title: Design, Synthesis, and Pharmacological Evaluation of Novel N-Acylhydrazone Derivatives as Potent Histone Deacetylase 6/8 Dual Inhibitors.
abstract: This manuscript describes a novel class of N-acylhydrazone (NAH) derivatives that act as histone deacetylase (HDAC) 6/8 dual inhibitors and were designed from the structure of trichostatin A (1). Para-substituted phenyl-hydroxamic acids presented a more potent inhibition of HDAC6/8 than their meta analogs. In addition, the effect of compounds (E)-4-((2-(4-(dimethylamino)benzoyl)hydrazono)methyl)-N-hydroxybenzamide (3c) and (E)-4-((2-(4-(dimethylamino)benzoyl)-2-methylhydrazono)methyl)-N-hydroxybenzamide (3f) on the acetylation of α-tubulin revealed an increased level of acetylation. These two compounds also affected cell migration, indicating their inhibition of HDAC6. An analysis of the antiproliferative activity of these compounds, which presented the most potent activity, showed that compound 3c induced cell cycle arrest and 3g induced apoptosis through caspase 3/7 activation. These results suggest HDAC6/8 as a potential target of future molecular therapies for cancer.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Rodrigues
authors.affiliation: Laboratório de Biologia Animal Integrativa, Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas , 37130-000 Alfenas, Minas Gerais, Brazil.
authors.forename: Guilherme À
authors.initials: GÀ
authors.lastname: Ferreira-Silva
authors.affiliation: Coordenação de Pesquisa, Instituto Nacional de Câncer , 20231-050 Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Ana C S
authors.initials: AC
authors.lastname: Ferreira
authors.affiliation: Coordenação de Pesquisa, Instituto Nacional de Câncer , 20231-050 Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Renan A
authors.initials: RA
authors.lastname: Fernandes
authors.affiliation: Coordenação de Pesquisa, Instituto Nacional de Câncer , 20231-050 Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Jolie K
authors.initials: JK
authors.lastname: Kwee
authors.affiliation: Departamento de Química, Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro , 23970-000 Seropédica, Rio de Janeiro, Brazil.
authors.forename: Carlos M R
authors.initials: CM
authors.lastname: Sant'Anna
authors.affiliation: Laboratório de Biologia Animal Integrativa, Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas , 37130-000 Alfenas, Minas Gerais, Brazil.
authors.forename: Marisa
authors.initials: M
authors.lastname: Ionta
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000187:drug effects*; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000494:pharmacology*; D008958:Models, Molecular; D051381:Rats; D012097:Repressor Proteins / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006835:Hydrazones; D012097:Repressor Proteins; D014404:Tubulin; D020169:Caspases; C433811:HDAC6 protein, human; C409470:HDAC8 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases