One of the largest problems in current medicine is the shortage of organs for transplant due to technological limitations in the storage of organs for any length of time. A possible solution to this problem would involve cryopreservation. However, current cryopreservatives such as sucrose or DMSO have concerning cytotoxic issues that limit their possible applications. A major cause of cryoinjury is the uncontrolled recrystallization of inter and intra-cellular ice crystals that occurs during the thawing process leading to mechanical damage and dehydration. The Ben lab has thus been interested in the design of compounds that are capable of inhibiting this process but do not possess other undesirable properties found in the native compounds. These synthetic analogues have been shown to increase cellular viability post-thaw. A series of mixed α/β glycopeptides are prepared and analyzed for antifreeze properties. The results of this study imply that it is not the gross conformation of the glycopeptide that is responsible for activity, but rather that intramolecular relationships may be responsible for disrupting the reorganization of ice. A technique was devised for the incorporation of triazoles into the analogues to investigate the importance of the linker and to greatly simplify the synthesis of a library of glycoconjugates. It was found that the IRI activity of glycopeptides is very sensitive to the distance between carbohydrate and peptide backbone. The electron density at the anomeric oxygen is an important parameter with respect to intramolecular networks. A series of substituted galactosides is presented that modify the electronics of the anomeric oxygen. The results demonstrate that decreasing electron density at this position appears to improve IRI activity in a predictable manner. To better understand the remarkable IRI activity of a key analogue, it was systematically truncated. This study led to the serendipitous discovery of a series of very highly IRI active analogues that do not contain a peptide backbone. These compounds represent the first non-glycopeptides that can show very significant IRI activity even at very low concentrations. The final portion of the thesis reports the efforts towards the preparation of a carbasugar analogue of AFGP-8.

Obesity constitutes a problem whose manifestations have consequences in almost every field of the medicine and nowadays there is a lack of pharmacological therapy alternatives for its long term treatment. Lipidic compounds as endocannabinoids and PPAR-α ligands are known to play an important role in the modulation of appetite and metabolism. Three series of fatty acid derivatives of catechol compounds were synthesized and their biological activity evaluated. Some of the synthesized compounds presented LDL antioxidant activity and/or food intake modulation in an animal model and their mechanism of action was also evaluated. The pharmacodynamics of the synthesized compounds could be explained by CB1 and PPAR-α interactions nevertheless it does not explain the activity of all compounds. / La obesidad es un problema cuyas manifestaciones tienen consecuencias en casi todos los campos de la medicina y actualmente existe una escasez de terapias farmacológicas para su tratamiento de uso continuo. Se sabe que algunos compuestos lipídicos como los endocanabinoides y ligandos del PPAR-α participan de manera importante en la modulación del apetito y en el metabolismo. Tres series de compuestos derivados de ácidos grasos con compuestos catecólicos fueron sintetizadas y sus actividades biológicas fueron evaluadas. Algunos de los compuestos presentó inhibición de la oxidación de la LDL y/o modulación de la ingesta en modelo animal y sus mecanismos de acción fueron también evaluados. La actividad de los compuestos pasa por interacciones con el receptor CB1 y el PPAR-α pero estas interacciones no explican la actividad de todos los compuestos

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The earliest landmark in computer technology was construction of the Electronic Numerial Integrator and Computer, ENIAC. Computational switching was performed with vacuum tubes and relays, rather large in size, making this computer rather unwieldy. The next milestone came with the integration of transistors into computers as the switching component. Since then, transistors have been miniaturised dramatically, resulting in the amount of components integrated on a computer chip increasing logarithmically with time. The components are nowadays so small and so densely packed that problems with leak currents and cross-talk can arise and the lower limit for transistor size will soon be reached. In order to meet increasing demands on the size and performance of electronics, a new paradigm is due – the molecular electronics approach. Oligothiophenes have been shown to possess the physical and chemical characteristics required for electron/energy transport in molecular systems. However oligothiophenes must be electronically coupled to other components within a molecular circuit for them to be functional. In this work, different modes of incorporation of [2,2’]-bipyridinyl functionalities onto the ends of prototypic oligothiophene wires have been examined. The bipyridine connectors allow complexation to metal centres which can then function as a source or sink of electrons in the circuit. Ruthenium tris-bipyridine complexes, in particular, possess interesting electrochemical and photophysical characteristics, making them suitable for use in molecular electronics. This thesis reports synthetic strategies to a range of novel ligands based on the [2,2’]-bipyridinyl system, together with a study of the redox and fluorescence properties of their ruthenium tris-bipyridine complexes. The mode of connection between the chelating bipyridine and the first member of the oligothiophene chain was found to have a profound effect upon the fluorescence lifetimes and intensities of the resulting complexes. The discovery of complexes exhibiting long and intense fluorescence (a requirement for directed electron/energy transfer within molecular networks) thus forms an important design element in future prototypes.

Orientador: Vanderlan da Silva Bolzani / Coorientador: Ian Castro Gamboa / Banca: Cintia Duarte de Freitas Milagre / Banca: Adriano Defini Andricopulo / Banca: Fernando Antônio Santos Coelho / Banca: Alcindo Aparecido dos Santos / Resumo: As leishmanioses englobam um espectro de doenças que afetam o ser humano e outros mamíferos nas regiões tropicais e subtropicais do planeta. São causadas por pelo menos 20 tipos de parasitas pertencentes ao gênero Leishmania, e apresentam diversas e complexas manifestações clínicas. Podem ser encontradas em mais de 88 países, sendo que o Brasil é um dos países endêmicos onde a doença está mais disseminada. Em 2010 foram confirmados 21.981 casos de leishmaniose tegumen-tar e 3536 de leishmaniose visceral, com 219 mortes. No mundo cerca de 350 mi-lhões de pessoas estão expostas à infecção e acredita-se que cerca de 12 milhões estejam infectadas, com cerca de 1-2 milhões de novos casos por ano e 60 mil óbi-tos. Pensando nisso, o presente estudo visou obter novas substâncias candidatas a serem utilizadas no combate as chamadas "Doenças Tropicais Negligenciadas", mais especificamente a Leishmaniose. Neste trabalho foram sintetizados doze aná-logos de meroterpenos, sendo nove compostos inéditos e ainda os compostos natu-rais isolados de Psidium guajava (psidial A, guajadial e pisguadial B), utilizando uma rota curta e linear e com rendimento global em torno de 20%. Um estudo sobre o mecanismo da reação de cicloadição [4+2] possibilitou determinar as barreiras de energia envolvidas nas transformações e permitiu compreender algumas limitações da metodologia empregada. Nos testes biológicos, os análogos sintéticos se mostra-ram promissores para combater a forma promastigota de Leishma... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Leishmaniasis encompasses a spectrum of diseases that affect humans and other mammals in the tropical and subtropical regions of the planet. They are caused by at least 20 types of parasites belonging to the genus Leishmania, and present diverse and complex clinical manifestations. They can be found in more than 88 countries, and Brazil is one of the endemic countries where the disease is most widespread. In 2010, 21,981 cases of tegumentary leishmaniasis and 3536 cases of visceral leish-maniasis were confirmed, with 219 deaths. Around 350 million people worldwide are exposed to the infection and an estimated 12 million are believed to be infected, with about 1-2 million new cases per year and 60,000 deaths. With this in mind, the pre-sent study aimed to obtain new candidate substances to be used in the fight against "Neglected Tropical Diseases", more specifically Leishmaniasis. In this work, twelve meroterpene analogs were synthesized, with nine new compounds and the natural compounds isolated from Psidium guajava (psidial A, guajadial and pisguadial B) using a short and linear route with a global yield of around 20%. A study of the mechanism of the cycloaddition reaction [4 + 2] made it possible to determine the energy barriers involved in the transformations and allowed to understand some limitations of the methodology used. In biological tests, synthetic analogues were shown to be promising to combat the promastigote form of Leishmania infantum, with EC50 values between ... (Complete abstract click electronic access below) / Doutor

This thesis describes the development of a synthetic route towards daphlongeranine B, an alkaloid isolated from the fruits of Daphniphyllum longeracemosum, by utilising an intramolecular Michael addition to form its unique tricyclic core. <strong>Chapter 1</strong> gives a general introduction to the family of Daphniphyllum alkaloids together with some recent examples, from the literature, illustrating some synthetic attempts towards structurally similar alkaloids. This chapter also features our retrosynthetic analysis of daphlongeranine B. <strong>Chapter 2</strong> details the synthesis of the model spirocyclic enone 72 which was the vital building block needed to investigate the key intramolecular Michael addition. This key reaction was then successfully validated and access to the unique tricyclic core 64 of daphlongeranine B was made possible. <strong>Chapter 3</strong> expands the scope of the key intramolecular Michael addition step. This chapter first describes a synthetic route to the Î2-substituted spirocyclic enone 112 and subsequently validates the key intramolecular Michael addition step to give the tricyclic core 138 of daphlongeranine B. <strong>Chapter 4</strong> details a synthetic route towards the spirocyclic fragment 141 by utilising a Baker's yeast reduction and a tandem addition/cyclisation reaction.