Targeting the ubiquitin-proteasome system: four-membered ring inhibitors of proteasome

Detalhes bibliográficos
Autor(a) principal: Heydarpour Klidsar, Maryam
Data de Publicação: 2019
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/54833
Resumo: Tese de mestrado, Química Farmacêutica e Terapêutica, 2019, Universidade de Lisboa, Faculdade de Farmácia.
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spelling Targeting the ubiquitin-proteasome system: four-membered ring inhibitors of proteasomeUbiquitin-proteasome systemß-lactam scaffoldProteasome inhibitorChymotrypsin-like (CTL) activityTeses de mestrado - 2019Ciências da SaúdeTese de mestrado, Química Farmacêutica e Terapêutica, 2019, Universidade de Lisboa, Faculdade de Farmácia.The ubiquitin-proteasome system (UPS) plays a pivotal role in the degradation of proteins in cellular homeostasis, with the 20S proteasome (core particle, CP) being the proteolytic key component of the UPS. The catalytic active sites of the cylinder-shaped, multimeric, CP are formed by N-terminal threonines, which are located at subunits β1, β2, and β5 in the inner cavity of a barrel-like structure. Several natural β-lactones such as Omuralide and Marizomib, were found to predominantly bind to subunit β5 that harbors the chymotrypsin-like (CTL) activity. Although at least one β-lactone is now in clinical use, this scaffold is very reactive and thus prone to metabolic inactivation and off-target effects. Our group has developed β-lactam-based systems as inhibitors of serine proteases from the chymotrypsin super-family. These inhibitors can be appropriately modified to modulate not only the molecular recognition by the enzyme, but also the intrinsic reactivity towards the catalytic amino acid. In this project we tried to design and synthesize a small library of 4-oxo-β-lactams compounds as proteasome inhibitors, containing the structural motifs for molecular recognition by proteasome, and we evaluated the inhibitory activity against the proteasomes, using a fluorometric proteasome 20S assay. This is a homogeneous fluorescent assay that measures the CTL protease activity solution or in cultured cells. Unfortunately, the compounds synthesized in this project did not show a considerable inhibitory effect on proteasome. The best compound in this series was compound 39.Moreira, Rui Ferreira AlvesRepositório da Universidade de LisboaHeydarpour Klidsar, Maryam2022-10-19T14:09:49Z2019-06-172019-06-17T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10451/54833TID:202272575enginfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T17:01:28Zoai:repositorio.ul.pt:10451/54833Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:05:36.119641Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Targeting the ubiquitin-proteasome system: four-membered ring inhibitors of proteasome
title Targeting the ubiquitin-proteasome system: four-membered ring inhibitors of proteasome
spellingShingle Targeting the ubiquitin-proteasome system: four-membered ring inhibitors of proteasome
Heydarpour Klidsar, Maryam
Ubiquitin-proteasome system
ß-lactam scaffold
Proteasome inhibitor
Chymotrypsin-like (CTL) activity
Teses de mestrado - 2019
Ciências da Saúde
title_short Targeting the ubiquitin-proteasome system: four-membered ring inhibitors of proteasome
title_full Targeting the ubiquitin-proteasome system: four-membered ring inhibitors of proteasome
title_fullStr Targeting the ubiquitin-proteasome system: four-membered ring inhibitors of proteasome
title_full_unstemmed Targeting the ubiquitin-proteasome system: four-membered ring inhibitors of proteasome
title_sort Targeting the ubiquitin-proteasome system: four-membered ring inhibitors of proteasome
author Heydarpour Klidsar, Maryam
author_facet Heydarpour Klidsar, Maryam
author_role author
dc.contributor.none.fl_str_mv Moreira, Rui Ferreira Alves
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Heydarpour Klidsar, Maryam
dc.subject.por.fl_str_mv Ubiquitin-proteasome system
ß-lactam scaffold
Proteasome inhibitor
Chymotrypsin-like (CTL) activity
Teses de mestrado - 2019
Ciências da Saúde
topic Ubiquitin-proteasome system
ß-lactam scaffold
Proteasome inhibitor
Chymotrypsin-like (CTL) activity
Teses de mestrado - 2019
Ciências da Saúde
description Tese de mestrado, Química Farmacêutica e Terapêutica, 2019, Universidade de Lisboa, Faculdade de Farmácia.
publishDate 2019
dc.date.none.fl_str_mv 2019-06-17
2019-06-17T00:00:00Z
2022-10-19T14:09:49Z
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/10451/54833
TID:202272575
url http://hdl.handle.net/10451/54833
identifier_str_mv TID:202272575
dc.language.iso.fl_str_mv eng
language eng
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.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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