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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Síntese e avaliação de inibidores de histona acetiltransferases planejados a partir do ácido isoanacárdico / Synthesis and evaluation of histone acetyltransferases inhibitors planned from isoanacardic acid

Queiroz, Fellipe José Gomes 26 March 2015 (has links)
Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, 2015. / Submitted by Raquel Viana (raquelviana@bce.unb.br) on 2015-10-09T19:54:19Z No. of bitstreams: 1 2015_FellipeJoséGomesQueiroz_Parcial.pdf: 4549466 bytes, checksum: 8b3b2eefb20a4c4e5d0cfd09507eacd5 (MD5) / Approved for entry into archive by Raquel Viana(raquelviana@bce.unb.br) on 2015-10-09T19:57:56Z (GMT) No. of bitstreams: 1 2015_FellipeJoséGomesQueiroz_Parcial.pdf: 4549466 bytes, checksum: 8b3b2eefb20a4c4e5d0cfd09507eacd5 (MD5) / Made available in DSpace on 2015-10-09T19:57:56Z (GMT). No. of bitstreams: 1 2015_FellipeJoséGomesQueiroz_Parcial.pdf: 4549466 bytes, checksum: 8b3b2eefb20a4c4e5d0cfd09507eacd5 (MD5) / As principais doenças inflamatórias intestinais – doença de Crohn e colite ulcerativa – apresentam caráter inflamatório idiopático agudo ou crônico que envolve a cascata de sinalização NF-kB por meio dos receptores Toll-like e TNF-α. No âmbito das modificações pós-translacionais, as acetilações reversíveis de resíduos de lisina nas subunidades p50 e p65 de NF-kB – promovidas por histonas acetiltransferases (HAT) – modulam as respostas inflamatórias dependentes desta via. Neste contexto, inibidores de HATs e.g. p300 e GCN5, regulam as funções do NF-kB induzidas por TNF e IL-1β e compreendem estratégia terapêutica para o tratamento da UC. Descrevemos neste trabalho o planejamento, a síntese e a avaliação biológica de novos inibidores de histona acetiltransferases – p300 e GCN5 – obtidos a partir do ácido isoanacárdico. A estratégia sintética permitiu à obtenção de 25 derivados: 2 intermediários aldeídos, 3 ácidos carboxílicos, 5 amidas e 15 ésteres, em rendimentos que variaram de 78-98%. A avaliação biológica dos compostos-alvo frente às enzimas p300 e GCN5 evidenciaram a capacidade dos derivados LDT380 (28), LDT383 (35) e LDT407 (32) – que contém a subunidade carboxila – atuarem como inibidores de ambas acetiltransferases com IC50 variando de 11 μM a 51 μM para a enzima p300; e de 25 μM a 61 μM para a enzima GCN5. A confirmação da atividade inibitória dos compostos ativos por métodos ortogonais, os estudos de docking com p300 e GCN5, a avaliação sobre a translocação de NF-kB, bem como a avaliação em modelos experimentais in vivo compreendem as perspectivas desse trabalho. ______________________________________________________________________________________________ ABSTRACT / The major inflammatory bowel diseases - Crohn's disease and ulcerative colitis - show acute or chronic idiopathic inflammatory profiles that involve the NF-kB signaling cascade through Toll-like and TNF-α receptors. In the context of posttranslational modifications, reversible acetylation of lysine residues on p50 and p65 subunits of NF-kB - promoted by histone acetyltransferases (HAT) - modulate inflammatory responses dependent on this pathway. In this context, HATs inhibitors e.g. GCN5 and p300 regulate NF-kB functions induced by TNF and IL-1β and comprise therapeutic strategy for the treatment of UC. Herein we describe the design, synthesis and biological evaluation of new inhibitors of histone acetyl transferases - p300 and GCN5 - obtained from isoanacardic acid. The synthetic strategy allowed for obtaining 25 derivatives: 2 aldehyde intermediates, 3 carboxylic acids, 5 amides and 15 esters in yields ranging from 78-98%. Biological evaluation of target-compounds against the GCN5 and p300 enzymes revealed the ability of compounds LDT380 (28) LDT383 (35) and LDT407 (32) - containing the carboxyl subunit - to act as inhibitors of both acetyltransferases with IC50 ranging from 11 μM to 51 μM for p300; and from 25 μM and 61 μM for GCN5. The work’s perspectives include the confirmation of the inhibitory activity of the active compounds by orthogonal methods, docking studies with p300 and GCN5, studies on the translocation of NF-kB, ans posteriorly in vivo evaluation in experimental models of colitis.

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