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In this work, we explored one material from the broad family of 2D semiconductors, namely WSe2 to serve as an enabler for advanced, low-power, high-performance nanoelectronics and optoelectronic devices. A 2D WSe2 based field-effect-transistor (FET) was designed and fabricated using electron-beam lithography, that revealed an ultra-high mobility of ~ 625 cm2/V-s, with tunable charge transport behavior in the WSe2 channel, making it a promising candidate for high speed Si-based complimentary-metal-oxide-semiconductor (CMOS) technology. Furthermore, optoelectronic properties in 2D WSe2 based photodetectors and 2D WSe2/2D MoS2 based p-n junction diodes were also analyzed, where the photoresponsivity R and external quantum efficiency were exceptional. The monolayer WSe2 based photodetector, fabricated with Al metal contacts, showed a high R ~502 AW-1 under white light illumination. The EQE was also found to vary from 2.74×101 % - 4.02×103 % within the 400 nm -1100 nm spectral range of the tunable laser source. The interfacial metal-2D WSe2 junction characteristics, which promotes the use of such devices for end-use optoelectronics and quantum scale systems, were also studied and the interfacial stated density Dit in Al/2D WSe2 junction was computed to be the lowest reported to date ~ 3.45×1012 cm-2 eV-1. We also examined the large exciton binding energy present in WSe2 through temperature-dependent Raman and photoluminescence spectroscopy, where localized exciton states perpetuated at 78 K that are gaining increasing attention for single photon emitters for quantum information processing. The exciton and phonon dynamics in 2D WSe2 were further analyzed to unveil other multi-body states besides localized excitons, such as trions whose population densities also evolved with temperature. The phonon lifetime, which is another interesting aspect of phonon dynamics, is calculated in 2D layered WSe2 using Raman spectroscopy for the first time and the influence of external stimuli such as temperature and laser power on the phonon behavior was also studied. Furthermore, we investigated the thermal properties in 2D WSe2 in a suspended architecture platform, and the thermal conductivity in suspended WSe2 was found to be ~ 1940 W/mK which was enhanced by ~ 4X when compared with substrate supported regions. We also studied the use of halide-assisted low-pressure chemical vapor deposition (CVD) with NaCl to help to reduce the growth temperature to ∼750 °C, which is lower than the typical temperatures needed with conventional CVD for realizing 1L WSe2. The synthesis of monolayer WSe2 with high crystalline and optical quality using a halide assisted CVD method was successfully demonstrated where the role of substrate was deemed to play an important role to control the optical quality of the as-grown 2D WSe2. For example, the crystalline, optical and optoelectronics quality in CVD-grown monolayer WSe2 found to improve when sapphire was used as the substrate. Our work provides fundamental insights into the electronic, optoelectronic and quantum properties of WSe2 to pave the way for high-performance electronic, optoelectronic, and quantum-optoelectronic devices using scalable synthesis routes.

A new approach to the discovery of high absorbing semiconductors for solar cells was taken by working under a set of design principles and taking a systemic methodology. Three transition metal chalcogenides at varying states of development were evaluated within this framework. Iron pyrite (FeS���) is well known to demonstrate excellent absorption, but the coexistence with metallic iron sulfides was found to disrupt its semiconducting properties. Manganese diselenide (MnSe���), a material heavily researched for its magnetic properties, is proposed as a high absorbing alternative to iron pyrite that lacks destructive impurity phases. For the first time, a MnSe��� thin film was synthesized and the optical properties were characterized. Finally, CuTaS���, a known but never characterized material, is also proposed as a high absorbing semiconductor based on the design principles and experimental results. / Graduation date: 2013

Nanostructured materials play a vital role in almost all aspects of science and technology in the 21st century. The materials include nanoparticles, nanofilms, biological membranes etc. whose physicochemical properties are size-dependent. Thin films have wide range of applications in various branches of science. One of the efficient methods to form miniaturized structures for device applications is to fabricate nanostructured films on different substrates. Surfactant assembly on metallic and non-metallic surfaces based on self assembly and Langmuir-Blodgett technique offers a unique way to form thin films at molecular levels. The process of formation of unimolecular assemblies gives the flexibility of tuning the properties of underlying substrates for various applications including wetting characteristics, lubrication, passivation, mimicking biological phenomena etc. Towards this direction, self assembled monolayers (SAMs) of alkanethiols on gold and silver surfaces have been studied comprehensively for the past two decades. The reported literature on short chain length thiol-based monolayers is however, limited since the formation using conventional methods yield poor quality monolayers. The short chain length monolayers are useful in various applications like tribology, layer-by-layer assemblies, biosensors etc. Hence, it is essential to reproducibly form SAMs of various chain lengths and understand their properties. The present study is related to the formation of SAMs of alkanethiols and diselenides on gold and silver surfaces to form ordered and well-oriented monolayers. Monolayers of varying chain lengths (CH3(CH2)nSH where n = 3, 5, 7, 9, 11, 15) have been formed on gold and silver surfaces using different methods, (1) adsorption from neat thiols; (2) adsorption under electrochemical control and (3) adsorption from alcoholic solutions of the thiols. The characteristics features of the SAMs have been followed based on three different aspects, (i) structure and stability of the methylene groups (ii) interfacial characteristics involving the end group and the solvent and (iii) metal-head group interactions. The structure and stability of the monolayers have been followed based on vibrational spectroscopy and electrochemistry under different environment including thermal perturbations. The stability of the SAMs at different temperatures and subsequent changes associated with the orientation / packing has been monitored both in the dry state using reflection absorption infrared spectroscopy (RAIRS) and under electrochemical conditions using cyclic voltammetry and impedance analysis. Monolayers adsorbed from neat thiols show superior quality in terms of stability and structural arrangement. Short chain thiols with n = 3, 5, 7 show substantial stability when the adsorption is carried out from neat thiols. Figure 1 shows the RAIR spectra of hexanethiol SAM on gold adsorbed by three different procedures. Monolayers adsorbed under potential control behave very similar to the monolayers adsorbed from neat thiol as for as stability and structural orientation are concerned. Monolayers prepared using conventional methods of adsorption from alcoholic solutions are of inferior quality in terms of stability and arrangement especially for the short chain lengths. This is likely to be due to the fact that monolayers prepared using conventional methods may have intercalated solvent molecules within the monolayer assembly that degrade the integrity of the SAM leading to poor quality. The blocking characteristics of the monolayers for diffusing redox couple have been followed by determining the heterogeneous electron transfer rate constant using electrochemical techniques. The spectroscopic data and the electrochemical data follow similar trend indicating the superior quality of monolayer adsorbed from neat thiol in terms of stability as compared to conventionally prepared monolayers. Figure 1. RAIR spectra of hexanethiol-SAMs on Au(111) surface at 25C. The monolayers are formed by adsorption (A) from neat thiol (B) under potential control and (C) from alcoholic solution of the thiol. Wavenumber (cm-1) The interfacial characteristics of the monolayers (effect of end group functionality on the solvent properties) have been monitored on the basis of capacitance, contact angle and atomic force microscopy- measurements. Well-organized monolayers behave like good capacitors with relatively low values of double layer capacitance in presence of a liquid electrolyte as compared to the expected values based on known thickness and dielectric constant of the SAMs. This behavior can be explained by invoking the depletion of water density at the methyl terminated SAM-water interface where the solvent properties are different from that of bulk. Variation of one such property, dielectric constant, has been mapped using force measurement based on AFM. Dielectric constant of water changes from the bulk value of 78 to a low value as given in figure 2. This cross-over occurs within a span of 1-3 nm depending on the chain length of the thiol. Of the three procedures used, the ones based on the use of neat thiol and electrochemical adsorption result in well-oriented alkyl chains followed by highly oriented methyl terminal groups. This is responsible for the high hydrophobic nature of the interface and the subsequent observation of interfacial water properties. The SAMs prepared from ethanol fail to show the hydrophobic effects. Hydrophilic monolayers (NH2 terminated monolayers) fail to show depletion of water density at the interface indicating the importance of end group functionality in altering the interfacial characteristics of the monolayer. Figure 2. Spatial variation of dielectric permittivity of water at the hexanethiol SAM - water interface. The SAM is formed on gold (111) surface; (a) from ethanolic solution of the thiol (b) under electrochemical control (c) from neat thiol. The origin on the x-axis is the position of the methyl groups of SAM and the direction towards right side is in to the bulk water. The well-oriented SAMs have been used to follow the adsorption of a biopolymer. Zein protein is a prolamine of maize and is projected to be a biocompatible coating for food products and food containers. Hence, it is essential to prepare impermeable coatings of zein with different surface wetting properties. The adsorption of zein on highly ordered SAMs with hydrophobic or hydrophilic end group functionality has been studied and the orientation of the protein followed using spectroscopy, microscopy and electrochemistry. It is observed that zein shows higher affinity towards hydrophilic than hydrophobic surfaces with small foot print size on the Figure 3. Orientation of zein protein on hydrophilic and hydrophobic SAM as deciphered from the experimental data. hydrophilic surface resulting in large surface coverage. Figure 3 shows the schematics of zein deposits on hydrophilic and hydrophobic SAM surfaces determined based on spectroscopy, quartz crystal microbalance and electrochemical studies. The AFM shows cylindrical, rod-like and disc-like features of zein on hydrophilic surfaces that form the base units for the growth of cylindrical structures of zein. The published literature on the studies on SAMs on silver surfaces reveals that there is no consensus on the structure of the monolayers on silver. This may be due to the difficulty in getting pristine oxide-free surfaces in the case of silver and this is likely to affect the monolayer quality. Hence, it is decided to prepare SAMs of alkanethiols on silver and study their characteristics. Subtle differences between the monolayers adsorbed from neat thiol and from alcoholic solutions of thiols have been observed in terms of stability and permeability. Atomic force microscopic studies illustrate the presence of depletion of water at the SAM-aqueous interface. Diselenide-based monolayers have been formed on gold to understand the head group-substrate interactions on the monolayer properties. The disorder observed on short chain diselenide-based monolayers formed from alcoholic solutions can be eliminated by adsorption from neat compounds as described for the thiols. A preliminary account on the stability of SAMs under hydrodynamic conditions has been given based on rotating disc electrode voltammetry. It is observed that the SAMs get well-ordered when the electrode is rotated at a fast rate leading to the hypothesis that the monolayer assembly gets annealed as a function of the rotation rate. The thesis is planned as follows: Chapter 1 gives general introduction about organic thin films with particular emphasis on self-assembled monolayers on gold and silver, their characteristics in terms of stability, interfacial properties and adsorption behaviour. Chapter 2 deals with the experimental methodologies and schematics used for the preparation and characterization of the monolayers. Chapter 3 is on the contribution of alkyl spacer to the stability of the monolayers studied using spectroscopy and electrochemistry. Chapter 4 deals with the interfacial properties of the SAMs in presence of aqueous medium. In order to emphasize the importance of the terminal functional groups, adsorption of zein has been demonstrated on surfaces of controlled wettablity. Chapter 5 explains the formation and stability of monolayers of short and long chain alkyl diselenides on gold surfaces. Chapter 6 gives the structural and interfacial characteristics of alkanethiol monolayers on silver surfaces. The stability and subsequent changes of alkanethiol monolayers under hydrodynamic conditions has been discussed in the appendix section.(For fig pl refer pdf file.)

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Alzheimer s disease (AD) is a progressive neurodegenerative disorder, mainly characterized by memory and intellectual capacity loss. AD is characterized by deposition of amyloid-β peptide, neurofibrillary tangles, neuroinflammation, energy metabolism impairment, oxidative stress and synaptic dysfunction and loss. Its multiple pathological pathways contribute to the difficulty of AD treatment and prevention. Thus, the development of new therapies for AD curing or treatment is a challenge. The purpose of this study was to indicate an organoselenium moiety, p,p -dimethoxyl-diphenyl diselenide [(MeOPhSe)2], as a promising alternative for the treatment and prevention of sporadic dementia of Alzheimer-type (SDAT), using an experimental model of dementia induced by intracerebroventricular (i.c.v.) injection of streptozotocin (STZ) in rodents. Initially, it was investigated the prophylactic action of (MeOPhSe)2. For this, mice were treated with (MeOPhSe)2 (25 mg/kg, by gavage) and STZ (2μl of 2,5mg/ml solution; i.c.v.) or vehicles, and 48h after that, the treatment was repeated. The tasks of step-down-type passive-avoidance (SDPA), Y-maze and Morris water-maze (MWM), that followed this treatment, showed that (MeOPhSe)2 protected against the impairment in learning and memory caused by i.c.v. injection of STZ in mice. (MeOPhSe)2 protected against the increase in reactive species (RS) and the reduction of glutathione (GSH) levels, as well as modulated the antioxidant enzymes. (MeOPhSe)2 inhibited the acetylcholinesterase (AChE) activity, which was increased by STZ. Subsequently, it was investigated the effectiveness of (MeOPhSe)2 in reversing the cognitive impairment and neuronal damage induced by STZ. Therefore, rats were injected with STZ (1.0 mg/8μl; 4μl/ventricle) twice, 48h apart. After 21 days of STZ injection, regular diet fed rats were supplemented with 10ppm of (MeOPhSe)2 during 30 days. At the end of this period, it was observed that (MeOPhSe)2 dietary supplementation reversed STZ-induced memory impairment in MWM, SDPA and object recognition tasks. The results on SDPA and object recognition tasks demonstrated that the (MeOPhSe)2 improved memory in rats per se. STZ enhanced the RS and protein nitration levels in cortex and decreased GSH levels on hippocampus of rats, (MeOPhSe)2 reversed these alterations. (MeOPhSe)2 normalized AChE activity (which was enhanced by STZ) in both cortex and hippocampus, but did not reverse the deficit in cerebral glucose metabolism (ATP turnover was decrease by STZ). (MeOPhSe)2 was effective in reducing STZ-induced neuronal (apoptosis) loss. Moreover, (MeOPhSe)2 suppressed neuroinflammation induced by STZ in the rats hippocampus. The organoselenium inhibited activation of microglia and astrogliosis. Based on these results, it was concluded that: 1) (MeOPhSe)2 protected and reversed the cognitive abilities decline; 2) the mechanisms involved in the neuroprotective effect of (MeOPhSe)2 are: antioxidant, AChE inhibitor; inflammation suppressor; 3) (MeOPhSe)2 did not alter the energy metabolism; and 4) (MeOPhSe)2 reduced the neuronal death. Therefore, the present study demonstrated that (MeOPhSe)2 is a promising alternative for the drug studies for treatment of cognitive disorders such as SDAT. / A doença de Alzheimer (DA) é uma síndrome neurodegenerativa progressiva caracterizada principalmente por uma perda da memória e da capacidade intelectual. Ela é caracterizada pelo depósito de fragmentos β-amilóides; emaranhados neurofibrilares; neuroinflamação; déficit do metabolismo energético; estresse oxidativo e deficiência da neurotransmissão. As múltiplas vias patológicas da DA dificultam sua prevenção e tratamento. Logo, o desenvolvimento de novas terapias para a DA é um desafio. Por esta razão, este trabalho procurou apontar uma nova molécula orgânica contendo selênio, o disseleneto de p-metoxi fenila [(MeOPhSe)2], como uma alternativa promissora para o tratamento e prevenção da demência decorrente da DA (DEDA), usando um modelo experimental de demência induzida pela injeção intracerebroventricular (i.c.v.) de estreptozotocina (ETZ) em roedores. Inicialmente, avaliou-se o efeito profilático do (MeOPhSe)2. Para tal, camundongos receberam uma dose oral do organoselênio (25mg/kg, gavage) 30 minutos antes da ETZ (2μl de uma solução 2,5mg/ml), esse procedimento foi repetido 48horas depois. Os testes da esquiva passiva, do labirinto em Y e aquático de Morris, que sucederam esse tratamento, revelaram que o (MeOPhSe)2 protegeu os camundongos do prejuízo cognitivo induzido pela ETZ. O (MeOPhSe)2 protegeu o tecido cerebral do aumento das espécies reativas (ER) e da diminuição dos níveis de glutationa (GSH) induzidos pela ETZ, assim como modulou a atividade de enzimas antioxidantes. O (MeOPhSe)2 inibiu a atividade da acetilcolinesterase (AChE), a qual foi estimulada pela ETZ. Posteriormente, investigou-se a efetividade do (MeOPhSe)2 em reverter o prejuízo cognitivo e os danos neuronais induzidos pela ETZ. Para isso, a ETZ foi injetada nos ratos (1μg/8μl, 4μl/ventrículo) em 0 e 48horas. Passados 21dias, iniciou-se uma suplementação dietética com 10ppm de (MeOPhSe)2 durante 30dias. Ao final deste período, observou-se que o (MeOPhSe)2 restaurou as habilidades cognitivas prejudicadas pela ETZ nos ratos, nos testes do labirinto aquático de Morris, esquiva passiva e reconhecimento do objeto. Os resultados referentes aos testes do reconhecimento do objeto e da esquiva passiva apontaram que o (MeOPhSe)2 melhorou per se a memória dos ratos. A ETZ aumentou os níveis de ER e de nitração de proteínas no córtex e diminuiu os níveis de GSH no hipocampo dos ratos, o (MeOPhSe)2 reverteu estas alterações. O organoselênio inibiu a atividade da AChE (aumentada pela ETZ) tanto no córtex como no hipocampo dos ratos, mas não modulou o metabolismo da glicose (ETZ diminuiu ATP-turnover). O (MeOPhSe)2 evitou a perda neuronal (apoptose) e inibiu os eventos neurodegenerativos (ativação da caspase-3) induzidos pela ETZ. O (MeOPhSe)2 suprimiu a neuroinflamação induzida pela ETZ no hipocampo dos ratos. O organoselênio inibiu a ativação das células gliais e astrócitárias. Baseado nestes resultados, conclui-se que: 1) O (MeOPhSe)2 protegeu e reverteu o declínio das habilidades cognitivas; 2) Os mecanismos envolvidos no efeito neuroprotetor do (MeOPhSe)2 são: antioxidante; inibidor da AChE; supressor da neuroinflamação; 3) O (MeOPhSe)2 não altera o metabolismo energético; e 4) O (MeOPhSe)2 reduziu a morte neuronal. Assim sendo, este trabalho demonstrou que o (MeOPhSe)2 é uma alternativa promissora para o estudo de drogas para o tratamento de desordens cognitivas como a DEDA.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / This work describes the synthesis and characterization of nineteen compounds derivative of diselenide and diselenoethers of bis(2-pyridyl) with metals of different degree of hardness. Among the nineteen obtained complex, seventeen had their structure elucidated by X-ray crystallography, besides others characterization methods, such as elemental analysis, infrared spectroscopy and mass spectrometry. Six different complexes were obtained when bis(2-pyridyl)diselenide was used as a ligand. These complexes involve metal centers of AuI, CuII, CuI, ReI, ReV and ReIII. Among the rhenium complexes, stands out the ReV complex that has a Se0 atom as a ligand, a rare exemple not previously reported in the literature. Bis(2-pyridyl)diselenoethers with one, three or four methylene groups between selenium atoms were synthesized and characterized. Among these three synthesized diselenoethers two are unprecedented in the literature (L2, L3). The methylene groups act as spacers, and were used in order to evaluate their influence across the complexation with different metals. It was observed that as longer is the carbon chain between the selenium atoms as higher is the tendency to polymer formation. The thirteen complexes obtained with the ligands bis(2-pyridyl)diselenoethers demonstrated follow a trend of complexation which agrees with Pearson's theory of acids and bases, wherein the nitrogen atoms of the ligands coordinate with harder metals and selenium atoms coordinate the softer metals. The obtained complexes were submitted to antioxidant activity tests. Tests of superoxide dismutase (SOD) showed that copper complexes 2, 7, 8, 13 and 18 had good antioxidant activity, with IC50 values less than 0.66 μM. Among these compounds the complex [Cu4I4(L1)2] (8) presented the best IC50 value in 0.08 μM. These results demonstrate that the Cu compounds mentioned have great potential to be used as mimetics of superoxide dismutase enzyme (SOD). In addition, the system CuI/bis(2-pyridyl)diselenoether showed as an efficient catalyst for the formation of a new C-S bond by cross-coupling reactions using glycerol as solvent. Still, the catalytic activity for the complex 8 was also tested for this type of reaction. Both of these catalytic systems provide the desired products in good to excellent yields when compared to the literature. / Este trabalho apresenta a síntese e caracterização de dezenove compostos derivados do disseleneto e disselenoéteres de bis(2-piridina) com metais de diferente dureza. Dos dezenove complexos obtidos, dezessete tiveram sua estrutura elucidada por difração de raios X em monocristal, além de outros métodos de caracterização como análise elementar, espectroscopia de infravermelho e espectrometria de massas. Seis diferentes complexos foram obtidos quando utilizou-se o disseleneto de bis(2-piridina) como ligante. Estes complexos envolvem os íons AuI, CuII, CuI, ReI, ReV e ReIII. Dentre os complexos de rênio, destaca-se o complexo de ReV que possui um átomo de Se0 como ligante, um caso raro até então não reportado na literatura. Disselenoéteres de bis(2-piridina) com um, três ou quatro carbonos metilênicos entre os átomos de selênio foram sintetizados e caracterizados. Dos três disselenoéteres sintetizados, dois são inéditos na literatura (L2, L3). Os grupos metilênicos atuam como espaçadores e foram utilizados com o objetivo de avaliar a sua influência frente à complexação com metais de transição de diferente dureza. Observou-se que quanto maior a cadeia carbônica entre os átomos de selênio maior é a tendência para a formação de polímeros. Os treze complexos obtidos com ligantes disselenoéteres de bis(2-piridina) demostraram seguir uma tendência de complexação que está de acordo com a teoria de Pearson sobre ácidos e bases, no qual os átomos de nitrogênio dos ligantes se coordenam a metais mais duros e os átomos de selênio se coordenam a metais mais macios. Os complexos obtidos foram submetidos a testes de atividade antioxidante. Os testes da atividade superóxido dismutase (SOD) demonstraram que os compostos de Cu 2, 7, 8, 13 e 18 apresentaram boa atividade antioxidante, com valores de IC50 menores que 0,66 μM. Dentre esses compostos o complexo [Cu4I4(L1)2] (8) foi o que apresentou o melhor valor de IC50 em 0,08 μM. Esses resultados demonstram que os compostos de Cu citados apresentam bons potenciais para serem empregados como miméticos da enzima superóxido dismutase (SOD). Adicionalmente, o sistema CuI/disselenoéter de bis(2-piridina) mostrou-se eficiente na catálise de reações de acoplamento para a formação de uma nova ligação C-S utilizando glicerol como solvente. Também testou-se a atividade catalítica do complexo 8 para este tipo de reação. Ambos os sistemas catalíticos deram origem a produtos com rendimentos de bons a excelentes quando comparados ao reportado na literatura.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Experimental models of seizure in animals have represented an important role for the understanding of the physiological and behavioural alterations associated with the human epilepsy. The induction of partial or generalized seizures is an efficient method for evaluating both the susceptibility to seizures and to investigate new anticonvulsant agents. In this sense, studies showed that the convulsive actions of the diphenyl diselenide (PhSe)2 and 2,3-dimercaptopropanol (BAL) compounds are inhibited by diazepam and phenobarbital, two classic allosteric modulators of the GABAergic system. Therefore, arises the interest of to investigate the interaction of the (PhSe)2 and BAL compounds with convulsive agents that act via blockade and/or modulation of the GABAergic system. This is the case of the pentylenetetrazol (PTZ), which exerts its convulsive action by blocking of Cl- channel of the GABAA receptor complex. Taking into account these facts, the present study had as first objective to investigate the effects of the pre-administration of (PhSe)2 and BAL in the model of chemical seizure PTZ-induced in mice (Article 1). For this purpose, mice were pretreated with (PhSe)2 (150 μmol/kg, i.p.) or BAL (250, 500, or 1000 μmol/kg, i.p.) 10 minutes prior to administration of PTZ. The obtained results showed that the pretreatment with (PhSe)2 reduced the latency for seizure PTZ-induced at doses of 40 and 60 mg/kg, beyond to cause a decrease in the latency for death PTZ-induced at dose of 60 mg/kg. However, the convulsive and lethal action PTZ-induced at dose of 80mg/kg was not affected by the pretreatment with (PhSe)2. Similarly, the pretreatment of the animals with BAL reduced the latency for seizure induced by 40 and 50 mg/kg PTZ. In addition, the latency for death PTZ-induced at dose of 40 mg/kg was significantly decreased by the pretreatment with BAL in all doses tested. Particularly, in the dose of 50 mg/kg of PTZ, a significant decrease in the latency for death occurred only when the mice were pretreated with 500 and 1000 μmol/kg of BAL. These results show that (PhSe)2 and BAL act in synergysm with PTZ potentializing its convulsive action, possibly through a modulation of the GABAergic system. Tacking into account the structural similarities between (PhSe)2 and diphenyl ditelluride (PhTe)2 compounds, our further objective was to investigate the effects of the (PhSe)2 and (PhTe)2 compounds on a model of chemical seizure 4-aminopyridine (4-AP)-induced in mice (Article 2). The convulsive action of this agent occurs through a blockade of K+ channels and activation of Ca2+ channels, with consequent release of neurotransmitters, predominantly the glutamate. Moreover, it was investigated the brain lipid peroxidation level after treatment of the animals with 4-AP, as well the effect of the pretretament with the (PhSe)2 and (PhTe)2 compounds on this level. For this purpose, mice were pretreated with (PhSe)2 and (PhTe)2 (50, 100, or 150 μmol/kg, s.c.) 30 minutes before administration of 4-AP (12 mg/kg, i.p.). The obtained results showed that the pretreatment with (PhSe)2 and (PhTe)2 (50, 100, and 150 μmol/kg) significantly increased the latency for clonic and tonic seizure, as well as inhibited the death 4-AP-induced. In addition, it was observed a significant increase in the brain lipid peroxidation levels after treatment with 4-AP, which was significantly inhibited by pretreatment with the (PhSe)2 and (PhTe)2 compounds. Therefore, these results show that (PhSe)2 and (PhTe)2 increase the latency for seizures, as well as inhibit the death 4-AP-induced. It is possible that this effect result of the modulation of redox sites of NMDA receptors, and/or modulation in the Ca2+ channels activity with consequent alteration in the neurotransmitters release. Moreover, the work provided evidences for the anticonvulsant and antioxidant properties of the (PhSe)2 and (PhTe)2 compounds, which point out for its neuroprotective properties in this model. Of general model, the utilization of the models of chemical seizure PTZ- or 4-AP-induced in mice was a useful method in the investigation of the actions on central nervous system of the (PhSe)2, (PhTe)2, and BAL compounds. The use of these convulsive models provided evidences about the convulsive actions, as well as possible mechanisms of action of the evaluated compounds. / Modelos experimentais de convulsão em animais têm representado um papel importante para a compreensão das alterações fisiológicas e comportamentais associadas com a epilepsia humana. A indução de convulsões parciais ou generalizadas é um método eficiente para avaliar tanto a susceptibilidade às convulsões quanto investigar novos agentes anticonvulsivantes. Neste sentido, estudos demonstraram que as ações convulsivantes dos compostos disseleneto de difenila (PhSe)2 e 2,3-dimercaptopropanol (BAL) são inibidas por diazepam e fenobarbital, dois moduladores alostéricos clássicos do sistema GABAérgico. Logo, surge o interesse de investigar os efeitos da interação dos compostos (PhSe)2 e BAL e agentes convulsivantes que ajam através do bloqueio e/ou modulação do sistema GABAérgico. Este é o caso do agente pentilenotetrazol (PTZ), o qual exerce sua ação convulsiva por meio de um bloqueio do canal de Cl- do complexo do receptor GABAA. Considerando estes fatos, o presente estudo teve como primeiro objetivo investigar os efeitos da pré-administração de (PhSe)2 e BAL no modelo de convulsão química induzida por PTZ em camundongos (Artigo 1). Para este propósito, camundongos foram pré-tratados com (PhSe)2 (150 μmol/kg, i.p.) ou BAL (250, 500 ou 1000 μmol/kg, i.p.) 10 minutos antes da administração de PTZ. Os resultados obtidos demonstraram que o pré-tratamento com (PhSe)2 reduziu a latência para a convulsão induzida por PTZ nas doses de 40 e 60 mg/kg, além de causar um decréscimo na latência para a morte induzida por PTZ na dose de 60 mg/kg. Entretanto, a ação convulsivante e letal induzida por PTZ na dose de 80 mg/kg não foi afetada pelo pré-tratamento com (PhSe)2. Similarmente, o pré-tratamento dos animais com BAL reduziu a latência para a convulsão induzida por 40 e 50 mg/kg de PTZ. Além disso, a latência para a morte induzida por PTZ na dose de 40 mg/kg foi significativamente diminuída pelo pré-tratamento com BAL em todas as doses testadas. Particularmente, na dose de 50 mg/kg de PTZ, decréscimo significativo na latência para a morte ocorreu somente quando os camundongos foram pré-tratados com 500 e 1000 μmol/kg de BAL. Estes resultados demonstram que o (PhSe)2 e BAL agem em sinergismo com o PTZ potencializando sua ação convulsiva, possivelmente através de uma modulação do sistema GABAérgico. Tendo em vista as similaridades estruturais entre os compostos (PhSe)2 e ditelureto de difenila (PhTe)2, nosso próximo objetivo foi investigar o efeito dos compostos (PhSe)2 e (PhTe)2 sobre um modelo de convulsão química induzida por 4-aminopiridina (4-AP) em camundongos (Artigo 2). A ação convulsiva deste agente ocorre através do bloqueio de canais de K+ e ativação de canais de Ca2+, com conseqüente liberação de neurotransmissores, predominantemente o glutamato. Além disso, foram investigados os níveis de peroxidação lipídica cerebral após o tratamento dos animais com 4-AP, bem como o efeito do pré-tratamento com os compostos (PhSe)2 e (PhTe)2 sobre esses níveis. Para este fim, camundongos foram pré-tratados com (PhSe)2 e (PhTe)2 (50, 100 ou 150 μmol/kg, s.c.) 30 minutos antes da administração de 4-AP (12 mg/kg, i.p.). Os resultados obtidos demonstraram que o pré-tratamento com (PhSe)2 e (PhTe)2, nas doses de 50, 100 e 150 μmol/kg, aumentou significativamente a latência para a convulsão clônica e tônica, bem como inibiu a morte induzida por 4-AP. Além disso, observamos um significativo aumento nos níveis de peroxidação lipídica cerebral após o tratamento com 4-AP, o qual foi significativamente inibido pelo pré-tratamento com os compostos (PhSe)2 e (PhTe)2. Portanto, estes resultados demonstram que (PhSe)2 e (PhTe)2 aumentam a latência para as convulsões, bem como inibem a morte induzida por 4-AP. É possível que este efeito resulte da modulação de sítios redox de receptores NMDA, e/ou modulação na atividade de canais de Ca2+ com conseqüente alteração na liberação de neurotransmissores. Além disso, o trabalho forneceu evidências para as propriedades anticonvulsivas e antioxidantes dos compostos (PhSe)2 e (PhTe)2, as quais apontam para suas propriedades neuroprotetoras neste modelo. De forma geral, a utilização dos modelos de convulsão química induzida por PTZ e 4-AP em camundongos foi um método útil na investigação das ações sobre o sistema nervoso central dos compostos (PhSe)2, (PhTe)2 e BAL. O emprego destes modelos convulsivos forneceu evidências acerca das ações convulsivas, bem como possíveis mecanismos de ação dos compostos avaliados.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Environmental contamination caused by frequent use of herbicides in agriculture has increased in last decades. The quinclorac and clomazone herbicides are widely used in agriculture, which can cause contamination to organisms, such as fish. However, it is necessary studies in order to minimize the toxic effects of these compounds on aquatic ecosystems. Micronutrients such as selenium, which is essential in the nutrition of fish, may have antioxidant functions against oxidative damage caused by herbicides. The objective of this study was to verify whether a diet supplemented with diphenyl diselenide [(PhSe)2], has a protective effect against damage induced by herbicides quinclorac and clomazone in fish species Cyprinus carpio (carp) and Rhamdia sp. (silver catfish). In the first experiment, carp were fed a diet without (PhSe)2 or a diet containing 3.0 mg/Kg of (PhSe)2 for 60 days and after were exposed to 1 mg/L of quinclorac for 192 h. Thiobarbituric acid reactive substances (TBARS), protein carbonyl, non-protein thiols (SHNP), ascorbic acid (AA), and the activity of catalase (CAT), superoxide dismutase (SOD) and glutathione S-transferase (GST) were determined in liver, gills, brain and muscle of carp. The quinclorac increased TBARS levels in liver and gills, decreased NPSH levels in brain and muscle, AA in muscle, inhibited enzymes SOD in liver and GST in liver and brain. The (PhSe)2 reversed these effects by preventing the increase of TBARS in liver and gills and recovering GST activity in liver and NPSH in brain and muscle. In the second experiment, silver catfish were fed a diet without (PhSe)2 or a diet containing 3.0 mg/Kg of (PhSe)2 for 60 days and after were exposed to 1 mg/L of quinclorac for 192 h. We investigated the effect of (PhSe)2 on plasma metabolic changes, enzymes of intermediary metabolism, pro-oxidants parameters and antioxidant defense in the liver of silver catfish. The weight, length and hepatic somatic index (HSI) were also determined. Animals exposed to quinclorac showed a decrease at HSI, an increase lactate levels in plasma and in the enzymes fructose bifosfatase (FBPase), glucose-6-phosphatase (G6Pase), glycogen phosphorylase (GPase) and aspartate aminotransferase (AST) in liver. Furthermore, were observed increased of TBARS, decreased NPSH and AA levels and inhibition of SOD in liver of silver catfish. The (PhSe)2 was effective in protecting the liver of silver catfish by decreased TBARS, increasing NPSH levels, AA and the activity of SOD. However, the (PhSe)2 was not effective in recovery the effects caused by the increase of hepatic enzyme AST. In the third experiment investigated the ability of (PhSe)2 in reducing oxidative damage in the liver, gills and muscle of carp and silver catfish exposed to clomazone. Silver catfish and carp were fed with a diet without (PhSe)2 or a diet containing 3.0 mg/Kg of (PhSe)2 for 60 days and after were exposed to 1 mg/L of clomazone (192 h). At the end of the exposure period, oxidative parameters and antioxidant defenses were determined. Silver catfish exposed to clomazone showed increased TBARS in liver and muscle and protein carbonyl in liver and gills. In addition, decrease in levels of NPSH in liver and gills, AA in the liver and of enzyme glutathione peroxidase (GPx) in liver was observed. The (PhSe)2 reversed some effects caused by clomazone in silver catfish, preventing the increase in TBARS and protein carbonyl and by increasing NPSH and AA levels. Moreover, clomazone no caused apparent situation of oxidative stress in carp and thus cannot assess the role of (PhSe)2 in this species exposed to that herbicide. However, the (PhSe)2 in both species reduced per se the TBARS levels in liver and muscle, increased NPSH and AA levels and the activity of GPx in liver. Considering that exposure to herbicides is more frequent and that is the cause of several changes in fish, the results of these studies are of great importance, since the (PhSe)2 may represent an alternative to prevent or mitigate toxicity caused by herbicides in different fish species of commercial importance. / A contaminação ambiental causada pelo uso frequente de herbicidas na agricultura tem aumentado nas últimas décadas. O quinclorac e o clomazone são herbicidas amplamente utilizados na agricultura, os quais podem causar contaminação a organismos, como os peixes. Entretanto é necessário estudos no sentido de minimizar os efeitos tóxicos desses compostos em ecossistemas aquáticos. Micronutrientes como o selênio, o qual é essencial na nutrição de peixes, podem ter funções antioxidantes contra danos oxidativos causados por herbicidas. Assim, o objetivo deste trabalho foi verificar se uma dieta suplementada com o disseleneto de difenila [(PhSe)2], possui efeito protetor contra danos induzidos pelos herbicidas quinclorac e clomazone em peixes das espécies Cyprinus carpio (carpas) e Rhamdia sp. (jundiás). No primeiro experimento carpas foram alimentadas com uma dieta sem (PhSe)2 ou uma dieta contendo 3.0 mg/Kg de (PhSe)2 por 60 dias e após foram expostas a 1 mg/L do quinclorac por 192 horas. Substâncias reativas ao ácido tiobarbitúrico (TBARS), carbonilação de proteínas, tióis não proteicos (SHNP), ácido ascórbico (AA), bem como a atividade das enzimas catalase (CAT), superóxido dismutase (SOD) e glutationa S-transferase (GST) foram determinados em fígado, brânquias, cérebro e músculo de carpas. O quinclorac aumentou os níveis de TBARS em fígado e brânquias, diminuiu os níveis de SHNP em cérebro e músculo e de AA no músculo e inibiu as enzimas SOD em fígado e GST em fígado e cérebro. O (PhSe)2 reverteu esses efeitos prevenindo o aumento do TBARS em fígado e brânquias e recuperando a atividade da GST em fígado e SHNP em cérebro e músculo. No segundo experimento jundiás foram alimentados com uma dieta sem (PhSe)2 ou uma dieta contendo 3.0 mg/Kg de (PhSe)2 por 60 dias e após expostos a 1 mg/L do quinclorac por 192 horas. Investigou-se o efeito do (PhSe)2 sobre as alterações metabólicas no plasma, enzimas do metabolismo intermediário, bem como parâmetros pró-oxidantes e de defesa antioxidante em fígado dos jundiás. O peso, comprimento e índice hepatossomático (IHS) também foram determinados. Animais expostos ao quinclorac apresentaram diminuição no IHS, aumento nos níveis de lactato em plasma e das enzimas frutose bifosfatase (FBPase), glicose 6-fosfatase (G6Pase), glicogênio fosforilase (GPase) e da asparato aminotransferase (AST) em fígado. Além disso, foram observadas aumento do TBARS, diminuição nos níveis de SHNP e AA e inibição da enzima SOD no fígado dos jundiás. O (PhSe)2 foi efetivo em proteger o tecido hepático dos jundiás por diminuir o TBARS, aumentar os níveis de SHNP, AA, e a atividade da SOD. Porém o (PhSe)2 não foi eficaz na recuperação dos efeitos causados pelo aumento da enzima hepática AST. No terceiro experimento investigou-se a capacidade do (PhSe)2 em reduzir o dano oxidativo em fígado, brânquias e músculo de carpas e jundiás expostos ao clomazone. Jundiás e carpas foram alimentados com uma dieta sem (PhSe)2 ou uma dieta contendo 3.0 mg/Kg de (PhSe)2 por 60 dias e após foram expostos a 1 mg/L do clomazone (192 horas). No final do período de exposição, parâmetros oxidativos e defesas antioxidantes foram determinados. Jundiás expostos ao clomazone apresentaram aumento do TBARS em fígado e músculo e da proteína carbonil em fígado e brânquias. Além da diminuição nos níveis de SHNP em fígado e brânquias, AA em fígado e inibição da enzima glutationa peroxidase (GPx) em fígado. O (PhSe)2 reverteu alguns efeitos causados pelo clomazone em jundiás, prevenindo o aumento do TBARS e da proteína carbonil e aumentando os níveis de SHNP e AA. Por outro lado, o clomazone não causou uma aparente situação de estresse oxidativo em carpa e assim não podemos avaliar o papel do (PhSe)2 nesta espécie exposto a esse herbicida. Porém o (PhSe)2 em ambas as espécies diminuiu per se os níveis de TBARS em fígado e músculo, aumentou os níveis de SHNP e AA e atividade da enzima GPx em fígado. Considerando-se que a exposição aos herbicidas é cada vez mais frequente e que é a causa de diversas alterações em peixes, os resultados desses trabalhos são de grande importância, uma vez que o (PhSe)2 pode representar uma alternativa para prevenir ou atenuar a toxicidade causada por herbicidas em diferentes espécies de peixes de importância comercial.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Treatment with neuroleptic drugs has been associated to side effects like tardive diskynesia and hepatic damage. In spite of the several reports of hepatotoxicity after neuroleptic administration, few data are available in the literature about these effects and the precise mechanisms by which neuroleptics induce hepatotoxicity remain unclear. In the same way, there are few studies about the effects of neuroleptics on kidney. In this way, the first aim of the present work was to assess the effects of chronic exposure to fluphenazine in liver and kidney of rats, as well as the protective effect of diphenyl diselenide on the fluphenazine-induced damage (article 1). Long-term treatment with fluphenazine caused an increase in lipid peroxidation levels in liver and kidney homogenates, a decrease in hepatic SOD activity, and an increase in hepatic CAT activity. Diphenyl diselenide was able to protect liver and kidney from lipid peroxidation, ameliorate SOD activity in liver, and prevent the increase in hepatic CAT activity. Diphenyl diselenide treatment did not affect δ-ALA-D activity, but fluphenazine and/or in combination with diphenyl diselenide showed an inhibitory effect on δ-ALA-D activity in liver and kidney. The second objective of this study was to determine whether the treatment with haloperidol (HP), valerian or both in association impairs liver or kidney functions (article 2). Valerian did not affect oxidative stress parameters in the liver or kidney of rats. HP only increased glutathione (GSH) depletion in liver, but not in kidney. However, when HP was associated with valerian, an increase in lipid peroxidation levels and reactive species production was observed in the hepatic tissue. HP and valerian when administered independently did not affect the activity of hepatic and renal δ-ALA-D, however, these drugs administered concomitantly provoked an inhibition of hepatic δ-ALA-D activity. Serum aspartate aminotransferase (AST) activity was not altered by any treatment. However, serum alanine aminotransferase (ALT) activity was higher in the HP group and HP plus valerian group. Taken together, these results indicate the relationship between the treatment with flufenazine and the oxidative stress, and also point to the protective role of diphenyl diselenide on the oxidative damage induced by fluphenazine in liver. Our data also suggest adverse interactions between haloperidol and valerian treatments causing hepatic damage related to oxidative stress. / O tratamento com drogas neurolépticas tem sido associado a efeitos colaterais como a discinesia tardia (DT) e o dano hepático. Apesar dos inúmeros casos de hepatotoxicidade após a administração de neurolépticos, são escassos os dados na literatura a respeito desses efeitos e o mecanismo exato pelo qual neurolépticos induzem hepatotoxicidade permanece incerto. Da mesma forma, existem poucos estudos relatando os efeitos dos neurolépticos sobre o rim. Dessa forma, o primeiro objetivo deste trabalho foi avaliar os efeitos da exposição crônica à flufenazina em fígado e rim de ratos bem como o efeito protetor do disseleneto de difenila sobre o dano induzido por flufenazina (artigo 1). O tratamento prolongado com flufenazina causou um aumento na peroxidação lipídica no fígado e no rim, uma diminuição na atividade da SOD hepática, e um aumento na atividade da CAT hepática. O disseleneto de difenila foi capaz de proteger o fígado e o rim da peroxidação lipídica, melhorou a atividade da SOD no fígado, e preveniu o aumento na atividade da CAT no fígado. O tratamento com disseleneto de difenila não afetou a atividade da δ-ALA-D, mas a flufenazina e/ou em combinação com disseleneto de difenila demonstrou ter efeito inibitório sobre a atividade da δ-ALA-D no fígado e no rim. O segundo objetivo deste estudo foi determinar se o tratamento com haloperidol (HP), valeriana ou a associação de ambas as drogas pode alterar as funções hepáticas e renais (artigo 2). A valeriana não afetou nenhum parâmetro de estresse oxidativo no fígado e no rim dos ratos. O HP apenas aumentou a depleção de glutationa (GSH) no fígado, mas não no rim. Entretanto, quando o HP foi associado com a valeriana, um aumento na peroxidação lipídica e produção de espécies reativas foram observados no tecido hepático. HP e valeriana quando administrados independentemente não afetaram a atividade da δ-ALA-D hepática e renal, contudo, quando estas drogas foram administradas concomitantemente provocaram uma inibição da atividade da δ-ALA-D hepática. A atividade da aspartato aminotransferase (AST) do soro não foi alterada por nenhum dos tratamentos. No entanto, a atividade da alanina aminotransferase (ALT) do soro estava aumentada nos grupos tratados com HP e HP mais flufenazina. Juntos estes resultados indicam uma relação entre o tratamento com flufenazina e o estresse oxidativo, e também apontam para o papel protetor do disseleneto de difenila no dano oxidativo induzido por flufenazina no fígado. Nossos dados também sugerem interações adversas no tratamento com haloperidol e valeriana, ocasionando dano hepático associado ao estresse oxidativo.

La conception de ligands est d'une grande importance pour le développement de la catalyse métallique, conformément à une approche de chimie durable.La première partie de cette thèse porte sur une revue bibliographique détaillée des ligands phosphorés couramment employés dans les systèmes catalytiques pour les réactions de couplage carbone‒carbone catalysées au palladium. La deuxième partie traite du contrôle conformationnel du squelette ferrocénique dans les ligands polyphosphines. Ce contrôle conformationnel vise à induire des interactions inédites entre deux atomes de phosphore, et également avec des centres métalliques. De nouveaux anions cyclopentadiényles substitués et encombrés ont été synthétisés, et ont permis de réaliser la synthèse de triphosphines ferrocéniques inédites. Les réactions avec le fer (II) des sels d'anions cyclopentadiényles substitués par des groupements encombrés (tertio-butyle, trityle, super-trityle) et des groupements phosphino enrichis ou appauvris en électrons (isopropyle, cyclohexyle, furyle) ont conduit à une série de nouveaux ligands polyphosphines ferrocéniques multidentes. Leurs coordinations à des sels de palladium ou de platine ont été étudiées. Les complexes de coordination correspondants ont été isolés avec de très bons rendements et caractérisés en solution par RMN 1H, 13C, 31P et à l'état solide par Diffraction des Rayons X.La troisième partie décrit la synthèse et la caractérisation de diphosphines ferrocéniques inédites. Des investigations ont été menées en électrochimie sur ces ligands et les propriétés électroniques des dérivés séléniés correspondants ont été étudiées par RMN 31P‒77Se.Ces ligands se sont montrés des auxiliaires efficaces pour l’arylation pallado-catalysée d’hétéroaromatiques dans l’activation C‒H ou dans le couplage C‒O, surtout à faible charge de catalyseur, en accord avec les exigences du développement de chimie durable / The design of ligands is of great importance for the development of metal catalysis, in keeping with an ever more sustainable approach of chemistry.The first part of this thesis focuses on a detailed literature review of phosphorus ligands commonly used in catalytic systems for the coupling reactions catalyzed carbon-carbon palladium.The second part deals with the conformational control of the ferrocene backbone within polyphosphine ligands. This conformational control aims at inducing unedited interactions between phosphorus atoms, and also with metal centers. New substituted and hindered cyclopentadienyl rings were synthesized, which allow the assembling of original ferrocenyl triphosphines. The reactions with iron(II) salts of cyclopentadienyl anions substituted with hindering groups (tert-butyl, trityl, super-trityl) and holding either electron-donor or electron-withdrawing phoshino groups (isopropyl, cyclohexyl, furyl) afford a set of novel multidentate ferrocenyl phosphine ligands. Their coordinations towards palladium and platinum were studied. The corresponding coordination complexes were isolated in high yields and fully characterized in solution by multinuclear 1H, 13C, 31P NMR and in solid state by X-Ray cristallography.The third part describes the synthesis and characterization of original ferrocenyl diphosphines. Electrochemical investigation of these ligands and electronic properties of their corresponding diselenide derivatives by NMR 31P‒77Se coupling constants were studied.These ligands were found efficient auxiliaries for palladium-catalyzed arylation of heteoaromatics through C–H bond activation or C‒O coupling, especially at low loading of catalyst, in agreement with sustainable chemistry development requirement