No description available.

The utilization of click chemistry to perform inter- and intramolecular ligation on DNA has become ubiquitous in the literature. Advances in copper (I) stabilizing ligands that prevent DNA degradation via redox pathways have provided nucleic acid researchers access to the efficiency and quantitative nature of the click reaction. The majority of ligation procedures in the literature are performed in solution after DNA assembly and modification with alkyne reporter groups. However, without specialty alkyne reagents that can be sequentially and selectively deprotected, the solution phase method requires that the click reaction be performed on all DNA-attached alkynes simultaneously. Therefore, the variability of the azide reagent is limited to a singular R group. However, performing the click reaction on DNA during synthetic elongation (immediately after each alkyne installation) allows for the possibility of performing multiple click reactions with variable azide reagents. Unfortunately, most solid phase click procedures require long reaction times or the utilization of microwave irradiation to accelerate the reaction. The development of methods for the ligation of azides to alkynes without the use of microwave irradiation on solid phase is potentially very useful. Herein, we report a simple, efficient, and robust solid phase synthetic method for the ligation of azido-diamondoids to the alkyne-modified phosphate backbone of DNA with click chemistry using [Cu(CH₃CN)₄]PF₆ without stabilizing ligand. Interestingly, it was found that as the size of diamondoid increased, a corresponding increase in melting temperature of hybridized duplexes was observed. The developed method has the potential to complement existing DNA ligation procedures for applications in biotechnology and diagnostics. Interest in peptides incorporating boronic acid moieties is increasing due to their potential as therapeutics/diagnostics for a variety of diseases such as cancer. The utility of peptide boronic acids may be expanded with access to vast libraries that can be deconvoluted rapidly and economically. Unfortunately, current detection protocols using mass spectrometry are laborious and confounded by boronic acid trimerization, which requires time consuming analysis of dehydration products. These issues are exacerbated when the peptide sequence is unknown, as with de novo sequencing, and especially when multiple boronic acid moieties are present. Thus, a rapid, reliable and simple method for peptide identification is of utmost importance. Herein, we report the identification and sequencing of linear and branched peptide boronic acids containing up to five boronic acid groups by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). Protocols for preparation of pinacol boronic esters were adapted for efficient MALDI analysis of peptides. Additionally, a novel peptide boronic acid detection strategy was developed in which 2,5-dihydroxybenzoic acid (DHB) served as both matrix and derivatizing agent in a convenient, in situ, on-plate esterification. Finally, we demonstrate that DHB-modified peptide boronic acids from a single bead can be analyzed by MALDI-MSMS analysis, validating our approach for the identification and sequencing of branched peptide boronic acid libraries. It is well known that RNA ligands incorporating basic and intercalating moieties display high RNA affinity. Unfortunately, these ligands are also often plagued by promiscuous binding to off-target substrates. Due to the potential utility of RNA ligands in biology and medicine, it is imperative to elucidate RNA binders which display high specificity as well as affinity. Boronic acid peptides promise unique RNA binding motifs through the interaction between the empty p-orbital of boron and the 2'-hydroxyl group of RNA. Herein, we describe the incorporation of lysine and phenylalanine boronic acid analogues into a branched peptide combinatorial library in an effort to impart increased selectivity towards the HIV-1 Rev Response Element (RRE). We were able to easily select and deconvolute 6 resulting "hit" peptides from 65,536 unique library members by high throughput screening and de novo sequencing. Although we were unable to evaluate peptide selectivity towards RRE due to general insolubility in aqueous media, we demonstrated the efficient deconvolution of a branched peptide library that incorporates boronic acids. / Ph. D.

La thèse porte sur le développement de stratégies non conventionnelles de peptides contraints et la modulation des structures secondaires pour augmenter la reconnaissance biologique de ces peptides.Les peptides jouent un rôle important dans de nombreux processus et sont donc d’un intérêt grandissant pour l’industrie pharmaceutique. Cependant, leur utilisation comme médicament reste limitée à cause de leur flexibilité conformationnelle, leur sensibilité aux protéases et leur faible biodisponibilité et pharmacodynamie. Dans ce contexte, la caractérisation des interactions ligands-récepteurs est cruciale pour comprendre les processus de reconnaissance et le design d’agonistes sélectifs, potentiels nouveaux médicaments. Ainsi, le développement d’outils portant des modifications structurales présente un intérêt grandissant pour trouver de nouveaux médicaments. Ces changements structuraux permettent d’affiner les conformations privilégiées et donc de comprendre la spécificité d’interactions par rapport à des sous-types de récepteurs ayant des propriétés physicochimiques et pharmacologiques particulières.Dans la première partie de ce travail, une stratégie optimisée pour la synthèse de fragments N-terminaux (1-34) de la séquence PTHrP.PTHrP(1-34)NH2 est décrite : H-Ala1-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp10-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg20-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu30-Ile-His-Thr-Ala-NH2. D’un point de vue synthètique, la formation de clusters dus à la présence de plusieurs résidus arginine, l’encombrement stérique, la longueur de la séquence et la présence de résidus hydrophobes dans la partie 19-28 du PTHrP rendent la synthèse difficile et donnent un enjeu important à la synthèse. C’est pourquoi, nous avons focalisé nos efforts sur l’optimisation du protocole opératoire. En particulier, nous avons montré l’intérêt d’utiliser une activation sous microondes pour la synthèse, avantages en termes de rendement et de pureté du peptide. La synthèse de PTHrP(1-34) a été optimisée à la fois sous activation par la temperature et sous microondes dans des conditions identiques. Les micoondes ont aussi été utilisé pour la synthèse de PTHrP(1-34)NH2. L’élongation de la chaine peptidique a été suivie par l’analyse UPLC-ESI-MS des fragments obtenus après micro clivage assisté par micro ondes. Cette stratégie nopus a permis , à travers la caractérisation des séquences délétées, d’identifier les points critiques de la synthèse, nécessitant les microondes. Dans la seconde partie de la thèse, ont été entreprises le design et la synthèse d’une série de cyclopeptides (i-to-i+5) 1,4- et 4,1-disubstitués pontés par un triazole, analogues de MTII. MTII, Ac-Nle4-c[Asp5-D-Phe7-Lys10]αMSH4-10-NH2 est un super agoniste agissant d’une manière non sélective des récepteurs de la mélanocortine MC1R, MC3R, MC4s, et MC5s. Ce peptide est caractérisé par un lien lactame entre les résidus Asp5 et Lys 10 stabilisant une structure β-turn, cruciale pour l’activité.Cependant MTII n’est pas sélectif des différents sous-type des récepteurs de la mélanocortine. L’importance particulière du système mélanocortine souligne le besoin de trouvé des analogues plus sélectifs, présentant une meilleure pharmacocinétique et une meilleure biodisponibilité. L’introduction du triazole [1,2,3] utilise dans nos analogues vise à stabiliser une conformation , à la place du lien lactame de MTII. La diversité est apportée par une variation de la position du triazole de i à i+5. Il est obtenu par une cycloaddition alcyne/azoture catalysée par le Cu(I) (CuAAC), générant très sélectivement l’adduit 1,4. Les analogues clickés de MTII présentant une position différente du triazole ont été synthétisé en phase solide et en solution. Les études conformationnelles et biologiques ont été conduites pour identifier l’analogue présentant la meilleure conformation β-turn conduisant à la meilleure activité biologique. / PhD Thesis of Chiara TESTANon conventional synthetic strategies of stapled peptides: modulation of secondary structures to optimise biological recognitionPeptides play an important role in many biologically relevant processes and are of outstanding interest in pharmaceutical research. However their use as drugs is limited by their conformational flexibility, instability to proteases, poor oral bioavailability, and pharmacodynamics. In this contest the characterization of ligand-receptor interactions is crucial to understand the biological processes and to design potent and selective agonist, which could be used as new drug candidates.Therefore, the development of an expansive toolbox of structural modifications that can be used to fine tune the predominant conformations to achieve modulation of specificity toward receptor subtypes, physicochemical and pharmacological properties continues to be of great interest in the development of peptide-based drugs.In the first part of the work it is described an optimized strategy for the synthesis of the N-terminal fragments (1-34) of PTHrP.PTHrP(1-34)NH2 sequence is: H-Ala1-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp10-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg20-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu30-Ile-His-Thr-Ala-NH2. Considering the presence of clusters of arginines, sterically hindered and hydrophobic amino acid residues in the 19-28 sequence of PTHrP, and the considerable length of the peptide, the synthesis of PTHrP(1-34)NH2 is quite challenging. Therefore we focused our effort in the optimization of a synthetic protocol for this peptide. In particular, we showed the advantages that the use of microwaves have, in obtaining the best results in terms of yield and purity of the final peptide. The synthesis of PTHrP(1-34) was performed following the conventional RT and the MW-assisted SPPS protocol. In both cases the synthesis was performed using the same instrument, the same excess of reagents and molar ratios.Microwaves have also been used to monitor the synthesis of the peptide PTHrP(1-34)NH2. In fact, during the elongation of the peptide chain were analyzed by UPLC-ESI-MS intermediate fragments obtained through micro-cleavages assisted by microwaves. This strategy has allowed us, through the characterization of sequences of deletion, to understand what are the critical points of the synthesis that may require the use of microwaves.In the second part of the thesis we reported the design and the synthesis of a series of (i-to-i+5) 1,4- and 4,1-disubstituted [1,2,3]triazole-bridged cyclopeptides, derived from the scaffold of MTII. MTII, Ac-Nle4-c[Asp5-D-Phe7-Lys10]αMSH4-10-NH2, is a potent long acting non-selective super-agonist of melanocortin receptors MC1R, MC3R, MC4s, and MC5s. This peptide is characterized by lactam bridge between residues Asp5 and Lys10 stabilizing a type-II β-turn structure, that is critical for its bioactivity. Nevertheless, MTII is not selective for the different subtype of melanocortin receptors. The particular importance of melanocortin system, underscores the unmet need for highly selective, pharmacokinetically diverse, and bioavailable agonists and antagonists analogs. The introduction of [1,2,3]triazole was aimed to stabilize a β-turn conformation replacing the lactam bridge of MTII with an i-to-i+5 side chain-to-side chain cyclization via CuI-catalyzed azido-to-alkyne 1,3-dipolar cycloaddition (CuAAC) generating 1,4- or 4,1-disubstituted [1,2,3]triazolyl-containing ring structures. Clicked MT-II analogs presenting different permutations of bridges, containing 4 or 5 methylenes, and a triazolyl moiety were synthesized by a combination of solid phase assembly of the peptide and in solution CuAAC. Conformational and biological studies were performed on the peptides synthesized to identify the location and direction of the [1,2,3]triazolyl in the bridge that best reproduce the β-turn conformation leading to highly potent and sel

Les MOFs résultent de l’organisation de polyèdres métalliques reliés par des molécules organiques chélatantes pour former un réseau poreux. La construction de solides hybrides organiques/inorganiques permet d’imaginer un très grand nombre de matériaux aux propriétés structurales et physico-chimiques variées. Le confinement du substrat dans une structure rigide, associé à des propriétés particulières des clusters métalliques ainsi qu’à des parois pouvant être fonctionnalisées, fournissent un environnement catalytique unique, plaçant les MOF à la frontière entre les espèces types zéolites et les enzymes. Cependant, il existe aujourd’hui très peu de MOFs possédant plus d’une fonction catalytique. Néanmoins, les propriétés catalytiques des MOFs peuvent être améliorées de façons non négligeables grâce aux méthodes de post-fonctionalisation. Dans ce travail, nous reportons le développement d’une méthode de post-fonctionnalisation originale des amino-MOFs. La première étape consiste à convertir la fonction amine en fonction azoture. Puis, sans isolation ni purification, le MOF fonctionnalisé est obtenu par « Click Chemistry » en ajoutant l’alcyne correspondant. Cette méthode peut être appliquée à tous les types d’amino-MOFs et à quasi toutes les fonctions chimiques que l’on souhaite greffer. Une large librairie de nouveaux matériaux a ainsi été obtenue et complètement caractérisée. Cette méthode a aussi été utilisée pour créer des MOFs catalytiques à façon pour une réaction de transesterification, ainsi que pour l’investigation de nouvelles applications plus fines (niches industrielle) / MOFs result from the association of metallic clusters connected by organic linkers to form a net. It is acknowledged that ultimately MOFs could mimic “enzymes” using “molecular recognition” concept to allow high chemio-, regio-, enantio-selectivity. We could indeed anticipate MOFs as potential “artificial enzymes” that can combine several properties at the nanometer scale in a concerted fashion. However to date, the number of MOFs with more than one reactive “catalytic” function is rather scarce. A key to address advanced MOF materials suitable for more sophisticated applications is to add functionalities of greater complexity in a controlled manner. The ability to modify the chemical environment of the cavities within MOFs would allow tuning of the interactions with guest species, and serve as a route to tailor the chemical reactivity of the framework. However, the introduction of reactive chemical functions by self-assembly methods is not a trivial task. In this work, we report an original PSM method starting from amino derived MOFs. The first step consists in converting the amino group into azide (N3). Without isolation nor purification, the desired functionalized material is obtained by grafting the corresponding alkyne using “Clik Chemistry”. This method can be applied to all kind of amino-MOFs and to all kind of grafted chemical functions. A diverse library of original MOFs was synthesized and characterized. Finally, this method was used to engineer catalytic MOFs for the transesterification of ethyldecanoate with methanol or to investigate applications in specialized industrial niches

O-GlcNAcilação, ou modificação por O-GlcNAc, consiste na glicosilação de proteínas envolvidas em processos celulares fundamentais, e a sua desregulação tem sido associada a importantes doenças tais como diabetes tipo 2, doenças neurodegenerativas, cardiovasculares e câncer. A O-GlcNAcilação é regulada por duas enzimas: O-GlcNAc transferase (OGT) e O-GlcNAcase (OGA). Muitos inibidores da OGA descritos apresentam falta de seletividade entre a OGA e as isoenzimas Hex A e B lisossomais, o que pode ocasionar acúmulo de gangliosídeos no interior dos lisossomos e doenças neurodegenerativas. Desta forma, visando a obtenção de inibidores mais seletivos, foram propostos neste estudo a síntese e avaliação biológica de compostos derivados de N-acetilglicosamina, contendo na posição C-2 o anel 1,2,3-triazólico 1,4-di-substituído com diferentes cadeias laterais, na maioria contendo anéis aromáticos na sua extremidade, e a investigação da influência da extensão da cadeia entre os anéis na cavidade da OGA. Foram obtidos os derivados triazólicos 1, 2 (no estudo anterior) e 8a-j (no presente trabalho), em rendimentos bons a moderados, por meio da estratégia de click chemistry, envolvendo a reação de CuAAC entre o intermediário azido glicopiranosídeo 6, e dez diferentes alcinos, dos quais cinco foram previamente sintetizados (9 - 11, 14 e 15), e cinco disponíveis comercialmente. Para a síntese dos precursores acetilênicos 9 - 11, 14 e 15 foram utilizadas diferentes estratégias sintéticas de acordo com cada alcino, como, por exemplo, reações de substituição nucleofílica e aminação redutiva. Os derivados triazólicos foram obtidos como mistura de anômeros ?:? na proporção de 10:1, respectivamente. Devido à seletividade da enzima OGA apenas para substratos ?, os compostos 8a-h foram purificados por CLAE-DAD para separação das misturas. Posteriormente, foi possível realizar a cristalização do azido 6 em etanol, com consequente separação do anômero ? deste intermediário, o que auxiliou na etapa sintética dos derivados 8i e 8j como anômeros puros. Os ensaios de MTT não evidenciaram citotoxicidade para os compostos, avaliados em 1,0 ?M. Os ensaios de western blot e enzimáticos dos derivados 1, 2 e 8a-j demonstraram que apenas os compostos 1, 8i e 8j foram ativos para OGA, com valores de IC50 de 0,49, 0,52 e 0,72 ?M, respectivamente. A partir deste resultado, foi possível sugerir que a extensão ideal da cadeia ligada entre os anéis triazólico e aromático é de dois carbonos (1), podendo acomodar um heteroátomo de nitrogênio (8i) ou oxigênio (8j). Ademais, os ensaios enzimáticos dos compostos 1, 8i e 8j, avaliados para as Hex A e B, apresentaram IC50 de 550, 569 e 571 ?M, respectivamente, sugerindo alta seletividade destes compostos para a OGA em detrimento das isoenzimas lisossomais. Com o trabalho desenvolvido em parceria com a Dra. Nuria E. Campillo (CSIC) foram planejados novos derivados não-carboidratos capazes de realizar interações com importantes resíduos do sítio catalítico da OGA e com potencial atividade biológica. / O-GlcNAcylation, or O-GlcNAc modification, consists of the glycosylation of proteins involved in fundamental cellular processes, and its deregulation has been linked to important diseases such as type 2 diabetes, neurodegenerative, cardiovascular diseases, and cancer. O-GlcNAcylation is regulated by two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Many OGA inhibitors described exhibit lack of selectivity between OGA and the lysosomal isoenzymes Hex A and B, which can result in the accumulation of gangliosides within the lysosomes and neurodegenerative diseases. Therefore, aiming to obtain more selective inhibitors, this study proposed the synthesis and biological evaluation of N-acetylglucosamine derivatives, containing at the C-2 position the 1,4-di-substituted 1,2,3-triazole ring bearing different side chains, most of them containing aromatic ring at their end, and the investigation of the side chain extension influence between the rings into OGA active site pocket. It was obtained the triazole derivatives 1, 2 (in the previous study) and 8a-j (in the current project) in good to moderate yield through the click chemistry strategy, involving the CuAAC reaction between azide glucopyranoside intermediate 6 and ten different alkynes, which five were previously synthetized (9 - 11, 14 and 15), and five commercial available. For the synthesis of the acetylenic precursors 9 - 11, 14 and 15 it was employed different synthetic strategies according to each alkyne, for example nucleophilic substitution reactions and reductive amination. The triazole derivatives were obtained as a mixture of ?:? anomers in the proportion of 10:1, respectively. Due to the OGA selectivity to ? substrates, compounds 8a-h were purified by HPLC-DAD in order to separate the mixtures. Later in this study, it was possible to obtain the crystallization of azide 6 in ethanol, resulting in the separation of the ? anomer from this precursor, which assisted in the synthetic step of the derivatives 8i and 8j as pure anomers. The MTT assays did not show cytotoxicity for the synthesized compounds, evaluated at 1.0 ?M. The western blot and the enzymatic assays, evaluated for compounds 1, 2 and 8a-j, demonstrated that only compounds 1, 8i e 8j were active towards OGA, with IC50 values of 0.49, 0.52 e 0.72 ?M, respectively. From this result, it was possible to suggest that the ideal side chain extension linked between the triazole and aromatic rings is of two-carbon atoms (1), being able to accommodate one heteroatom of nitrogen (8i) or oxygen (8j). Furthermore, the enzymatic assays, evaluated for compounds 1, 8i e 8j against Hex A and B, exihibted IC50 of 550, 569 e 571 ?M, respectively, suggesting a high selectivity of these compounds to OGA rather than the two lysosomal isoenzymes. In the project developed in partnership with Dra. Nuria E. Campillo (CSIC) it was designed new non-carbohydrates compounds capable of interacting with important residues of the OGA catalytic site with potential biological activity.

A tripanossomíase sul-americana, também conhecida como Doença de Chagas é uma enfermidade endêmica da América Latina.A doença é causada pelo protozoário Trypanosoma cruzi, cuja transmissão em seres humanos e outros mamíferos ocorrem, principalmente, através das fezes do inseto \"barbeiro\" (triatoma infestans) infectado.Desde a descoberta já foram realizadas inúmeras tentativas de tratamento sem obter quimioterapia eficaz. Hoje o tratamento é realizado pelo uso do fármaco nitroheterocíclico benznidazol. Porém esse composto só é utilizado na fase aguda da doença e tem sua eficácia variada de acordo com a área geográfica, provavelmente como consequência de variação de cepas do parasita e apresenta graves efeitos colaterais. Uma ferramenta interessante em Química Medicinal é o uso do bioisosterismo para a síntese de moléculas análogas, que por possuírem propriedades biológicas relacionáveis geralmente atuam no mesmo alvo farmacológico como agonistas ou antagonistas. Por outro lado, as reações relacionadas às condensações de cicloadição 1,3 dipolar catalisadas por Cu(I), envolvendo estratégias de \"click chemistry\" tem como pontos positivos o fato de geralmente não formarem subprodutos, serem de fácil execução e apresentarem rendimentos elevados. Partindo de dois compostos comerciais (benzilamina e cloreto de cloro acetila) efetuou-se a síntese de uma biblioteca de vinte e três compostos análogos ao benznidazol através de uma rota sintética curta e de fácil execução. Foram realizados ensaios de atividade tripanocida envolvendo a cepa Tulahuen de T.cruzi, bem como ensaios de citotoxicidade. / The South American trypanosomiasis, also known as Chagas\' disease is an endemic disease in Latin America. The disease is caused by the protozoan Trypanosoma cruzi, whose transmission in humans and other mammals occur primarily through the faeces of the insect \"barbeiro\" (triatoma infestans) infection. Since the discovery already been carried out many attempts to obtain effective chemotherapy treatment. Today\'s treatment is accomplished through the use of the drug nitro-heterocyclic benznidazole. However this compound is only used in the acute phase of the disease and its effectiveness is varied in accordance with the geographical area, probably as a consequence of the variation of strains of the parasite and presents serious side effects. An interesting tool in medicinal chemistry is the use of bioisosterism for the synthesis of analogous molecules, which possess biological properties relatable generally act on the same target as pharmacological agonists or antagonists. Moreover, the reactions related to condensations of 1.3 dipolar cycloaddition catalyzed by Cu(I), involving strategies \"click chemistry\" has the strengths of the fact usually do not form byproducts, being easy to perform and present high yields. Starting from two commercial compounds benzylamine and chloro acetyl chloride) we performed the synthesis of a library of twenty-three analog compounds to benznidazole via a synthetic route short and easy to perform. Tests of trypanocidal activity involving Tulahuen strain of T. cruzi, and cytotoxicity assays.

No presente trabalho, foi desenvolvida uma metodologia sintética para a funcionalização de um monossacarídeo derivado da D-glicose através do Rearranjo de Ferrier, utilizando-se um sal de organotrifluoroborato de potássio como nucleófilo. Em seguida, foi feita a reação de cicloadição azida-acetileno com cobre, através de estratégias simples e eficientes, que seguem a filosofia da click chemistry, permitindo a preparação de uma série de compostos com grande diversidade estrutural, possuindo dois anéis heterocíclicos e diversos substituintes, com promissora atividade biológica. Dando continuidade ao projeto, foi feita a metanólise dos grupamentos acetila, com carbonato de potássio e metanol. Assim, as novas moléculas adquirem maior hidrofilicidade e podem ser enviadas para novos testes biológicos, para fins de comparação com as anteriores. A partir dos compostos desprotegidos, foi feita a mesilação seletiva da hidroxila primária do açúcar e a substituição com selenolato de sódio, com a obtenção de seleno-carboidratos inéditos. Em uma segunda etapa do trabalho, exploramos a reatividade do núcleo triazólico, com a reação de troca Te/Li seguida de captura por eletrófilo. O material de partida foi sintetizado a partir do fenil acetileno. Com o triazol telurado em mãos, partimos para as reações de troca e captura por eletrófilo. Utilizamos diferentes tipos de eletrófilos, como aldeídos, cetonas, iodetos, dentre outros. / We developed a synthetic methodology for the functionalization of a monosaccharide derived from D-glucose, using the Ferrier rearrangement with a potassium organotrifluoroborate salt as the nucleophile. This way, a series of coumpounds with high structural diversity and two heterocyclic rings having different substituents were produced, using the azide-acetylene cycloaddition reaction. Through this simple and efficient methodology, that follows the \"click chemistry\" philosophy, we could synthesize molecules with promising biological activity. Continuing the project, we performed the methanolysis of the acetyl groups, with potassium carbonate and methanol. Thus, the new molecules become more hydrophilic and could be sent to new biological tests, for a comparison with the previous ones. From the deprotected compounds, we were able to mesilate the primary hydroxyl and substitute it with sodium selenolate, obtaining novel selenium-carbohydrates. In a second part of our work, we were able to exploit the triazole reactivity trough the Te/Li exchange reaction followed by the electrophile capture. The starting material was obtained from phenyl acetylene. With the teluratte in our hands, we set out to the exchange reactions, using several types of electrophiles, such as aldehydes, ketones, iodide, among others.

No capítulo 1 apresentamos uma síntese eficiente de compostos 5-organoteluro-1H- 1,2,3-triazóis realizada via reação de cicloadição [3+2] entre azidas orgânicas e alquinos substituídos com organotelúrio. Além disso, os 5-organoteluro-1H-1,2,3-triazóis foram funcionalizados na posição 5 do anel triazólico por reação de acoplamento cruzado de Sonogashira. A regioquímica dos produtos de cicloadição foram descritas com base em experimentos de RMN, cálculos teóricos e cristalografia de raio-x. Apresentamos uma proposta mecanística para a cicloadição mediada por cobre, baseada em experimentos de espectrometria de massas de alta resolução. No capítulo 2, investigamos a eficiência de reações one-pot com indol, cloreto de oxalila e diferentes nucleófilos para obtermos derivados do indol-3-glioxila em condições adequadas. Do mesmo modo, envolvendo a adição de azidas orgânicas, levando à síntese de indol-3-glioxil-1,2,3-triazóis, os produtos foram obtidos com rendimentos que variaram de 59 a 85%. / In chapter 1 we present an efficient synthesis of 5-organotelluro-1H-1,2,3-triazole compounds that was accomplished via the [3+2]-cycloaddition reaction of organoazides and organotelluro alkynes. Additionally, 5-organotelluro-1H-1,2,3-triazoles were readily functionalized at the 5-position via the Sonogashira cross-coupling reaction, leading to highly functionalised triazoles. The regiochemistry of the products was assessed by bidimensional NMR experiments, theoretical calculations and x-ray crystallography. We presented a mechanistic proposal for the cycloaddition mediated by copper, based on high resolution mass spectrometry experiments. In chapter 2 we investigated a general and efficient reaction of indole with oxalyl chloride and nucleophiles providing indole-3-glyoxyl derivatives which has been developed in mild conditions. In the same fashion, the other reaction involved the addition of organic azides leading to the synthesis of indole-3-glyoxyl-1,2,3-triazoles, which proceeds smoothly generating the products in moderate to high yields.

No capítulo 1 apresentamos uma síntese eficiente de compostos 5-organoteluro-1H- 1,2,3-triazóis realizada via reação de cicloadição [3+2] entre azidas orgânicas e alquinos substituídos com organotelúrio. Além disso, os 5-organoteluro-1H-1,2,3-triazóis foram funcionalizados na posição 5 do anel triazólico por reação de acoplamento cruzado de Sonogashira. A regioquímica dos produtos de cicloadição foram descritas com base em experimentos de RMN, cálculos teóricos e cristalografia de raio-x. Apresentamos uma proposta mecanística para a cicloadição mediada por cobre, baseada em experimentos de espectrometria de massas de alta resolução. No capítulo 2, investigamos a eficiência de reações one-pot com indol, cloreto de oxalila e diferentes nucleófilos para obtermos derivados do indol-3-glioxila em condições adequadas. Do mesmo modo, envolvendo a adição de azidas orgânicas, levando à síntese de indol-3-glioxil-1,2,3-triazóis, os produtos foram obtidos com rendimentos que variaram de 59 a 85%. / In chapter 1 we present an efficient synthesis of 5-organotelluro-1H-1,2,3-triazole compounds that was accomplished via the [3+2]-cycloaddition reaction of organoazides and organotelluro alkynes. Additionally, 5-organotelluro-1H-1,2,3-triazoles were readily functionalized at the 5-position via the Sonogashira cross-coupling reaction, leading to highly functionalised triazoles. The regiochemistry of the products was assessed by bidimensional NMR experiments, theoretical calculations and x-ray crystallography. We presented a mechanistic proposal for the cycloaddition mediated by copper, based on high resolution mass spectrometry experiments. In chapter 2 we investigated a general and efficient reaction of indole with oxalyl chloride and nucleophiles providing indole-3-glyoxyl derivatives which has been developed in mild conditions. In the same fashion, the other reaction involved the addition of organic azides leading to the synthesis of indole-3-glyoxyl-1,2,3-triazoles, which proceeds smoothly generating the products in moderate to high yields.

No presente trabalho, foi desenvolvida uma metodologia sintética para a funcionalização de um monossacarídeo derivado da D-glicose através do Rearranjo de Ferrier, utilizando-se um sal de organotrifluoroborato de potássio como nucleófilo. Em seguida, foi feita a reação de cicloadição azida-acetileno com cobre, através de estratégias simples e eficientes, que seguem a filosofia da click chemistry, permitindo a preparação de uma série de compostos com grande diversidade estrutural, possuindo dois anéis heterocíclicos e diversos substituintes, com promissora atividade biológica. Dando continuidade ao projeto, foi feita a metanólise dos grupamentos acetila, com carbonato de potássio e metanol. Assim, as novas moléculas adquirem maior hidrofilicidade e podem ser enviadas para novos testes biológicos, para fins de comparação com as anteriores. A partir dos compostos desprotegidos, foi feita a mesilação seletiva da hidroxila primária do açúcar e a substituição com selenolato de sódio, com a obtenção de seleno-carboidratos inéditos. Em uma segunda etapa do trabalho, exploramos a reatividade do núcleo triazólico, com a reação de troca Te/Li seguida de captura por eletrófilo. O material de partida foi sintetizado a partir do fenil acetileno. Com o triazol telurado em mãos, partimos para as reações de troca e captura por eletrófilo. Utilizamos diferentes tipos de eletrófilos, como aldeídos, cetonas, iodetos, dentre outros. / We developed a synthetic methodology for the functionalization of a monosaccharide derived from D-glucose, using the Ferrier rearrangement with a potassium organotrifluoroborate salt as the nucleophile. This way, a series of coumpounds with high structural diversity and two heterocyclic rings having different substituents were produced, using the azide-acetylene cycloaddition reaction. Through this simple and efficient methodology, that follows the \"click chemistry\" philosophy, we could synthesize molecules with promising biological activity. Continuing the project, we performed the methanolysis of the acetyl groups, with potassium carbonate and methanol. Thus, the new molecules become more hydrophilic and could be sent to new biological tests, for a comparison with the previous ones. From the deprotected compounds, we were able to mesilate the primary hydroxyl and substitute it with sodium selenolate, obtaining novel selenium-carbohydrates. In a second part of our work, we were able to exploit the triazole reactivity trough the Te/Li exchange reaction followed by the electrophile capture. The starting material was obtained from phenyl acetylene. With the teluratte in our hands, we set out to the exchange reactions, using several types of electrophiles, such as aldehydes, ketones, iodide, among others.