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dc.contributor.authorBezerra, Lucas Caruso Araujo
dc.date.accessioned2023-12-22T03:03:57Z-
dc.date.available2023-12-22T03:03:57Z-
dc.date.issued2021-02-26
dc.identifier.citationBEZERRA, Lucas Caruso Araujo. Planejamento, síntese e avaliação biológica de novas chalconas como potenciais agentes anti-prion. 2021. 161 f. Dissertação (Mestrado de Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, 2021 .por
dc.identifier.urihttps://rima.ufrrj.br/jspui/handle/20.500.14407/14646-
dc.description.abstractAs doenças relacionadas a eventos de enovelamento incorreto de proteínas são uma família de desordens neurológicas debilitantes, degenerativas, progressivas, fatais e atualmente intratáveis. Na doença priônica, a proteína priônica normal (PrPC) é convertida à isoforma infectante (PrPSc) rica em folhas β, de difícil degradação por proteases e propensas a formar agregados fibrilares responsáveis pela neurotoxicidade da isoforma patogênica. Embora muitos compostos tenham demonstrado inibir o processo de conversão à PrPSc, até o momento não há terapia eficaz para esse tipo de doença visto que a maioria dos compostos estudados in vitro possuem perfil farmacocinético desfavorável. Este trabalho propõe a síntese de cinco séries (Série A, B, C, D e E) de chalconas, baseadas no protótipo J8, desenvolvidas como possíveis compostos anti-príon capazes de atuar como chaperona química na estabilização conformacional da isoforma não infectante PrPC, impedindo a formação de PrPSc. A primeira série (Série A) de compostos foi totalmente sintetizada com rendimentos satisfatórios através da condensação de Claisen-Schmidt seguido da reação de acoplamento cruzado de Buchwald- Hartwig. Das sete chalconas sintetizadas para série A, quatro delas apresentaram um ótimo perfil biológico, conseguindo inibir a interconversão, in vitro, de PrPC em PrPSc em até 80% na concentração de 10 M, cujos valores superaram os obtidos para o protótipo J8. Alguns compostos finais das séries B, C e E já foram sintetizados, demonstrando que a rota sintética empregada é eficiente, enquanto o desenvolvimento sintético da série D encontra-se interrompido no penultimo intermediário-chave. Os compostos de todas as séries foram submetidos a estudos in silico de docking molecular e possibilitaram a melhor compreensão do sítio de ligação da proteína priônica e o perfil de interação entre as chalconas e a PrP121-231. Os estudos de docking molecular realizados para série D sugerem que estes são os derivados mais promissores de todas as séries, cujos valores de energia de ligação se mostraram melhores que os encontrados para as chalconas da série A, que já possuem um ótimo perfil farmacológicopor
dc.description.sponsorshipCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superiorpor
dc.formatapplication/pdf*
dc.languageporpor
dc.publisherUniversidade Federal Rural do Rio de Janeiropor
dc.rightsAcesso Abertopor
dc.subjectDoença priônicapor
dc.subjectBuchwald-Hartwigpor
dc.subjectN-arilaçãopor
dc.subjectPrion diseaseeng
dc.subjectBuchwald-Hartwigeng
dc.subjectN-arylationeng
dc.titlePlanejamento, síntese e avaliação biológica de novas chalconas como potenciais agentes anti-prionpor
dc.title.alternativePlanning, synthesis and biological evaluation of new chalcones as potential anti-prion agentseng
dc.typeDissertaçãopor
dc.description.abstractOtherAs doenças relacionadas a eventos de enovelamento incorreto de proteínas são uma família de desordens neurológicas debilitantes, degenerativas, progressivas, fatais e atualmente intratáveis. Na doença priônica, a proteína priônica normal (PrPC) é convertida à isoforma infectante (PrPSc) rica em folhas β, de difícil degradação por proteases e propensas a formar agregados fibrilares responsáveis pela neurotoxicidade da isoforma patogênica. Embora muitos compostos tenham demonstrado inibir o processo de conversão à PrPSc, até o momento não há terapia eficaz para esse tipo de doença visto que a maioria dos compostos estudados in vitro possuem perfil farmacocinético desfavorável. Este trabalho propõe a síntese de cinco séries (Série A, B, C, D e E) de chalconas, baseadas no protótipo J8, desenvolvidas como possíveis compostos anti-príon capazes de atuar como chaperona química na estabilização conformacional da isoforma não infectante PrPC, impedindo a formação de PrPSc. A primeira série (Série A) de compostos foi totalmente sintetizada com rendimentos satisfatórios através da condensação de Claisen-Schmidt seguido da reação de acoplamento cruzado de Buchwald- Hartwig. Das sete chalconas sintetizadas para série A, quatro delas apresentaram um ótimo perfil biológico, conseguindo inibir a interconversão, in vitro, de PrPC em PrPSc em até 80% na concentração de 10 M, cujos valores superaram os obtidos para o protótipo J8. Alguns compostos finais das séries B, C e E já foram sintetizados, demonstrando que a rota sintética empregada é eficiente, enquanto o desenvolvimento sintético da série D encontra-se interrompido no penultimo intermediário-chave. Os compostos de todas as séries foram submetidos a estudos in silico de docking molecular e possibilitaram a melhor compreensão do sítio de ligação da proteína priônica e o perfil de interação entre as chalconas e a PrP121-231. Os estudos de docking molecular realizados para série D sugerem que estes são os derivados mais promissores de todas as séries, cujos valores de energia de ligação se mostraram melhores que os encontrados para as chalconas da série A, que já possuem um ótimo perfil farmacológico.eng
dc.contributor.advisor1Kümmerle, Arthur Eugen
dc.contributor.advisor1ID053.978.487-78por
dc.contributor.advisor1Latteshttp://lattes.cnpq.br/5598000938584486por
dc.contributor.referee1Kümmerle, Arthur Eugen
dc.contributor.referee1ID053.978.487-78por
dc.contributor.referee1Latteshttp://lattes.cnpq.br/5598000938584486por
dc.contributor.referee2Castro, Rosane Nora
dc.contributor.referee2IDhttps://orcid.org/0000-0001-8983-3786por
dc.contributor.referee2Latteshttp://lattes.cnpq.br/5479814788308057por
dc.contributor.referee3Pinho, Vagner Dantas
dc.contributor.referee3Latteshttp://lattes.cnpq.br/8226081677916407por
dc.contributor.referee4Graebin, Cedric Stephan
dc.contributor.referee4IDhttps://orcid.org/0000-0003-1410-1227por
dc.contributor.referee4Latteshttp://lattes.cnpq.br/4900857097448760por
dc.contributor.referee5Barbosa, Maria Letícia de Castro
dc.contributor.referee5Latteshttp://lattes.cnpq.br/0722721630520953por
dc.creator.ID134.574.847-75por
dc.creator.IDhttps://orcid.org/0000-0003-1300-5284por
dc.creator.Latteshttp://lattes.cnpq.br/1644908326484939por
dc.publisher.countryBrasilpor
dc.publisher.departmentInstituto de Químicapor
dc.publisher.initialsUFRRJpor
dc.publisher.programPrograma de Pós-Graduação em Químicapor
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