Planejamento, síntese e avaliação antitumoral de derivados di-idropirimidinonas e imidazopiridinas derivadas de 3-ceto-cumarinas substituídas

Detalhes bibliográficos
Ano de defesa: 2020
Autor(a) principal: Ribeiro, Felipe Vitório lattes
Orientador(a): Kümmerle, Arthur Eugen lattes
Banca de defesa: Kümmerle, Arthur Eugen lattes, Castro, Rosane Nora lattes, Lacerda, Renata Barbosa lattes, Mariz e Miranda, Leandro Soter de lattes, Vieira, Daniel Pais Pires lattes
Tipo de documento: Tese
Tipo de acesso: Acesso aberto
Idioma: por
Instituição de defesa: Universidade Federal Rural do Rio de Janeiro
Programa de Pós-Graduação: Programa de Pós-Graduação em Química
Departamento: Instituto de Química
País: Brasil
Palavras-chave em Português:
Câncer
DHPM
Mecanismo reacional
Novobiocin
Reação multicomponente
Palavras-chave em Inglês:
Cancer
coumarins
DHPM
reaction mechanism
monastrol
novobiocin
multicomponent reaction
Área do conhecimento CNPq:
Química
Link de acesso: https://rima.ufrrj.br/jspui/handle/20.500.14407/10253
Resumo: Câncer é um termo usado para doenças em que células anormais se dividem sem controle e são capazes de invadir outros tecidos, podendo se espalhar para lugares distantes no corpo através dos sistemas sanguíneos e linfáticos por um processo conhecido como metástase, sendo considerado pela Organização Mundial da Saúde um dos maiores problemas de saúde enfrentados pela humanidade neste século. Dentre as várias classes terapêuticas para o tratamento do câncer se encontram as cumarinas e imidazopiridinas, que são alvos de contínuas investigações de interesse biológico devido às suas propriedades farmacológicas e diferentes mecanismos de ação. Dessa forma, a presente tese propõe o planejamento, a síntese de uma série de análogos di-idropirimidinônicos ao monastrol, a determinação da via mecanística reacional, visto que sua obtenção passa por uma reação tricomponente de Biginelli, e sua avaliação biológica. O planejamento, síntese, caracterização e avaliação antiproliferativa de novas imidazopirinas também é foco deste trabalho. As séries aqui descritas foram planejadas através de hibridação molecular do núcleo di-idropirimidinona ou imidazopirina com a subunidade cumarínica. Ambos os núcleos são comprovadamente ativos sobre linhagens de células tumorais. Portanto este trabalho tem como objetivo estudar o processo de síntese das séries planejadas, seu escopo reacional e avaliar suas propriedades antiproliferativas. As séries foram sintetizadas através de reações clássicas de química orgânica. Todas as séries foram caracterizadas por métodos físicos e químicos de análise. Este é o primeiro relato provando por EM-IE e cálculos teóricos que o núcleo cumarínico e o seu mecanismo reacional multicomponente curiosamente passa através de um intermediário de Knoevenagel, que foi considerado improvável pela literatura. As bibliotecas de novos compostos foram obtidas com rendimentos de baixos a excelentes (23-96%), tendo sua estrutura final confirmada, também, por estudos de difração de raios-X. Dentre as di-idropirimidinonas as que se mostram mais ativas frente a célula tumoral PC-3 foram as que possuem um grupo dietilamino da posição 7 da cumarina (CI50 = 3,28 μM) e as com mais semelhança estrutural com o monastrol (CI50 = 8,89 μM), a maioria das substancias testadas foram mais ativas que o monastrol (CI50 = 22,02 μM). E dentre as imidazopiridinas esse perfil de substituição também é o mais ativo (CI50 = 2,07 μM frente a célula B16-F10), sendo dez vezes mais seletiva para a referida célula em comparação a células saudáveis. Pode-se observar então uma análise de relação estrutura atividade muito interessante e compostos promissores em potência e seletividade
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spelling Ribeiro, Felipe VitórioKümmerle, Arthur Eugen053.978.487-78http://lattes.cnpq.br/5598000938584486Kümmerle, Arthur Eugen053.978.487-78http://lattes.cnpq.br/5598000938584486Castro, Rosane Norahttps://orcid.org/0000-0001-8983-3786http://lattes.cnpq.br/5479814788308057Lacerda, Renata Barbosahttp://lattes.cnpq.br/2068820144272983Mariz e Miranda, Leandro Soter dehttps://orcid.org/0000-0003-0634-5846http://lattes.cnpq.br/7387849390654555Vieira, Daniel Pais Pireshttp://lattes.cnpq.br/8564684974338964124.035.327-89http://lattes.cnpq.br/63823828671143532023-12-21T18:59:37Z2023-12-21T18:59:37Z2020-03-06RIBEIRO, Felipe Vitório. Planejamento, síntese e avaliação antitumoral de derivados di-idropirimidinonas e imidazopiridinas derivadas de 3-ceto-cumarinas substituídas. 2020. 252 f. Tese (Doutorado em Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, 2020.https://rima.ufrrj.br/jspui/handle/20.500.14407/10253Câncer é um termo usado para doenças em que células anormais se dividem sem controle e são capazes de invadir outros tecidos, podendo se espalhar para lugares distantes no corpo através dos sistemas sanguíneos e linfáticos por um processo conhecido como metástase, sendo considerado pela Organização Mundial da Saúde um dos maiores problemas de saúde enfrentados pela humanidade neste século. Dentre as várias classes terapêuticas para o tratamento do câncer se encontram as cumarinas e imidazopiridinas, que são alvos de contínuas investigações de interesse biológico devido às suas propriedades farmacológicas e diferentes mecanismos de ação. Dessa forma, a presente tese propõe o planejamento, a síntese de uma série de análogos di-idropirimidinônicos ao monastrol, a determinação da via mecanística reacional, visto que sua obtenção passa por uma reação tricomponente de Biginelli, e sua avaliação biológica. O planejamento, síntese, caracterização e avaliação antiproliferativa de novas imidazopirinas também é foco deste trabalho. As séries aqui descritas foram planejadas através de hibridação molecular do núcleo di-idropirimidinona ou imidazopirina com a subunidade cumarínica. Ambos os núcleos são comprovadamente ativos sobre linhagens de células tumorais. Portanto este trabalho tem como objetivo estudar o processo de síntese das séries planejadas, seu escopo reacional e avaliar suas propriedades antiproliferativas. As séries foram sintetizadas através de reações clássicas de química orgânica. Todas as séries foram caracterizadas por métodos físicos e químicos de análise. Este é o primeiro relato provando por EM-IE e cálculos teóricos que o núcleo cumarínico e o seu mecanismo reacional multicomponente curiosamente passa através de um intermediário de Knoevenagel, que foi considerado improvável pela literatura. As bibliotecas de novos compostos foram obtidas com rendimentos de baixos a excelentes (23-96%), tendo sua estrutura final confirmada, também, por estudos de difração de raios-X. Dentre as di-idropirimidinonas as que se mostram mais ativas frente a célula tumoral PC-3 foram as que possuem um grupo dietilamino da posição 7 da cumarina (CI50 = 3,28 μM) e as com mais semelhança estrutural com o monastrol (CI50 = 8,89 μM), a maioria das substancias testadas foram mais ativas que o monastrol (CI50 = 22,02 μM). E dentre as imidazopiridinas esse perfil de substituição também é o mais ativo (CI50 = 2,07 μM frente a célula B16-F10), sendo dez vezes mais seletiva para a referida célula em comparação a células saudáveis. Pode-se observar então uma análise de relação estrutura atividade muito interessante e compostos promissores em potência e seletividadeCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorCancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues, and can spread to distant places in the body through the blood and lymphatic systems through a process known as metastasis, being considered by the World Health Organization. One of the biggest health problems facing humanity in this century. Among the various therapeutic classes for the treatment of cancer are coumarins and imidazopyridines, which are the target of continuous investigations of biological interest due to their pharmaceutical properties and different mechanisms of action. Thus, the present thesis proposes the planning, the synthesis of a series of dihydropyrimidinonic analogues to monastrol, the determination of the mechanistic reaction pathway, since its attainment goes through a Biginelli three-component reaction, and its biological evaluation. The planning, synthesis, characterization and antiproliferative evaluation of new imidazopyrines is also a focus of this work. The series described here were planned through molecular hybridization of the dihydropyrimidinone or imidazopyrine nucleus with the coumarin subunit. Both nuclei are proven to be active on tumor cell lines. Therefore, this work aims to study the synthesis process of the planned series, its reaction scope and to evaluate its antiproliferative properties. The series were synthesized through classic reactions of organic chemistry. All series were characterized by physical and chemical methods of analysis. This is the first report proving by MS-ESI and theoretical calculations that the coumarin nucleus and its multicomponent reaction mechanism curiously passes through a Knoevenagel intermediate, which was considered unlikely in the literature. The libraries of new compounds were obtained with low to excellent yields (23-96%), and their final structure was also confirmed by X-ray diffraction studies. Among the dihydropyrimidinones the ones that are most active against the PC-3 tumor cell were those that have a coumarin position 7 diethylamino (IC50 = 3.28 μM) and those with more structural similarity to monastrol (IC50 = 8, 89 μM), most of the tested substances were more active than monastrol (IC50 = 22.02 μM). And among imidazopyridines, this substitution profile is also the most active (IC50 = 2.07 μM for cell B16-F10), being ten times more selective for that cell compared to healthy cells. You can then see a very interesting structure-to-activity analysis and promising compounds in potency and selectivityapplication/pdfporUniversidade Federal Rural do Rio de JaneiroPrograma de Pós-Graduação em QuímicaUFRRJBrasilInstituto de QuímicaCâncerDHPMMecanismo reacionalNovobiocinReação multicomponenteCancercoumarinsDHPMreaction mechanismmonastrolnovobiocinmulticomponent reactionQuímicaPlanejamento, síntese e avaliação antitumoral de derivados di-idropirimidinonas e imidazopiridinas derivadas de 3-ceto-cumarinas substituídasPlanning, synthesis and antitumor evaluation of derivatives dihydropyrimidinone and imidazopyridine derived from substituted 3-keto-coumarinsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisAgência Nacional de Vigilância Sanitária. Disponível em: <https://consultas.anvisa.gov.br/#/medicamentos/q/?substancia=22353>. Acessado em 28 jul. 2018. ALVIM, H. G. O.; DE LIMA, T. B.; DE OLIVEIRA, H. C. B.; GOZZO, F. C.; DE MACEDO, J. 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dc.title.por.fl_str_mv Planejamento, síntese e avaliação antitumoral de derivados di-idropirimidinonas e imidazopiridinas derivadas de 3-ceto-cumarinas substituídas
dc.title.alternative.eng.fl_str_mv Planning, synthesis and antitumor evaluation of derivatives dihydropyrimidinone and imidazopyridine derived from substituted 3-keto-coumarins
title Planejamento, síntese e avaliação antitumoral de derivados di-idropirimidinonas e imidazopiridinas derivadas de 3-ceto-cumarinas substituídas
spellingShingle Planejamento, síntese e avaliação antitumoral de derivados di-idropirimidinonas e imidazopiridinas derivadas de 3-ceto-cumarinas substituídas
Ribeiro, Felipe Vitório
Câncer
DHPM
Mecanismo reacional
Novobiocin
Reação multicomponente
Cancer
coumarins
DHPM
reaction mechanism
monastrol
novobiocin
multicomponent reaction
Química
title_short Planejamento, síntese e avaliação antitumoral de derivados di-idropirimidinonas e imidazopiridinas derivadas de 3-ceto-cumarinas substituídas
title_full Planejamento, síntese e avaliação antitumoral de derivados di-idropirimidinonas e imidazopiridinas derivadas de 3-ceto-cumarinas substituídas
title_fullStr Planejamento, síntese e avaliação antitumoral de derivados di-idropirimidinonas e imidazopiridinas derivadas de 3-ceto-cumarinas substituídas
title_full_unstemmed Planejamento, síntese e avaliação antitumoral de derivados di-idropirimidinonas e imidazopiridinas derivadas de 3-ceto-cumarinas substituídas
title_sort Planejamento, síntese e avaliação antitumoral de derivados di-idropirimidinonas e imidazopiridinas derivadas de 3-ceto-cumarinas substituídas
author Ribeiro, Felipe Vitório
author_facet Ribeiro, Felipe Vitório
author_role author
dc.contributor.author.fl_str_mv Ribeiro, Felipe Vitório
dc.contributor.advisor1.fl_str_mv Kümmerle, Arthur Eugen
dc.contributor.advisor1ID.fl_str_mv 053.978.487-78
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/5598000938584486
dc.contributor.referee1.fl_str_mv Kümmerle, Arthur Eugen
dc.contributor.referee1ID.fl_str_mv 053.978.487-78
dc.contributor.referee1Lattes.fl_str_mv http://lattes.cnpq.br/5598000938584486
dc.contributor.referee2.fl_str_mv Castro, Rosane Nora
dc.contributor.referee2ID.fl_str_mv https://orcid.org/0000-0001-8983-3786
dc.contributor.referee2Lattes.fl_str_mv http://lattes.cnpq.br/5479814788308057
dc.contributor.referee3.fl_str_mv Lacerda, Renata Barbosa
dc.contributor.referee3Lattes.fl_str_mv http://lattes.cnpq.br/2068820144272983
dc.contributor.referee4.fl_str_mv Mariz e Miranda, Leandro Soter de
dc.contributor.referee4ID.fl_str_mv https://orcid.org/0000-0003-0634-5846
dc.contributor.referee4Lattes.fl_str_mv http://lattes.cnpq.br/7387849390654555
dc.contributor.referee5.fl_str_mv Vieira, Daniel Pais Pires
dc.contributor.referee5Lattes.fl_str_mv http://lattes.cnpq.br/8564684974338964
dc.contributor.authorID.fl_str_mv 124.035.327-89
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/6382382867114353
contributor_str_mv Kümmerle, Arthur Eugen
Kümmerle, Arthur Eugen
Castro, Rosane Nora
Lacerda, Renata Barbosa
Mariz e Miranda, Leandro Soter de
Vieira, Daniel Pais Pires
dc.subject.por.fl_str_mv Câncer
DHPM
Mecanismo reacional
Novobiocin
Reação multicomponente
topic Câncer
DHPM
Mecanismo reacional
Novobiocin
Reação multicomponente
Cancer
coumarins
DHPM
reaction mechanism
monastrol
novobiocin
multicomponent reaction
Química
dc.subject.eng.fl_str_mv Cancer
coumarins
DHPM
reaction mechanism
monastrol
novobiocin
multicomponent reaction
dc.subject.cnpq.fl_str_mv Química
description Câncer é um termo usado para doenças em que células anormais se dividem sem controle e são capazes de invadir outros tecidos, podendo se espalhar para lugares distantes no corpo através dos sistemas sanguíneos e linfáticos por um processo conhecido como metástase, sendo considerado pela Organização Mundial da Saúde um dos maiores problemas de saúde enfrentados pela humanidade neste século. Dentre as várias classes terapêuticas para o tratamento do câncer se encontram as cumarinas e imidazopiridinas, que são alvos de contínuas investigações de interesse biológico devido às suas propriedades farmacológicas e diferentes mecanismos de ação. Dessa forma, a presente tese propõe o planejamento, a síntese de uma série de análogos di-idropirimidinônicos ao monastrol, a determinação da via mecanística reacional, visto que sua obtenção passa por uma reação tricomponente de Biginelli, e sua avaliação biológica. O planejamento, síntese, caracterização e avaliação antiproliferativa de novas imidazopirinas também é foco deste trabalho. As séries aqui descritas foram planejadas através de hibridação molecular do núcleo di-idropirimidinona ou imidazopirina com a subunidade cumarínica. Ambos os núcleos são comprovadamente ativos sobre linhagens de células tumorais. Portanto este trabalho tem como objetivo estudar o processo de síntese das séries planejadas, seu escopo reacional e avaliar suas propriedades antiproliferativas. As séries foram sintetizadas através de reações clássicas de química orgânica. Todas as séries foram caracterizadas por métodos físicos e químicos de análise. Este é o primeiro relato provando por EM-IE e cálculos teóricos que o núcleo cumarínico e o seu mecanismo reacional multicomponente curiosamente passa através de um intermediário de Knoevenagel, que foi considerado improvável pela literatura. As bibliotecas de novos compostos foram obtidas com rendimentos de baixos a excelentes (23-96%), tendo sua estrutura final confirmada, também, por estudos de difração de raios-X. Dentre as di-idropirimidinonas as que se mostram mais ativas frente a célula tumoral PC-3 foram as que possuem um grupo dietilamino da posição 7 da cumarina (CI50 = 3,28 μM) e as com mais semelhança estrutural com o monastrol (CI50 = 8,89 μM), a maioria das substancias testadas foram mais ativas que o monastrol (CI50 = 22,02 μM). E dentre as imidazopiridinas esse perfil de substituição também é o mais ativo (CI50 = 2,07 μM frente a célula B16-F10), sendo dez vezes mais seletiva para a referida célula em comparação a células saudáveis. Pode-se observar então uma análise de relação estrutura atividade muito interessante e compostos promissores em potência e seletividade
publishDate 2020
dc.date.issued.fl_str_mv 2020-03-06
dc.date.accessioned.fl_str_mv 2023-12-21T18:59:37Z
dc.date.available.fl_str_mv 2023-12-21T18:59:37Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
status_str publishedVersion
dc.identifier.citation.fl_str_mv RIBEIRO, Felipe Vitório. Planejamento, síntese e avaliação antitumoral de derivados di-idropirimidinonas e imidazopiridinas derivadas de 3-ceto-cumarinas substituídas. 2020. 252 f. Tese (Doutorado em Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, 2020.
dc.identifier.uri.fl_str_mv https://rima.ufrrj.br/jspui/handle/20.500.14407/10253
identifier_str_mv RIBEIRO, Felipe Vitório. Planejamento, síntese e avaliação antitumoral de derivados di-idropirimidinonas e imidazopiridinas derivadas de 3-ceto-cumarinas substituídas. 2020. 252 f. Tese (Doutorado em Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, 2020.
url https://rima.ufrrj.br/jspui/handle/20.500.14407/10253
dc.language.iso.fl_str_mv por
language por
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