Busca avançada
Ano de início
Entree


Optimization of Resveratrol Used as a Scaffold to Design Histone Deacetylase (HDAC-1 and HDAC-2) Inhibitors

Texto completo
Autor(es):
Urias, Beatriz Silva ; Pavan, Aline Renata ; Albuquerque, Gabriela Ribeiro ; Prokopczyk, Igor Muccilo ; Ferreira Alves, Tania Mara ; Ferreira de Melo, Thais Regina ; Rodrigues Sartori, Geraldo ; Martins da Silva, Joao Herminio ; Chin, Chung Man ; Dos Santos, Jean Leandro
Número total de Autores: 10
Tipo de documento: Artigo Científico
Fonte: PHARMACEUTICALS; v. 15, n. 10, p. 18-pg., 2022-10-01.
Resumo

Histone deacetylases (HDAC) are epigenetic enzymes responsible for repressing gene expression through the deacetylation of histone lysine residues. Therefore, inhibition of HDACs has become an interesting approach for the treatment of several diseases, including cancer, hematology, neurodegenerative, immune diseases, bacterial infections, and more. Resveratrol (RVT) has pleiotropic effects, including pan-inhibition of HDAC isoforms; however, its ability to interfere with membranes requires additional optimization to eliminate nonspecific and off-target effects. Thus, to explore RVT as a scaffold, we designed a series of novel HDAC-1 and -2 inhibitors containing the 2-aminobenzamide subunit. Using molecular modeling, all compounds, except unsaturated compounds (4) and (7), exhibited a similar mode of interaction at the active sites of HDAC 1 and 2. The docking score values obtained from the study ranged from -12.780 to -10.967 Kcal/mol. All compounds were synthesized, with overall yields ranging from 33% to 67.3%. In an initial screening, compounds (4), (5), (7), and (20)-(26), showed enzymatic inhibitory effects ranging from 1 to 96% and 6 to 93% against HDAC-1 and HDAC-2, respectively. Compound (5), the most promising HDAC inhibitor in this series, was selected for IC50 assays, resulting in IC50 values of 0.44 mu M and 0.37 mu M against HDAC-1 and HDAC-2, respectively. In a panel of selectivity against HDACs 3-11, compound (5) presented selectivity towards Class I, mainly HDAC-1, 2, and 3. All compounds exhibited suitable physicochemical and ADMET properties as determined using in silico simulations. In conclusion, the optimization of the RVT structure allows the design of selective HDAC inhibitors, mainly targeting HDAC-1 and HDAC-2 isoforms. (AU)

Processo FAPESP: 18/11079-0 - Síntese e atividade antituberculose de novos derivados N-óxidos planejados para o tratamento da tuberculose multirresistente
Beneficiário:Jean Leandro dos Santos
Modalidade de apoio: Auxílio à Pesquisa - Regular
Processo FAPESP: 17/07789-0 - Síntese de derivados 2-amino-benzamídicos planejados como indutores de hemoglobina fetal
Beneficiário:Gabriela Ribeiro Albuquerque
Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
Processo FAPESP: 18/19523-7 - Planejamento, síntese e avaliação farmacológica de derivados de hidroxiuréia planejados como inibidores de histona deacetilase para Anemia Falciforme
Beneficiário:Aline Renata Pavan
Modalidade de apoio: Bolsas no Brasil - Doutorado
Processo FAPESP: 15/19531-1 - Inibição de histona deacetilase (HDAC-1 e HDAC-2) como alvos para indução de Hemoglobina Fetal na Anemia Falciforme
Beneficiário:Jean Leandro dos Santos
Modalidade de apoio: Auxílio à Pesquisa - Regular
Processo FAPESP: 15/21252-3 - Síntese e Avaliação Farmacológica de novos análogos da talidomida/pomalidomida reguladores de mecanismos epigenéticos
Beneficiário:Aline Renata Pavan
Modalidade de apoio: Bolsas no Brasil - Mestrado
Processo FAPESP: 19/09456-3 - Síntese de inibidores seletivos HDAC 1 e 2 planejados como indutores de hemoglobina fetal
Beneficiário:Beatriz Silva Urias
Modalidade de apoio: Bolsas no Brasil - Iniciação Científica