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Previous issue date: 2015-08-27 / CAPES / CNPq / FAPERJ / Cancer is a generic term related to more than 100 types of diseases which resemble each other by their disorganized cellular growth. HSP90 are ATP-dependent chaperones responsible for the activation and stabilization of more than 200 proteins. Most of these proteins are connected to cancer and need HSP90 to execute their activities. Thus, HSP90 inhibitors may indirect inhibit plenty oncogenic proteins. According to the literature, there are N-terminal and C-terminal domains, nevertheless, C-terminal inhibitors present more advantages. Then, the advancement of C-terminal inhibitors represents an applicable alternative and an intense field of study. Novobiocin is the first compound identified as C-terminal domain inhibitor. Nowadays, Novobiocin analogues have been synthesized, besides its structure-activity relationship elucidated in order to develop more potents analogues. For that reason, the goal of this project is to obtain 2 analogue series of Novobiocin. The scheme of these series was based on maintaining the coumaniric part presented on Novobiocin: isosteric replacement of the amide group that binds coumarin to the 4-hydroxy-3-(3-methylbut-2-yl)-benzamide, by the [1,2,3]-triazole; and exploration of methyl groups (AN1) and hydroxyl (AN2) in substitution of subunit noviose. AN1 series (76a-g) and AN2 (77a-g) were synthesized from the followed reactions: 7-hydroxy-coumarine o-methylation (83); 7-methoxy-coumarine 3-bromation (82); Sonogashira cross-coupling from 3-bromo-7-R-coumarine (81a-b); 7-R-3-((trimethylsilyl)ethynyl-coumarine trimethylsilyl deprotection (88a-b); and lastly, synthesis of the triazole ring, through cicloaddition reaction, 1,3-dipolar catalysed by copper (CuAAc), using 3-ethynyl-7-R-coumarine (80a-b) and aromatic azides. It is worth taking into consideration that 3-bromo-7-R-coumarine (81b) was obtained from the key compound, 3-bromo-7-R-methoxy-coumarine (81a) by o-demethylation reaction. 12 compounds were obtained (76a-g) and 8 of them (76a-b, 77d) were nicely purified and then, characterized by spectroscopic techniques (IR, 1H and 13C NMR). The ?one-pot? synthesis of 7-methoxy-3-(1H-1,2,3-triazole-4-phenyl)-coumarine 76b from 88a compound (Yield=86%) was more efficient than the one realized in two steps (global yield=47,2%). Results are potential and satisfactory, moreover there is no citation in any literature about biological activities of the synthesized compounds. Continuing this work, the pure compounds (76a-b, 77d) will be tested on breast cancer cell lines SkBr3 and MCF-7. / O c?ncer ? um termo gen?rico que se refere a um conjunto de mais de 100 tipos de doen?as, as quais se assemelham pelo crescimento celular desordenado. As HSP90 s?o chaperonas ATP-dependente respons?veis pela ativa??o e estabiliza??o de mais de 200 prote?nas. Muitas destas prote?nas s?o relacionadas ao c?ncer e necessitam da HSP90 para exercerem suas atividades. Assim, inibidores da HSP90 s?o promissores, pois possibilitam inibir de maneira indireta v?rias prote?nas oncog?nicas simultaneamente. S?o descritos inibidores dos dom?nios N-terminal e C-terminal, sendo estes mais vantajoso que aqueles. O Novobiocin foi o primeiro composto identificado como inibidor do dom?nio C-terminal da HSP90. Atualmente, diversos an?logos ao Novobiocin tem sido sintetizados, afim de se estabelecer a rela??o estrutura-atividade, objetivando desenvolver an?logos mais potentes. Assim, o objetivo deste trabalho foi obter duas s?ries an?logas ao Novobiocin. O planejamento das s?ries foi baseado na manuten??o do n?cleo cumar?nico presente no Novobiocin; troca isost?rica do grupo amida, que liga a cumarina ao anel 4-hidroxi-3-(3-metillbut-2-il)-benzamida, pelo anel [1,2,3]-triazol; e explora??o de grupos metoxila (AN1) e hidroxila (AN2) em substitui??o ? subunidade noviose. As s?ries AN1 (76a-g) e AN2 (77a-g) foram sintetizadas a partir das rea??es de: O-metila??o da 7-hidroxi-cumarina (83); broma??o da posi??o 3 da 7-met?xi-cumarina (82); rea??o de acoplamento cruzado de Sonogashira, a partir da 3-bromo-7-R-cumarina (81a-b); desprote??o do grupamento trimetilsilila da 7-R-3-((trimetilsilil)etenil)-cumarina (88a-b); e por fim, s?ntese do anel triaz?lico, atrav?s da rea??o de cicloadi??o 1,3-dipolar catalisada por cobre (CuAAc), utilizando 3-etenil-7-R-cumarina (80a-b) e azidas arom?ticas. Vale ressaltar que, a 3-bromo-7-hidr?xi-cumarina (81b) foi obtida a partir do composto chave, 3-bromo-7-met?xi-cumarina (81a) via rea??o de O-demetila??o. Obteve-se 12 compostos (76a-g e 77a-g) sendo que 8 (76a-b, 77d) foram, satisfatoriamente, purificados e, ent?o, caracterizados por t?cnicas espectrosc?picas (IV, RMN H e C). Tamb?m foi constatado que a s?ntese ?one-pot? de 7-metoxi-3-(1H-1,2,3-triazol-4-fenil)-cumarina 76b partir do composto 88a (R=86%) foi mais eficiente que a realizada em duas etapas, desilina??o/CuAAc (Rglobal= 47,2%). Os resultados s?o satisfat?rios e promissores, al?m disso n?o h? na literatura descri??o das atividades biol?gica dos compostos sintetizados. Em continua??o a este trabalho, os compostos puros (76a-b, 77d) ser?o devidamente ensaiados frente a c?lulas das linhagens de c?ncer de mama SkBr3 e MCF-7.
| Identifer | oai:union.ndltd.org:IBICT/oai:localhost:jspui/1875 |
| Date | 27 August 2015 |
| Creators | FRANCO, Daiana de Fatima Portella |
| Contributors | K?mmerle, Arthur Eugen, K?mmerle, Arthur Eugen, Lacerda, Renata Barbosa, Pinheiro, S?rgio |
| Publisher | Universidade Federal Rural do Rio de Janeiro, Programa de P?s-Gradua??o em Qu?mica, UFRRJ, Brasil, Instituto de Ci?ncias Exatas |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da UFRRJ, instname:Universidade Federal Rural do Rio de Janeiro, instacron:UFRRJ |
| Rights | info:eu-repo/semantics/openAccess |
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