Optimization of resveratrol used as a scaffold to design histone deacetylase (HDAC-1 and HDAC-2) inhibitors

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dc.contributor.authorUrias, Beatriz Silva [UNESP]
dc.contributor.authorPavan, Aline Renata [UNESP]
dc.contributor.authorAlbuquerque, Gabriela Ribeiro [UNESP]
dc.contributor.authorProkopczyk, Igor Muccilo [UNESP]
dc.contributor.authorAlves, Tânia Mara Ferreira [UNESP]
dc.contributor.authorde Melo, Thais Regina Ferreira [UNESP]
dc.contributor.authorSartori, Geraldo Rodrigues
dc.contributor.authorda Silva, João Hermínio Martins
dc.contributor.authorMan Chin, Chung [UNESP]
dc.contributor.authorDos Santos, Jean Leandro [UNESP]
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.date.accessioned2023-08-02T13:02:22Z
dc.date.available2023-08-02T13:02:22Z
dc.date.issued2022-10-13
dc.description.abstractHistone 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 µM and 0.37 µM 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.en
dc.description.affiliationFaculdade de Ciências Farmacêuticas - UNESP Araraquara
dc.description.affiliationInstituto de Química - UNESP Araraquara
dc.description.affiliationLaboratory of Structural and Functional Biology Applied to Biopharmaceuticals, Oswaldo Cruz Foundation (Fiocruz)
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipPró-Reitoria de Pesquisa (PROPe UNESP)
dc.description.sponsorshipIdFAPESP: 2019/09456-3
dc.description.sponsorshipIdFAPESP: 2015/21252-3
dc.description.sponsorshipIdFAPESP: 2018/19523-7
dc.description.sponsorshipIdFAPESP: 2017/07789-0
dc.description.sponsorshipIdFAPESP: 2015/19531-1
dc.description.sponsorshipIdFAPESP: 18/11079-0
dc.description.sponsorshipIdCAPES: 001
dc.identifier.issn1424-8247
dc.identifier.lattes3043571135573197
dc.identifier.lattes4448046955276514
dc.identifier.lattes5969091774569939
dc.identifier.lattes2385059666225663
dc.identifier.lattes2711137157839870
dc.identifier.lattes5435899068903487
dc.identifier.lattes9734333607975413
dc.identifier.lattes5737933639516944
dc.identifier.orcid0000-0002-4637-4089
dc.identifier.orcid0000-0002-4932-7720
dc.identifier.orcid0000-0003-2139-6887
dc.identifier.orcid0000-0003-0848-9288
dc.identifier.orcid0000-0001-5613-7194
dc.identifier.orcid0000-0003-1534-9857
dc.identifier.orcid0000-0003-4141-0455
dc.identifier.orcid0000-0002-2460-2829
dc.identifier.urihttp://hdl.handle.net/11449/250089
dc.language.isoeng
dc.publisherMDPI
dc.relation.ispartofPharmaceuticalspt
dc.rights.accessRightsAcesso aberto
dc.subjecthistone deacetylaseen
dc.subjectresveratrolen
dc.subjectenzymatic inhibitionen
dc.subjectgene regulationen
dc.subjectnew drugsen
dc.titleOptimization of resveratrol used as a scaffold to design histone deacetylase (HDAC-1 and HDAC-2) inhibitorsen
dc.typeArtigo
unesp.campusUniversidade Estadual Paulista (Unesp), Faculdade de Ciências Farmacêuticas, Araraquarapt
unesp.departmentFármacos e Medicamentos - FCFpt

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