Made available in DSpace on 2018-06-27T18:56:35Z (GMT). No. of bitstreams: 2 Luciana dos Santos Lopes.pdf: 903442 bytes, checksum: 9241c2c46a0d205e6d9e1b049687e5f7 (MD5) Luciana dos Santos Lopes.pdf.jpg: 3030 bytes, checksum: 0c80e97bb571acad00dbccdd7ce7c921 (MD5) Previous issue date: 2009-01-19 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The NTPDase (apirase-ect, ect-difosfoidrolase, CD39, EC 3.6.1.5) hydrolyses tri nucleotides and/or diphosphate. It is an ectonucleotidase, identified as the antigen surface of lymphoid cells, whose greatest expression leads to an increase in activity of ATPase and ADPase and these cells through the hydrolysis of ATP and ADP. The inhibitor of ecto-nucleotidases may represent valuable therapeutic tools to amplify the biological effects of extracellular nucleotides, since they induce apoptosis in lymphocytes, causing a state of immunosuppression. It is known through the literature that sodium azide produces a significant inhibition in the hydrolysis of ATP and ADP, caused this enzyme when it is used in concentrations around 20mM. The azides are chemical components widely used in organic synthesis, and remarkably stable in biological environment. The aim of this study was to determine the inhibitory effects of an organic azide derived from acetic acid in the hydrolysis of ATP and ADP, which is the activity of NTPDase of human lymphocytes. Since changes in distribution and activity of this enzyme have been reported in various pathological conditions, demonstrating its participation in the activation of lymphocyte, it is believed that the identification of new compounds inhibiting NTPDase will contribute to treatment of diseases where there is a need for immunosuppression, as allergies and autoimmune diseases. After incubation of lymphocytes in medium containing different concentrations of azide organic, there was a significant inhibition of ADP in the hydrolysis when used concentrations of 10 and 20 mM, and this of 50 and 77% respectively. Unverified inhibitory effects on the ATP hydrolysis with organic azide. A changed the hydrolysis of nucleotide adenine diphosphate, indicating that the substance could be used as an inhibitor of mixed NTPDase. / A NTPDase (ecto-apirase, ecto-difosfoidrolase, CD39, EC 3.6.1.5) hidrolisa nucleotídeos tri e/ou difosfatados. É uma ectonucleotidase, identificada como antígeno de superfície de células linfóides, cuja maior expressão leva a um aumento das atividades de ATPase e ADPase nestas células. Os inibidores de ecto-nucleotidases podem representar valiosas ferramentas terapêuticas para amplificar os efeitos biológicos dos nucleotídeos liberados no meio extracelular, uma vez que estes induzem apoptose nos linfócitos, causando um estado de imunodepressão. Sabe-se através da literatura que azida sódica, quando utilizada em concentrações em torno de 20mM, produz uma significativa inibição na hidrólise de ATP e ADP causada por esta enzima. As azidas são componentes químicos muito usados em sínteses orgânicas, sendo notavelmente estáveis em ambiente biológico. Este trabalho, procurou determinar os efeitos inibitórios de uma azida orgânica derivada do ácido acético na hidrólise de ATP e ADP, ou seja, na atividade da NTPDase de linfócitos humanos. Uma vez que alterações na atividade e distribuição desta enzima têm sido relatadas em várias condições patológicas, demonstrando sua participação na ativação do linfócito, acredita-se que a identificação de novos compostos inibidores da enzima NTPDase venha a contribuir em patologias onde há necessidade de uma imunossupressão, como em alergias e doenças autoimunes. Após incubação dos linfócitos em meio contendo diferentes concentrações de azida orgânica, verificou-se uma inibição significativa na hidrólise do ADP quando utilizadas as concentrações de 10 e 20 mM, sendo esta de 50 e 77%, respectivamente. Não foram verificados efeitos inibitórios sobre a hidrólise do ATP. A azida orgânica alterou a hidrólise dos nucleotídeos da adenina difosfatados, indicando que esta substância poderia ser utilizada como um inibidor da NTPDase, cujo tipo de inibição causada seria mista.

Various anticancer and antibacterial agents have been synthesized via azide chemistry by taking advantage of carbohydrate. Starting from the synthesis of 14 glycosyl azides, a library of carbohydrate-oxazolidinone conjugates and a library of carbohydrate-cyclopamine conjugates with biological interests were synthesized based on a highly efficient "click reaction" assisted by sonication. Some of the conjugates have improved solubility and enhanced anticancer activity. A library of neomycin B derivatives with various modifications at the 5" position has been synthesized. Two leads exhibit prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Antibacterial activities were measured when combined with other clinically used antibiotics and significant synergistic activities were observed. Three different classes of aryl N-glycosides have been synthesized by employing 1,4-naphthoquinone and glycosyl azides undergoing a [2+3] cycloaddition. Alkyl azides can also undergo the same cycloaddition. After the removal of the protecting group, a library of 9,10-anthraquinone derivatives with potential anticancer activity and a library of 2-aminomethylene-1,3-indanediones with novel antibacterial activity have been developed, respectively. A one-pot three-component [2+3] cycloaddition for the synthesis of 1-alkyl 1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione and 2-alkyl 2H-naphtho[2,3-d][1,2,3] triazole-4,9-dione has been developed. By taking the advantage of their difference in basicity, both products can be obtained in good purity. Using an allylic azide rearrangement, a convenient method has been developed for the synthesis of several 2',3'-dideoxyaminoglycosides. The antibacterial activity of these novel aminoglycosides also confirms the indispensable role of the 2'-NH2 group for both neomycin and kanamycin classes of aminoglycosides. A novel structural motif containing the hexylaminocarbonyl groups at O-5 and/or O-6 of 2',3'-dideoxyneamine could lead to the production of new aminoglycosides against resistant bacteria.

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A major purpose of this research was to investigate the mechanism of aryl azide addition to allenes. Much evidence has accumulated in support of a concerted mechanism for aryl azide additions to simple alkenes. Consistent with these findings, this addition is a symmetry allowed process. The analagous aryl azide additions to allenes have received little mechanistic study. The approach taken in this work was to probe the mechanism by using optically active 1,2-cyclonanadiene, observing the stereochemistry of the adduct formed upon addition of phenyl azide. Another goal was to investigate the isomerization of the phenyl azide-1,2-cylononadiene adduct, 10-phenyl-10,11,12-triaza-△ 11 -bicyclo [7. 3. 0] duodec-1-ene (7) to the previously unknown aromatic isomer 4,5-heptamethylene-1-phenyl-1,2,3-triazole (14).

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