.10 μM and 19.09 μM for HCT116 and A549 cell line respectively. Exposure in fibroblasts revealed a 9.18 μM IC50. Hoechst staining assays further revealed the compound’s predisposition to induce chromatin condensation and nuclear fragmentation in HCT116 upon exposure to K4 which was later demonstrated by flow cytometry and annexin V-FITC/propidium iodide double staining analysis (under 50 % cell death induction). The compound further revealed the ability to interact with major macromolecules such as DNA (Kb = 2.17x105 M-1), inducing structural brakes and retardation, and further affecting cell cycle progression revealing delay in S-phase. Moreover BSA interactions were also visible however not conclusive. Proteome profiling revealed overexpression of proteins involved in metabolic activity and underexpression of proteins involved in apoptosis thus corroborating Hoechst and apoptosis flow cytometry data. K4 nanoformulation suffered from several hindrances and was ill succeeded in part due to K4’s poor solubility in aqueous buffers. Other approaches were considered in this regard. Combined chemotherapy assays revealed high cytotoxicity for afatinib and lapatinib strategies. Lapatinib and K4 proteome profiling further revealed high apoptosis rates, high metabolic activity and activation of redundant proteins as part of compensatory mechanisms.

Nickel(II) complexes of bidentate N-N′ ligands containing mixed pyrazole, pyrimidine and pyridine aromatic rings as catalysts for ethylene polymerisation

This work describes the synthesis and characterisation of Ni(II) complexes of the following neutral bidentate nitrogen ligands containing pyrazole (pz), pyrimidine (pm) and pyridine (py) aromatic rings: 2-pyrazol-1-yl-pyrimidine (pzpm), 2-(4-methyl-pyrazol-1-yl)-pyrimidine (4-Mepzpm), 2-(4-bromo-pyrazol-1-yl)-pyrimidine (4-Brpzpm), 2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidine (pz*pm), 2-pyrazol-1-yl-pyridine (pzpy) and bis(3,5-dimethylpyrazol-1-yl)phenylmethane (bpz*mph). The complexes [NiBr2(pzpm)] (1), [NiBr2(4-Mepzpm)] (2), [NiBr2(4-Brpzpm)] (3), [NiBr2(pz*pm)] (4), [NiBr2(pzpy)] (5) and [NiBr2(bpz*mph)] (6) were tested as catalysts for ethylene polymerisation, in the presence of the cocatalysts methylaluminoxane (MAO) or diethylaluminium chloride (AlEt2Cl), the catalyst systems 1-3/MAO showing moderate to high activities up to the temperature of 20 °C only in the presence of MAO, whereas 4-6/MAO revealed to be inactive. Other related Pd(II) complexes, already reported in previous works, such as [PdClMe(pzpm)], [PdClMe(pz*pm)], [PdClMe(pzpy)] and [PdClMe(bpz*mph)], also showed to be inactive in the polymerisation of ethylene, when activated by MAO or AlEt2Cl. Selected samples of polyethylene products were characterised by GPC/SEC, 1H and 13C NMR and DSC, showing to be low molecular weight polymers with Mn values ranging from ca. 550 to 1500 g mol−1 and unusually low dispersities of 1.2–1.7, with total branching degrees generally varying between 2 and 12%, melting temperatures from 40 to 120 °C and crystallinities from 40 to 70%.

Platinum (II) and palladium (II) complexes with (N,N') and (C,N,N') ligands derived from pyrazole as anticancer and antimalarial agents: synthesis, characterization and in vitro activities

The study of the reactivity of three 1-(2-dimethylaminoethyl)-1H-pyrazole derivatives of general formula [1-(CH2)2NMe2}-3,5-R2-pzol] {where pzol represents pyrazole and Rdouble bond; length as m-dashH (1a), Me (1b) or Ph (1c)} with [MCl2(DMSO)2] (Mdouble bond; length as m-dashPt or Pd) under different experimental conditions allowed us to isolate and characterize cis-[M{κ2-N,N′-{[1-(CH2)2NMe2}-3,5-R2-pzol])}Cl2] {MMdouble bond; length as m-dashPtPt (2a-2c) or Pd (3a-3c)} and two cyclometallated complexes [M{κ3-C,N,N′-{[1-(CH2)2NMe2}-3-(C5H4)-5-Ph-pzol])}Cl] {Mdouble bond; length as m-dashPt(II) (4c) or Pd(II) (5c)}. Compounds 4c and 5c arise from the orthometallation of the 3-phenyl ring of ligand 1c. Complex 2a has been further characterized by X-ray crystallography. Ligands and complexes were evaluated for their in vitro antimalarial against Plasmodium falciparum and cytotoxic activities against lung (A549) and breast (MDA MB231 and MCF7) cancer cellular lines. Complexes 2a-2c and 5c exhibited only moderate antimalarial activities against two P. falciparum strains (3D7 and W2). Interestingly, cytotoxicity assays revealed that the platinacycle 4c exhibits a higher toxicity than cisplatin in the three human cell lines and that the complex 2a presents a remarkable cytotoxicity and selectivity in lung (IC50 = 3 μM) versus breast cancer cell lines (IC50 > 20 μM). Thus, complexes 2c and 4c appear to be promising leads, creating a novel family of anticancer agents. Electrophoretic DNA migration studies in presence of the synthesized compounds have been performed, in order to get further insights into their mechanism of action.

Sulfitos duplos contendo cobre (I) e um metal de transição M(II) tipo Cu2SO3.M(II)SO3.2H 2O [M(II) = Cu(II), Fe(II), Mn(II) e Cd(II)]: preparação e seletividade na incorporação de M(II)

The metal-catalyzed autooxidation of S(IV) has been studied for more than a century without a consensus being obtained as to reaction rates, rate laws or mechanisms. The main objective in this work was to explore the reaction between Cu(II) and SO2 in the presence of M(II), paying special attention to the formation of double sulfites like Cu2SO3.M(II)SO3.2H 2O. The two principal aspects studied were: i) a new way to prepare double sulfites with high purity degree and the selectivity in the M(II) incorporation during the salt formation.

Análise das isotermas de adsorção de Cu(II), Cd(II), Ni(II) e Zn(II) pela N-(3,4-dihidroxibenzil) quitosana empregando o método da regressão não linear

Adsorption of Cu(II), Ni(II), Pb(II) and Zn(II) ions from aqueous solutions by N-(3,4-dihydroxybenzyl) chitosan have been carried out. The Langmuir (L), Freundlich (F), Langmuir - Freundlich (LF), Redlich-Peterson (RP) and Tóth (T) adsorption isotherms models have been applied to fit the experimental data. Nonlinear regression computational program "Enzefitte", which is a library of the more commonly used adsorption isotherm equations for obtaining tabular outuput suitable for plotting theoretical of fitted isotherms, has been used to estimate the adsorption parameters. These parameters were used to calculate the amount adsorbed q calc., a function of concentration (C).

Caracterização de amostras comerciais de vermicomposto de esterco bovino e avaliação da influência do pH e do tempo na adsorção de Co(II), Zn(II) and Cu(II)

Some commercial samples of vermicompost from bovine manure (humus) were characterized by thermogravimetry with respect to humidity, organic matter and ash contents, the percentages of which range from 6.55 to 5.35%, 53.01 to 69.96% and 46.44 to 66,14%, respectively. The capacity of adsorption of Cu2+, Zn2+ and Co2+ ions by these samples has been evaluated as a function of pH and time. The contents of several metal ions in the original vermicompost samples have been determined by flame atomic absorption spectrometry after digestion in a microwave oven. The high nitrogen content suggests that the earthworms used in the maturation procedure lead to an efficient degradation of organic matter. The metal retention was affected by both pH and adsorption time. The results also show that adsorption follows the order Cu2+ > Zn2+ > Co2+.

Comparação da eficiência do processo de ozonização e ozonização catalítica (Mn II e Cu II) na degradação de fenol

This paper discusses the results obtained with homogeneous catalytic ozonation [Mn (II) and Cu (II)] in phenol degradation. The reduction of total phenols and total organic carbon (TOC) and the ozone consumption were evaluated. The efficiency in phenol degradation (total phenol removal) at pH 3, with the catalytic process (Mn (II)), increased from 37% to 55% while the TOC removal increased from 4 to 63% in a seven-minute treatment. The ozonation process efficiency at pH 10 was 43% and 39% for phenol and TOC removal, respectively. The presence of both metallic ions (Mn2+ and Cu+2) in the ozonation process resulted in a positive effect.

Estudo da labilidade de Cu(II), Cd(II), Mn(II) e Ni(II) em substâncias húmicas aquáticas utilizando-se membranas celulósicas organomodificadas

In this work commercial filters papers were organomodified with tetraethylorthosilicate (TEOS) and 3-aminopropyltriethoxysilane (3-APTS), aiming at the development of a new analytical procedure for in-situ speciation of labile and inert metal species in aquatic systems. Parameters that exert influence on the metal lability such as pH, chelating time, concentration and characteristics of the organic matter were studied in the laboratory using tests for metal recuperation. The results showed slower kinetics for Cu ion than for Ni, Mn and Cd in the absence of aquatic humic substances (AHS). The relative lability observed for complexed metals in aquatic humic substances using organomodified filter papers was Cu>>Cd>Ni>Mn. The pH values, structural characteristics and concentration of AHS exert strong influence on the lability of the metals. The results obtained showed that the utilization of organomodified filter papers can be an interesting and promising alternative for in situ characterization of metal lability in aquatic systems.

Planejamento estatístico de experimentos como uma ferramenta para otimização das condições de biossorção de Cu(II) em batelada utilizando-se casca de nozes pecã como biossorvente

In order to reduce the total number of experiments for achieving the highest amount of adsorbed Cu2+ (qmax) using pecan nutshells (Carya illinoensis) as biosorbent, a full 2(4) factorial design with two central points was carried out (mass of biosorbent- m, pH, initial metallic ion concentration- C0, time of contact- t). In order to continue the optimization of the system, a central composite surface analysis design with two factors and five central points was carried out. The maximum amount of Cu2+ taken up by the pecan nutshells was 20 mg g-1. These results were confirmed by determining a Cu2+ isotherm using the best conditions attained by the statistical design of experiments.

Determinação voltamétrica por redissolução anódica de Cu(II) em águas residuárias empregando um eletrodo de pasta de carbono modificado com quitosana

The electrochemical applications of a CPE modified with chitosan for the determination of Cu(II) in wastewater samples using anodic stripping voltammetry are described. The best voltammetric response was observed for a paste containing 25% m/m of chitosan. A 0.10 mol L-1 NaNO3 solution (pH 6.5) as supporting electrolyte, a pre-concentration potential of -0.20 V, pre-concentration time of 270 s and a scan rate of 25 mV s-1 were selected. The calibration graph was linear in the Cu(II) concentration range from 2.0 x 10-7 to 7.4 x 10-6 mol L-1, with a detection limit of 8.3 x 10-8 mol L-1.

Titulações potenciométricas de cátions metálicos tendo como eletrodo indicador o sistema Cu/Cu(II)-EDTA

In potentiometric titrations of metal cations with EDTA the Hg/HgY2- system is usually used to detect the end point. However, the use of mercury has been discouraged in analytical procedures due to its toxicity. In this work the Cu/CuY2- system was used as indicator electrode for potentiometric titrations of some metal cations with EDTA. The solutions of Cu2+, Cd2+, Mn2+, Co2+ and Zn2+ were titrated with Na2EDTA solution in the presence of a small concentration of the CuY2- complex using a copper wire as indicator electrode. The potentiometric titrations with the Cu/CuY2- system showed good correlation when compared with an Hg/HgY2- system.

Aplicação de Zr/Ti-PILC no processo de adsorção de Cu(II), Co(II) e Ni(II) utilizando modelos físico-químicos de adsorção e termodinâmica do processo

The aim of this investigation is to study how Zr/Ti-PILC adsorbs metals. The physico-chemical proprieties of Zr/Ti-PILC have been optimized with pillarization processes and Cu(II), Ni(II) and Co(II) adsorption from aqueous solution has been carried out, with maximum adsorption values of 8.85, 8.30 and 7.78 x10-1 mmol g-1, respectively. The Langmuir, Freundlich and Temkin adsorption isotherm models have been applied to fit the experimental data with a linear regression process. The energetic effect caused by metal interaction was determined through calorimetric titration at the solid-liquid interface and gave a net thermal effect that enabled the calculation of the exothermic values and the equilibrium constant.

Caracterização de escamas do peixe piau (Leporinus elongatus) e sua aplicação na remoção de Cu(II) de meio aquoso

Characterization of fish scales of Leporinus elongatus and their application in the removal of Cu(II) from aqueous solutions are described. It was observed that the scales are mainly formed by hydroxyapatite and type I collagen. Adsorption of Cu(II) was performed using batch experiments at 25 0C. The ANOVA statistical results have shown that the Langmuir model was successful applied to determine the maximum adsorption capacity of 2.686 x10-4 mol g-1 and the Langmuir equilibrium parameter (b) of 168.8 L mol-1. The Langmuir separation parameter, R L, has shown favorable adsorption of Cu(II) on the scales.

Preparação de membranas de acetato de celulose organomodificadas para adsorção dos íons Cu(II), Cd(II), Mn(II) e Ni(II)

Cellulose acetate polymeric membranes had been prepared by a procedure of two steps, combining the method of phase inversion and the technique of hydrolysis-deposition. The first step was the preparation of the membrane, and together was organomodified with tetraethylortosilicate and 3-aminopropyltrietoxysilane. Parameters that exert influence in the complexation of the metallic ion, as pH, time of complexation, metal concentration, had been studied in laboratory using tests of metal removal. The membranes had presented resistance mechanics and reactivity to cations, being able to be an alternative for the removal, daily pay-concentration or in the study of the lability of metals complexed.

Activity and sulfur resistance of Rh(I) and Pd(II) complexes

Two complexes of Rh(I) and Pd(II) with chloride and tridecylamine ligands were obtained and characterized by Elementary Analysis and by XPS and FTIR spectroscopies. Complexes anchored on γ-Al2O3 were tested in the styrene semi-hydrogenation reaction carried out in the absence or presence of a sulfur poison. Although both low loaded catalysts were highly selective, the Pd(II) complex was three times more active than the Rh(I) complex. The rhodium complex was more sulfur resistant but less active than the palladium complex. Differences in conversion and sulfur resistance between both complexes could be related to electronic and/or geometric effects.