Síntese de galactosídeos de arila inibidores potenciais de trans-sialidase de Trypanosoma Cruzi
Autor(a) principal: | |
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Data de Publicação: | 2012 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFMG |
Texto Completo: | http://hdl.handle.net/1843/EMCO-936JAQ |
Resumo: | Trypanosoma cruzi trans-sialidase (TcTS) is a surface enzyme that catalyses the transfer of residues of the monosaccharide sialic acid from host sialoglycoconjugates to the mucins, abundant proteins expressed on the parasite surface. Physiologically TcTs actively participates of the mechanisms of evasion from the immune system, cell invasion and blood cell apoptosis. This enzyme is, therefore, essential for the development of Chagas Disease, and is considered a promising molecular target for drug design. Thus, the aim of the present work was the design and synthesis of D-galactose-derived potential inhibitors of TcTS using strategies of molecular modification, in special molecular simplification. Ten aryl galactosides modified at carbon-3 were synthesized and characterized for evaluation against TcTS by spectrofluorimetry. By using classical carbohydrate chemistry 4-methoxycarbonylphenyl -D-galactopyranoside and 4-methoxycarbonyl-2-nitrophenyl -D-galactopyranoside were prepared. The regioselective 3-O-alkylation of both compounds was then carried out using methyl iodide, tert-butyl bromoacetate and bromoacetonitrile as electrophylic reagents. The regioselectivity was achieved by employing the dibutyltin oxide method, in which cyclic tin complexes are formed and, upon reaction with an alkyl halide, furnish 3-O-alkylated products, in general high yields and selectivity. The alkylated products bearing tert-butoxycarbonylmethyl or cyanomethyl groups were modified in order to obtain derivatives bearing at C-3 a carboxymethyl or a 5-tetrazolylmethyl group. |
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Síntese de galactosídeos de arila inibidores potenciais de trans-sialidase de Trypanosoma Cruzióxido de dibutilestanhoplanejamento de inibidoresalquilação regiosseletivagalactosídeos de arilaTrans-sialidase de Trypanosoma Cruziácido siálicoFarmáciaTrypanosoma cruzi trans-sialidase (TcTS) is a surface enzyme that catalyses the transfer of residues of the monosaccharide sialic acid from host sialoglycoconjugates to the mucins, abundant proteins expressed on the parasite surface. Physiologically TcTs actively participates of the mechanisms of evasion from the immune system, cell invasion and blood cell apoptosis. This enzyme is, therefore, essential for the development of Chagas Disease, and is considered a promising molecular target for drug design. Thus, the aim of the present work was the design and synthesis of D-galactose-derived potential inhibitors of TcTS using strategies of molecular modification, in special molecular simplification. Ten aryl galactosides modified at carbon-3 were synthesized and characterized for evaluation against TcTS by spectrofluorimetry. By using classical carbohydrate chemistry 4-methoxycarbonylphenyl -D-galactopyranoside and 4-methoxycarbonyl-2-nitrophenyl -D-galactopyranoside were prepared. The regioselective 3-O-alkylation of both compounds was then carried out using methyl iodide, tert-butyl bromoacetate and bromoacetonitrile as electrophylic reagents. The regioselectivity was achieved by employing the dibutyltin oxide method, in which cyclic tin complexes are formed and, upon reaction with an alkyl halide, furnish 3-O-alkylated products, in general high yields and selectivity. The alkylated products bearing tert-butoxycarbonylmethyl or cyanomethyl groups were modified in order to obtain derivatives bearing at C-3 a carboxymethyl or a 5-tetrazolylmethyl group.A trans-sialidase de Trypanosoma cruzi (TcTS) é uma enzima de superfície que catalisa a transferência de resíduos do monossacarídeo ácido siálico de sialogliconjugados do hospedeiro para proteínas mucinas amplamente distribuídas na superfície do parasita. Fisiologicamente a TcTS medeia ativamente mecanismos de escape da resposta imune contra T. cruzi, invasão celular e apoptose de células do tecido sanguíneo. Essa enzima, portanto, é essencial para o desenvolvimento da doença de Chagas, sendo reconhecidamente um alvo molecular bastante promissor para o desenvolvimento de fármacos. Nesse contexto, realizou-se neste trabalho o planejamento e a síntese de derivados de D-galactose inibidores potenciais de TcTS, utilizando estratégias de modificação molecular, especialmente simplificação molecular. Dez galactosídeos de arila modificados em C-3 foram sintetizados e caracterizados para serem ensaiados contra TcTS por espectrofluorimetria. Utilizando-se reações clássicas da química de carboidratos, foram sintetizados inicialmente o -D-galactopiranosídeo de 4-metoxicarbonilfenila e o -D-galactopiranosídeo de 4-metoxicarbonil-2-nitrofenila, a partir dos quais foram realizadas reações regiosseletivas de O-alquilação em C-3. Foram utilizados como eletrófilos iodeto de metila, bromoacetato de terc-butila e bromoacetonitrila. A seletividade foi obtida pelo emprego da técnica do óxido de dibutilestanho, que forma complexos cíclicos estanilados com os galactosídeos e conduz, na presença de agentes alquilantes, aos produtos substituídos em C-3, geralmente com elevado rendimento e seletividade. Posteriormente, os derivados com os substituintes terc-butoxicarbonilmetila e cianometila foram modificados, obtendo-se derivados com os grupos carboximetila e 5-tetrazolilmetila em C-3.Universidade Federal de Minas GeraisUFMGIvone CarvalhoRossimiriam Pereira de FreitasBruno Leonardo Silva2019-08-13T21:41:22Z2019-08-13T21:41:22Z2012-02-29info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/1843/EMCO-936JAQinfo:eu-repo/semantics/openAccessporreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMG2019-08-13T21:41:22Zoai:repositorio.ufmg.br:1843/EMCO-936JAQRepositório InstitucionalPUBhttps://repositorio.ufmg.br/oairepositorio@ufmg.bropendoar:2019-08-13T21:41:22Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false |
dc.title.none.fl_str_mv |
Síntese de galactosídeos de arila inibidores potenciais de trans-sialidase de Trypanosoma Cruzi |
title |
Síntese de galactosídeos de arila inibidores potenciais de trans-sialidase de Trypanosoma Cruzi |
spellingShingle |
Síntese de galactosídeos de arila inibidores potenciais de trans-sialidase de Trypanosoma Cruzi Bruno Leonardo Silva óxido de dibutilestanho planejamento de inibidores alquilação regiosseletiva galactosídeos de arila Trans-sialidase de Trypanosoma Cruzi ácido siálico Farmácia |
title_short |
Síntese de galactosídeos de arila inibidores potenciais de trans-sialidase de Trypanosoma Cruzi |
title_full |
Síntese de galactosídeos de arila inibidores potenciais de trans-sialidase de Trypanosoma Cruzi |
title_fullStr |
Síntese de galactosídeos de arila inibidores potenciais de trans-sialidase de Trypanosoma Cruzi |
title_full_unstemmed |
Síntese de galactosídeos de arila inibidores potenciais de trans-sialidase de Trypanosoma Cruzi |
title_sort |
Síntese de galactosídeos de arila inibidores potenciais de trans-sialidase de Trypanosoma Cruzi |
author |
Bruno Leonardo Silva |
author_facet |
Bruno Leonardo Silva |
author_role |
author |
dc.contributor.none.fl_str_mv |
Ivone Carvalho Rossimiriam Pereira de Freitas |
dc.contributor.author.fl_str_mv |
Bruno Leonardo Silva |
dc.subject.por.fl_str_mv |
óxido de dibutilestanho planejamento de inibidores alquilação regiosseletiva galactosídeos de arila Trans-sialidase de Trypanosoma Cruzi ácido siálico Farmácia |
topic |
óxido de dibutilestanho planejamento de inibidores alquilação regiosseletiva galactosídeos de arila Trans-sialidase de Trypanosoma Cruzi ácido siálico Farmácia |
description |
Trypanosoma cruzi trans-sialidase (TcTS) is a surface enzyme that catalyses the transfer of residues of the monosaccharide sialic acid from host sialoglycoconjugates to the mucins, abundant proteins expressed on the parasite surface. Physiologically TcTs actively participates of the mechanisms of evasion from the immune system, cell invasion and blood cell apoptosis. This enzyme is, therefore, essential for the development of Chagas Disease, and is considered a promising molecular target for drug design. Thus, the aim of the present work was the design and synthesis of D-galactose-derived potential inhibitors of TcTS using strategies of molecular modification, in special molecular simplification. Ten aryl galactosides modified at carbon-3 were synthesized and characterized for evaluation against TcTS by spectrofluorimetry. By using classical carbohydrate chemistry 4-methoxycarbonylphenyl -D-galactopyranoside and 4-methoxycarbonyl-2-nitrophenyl -D-galactopyranoside were prepared. The regioselective 3-O-alkylation of both compounds was then carried out using methyl iodide, tert-butyl bromoacetate and bromoacetonitrile as electrophylic reagents. The regioselectivity was achieved by employing the dibutyltin oxide method, in which cyclic tin complexes are formed and, upon reaction with an alkyl halide, furnish 3-O-alkylated products, in general high yields and selectivity. The alkylated products bearing tert-butoxycarbonylmethyl or cyanomethyl groups were modified in order to obtain derivatives bearing at C-3 a carboxymethyl or a 5-tetrazolylmethyl group. |
publishDate |
2012 |
dc.date.none.fl_str_mv |
2012-02-29 2019-08-13T21:41:22Z 2019-08-13T21:41:22Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1843/EMCO-936JAQ |
url |
http://hdl.handle.net/1843/EMCO-936JAQ |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais UFMG |
publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais UFMG |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFMG instname:Universidade Federal de Minas Gerais (UFMG) instacron:UFMG |
instname_str |
Universidade Federal de Minas Gerais (UFMG) |
instacron_str |
UFMG |
institution |
UFMG |
reponame_str |
Repositório Institucional da UFMG |
collection |
Repositório Institucional da UFMG |
repository.name.fl_str_mv |
Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG) |
repository.mail.fl_str_mv |
repositorio@ufmg.br |
_version_ |
1816829581861060608 |