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Kinetic studies, as well as the thermodynamics of the formation of the Cu(II)-Pyridine-2-azo-p-dimethylaniline complex ion in aqueous solutions, and in the presence of sodium dodecyl sulfate (SDS) are reported. The kinetic determinations of the formation of complex were performed using the temperature jump technique. The rate constants in the forward (k$\rm \sb{f}$) and backward (k$\rm\sb{b}$) directions had values of (2.10 $\pm$ 0.97) $\times\ 10\sp7$ scM$\rm \sp{-1}s\sp{-1}$ and (10.0 $\pm$ 0.35) $\rm \times\ 10\sp{2}\ \sb{s}\sp{-1}$ respectively in aqueous solution at 25$\sp\circ$C. The numerical values of the rate constants were analyzed satisfactorily according to the Eigen-Wilkins mechanism. The rate of the reaction was determined at different concentrations of SDS. Different effects on the rate of the reaction were observed as the concentration of SDS was changed. The rate of the reaction was enhanced as the concentration of SDS was increased, reaching a maximum at the critical micelle concentration (4.30 $\times$ 10$\sp{-3}$ M SDS), and decreasing slowly as the concentration of SDS became larger than the c.m.c. The kinetic results above the critical micelle concentration were successfully interpreted in terms of the Berezin model. These results indicate that the enhancement observed at the c.m.c. is due to a concentrative effect. The rate coefficient k$\rm \sb{f}$ and k$\rm \sb{b}$ were calculated at two concentrations of SDS. The forward rates of reaction obtained at 25$\sp\circ$C in the presence of SDS are: (3.13 $\pm$ 0.32) $\rm \times\ 10\sp7 M\sp{-1}s\sp{-1}$ at 4.30 $\times$ 10$\sp{-3}$ M SDS and (2.65 $\pm$ 0.21) $\rm \times\ 10\sp7 M\sp{-1}s\sp{-1}$ at 8.82 $\times$ 10$\sp{-3}$ M SDS. The activation enthalpy and entropy for the reaction were also determined at different concentrations of SDS. Both activation parameters showed a minimum at the c.m.c. of the surfactant with a corresponding maximum in the experimental $\rm k\sb{obs}$. Additives such as methyl sulfate and dodecyltrimethylammonium bromide showed no enhancement of the rate of reaction.

No presente trabalho, foram estudadas duas series de complexos mistos de cobre (II). A primeira serie de complexos, constituída pelos ligantes 3-hidroxipicolinato e 2-acetilpiridinatiossemicarbazona N(4) substituída, sendo o substituinte variado pelos grupos ciclohexil, etil e fenil, ou o 2-acetilpiridinabenzilditiocarbazato. A segunda serie, constituída pelas mesmas tiossemicarbazonas e ditiocarbazato, com o ligante 2-hidroxinicotinato no lugar do 3-hidroxipicolinato. Com a finalidade de avaliar a atividade contra Mycobacterium tuberculosis. <br /> Os complexos obtidos foram caracterizados em estado sólido, pelo ponto de fusão e por meio espectroscopia de absorção na região do infravermelho e difração de raios X em monocristais. Em solução foi utilizada a técnica de espectroscopia eletrônica. <br /> Foi feito o estudo da atividade biológica dos 8 compostos obtidos contra o Mycobacterium tuberculosis, sendo todos eles candidatos ativos e promissores no combate à bactéria, já que apresentam todos valores baixos de concentração inibitória mínima. Sendo que os complexos 2 ,3, 4 e 6 apresentam atividade melhor do que alguns dos fármacos já usados no tratamento como ciprofloxacino, ácido p-aminosalicílico, cicloserina, gentamicina, etambutol, kanamicina, tobramicina, claritromicina e tiacetazona. / In the present work were investigated two series of mixed complexes of coppe (II). The first of them is constituted by the ligands 3-hydroxypicolinate and 2-acetylpyridinedithiosemicabazate or 2-acetylpyridinethiossemicrzones N(4) substituted, were the substituted groups consist on cyclohexyl, ethyl and phenyl. The second series is formed by the same thiosemicarbazones and dithiocarbazate, but with the ligand 2-hydroxynicotinate, instead of 3-hydroxypicolinate. This, in order to evaluate the activity against Mycobaterium tuberculosis. <br /> The synthetized complexes have been characterized in solid state through the melting point and infrared spectroscopy and X-ray diffraction on single crystals. The characterization in solution was done by electronic spectroscopy. <br /> Assays were performed to determine the biological activity of the eight compounds synthetized against the Mycobacterium tuberculosis. All complexes have shown low minimal inhibitory concentration, being promising candidates for successive tests. It is observed that complex 2, 3, 4 and 6 exhibit better activity than some of the drugs used in the treatment such as ciprofloxacin, p-aminosalicylic acid, cycloserine, gentamicin, ethambutol, kanamycin, tobramycin, thiacetazone and clarithromycin.

No presente trabalho, foram estudadas duas series de complexos mistos de cobre (II). A primeira serie de complexos, constituída pelos ligantes 3-hidroxipicolinato e 2-acetilpiridinatiossemicarbazona N(4) substituída, sendo o substituinte variado pelos grupos ciclohexil, etil e fenil, ou o 2-acetilpiridinabenzilditiocarbazato. A segunda serie, constituída pelas mesmas tiossemicarbazonas e ditiocarbazato, com o ligante 2-hidroxinicotinato no lugar do 3-hidroxipicolinato. Com a finalidade de avaliar a atividade contra Mycobacterium tuberculosis. <br /> Os complexos obtidos foram caracterizados em estado sólido, pelo ponto de fusão e por meio espectroscopia de absorção na região do infravermelho e difração de raios X em monocristais. Em solução foi utilizada a técnica de espectroscopia eletrônica. <br /> Foi feito o estudo da atividade biológica dos 8 compostos obtidos contra o Mycobacterium tuberculosis, sendo todos eles candidatos ativos e promissores no combate à bactéria, já que apresentam todos valores baixos de concentração inibitória mínima. Sendo que os complexos 2 ,3, 4 e 6 apresentam atividade melhor do que alguns dos fármacos já usados no tratamento como ciprofloxacino, ácido p-aminosalicílico, cicloserina, gentamicina, etambutol, kanamicina, tobramicina, claritromicina e tiacetazona. / In the present work were investigated two series of mixed complexes of coppe (II). The first of them is constituted by the ligands 3-hydroxypicolinate and 2-acetylpyridinedithiosemicabazate or 2-acetylpyridinethiossemicrzones N(4) substituted, were the substituted groups consist on cyclohexyl, ethyl and phenyl. The second series is formed by the same thiosemicarbazones and dithiocarbazate, but with the ligand 2-hydroxynicotinate, instead of 3-hydroxypicolinate. This, in order to evaluate the activity against Mycobaterium tuberculosis. <br /> The synthetized complexes have been characterized in solid state through the melting point and infrared spectroscopy and X-ray diffraction on single crystals. The characterization in solution was done by electronic spectroscopy. <br /> Assays were performed to determine the biological activity of the eight compounds synthetized against the Mycobacterium tuberculosis. All complexes have shown low minimal inhibitory concentration, being promising candidates for successive tests. It is observed that complex 2, 3, 4 and 6 exhibit better activity than some of the drugs used in the treatment such as ciprofloxacin, p-aminosalicylic acid, cycloserine, gentamicin, ethambutol, kanamycin, tobramycin, thiacetazone and clarithromycin.

Copper is one of the most vital trace elements in ruminant nutrition. It is required for several metabolic activities and it is also an essential component of several physiologically important metalloenzymes. Thus copper deficiency in ruminants results in distinctive pathologies, and hence in significant economic losses to farmers. Copper deficiency results from very low copper in diet (primary copper deficiency) and interference with Cu absorption in the animal due to Mo and S in food or water (secondary copper deficiency). The molybdenum-induced copper deficiency that affects ruminants can be attributed to the formation of thiomolybdates (TMs)from molybdate and sulfide in the rumen. The TMs formed then react irreversibly with copper to form insoluble Cu-TM complex which ultimately end up being excreted, thus reducing copper bioavailability to the ruminant. <p>In this study, an attempt has been made to use computer simulations to model speciation of copper in rumen fluid in the presence of TMs with the aim of understanding the extent to which TMs affects the levels of copper in the rumen. <p>This was done by initially refining the computer model of copper speciation with respect to low molecular mass (LMM) ligands in bovine rumen with the aim of correcting the discrepancy that was observed during experimental validation of the computer model in a previous study. To this end, mass balance equations which describes the distribution of Cu(II) amongst the different ligands were encoded into a spreadsheet to calculate equilibrium concentration of all species. Formation constants obtained from literature as well as those obtained from studies in our group were used as input values in the spreadsheet. Results show that at average ruminal pH, the metal would be present mostly as carbonate and phosphate complexes. The results obtained from the computer model in the present study were validated using 1H NMR experiments on simulated rumen fluid as well as actual rumen fluid containing Cu(II); using acetic acid chemical shift as the probe for monitoring the speciation pattern. Excellent agreement was observed between the computer model and experimental results. Discrepancy was however observed upon introduction of copper lysine as copper source into the model. Incorporation of a mixed ligand complex of Cu(II), acetate and lysine into the computer model gave an excellent agreement between the computer model and experimental results. <p>The study was extended to include glycine, histidine, methionine and EDTA complexes as the copper source in both rumen saliva (McDougalls solution) and rumen fluid. Results show that only the histidine and EDTA complexes persist to any significant extent, in spite of the large number of competing ligands present in these matrices.<p>In this study, success has also been achieved in the integration of the slow (kinetically controlled) formation of TMs and copper-tetrathiomolybdate (TM4) complexation into the previously developed model for the rapidly equilibrating copper-ligand speciation. To simulate the formation of the TMs and Cu-TM4 complex with respect to time, the differential equations representing rate expressions for each chemical species were solved to obtain an analytical solution using the Laplace transform method. The analytical solutions obtained were encoded in a spreadsheet and calculated as function of time to obtain time dependent concentrations of TMs and Cu-TM4 complex. This was then integrated with previously developed model for the rapidly equilibrating copper-ligand speciation in the rumen. The kinetic data used in the simulation of the formation thiomolybdates was obtained fron literature wheras that for Cu-TM4 complexation was obtained from our lab using Cu(II) - Ion Selective Electrode. The results show that that in the presence of TM4 the, Cu(II) bound to low molecular ligands in the rumen is drastically reduced confirming the effect TM4 on Cu(II) observed in several in vitro studies.<p>The study shows that in thiomolybdate contaminated rumen environment, the bioavailability of copper is considerably reduced. Though metal bioavailabilities are hard to predict this approach could help better our understanding of this process.

Copper is one of the most important trace elements in ruminant nutrition. Its deficiency causes certain pathologies that can be cured by supplementation, by either five ("inorganic") or complexed ("chelated") forms. With the objective of being able to quantitatively compare the distribution of copper between the two forms of supplements, the speciation of copper in ruminant fluids was studied here. For this study, copper lysine supplement was used. It was necessary to first study the acid-base and complexation chemistry of lysine with copper (II). In addition, the complexation chemistry of glycine and histidine, were investigated. Mass balance equations were used to describe the distribution of copper (II) amongst different ligands. The results of the distribution of copper (II) ions in McDougall's solution (a simulated form of bovine saliva), indicate no significant differences in the distribution of copper using the different form of supplements. 1H NMR was used to validate the results from the computer model. Using a combination of the results from the saliva simulation model and the chemical shifts from the NMR studies, the chemical shift changes that would accompany the addition of copper (II) to McDougall's solution were predicted. Results from the models do not show any appreciable differences from experimental values. Rumen samples were collected. Important peaks in the 1H NMR spectrum were assigned. The spectrum indicated that acetic acid, resulting from the fermentation in the rumen, was a good probe for monitoring the speciation pattern. Speciation calculation indicated that the bulk of the copper would be bound to ammonia in the rumen. Changes in chemical shifts that result from the introduction of copper (II) to the rumen contents were predicted. Results were compared with experimental values. Agreement between the two sets of results was found to be satisfactory. The study shows that any advantages that result from the use of copper lysine supplement are not as a result of its remaining intact. Though metal bioavailabilities are hard to predict this approach could help better our understanding of this process. The methods developed here could be extended to other metal complexation problems in biological fluids. (Abstract shortened by UMI.)

Copper is one of the most vital trace elements in ruminant nutrition. It is required for several metabolic activities and it is also an essential component of several physiologically important metalloenzymes. Thus copper deficiency in ruminants results in distinctive pathologies, and hence in significant economic losses to farmers. Copper deficiency results from very low copper in diet (primary copper deficiency) and interference with Cu absorption in the animal due to Mo and S in food or water (secondary copper deficiency). The molybdenum-induced copper deficiency that affects ruminants can be attributed to the formation of thiomolybdates (TMs)from molybdate and sulfide in the rumen. The TMs formed then react irreversibly with copper to form insoluble Cu-TM complex which ultimately end up being excreted, thus reducing copper bioavailability to the ruminant. <p>In this study, an attempt has been made to use computer simulations to model speciation of copper in rumen fluid in the presence of TMs with the aim of understanding the extent to which TMs affects the levels of copper in the rumen. <p>This was done by initially refining the computer model of copper speciation with respect to low molecular mass (LMM) ligands in bovine rumen with the aim of correcting the discrepancy that was observed during experimental validation of the computer model in a previous study. To this end, mass balance equations which describes the distribution of Cu(II) amongst the different ligands were encoded into a spreadsheet to calculate equilibrium concentration of all species. Formation constants obtained from literature as well as those obtained from studies in our group were used as input values in the spreadsheet. Results show that at average ruminal pH, the metal would be present mostly as carbonate and phosphate complexes. The results obtained from the computer model in the present study were validated using 1H NMR experiments on simulated rumen fluid as well as actual rumen fluid containing Cu(II); using acetic acid chemical shift as the probe for monitoring the speciation pattern. Excellent agreement was observed between the computer model and experimental results. Discrepancy was however observed upon introduction of copper lysine as copper source into the model. Incorporation of a mixed ligand complex of Cu(II), acetate and lysine into the computer model gave an excellent agreement between the computer model and experimental results. <p>The study was extended to include glycine, histidine, methionine and EDTA complexes as the copper source in both rumen saliva (McDougalls solution) and rumen fluid. Results show that only the histidine and EDTA complexes persist to any significant extent, in spite of the large number of competing ligands present in these matrices.<p>In this study, success has also been achieved in the integration of the slow (kinetically controlled) formation of TMs and copper-tetrathiomolybdate (TM4) complexation into the previously developed model for the rapidly equilibrating copper-ligand speciation. To simulate the formation of the TMs and Cu-TM4 complex with respect to time, the differential equations representing rate expressions for each chemical species were solved to obtain an analytical solution using the Laplace transform method. The analytical solutions obtained were encoded in a spreadsheet and calculated as function of time to obtain time dependent concentrations of TMs and Cu-TM4 complex. This was then integrated with previously developed model for the rapidly equilibrating copper-ligand speciation in the rumen. The kinetic data used in the simulation of the formation thiomolybdates was obtained fron literature wheras that for Cu-TM4 complexation was obtained from our lab using Cu(II) - Ion Selective Electrode. The results show that that in the presence of TM4 the, Cu(II) bound to low molecular ligands in the rumen is drastically reduced confirming the effect TM4 on Cu(II) observed in several in vitro studies.<p>The study shows that in thiomolybdate contaminated rumen environment, the bioavailability of copper is considerably reduced. Though metal bioavailabilities are hard to predict this approach could help better our understanding of this process.

[pt] Diante das limitações e dos efeitos colaterais indesejáveis observados na terapia do câncer com os derivados de platina, muitos esforços têm sido feitos com o objetivo de obter novas drogas mais eficazes e menos tóxicas, capazes de promover a clivagem oxidativa ou hidrolítica da cadeia do DNA e de outras estruturas subcelulares fundamentais. Até o presente momento, alguns complexos de cobre já foram desenvolvidos, e mostraram excelente atividade in vitro contra uma variedade de tumores. Assim, o conhecimento sobre a citotoxidade e seletividade dos complexos de cobre(II) contendo ponte de hidróxido é, portanto, de importância na busca por novos fármacos para o tratamento do câncer. Além disso, por se tratar de um metal fisiológico, os compostos de cobre costumam ser menos tóxicos que os derivados de platina, diminuindo assim efeitos colaterais indesejados e com isso possibilitando o aumento do arsenal quimioterápico disponível para o tratamento da doença. Neste contexto, foram desenvolvidos no presente trabalho dois ligantes binucleantes derivados da isoniazida (INH). Um desses ligantes, o não-simétrico N-isonicotinoil-2-hidroxi-3-{[(2-hidroxibenzil)(2-piridilmetil)amino]-metil}-5-metilbenzaldeído hidrazona, é inédito. Já o outro, o ligante simétrico N,N’-diisonicotinoil-2-hidroxi-5-metilisoftaldeído diidrazona, foi originalmente sintetizado por uma equipe liderada por Chen, em 1992. A partir destes ligantes, quatro novos complexos binucleares de Cu(II) contendo pontes exógenas hidroxo e acetato, todos eles contendo uma ponte do tipo -hidroxo entre os metais, foram sintetizados e caracterizados por diversas técnicas instrumentais de análise. Além disso, foram feitos cálculos teóricos com o objetivo de auxiliar as propostas quanto à estrutura dos compostos. Trabalhos futuros serão realizados a fim de investigar a atividade biológica destes complexos. / [en] Considering the limitations and undesirable side effects observed in cancer therapy with platinum derivatives, many efforts have been made with the aim of obtaining new drugs more effective and less toxic, able to promote the hydrolytic cleavage or oxidative DNA chain other subcellular structures critical. Until now, some copper complexes have been developed and showed excellent in vitro activity against a variety of experimental tumors. Thus, knowledge on the cytotoxicity and selectivity compounds of copper (II) containing bridging hydroxide is therefore of importance in the search for new drugs for cancer treatment. Moreover, because it is a physiological metal, its compounds are usually less toxic than platinum derivatives, thus reducing unwanted side effects and thereby enabling the increase of chemotherapeutic arsenal available for treatment of the disease. In this context, were developed in this work binucleantes two ligands derived from isoniazid (INH). One of these ligands, the non-symmetrical N-isonicotinoil-2-hydroxy-3-{[(2-hydroxybenzyl) (2-piridilmetil) amino]-methyl}-5-hydrazone methylbenzaldehyde, is new. But the other, the symmetrical ligand N, N -diisonicotinoyl-2-hydroxy-5-methylisophthalaldehyde dihydrazone, was originally synthesized by a team led by Chen in 1992. From these ligands, four new binuclear complexes of Cu (II) bridges containing exogenous hydroxo and acetate, all of which contain a hydroxo-bridge type between the metals were synthesized and characterized by various instrumental techniques of analysis. In addition, theoretical calculations were made with the aim of helping the proposals regarding the structure of the compounds. Future works will be performed to investigate the biological activity of these complexes.