Design, Synthesis, and Pharmacological Evaluation of Novel N-Acylhydrazone Derivatives as Potent Histone Deacetylase 6/8 Dual Inhibitors.

Autor:	Rodrigues DA, Ferreira-Silva GÀ; 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., Ferreira AC; Coordenação de Pesquisa, Instituto Nacional de Câncer , 20231-050 Rio de Janeiro, Rio de Janeiro, Brazil., Fernandes RA; Coordenação de Pesquisa, Instituto Nacional de Câncer , 20231-050 Rio de Janeiro, Rio de Janeiro, Brazil., Kwee JK; Coordenação de Pesquisa, Instituto Nacional de Câncer , 20231-050 Rio de Janeiro, Rio de Janeiro, Brazil., Sant'Anna CM; Departamento de Química, Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro , 23970-000 Seropédica, Rio de Janeiro, Brazil., Ionta M; 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., Fraga CA
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2016 Jan 28; Vol. 59 (2), pp. 655-70. Date of Electronic Publication: 2016 Jan 13.
DOI:	10.1021/acs.jmedchem.5b01525
Abstrakt:	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.
Databáze:	MEDLINE
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