Complexos de metais de transição: aplicações no tratamento e diagnóstico da doença de Alzheimer
Autor(a) principal: | |
---|---|
Data de Publicação: | 2014 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFSCAR |
Texto Completo: | https://repositorio.ufscar.br/handle/ufscar/10720 |
Resumo: | Currently there are about 35.6 million people diagnosed with Alzheimer's disease (AD) in the world, and it is expected that this number will double by 2050. Causes of Alzheimer's disease are not yet known, but their symptoms are characterized the decline of cognitive function result of overactivity of the enzyme acetylcholinesterase (AChE); and accumulation of β-amyloid peptide (β-A) in the brain of patients. Therefore it is important to the development of drugs that act on the two problems of AD; cognitive decline (inhibition of AChE activity) and the identification of fibrillar aggregates of β-A (creation of new probes). For this purpose have been prepared and tested a series of luminescent complex; cis-[Ru(phen)2(4- ImAC)]PF6, cis-[Ru(phen)2(4-ImAAc)]PF6, cis-[Ru(phen)2(2-Apy)](PF6)2, where phen = 1,10-phenanthroline, ImAA = 4-imidazole acetic acid, ImAC = 4-imidazole carboxylic acid and Apy = 2-aminopyridine. The ruthenium complexes were synthesized, where its structural elucidation and purity were checked by NMR H1 spectroscopy and by microanalysis. The compounds are soluble in aqueous solutions and exhibit an intense and broad absorption and emission in the visible region. The complexes have relatively long life with 1 the order of 100 ns. The complexes showed moderate inhibition against the enzyme AChE, with an IC50 of about 10-20 μmol.L-1. From the images from confocal microscopy was possible to make the location of the complex inside the cells by luminescent emission, where the imidazole compounds were located specifically in the cytoplasmic portion of the cell, unlike the complex with aminopyridine, which was distributed homogeneously throughout cellular portion. It was possible to identify the formation of fibers from measurements of emission of the luminescent complex, since these complexes have intensity of luminescence variable with different types of Aβ aggregation. The fibrils were also confirmed by fluorescence microscopy emission lifetime. From the results of the complexes exhibit high pharmacological potential to the treatment of AD since they can be used in diagnosis (identification of the fibrils) and in the treatment of AD (AChE inhibition). |
id |
SCAR_cd526c5e5f050b571f40dc1b6b2aeedc |
---|---|
oai_identifier_str |
oai:repositorio.ufscar.br:ufscar/10720 |
network_acronym_str |
SCAR |
network_name_str |
Repositório Institucional da UFSCAR |
repository_id_str |
4322 |
spelling |
Lima, Márcia Valéria SilvaCarlos, Rose Mariahttp://lattes.cnpq.br/1589143355309943http://lattes.cnpq.br/71447725160002952da1f4b9-87f3-4c29-9070-d2c6bc80c3572018-11-27T22:34:38Z2018-11-27T22:34:38Z2014-11-26LIMA, Márcia Valéria Silva. Complexos de metais de transição: aplicações no tratamento e diagnóstico da doença de Alzheimer. 2014. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2014. Disponível em: https://repositorio.ufscar.br/handle/ufscar/10720.https://repositorio.ufscar.br/handle/ufscar/10720Currently there are about 35.6 million people diagnosed with Alzheimer's disease (AD) in the world, and it is expected that this number will double by 2050. Causes of Alzheimer's disease are not yet known, but their symptoms are characterized the decline of cognitive function result of overactivity of the enzyme acetylcholinesterase (AChE); and accumulation of β-amyloid peptide (β-A) in the brain of patients. Therefore it is important to the development of drugs that act on the two problems of AD; cognitive decline (inhibition of AChE activity) and the identification of fibrillar aggregates of β-A (creation of new probes). For this purpose have been prepared and tested a series of luminescent complex; cis-[Ru(phen)2(4- ImAC)]PF6, cis-[Ru(phen)2(4-ImAAc)]PF6, cis-[Ru(phen)2(2-Apy)](PF6)2, where phen = 1,10-phenanthroline, ImAA = 4-imidazole acetic acid, ImAC = 4-imidazole carboxylic acid and Apy = 2-aminopyridine. The ruthenium complexes were synthesized, where its structural elucidation and purity were checked by NMR H1 spectroscopy and by microanalysis. The compounds are soluble in aqueous solutions and exhibit an intense and broad absorption and emission in the visible region. The complexes have relatively long life with 1 the order of 100 ns. The complexes showed moderate inhibition against the enzyme AChE, with an IC50 of about 10-20 μmol.L-1. From the images from confocal microscopy was possible to make the location of the complex inside the cells by luminescent emission, where the imidazole compounds were located specifically in the cytoplasmic portion of the cell, unlike the complex with aminopyridine, which was distributed homogeneously throughout cellular portion. It was possible to identify the formation of fibers from measurements of emission of the luminescent complex, since these complexes have intensity of luminescence variable with different types of Aβ aggregation. The fibrils were also confirmed by fluorescence microscopy emission lifetime. From the results of the complexes exhibit high pharmacological potential to the treatment of AD since they can be used in diagnosis (identification of the fibrils) and in the treatment of AD (AChE inhibition).Atualmente existem cerca de 35,6 milhões de pessoas diagnósticadas com a doença de Alzheimer (DA) no mundo, e espera-se que este número duplique até 2050. As causas da doença de Alzheimer, ainda não são conhecidas, mas seus sintomas são caracterizados pelo declínio da função cognitiva resultado da superatividade da enzima acetilcolinesterase (AChE); e à acumulação do peptídeo β-amilóide (β-A) no cérebro dos doentes. Diante disso é importante o desenvolvimento de fármacos que atuem nos dois problemas da DA; tanto no declínio cognitivo (inibição da atividade da AChE) e na identificação dos agregados fibrilares de β-A (criação de novas sondas). Para esta finalidade foram preparados e ensaiados uma série de complexos luminescentes cis-[Ru(phen)2(4-ImAC)]PF6, cis- [Ru(phen)2(4-ImAAc)]PF6, cis-[Ru(phen)2(2-Apy)](PF6)2, onde phen=1,10- fenantrolina, ImAA= 4-imidazol ácido acético, ImAC= 4-imidazol ácido carboxílico e Apy= 2-aminopiridina. Os complexos de rutênio foram sintetizados, onde sua elucidação estrutural e grau de pureza foram verificados por espectroscopia de RMN de H1 e por análise elementar. Os compostos são solúveis em solução aquosa e exibem uma intensa e larga absorção e emissão na região do visível. Os complexos apresentaram tempo de vida relativamente longo, onde o 1 encontrado foi da ordem de 100 ns. Os complexos exibiram inibição moderada frente à enzima AChE, com um IC50 da ordem de 10-20 μmol.L-1. A partir da imagens de microscopia confocal foi possível fazer a localização dos complexos no interior celular, através da emissão luminescente, onde os compostos imidazólicos se localizaram especificadamente na porção citoplasmática das células, e o complexo com aminopiridina, se distribuiu de forma homogênea em toda a porção celular. Foi possível acompanhar a formação das fibras a partir das medidas de emissão dos complexos, uma vez que os compostos apresentam intensidade de luminescência variável aos diferentes tipos de agregação do β-A. As fibrilas também foram confirmadas por microscopia fluorescente de tempo de vida de emissão. A partir dos resultados os complexos exibem grande potencial farmacológico frente ao tratamento da DA, uma vez que podem ser utilizados tanto no diagnóstico (identificação das fibrilas) e no tratamento da DA (inibição da AChE).Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)porUniversidade Federal de São CarlosCâmpus São CarlosPrograma de Pós-Graduação em Química - PPGQUFSCarQuímica inorgânicaComplexos de rutênioFármacosAlzheimerDoença de AlzheimerChemistry inorganicRuthenium complexeDrugsAlzheimerAlzheimer's diseaseCIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICAComplexos de metais de transição: aplicações no tratamento e diagnóstico da doença de AlzheimerTransition metal complex as precursors for bioactive molecules: applications in the treatment of alzheimer's diseaseinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisOnline60060081ea1b7e-7dcf-438f-a839-b8cab12c5740info:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFSCARinstname:Universidade Federal de São Carlos (UFSCAR)instacron:UFSCARORIGINALTeseMVSL.pdfTeseMVSL.pdfapplication/pdf4417859https://repositorio.ufscar.br/bitstream/ufscar/10720/1/TeseMVSL.pdf4474f1b06b0eb350f14ccae4731fe9dfMD51LICENSElicense.txtlicense.txttext/plain; charset=utf-81957https://repositorio.ufscar.br/bitstream/ufscar/10720/2/license.txtae0398b6f8b235e40ad82cba6c50031dMD52TEXTTeseMVSL.pdf.txtTeseMVSL.pdf.txtExtracted texttext/plain173216https://repositorio.ufscar.br/bitstream/ufscar/10720/3/TeseMVSL.pdf.txt2b7ee05d67f7f4e853f4542449cd604bMD53THUMBNAILTeseMVSL.pdf.jpgTeseMVSL.pdf.jpgIM Thumbnailimage/jpeg8383https://repositorio.ufscar.br/bitstream/ufscar/10720/4/TeseMVSL.pdf.jpg93c9449522682c651a8f5955281a9ca1MD54ufscar/107202023-09-18 18:31:18.073oai:repositorio.ufscar.br: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Repositório InstitucionalPUBhttps://repositorio.ufscar.br/oai/requestopendoar:43222023-09-18T18:31:18Repositório Institucional da UFSCAR - Universidade Federal de São Carlos (UFSCAR)false |
dc.title.por.fl_str_mv |
Complexos de metais de transição: aplicações no tratamento e diagnóstico da doença de Alzheimer |
dc.title.alternative.eng.fl_str_mv |
Transition metal complex as precursors for bioactive molecules: applications in the treatment of alzheimer's disease |
title |
Complexos de metais de transição: aplicações no tratamento e diagnóstico da doença de Alzheimer |
spellingShingle |
Complexos de metais de transição: aplicações no tratamento e diagnóstico da doença de Alzheimer Lima, Márcia Valéria Silva Química inorgânica Complexos de rutênio Fármacos Alzheimer Doença de Alzheimer Chemistry inorganic Ruthenium complexe Drugs Alzheimer Alzheimer's disease CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICA |
title_short |
Complexos de metais de transição: aplicações no tratamento e diagnóstico da doença de Alzheimer |
title_full |
Complexos de metais de transição: aplicações no tratamento e diagnóstico da doença de Alzheimer |
title_fullStr |
Complexos de metais de transição: aplicações no tratamento e diagnóstico da doença de Alzheimer |
title_full_unstemmed |
Complexos de metais de transição: aplicações no tratamento e diagnóstico da doença de Alzheimer |
title_sort |
Complexos de metais de transição: aplicações no tratamento e diagnóstico da doença de Alzheimer |
author |
Lima, Márcia Valéria Silva |
author_facet |
Lima, Márcia Valéria Silva |
author_role |
author |
dc.contributor.authorlattes.por.fl_str_mv |
http://lattes.cnpq.br/7144772516000295 |
dc.contributor.author.fl_str_mv |
Lima, Márcia Valéria Silva |
dc.contributor.advisor1.fl_str_mv |
Carlos, Rose Maria |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/1589143355309943 |
dc.contributor.authorID.fl_str_mv |
2da1f4b9-87f3-4c29-9070-d2c6bc80c357 |
contributor_str_mv |
Carlos, Rose Maria |
dc.subject.por.fl_str_mv |
Química inorgânica Complexos de rutênio Fármacos Alzheimer Doença de Alzheimer |
topic |
Química inorgânica Complexos de rutênio Fármacos Alzheimer Doença de Alzheimer Chemistry inorganic Ruthenium complexe Drugs Alzheimer Alzheimer's disease CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICA |
dc.subject.eng.fl_str_mv |
Chemistry inorganic Ruthenium complexe Drugs Alzheimer Alzheimer's disease |
dc.subject.cnpq.fl_str_mv |
CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICA |
description |
Currently there are about 35.6 million people diagnosed with Alzheimer's disease (AD) in the world, and it is expected that this number will double by 2050. Causes of Alzheimer's disease are not yet known, but their symptoms are characterized the decline of cognitive function result of overactivity of the enzyme acetylcholinesterase (AChE); and accumulation of β-amyloid peptide (β-A) in the brain of patients. Therefore it is important to the development of drugs that act on the two problems of AD; cognitive decline (inhibition of AChE activity) and the identification of fibrillar aggregates of β-A (creation of new probes). For this purpose have been prepared and tested a series of luminescent complex; cis-[Ru(phen)2(4- ImAC)]PF6, cis-[Ru(phen)2(4-ImAAc)]PF6, cis-[Ru(phen)2(2-Apy)](PF6)2, where phen = 1,10-phenanthroline, ImAA = 4-imidazole acetic acid, ImAC = 4-imidazole carboxylic acid and Apy = 2-aminopyridine. The ruthenium complexes were synthesized, where its structural elucidation and purity were checked by NMR H1 spectroscopy and by microanalysis. The compounds are soluble in aqueous solutions and exhibit an intense and broad absorption and emission in the visible region. The complexes have relatively long life with 1 the order of 100 ns. The complexes showed moderate inhibition against the enzyme AChE, with an IC50 of about 10-20 μmol.L-1. From the images from confocal microscopy was possible to make the location of the complex inside the cells by luminescent emission, where the imidazole compounds were located specifically in the cytoplasmic portion of the cell, unlike the complex with aminopyridine, which was distributed homogeneously throughout cellular portion. It was possible to identify the formation of fibers from measurements of emission of the luminescent complex, since these complexes have intensity of luminescence variable with different types of Aβ aggregation. The fibrils were also confirmed by fluorescence microscopy emission lifetime. From the results of the complexes exhibit high pharmacological potential to the treatment of AD since they can be used in diagnosis (identification of the fibrils) and in the treatment of AD (AChE inhibition). |
publishDate |
2014 |
dc.date.issued.fl_str_mv |
2014-11-26 |
dc.date.accessioned.fl_str_mv |
2018-11-27T22:34:38Z |
dc.date.available.fl_str_mv |
2018-11-27T22:34:38Z |
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 |
LIMA, Márcia Valéria Silva. Complexos de metais de transição: aplicações no tratamento e diagnóstico da doença de Alzheimer. 2014. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2014. Disponível em: https://repositorio.ufscar.br/handle/ufscar/10720. |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufscar.br/handle/ufscar/10720 |
identifier_str_mv |
LIMA, Márcia Valéria Silva. Complexos de metais de transição: aplicações no tratamento e diagnóstico da doença de Alzheimer. 2014. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2014. Disponível em: https://repositorio.ufscar.br/handle/ufscar/10720. |
url |
https://repositorio.ufscar.br/handle/ufscar/10720 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.confidence.fl_str_mv |
600 600 |
dc.relation.authority.fl_str_mv |
81ea1b7e-7dcf-438f-a839-b8cab12c5740 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de São Carlos Câmpus São Carlos |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Química - PPGQ |
dc.publisher.initials.fl_str_mv |
UFSCar |
publisher.none.fl_str_mv |
Universidade Federal de São Carlos Câmpus São Carlos |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFSCAR instname:Universidade Federal de São Carlos (UFSCAR) instacron:UFSCAR |
instname_str |
Universidade Federal de São Carlos (UFSCAR) |
instacron_str |
UFSCAR |
institution |
UFSCAR |
reponame_str |
Repositório Institucional da UFSCAR |
collection |
Repositório Institucional da UFSCAR |
bitstream.url.fl_str_mv |
https://repositorio.ufscar.br/bitstream/ufscar/10720/1/TeseMVSL.pdf https://repositorio.ufscar.br/bitstream/ufscar/10720/2/license.txt https://repositorio.ufscar.br/bitstream/ufscar/10720/3/TeseMVSL.pdf.txt https://repositorio.ufscar.br/bitstream/ufscar/10720/4/TeseMVSL.pdf.jpg |
bitstream.checksum.fl_str_mv |
4474f1b06b0eb350f14ccae4731fe9df ae0398b6f8b235e40ad82cba6c50031d 2b7ee05d67f7f4e853f4542449cd604b 93c9449522682c651a8f5955281a9ca1 |
bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 MD5 |
repository.name.fl_str_mv |
Repositório Institucional da UFSCAR - Universidade Federal de São Carlos (UFSCAR) |
repository.mail.fl_str_mv |
|
_version_ |
1802136349750329344 |