Sintese e avaliação de peptidomiméticos contendo heterociclos de três membros como inibidores de catepsina L
Autor(a) principal: | |
---|---|
Data de Publicação: | 2017 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFSCAR |
Texto Completo: | https://repositorio.ufscar.br/handle/ufscar/10142 |
Resumo: | Cathepsin L is a lysosomal cysteine protease, that is related to many physiological processes, however overexpression and up- or downregulation may cause several pathologies. Therefore, cathepsin L became an interesting drug target. Peptidyl epoxides and aziridines are reported as potent cathepsin inhibitors.Previously, our research group has synthesized six new epoxi-α-acyloxycarboxamides through one-pot process starting with an organocatalyzed asymmetric epoxidation using catalyst I followed by Passerini reaction. Then, inhibitory assays against cathepsins K, L and V were performed, and the new compounds presented inhibition, mainly against cathepsin L. In order to further evaluate the structure-activity relationship of epoxi-α-acyloxycarboxamides 11 new compounds were synthesized. Among all, LPSN423 exhibited the best inhibitory activity. The mechanistic study showed that LSPN423 is a reversible tight binding uncompetitive inhibitor, which characterized by a high affinity enzyme-inhibitor complex. To further explore the application of 2,3-epoxi-aldehydes in multicomponent reactions, in addition to create a library of compounds to be evaluated against cathepsin L, Ugi reaction were performed sequentially to epoxidation. The 2-step procedure furnished the desired product with yields ranged from 22% to 68%. The new epoxi-α-acylaminocarboxamides were tested against cathepsin L and no significant activity was observed. The organocatalytic aziridination reaction is reported, however some drawbacks are associated with this reaction, such as the use of chlorinated solvents and large excess of base to promote the reaction. Thus, catalyst I allowed the use of the greener solvent mixture ethanol/water and a lower amount of base. Another drawback of this reaction is the unstable product, so to overcome this issue, the one-pot Passerini reaction was performed, right after the completion of the aziridination; the desired products were obtained from moderate to good yields. Preliminary evaluation of the new aziridine peptidomimetics indicates a potential activity of this class of compounds, although further studies are required. |
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Santos, Deborah Araujo dosCorrêa, Arlene Gonçalveshttp://lattes.cnpq.br/7425467156776144http://lattes.cnpq.br/50786179432444510cd85b5f-dfd4-43d3-b090-75cdc28f5cbd2018-06-06T17:53:22Z2018-06-06T17:53:22Z2017-12-01SANTOS, Deborah Araujo dos. Sintese e avaliação de peptidomiméticos contendo heterociclos de três membros como inibidores de catepsina L. 2017. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2017. Disponível em: https://repositorio.ufscar.br/handle/ufscar/10142.https://repositorio.ufscar.br/handle/ufscar/10142Cathepsin L is a lysosomal cysteine protease, that is related to many physiological processes, however overexpression and up- or downregulation may cause several pathologies. Therefore, cathepsin L became an interesting drug target. Peptidyl epoxides and aziridines are reported as potent cathepsin inhibitors.Previously, our research group has synthesized six new epoxi-α-acyloxycarboxamides through one-pot process starting with an organocatalyzed asymmetric epoxidation using catalyst I followed by Passerini reaction. Then, inhibitory assays against cathepsins K, L and V were performed, and the new compounds presented inhibition, mainly against cathepsin L. In order to further evaluate the structure-activity relationship of epoxi-α-acyloxycarboxamides 11 new compounds were synthesized. Among all, LPSN423 exhibited the best inhibitory activity. The mechanistic study showed that LSPN423 is a reversible tight binding uncompetitive inhibitor, which characterized by a high affinity enzyme-inhibitor complex. To further explore the application of 2,3-epoxi-aldehydes in multicomponent reactions, in addition to create a library of compounds to be evaluated against cathepsin L, Ugi reaction were performed sequentially to epoxidation. The 2-step procedure furnished the desired product with yields ranged from 22% to 68%. The new epoxi-α-acylaminocarboxamides were tested against cathepsin L and no significant activity was observed. The organocatalytic aziridination reaction is reported, however some drawbacks are associated with this reaction, such as the use of chlorinated solvents and large excess of base to promote the reaction. Thus, catalyst I allowed the use of the greener solvent mixture ethanol/water and a lower amount of base. Another drawback of this reaction is the unstable product, so to overcome this issue, the one-pot Passerini reaction was performed, right after the completion of the aziridination; the desired products were obtained from moderate to good yields. Preliminary evaluation of the new aziridine peptidomimetics indicates a potential activity of this class of compounds, although further studies are required.A catepsina L é uma cisteíno protease lisossomal, que está envolvida em vários processos fisiológicos. Entretanto, falhas na sua expressão e regulação desencadeiam processos patológicos, por esse motivo, a catepsina L se tornou um alvo terapêutico interessante. Peptídeos contendo anéis epóxido e aziridina são reportados como inibidores potentes de catepsinas. Em um estudo prévio desenvolvido pelo nosso grupo de pesquisa, 6 epoxi-α-aciloxicarboxamidas foram sintetizadas de maneira one-pot via reação de epoxidação assimétrica organocatalisada utilizando o catalisador I seguida da reação de Passerini. Testes relacionados à atividade dos compostos como inibidores de catepsinas K, V e L mostraram o potencial da nova classe, sobretudo frente à catepsina L. Neste trabalho, a coleção de epoxi-α-aciloxicarboxamidas foi ampliada com a síntese de mais 11 exemplos, a fim de melhor avaliar a relação estrutura-atividade desta classe de compostos frente à catepsina L. De toda a série, o LPSN423 apresentou a melhor inibição. Estudos sobre o mecanismo de inibição demonstraram que o LSPN423 é um inibidor reversível do tipo tight binding incompetitivo. Neste modo de inibição, o complexo enzima-inibidor apresenta elevada afinidade. Com o intuito de explorar a aplicação dos 2,3-epoxi-aldeídos assimétricos preparados pela metodologia desenvolvida no grupo de pesquisa, bem como criar uma biblioteca de compostos candidatos a inibidores de catepsina L, novas epoxi-α- acilaminocarboxamidas foram sintetizadas, desta vez empregando de forma sequencial a reação multicomponente de Ugi. Os rendimentos em duas etapas variaram de 22-68% para os cinco exemplos sintetizados. Os compostos desta série foram avaliados frente à catepsina L, porém, nenhum deles apresentou atividade inibitória significativa. A síntese de aziridinas assimétricas via organocatálise é reportada tendo como desvantagem a utilização de solventes clorados e excessos de base. O emprego do organocatalisador I proporcionou o uso de etanol:água como solvente e diminuição da quantidade de base. Uma limitação na síntese de β-formilaziridinas está na dificuldade de isolar os produtos, por esse motivo, aplicou-se a funcionalização da aziridina na reação de Passerini one-pot, na qual obteve-se o produto desejado com rendimentos moderados. A avaliação preliminar das aziridinas obtidas frente à inibição da catepsina L indica uma potencial atividade dessa classe de compostos, no entanto estudos mais aprofundados serão necessários.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNPq: 144095/2014-9porUniversidade Federal de São CarlosCâmpus São CarlosPrograma de Pós-Graduação em Química - PPGQUFSCarPeptidomiméticosOrganocatáliseReação multicomponenteInibidor da catepsina LReação de PasseriniReação de UgiEpóxidoAziridinaTight bindingCIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA::SINTESE ORGANICASintese e avaliação de peptidomiméticos contendo heterociclos de três membros como inibidores de catepsina LSynthesis and evaluation of peptidomimetics bearing three-membered heterocycles as cathepsin L inhibitorsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisOnline600600d0f2b9e6-a39b-4adb-8930-18725207ea16info:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFSCARinstname:Universidade Federal de São Carlos (UFSCAR)instacron:UFSCARORIGINALTese - Deborah Santos.pdfTese - Deborah Santos.pdfTese completaapplication/pdf12203832https://repositorio.ufscar.br/bitstream/ufscar/10142/1/Tese%20-%20Deborah%20Santos.pdfe193cc5eef9d1f8e0dd6df5a35d4cc55MD51doc PPGQ.pdfdoc PPGQ.pdfCarta comprovante assinada pela orientadoraapplication/pdf706491https://repositorio.ufscar.br/bitstream/ufscar/10142/3/doc%20PPGQ.pdf90df4e7187c05b6824acb979f9f1cafdMD53LICENSElicense.txtlicense.txttext/plain; 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dc.title.por.fl_str_mv |
Sintese e avaliação de peptidomiméticos contendo heterociclos de três membros como inibidores de catepsina L |
dc.title.alternative.eng.fl_str_mv |
Synthesis and evaluation of peptidomimetics bearing three-membered heterocycles as cathepsin L inhibitors |
title |
Sintese e avaliação de peptidomiméticos contendo heterociclos de três membros como inibidores de catepsina L |
spellingShingle |
Sintese e avaliação de peptidomiméticos contendo heterociclos de três membros como inibidores de catepsina L Santos, Deborah Araujo dos Peptidomiméticos Organocatálise Reação multicomponente Inibidor da catepsina L Reação de Passerini Reação de Ugi Epóxido Aziridina Tight binding CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA::SINTESE ORGANICA |
title_short |
Sintese e avaliação de peptidomiméticos contendo heterociclos de três membros como inibidores de catepsina L |
title_full |
Sintese e avaliação de peptidomiméticos contendo heterociclos de três membros como inibidores de catepsina L |
title_fullStr |
Sintese e avaliação de peptidomiméticos contendo heterociclos de três membros como inibidores de catepsina L |
title_full_unstemmed |
Sintese e avaliação de peptidomiméticos contendo heterociclos de três membros como inibidores de catepsina L |
title_sort |
Sintese e avaliação de peptidomiméticos contendo heterociclos de três membros como inibidores de catepsina L |
author |
Santos, Deborah Araujo dos |
author_facet |
Santos, Deborah Araujo dos |
author_role |
author |
dc.contributor.authorlattes.por.fl_str_mv |
http://lattes.cnpq.br/5078617943244451 |
dc.contributor.author.fl_str_mv |
Santos, Deborah Araujo dos |
dc.contributor.advisor1.fl_str_mv |
Corrêa, Arlene Gonçalves |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/7425467156776144 |
dc.contributor.authorID.fl_str_mv |
0cd85b5f-dfd4-43d3-b090-75cdc28f5cbd |
contributor_str_mv |
Corrêa, Arlene Gonçalves |
dc.subject.por.fl_str_mv |
Peptidomiméticos Organocatálise Reação multicomponente Inibidor da catepsina L Reação de Passerini Reação de Ugi Epóxido Aziridina |
topic |
Peptidomiméticos Organocatálise Reação multicomponente Inibidor da catepsina L Reação de Passerini Reação de Ugi Epóxido Aziridina Tight binding CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA::SINTESE ORGANICA |
dc.subject.eng.fl_str_mv |
Tight binding |
dc.subject.cnpq.fl_str_mv |
CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA::SINTESE ORGANICA |
description |
Cathepsin L is a lysosomal cysteine protease, that is related to many physiological processes, however overexpression and up- or downregulation may cause several pathologies. Therefore, cathepsin L became an interesting drug target. Peptidyl epoxides and aziridines are reported as potent cathepsin inhibitors.Previously, our research group has synthesized six new epoxi-α-acyloxycarboxamides through one-pot process starting with an organocatalyzed asymmetric epoxidation using catalyst I followed by Passerini reaction. Then, inhibitory assays against cathepsins K, L and V were performed, and the new compounds presented inhibition, mainly against cathepsin L. In order to further evaluate the structure-activity relationship of epoxi-α-acyloxycarboxamides 11 new compounds were synthesized. Among all, LPSN423 exhibited the best inhibitory activity. The mechanistic study showed that LSPN423 is a reversible tight binding uncompetitive inhibitor, which characterized by a high affinity enzyme-inhibitor complex. To further explore the application of 2,3-epoxi-aldehydes in multicomponent reactions, in addition to create a library of compounds to be evaluated against cathepsin L, Ugi reaction were performed sequentially to epoxidation. The 2-step procedure furnished the desired product with yields ranged from 22% to 68%. The new epoxi-α-acylaminocarboxamides were tested against cathepsin L and no significant activity was observed. The organocatalytic aziridination reaction is reported, however some drawbacks are associated with this reaction, such as the use of chlorinated solvents and large excess of base to promote the reaction. Thus, catalyst I allowed the use of the greener solvent mixture ethanol/water and a lower amount of base. Another drawback of this reaction is the unstable product, so to overcome this issue, the one-pot Passerini reaction was performed, right after the completion of the aziridination; the desired products were obtained from moderate to good yields. Preliminary evaluation of the new aziridine peptidomimetics indicates a potential activity of this class of compounds, although further studies are required. |
publishDate |
2017 |
dc.date.issued.fl_str_mv |
2017-12-01 |
dc.date.accessioned.fl_str_mv |
2018-06-06T17:53:22Z |
dc.date.available.fl_str_mv |
2018-06-06T17:53:22Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/doctoralThesis |
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doctoralThesis |
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publishedVersion |
dc.identifier.citation.fl_str_mv |
SANTOS, Deborah Araujo dos. Sintese e avaliação de peptidomiméticos contendo heterociclos de três membros como inibidores de catepsina L. 2017. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2017. Disponível em: https://repositorio.ufscar.br/handle/ufscar/10142. |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufscar.br/handle/ufscar/10142 |
identifier_str_mv |
SANTOS, Deborah Araujo dos. Sintese e avaliação de peptidomiméticos contendo heterociclos de três membros como inibidores de catepsina L. 2017. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2017. Disponível em: https://repositorio.ufscar.br/handle/ufscar/10142. |
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https://repositorio.ufscar.br/handle/ufscar/10142 |
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openAccess |
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Universidade Federal de São Carlos Câmpus São Carlos |
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Programa de Pós-Graduação em Química - PPGQ |
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UFSCar |
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Universidade Federal de São Carlos Câmpus São Carlos |
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