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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Síntese de derivados da curcumina com propriedade push-pull ligados a carboidratos

Gonçalves, Carolina Passarelli January 2017 (has links)
Orientador: Prof. Dr. Anderson Orzari Ribeiro / Tese (doutorado) - Universidade Federal do ABC. Programa de Pós-Graduação em Ciência e Tecnologia/Química, 2017. / Uma estatistica do IARC (Agencia Internacional de Pesquisa sobre o Cancer) preve que 19,5 milhoes de pessoas serao afetadas pela doenca no ano 2025. Diferentes tipos de cancer podem ser tratados por cirurgia, radioterapia, quimioterapia ou transplante de celulas. O composto 1,5-bis-(4-hidroxi-3-metoxifenil)-1,4-pentadien-3-ona (HB1) foi estudado pelo nosso grupo de pesquisa e exibiu destacada atividade antitumoral nos testes in vitro contra varias celulas tumorais humanas e mostrou uma taxa de toxicidade muito baixa. Outro composto importante obtido foi o composto 3-((Z)-3-cloro-3-(4-iodofenil) alilideno)pentano-2,4-diona (C21), que mostrou atraves de testes in vitro tambem uma elevada atividade antitumoral contra a celula tumoral B16F10 (IC50 = 0,73 ¿Êg/mL, na concentracao de 1 ¿Êg/mL apos 24 horas de tratamento) e baixa toxicidade contra celulas normais. Uma estrategia para aumentar a atividade antitumoral e a combinacao de hidratos de carbono com substancias biologicamente ativas. Um exemplo do efeito de associado a hidrato de carbono sao as interacoes especificas entre carboidratos e lectinas na parede celular, que contribuem para muitos processos de reconhecimento intercelular. O primeiro objetivo desta proposta foi a sintese de analogos de curcumina ligados a porcoes C-Glicosidicas. Iniciou-se com a C-Ramnosilacao utilizando a reacao de tricloroacetimidatos de tetra-O-benzil-rhamnosilo com fenois ricos em eletrons na presenca de triflato de trimetilsililo (TMSOTf) para obter ligacoes C-glicosidicas. Atraves da analise por RMN foi possivel observar a formacao do composto O- Glicosilado (15), o que e tambem muito interessante. A fim de obter os compostos (24) e (25) e subsequentemente obter novos compostos C-Glicosilados (28, 30, 35, 43 e 46) foram feitas varias reacoes sinteticas a partir da D-Galactose. O primeiro passo foi a acetilacao de todos os grupos hidroxilo livres e, em seguida, o grupo hidroxilo protegido com acetilo anomerico foi substituido por grupo bromo por tratamento com brometo de hidrogenio para obter o composto (17). Atraves da glicosilacao de Helferich, converteu-se o glicosido bromado (17) no galactopiranosido (18) um alilglicosido, que atraves das condicoes Zemplen proporcionou a obtencao do composto (19), que foi subsequentemente protegido pela reacao de benzilacao dando o composto (20). A desalquilacao anomerica foi realizada utilizando catalisada com cloreto de paladio (II), formando o produto (21), que foi convertido na lactona (22) pela oxidacao com o reagente de Dess-Martin. Com a reacao de Grignard, obteve-se o hemiacetal (23) e finalmente com trietilsilano e BF3.OEt2, obteve-se o composto (24) por reducao com rendimento significativo. A desprotecao total para grupos benzilas foi realizada por tricloreto de boro e o composto (25) foi sintetizado em uma hora com alto rendimento. / A statistic of IARC (International Agency for Research on Cancer) predicts that 19.5 million people will be affected by the disease in the year 2025th. Different types of cancer are treated by surgery, radiotherapy, chemotherapy or stem cell transplantation. The compound 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one (HB1) has been studied by our working group and exhibited high antitumoral activities regarding in vitro screening against several human tumor cell lines and showed very low toxicity rate. Another important compound obtained, was the compound 3-((Z)-3-chloro-3-(4-iodophenyl)allylidene)pentane-2,4-dione (C21), which has shown through in vitro tests also high antitumor activity against tumoral cell B16F10 (IC50 = 0.73 he specific interactions between carbohydrates and lectins on the cell wall, which contribute to many intercellular recognition processes. The first target of this proposal was the synthesis of curcumin analogues linked to C-Glycosidic moieties. It was started with the C-rhamnosylation using the reaction of tetra-O-benzyl-rhamnosyl trichloroacetimidates with electron-rich phenols in the presence of trimethylsilyl triflate (TMSOTf) to get C-glycosidic linkages. Unfortunately the C-Glycosylated compound was not obtained. Through NMR analysis it was possible to observe the formation of the O-Glycosylated compound (15), which seems to be also very interesting. In order to obtain the compound (24) and (25) and subsequently obtaining new C-Glycosylated compounds (28, 30, 35, 43 and 42) were made several synthetic reactions starting from D-Galactose. The first step was the acetylation of all free hydroxyl groups presents and then, the anomeric acetyl-protected hydroxy group was replaced by bromo group via hydrogen bromide treatment to obtain the compound (17). Through glycosylation Helferich the brominated glycoside (17) was converted into the galactopyranoside (18) an allyl-glycoside, which through Zemplen conditions afforded the compound (19), which was subsequently protected by benzylation reaction giving the compound (20). The anomeric dealkylation was performed using palladium (II) chloride-catalyzed, forming the product (21), which was converted into the lactone (22) by Dess-Martin periodinane oxidation. With the Grignard reaction, the hemiacetal (23) was obtained and finally with triethylsilane and BF3.OEt2, the compound (24) was obtained through reduction with significant yield. The total deprotection for benzyls groups was performed by boron trichloride and then de compound (25) was synthesized in one hour with high yield.

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