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N-Acylhydrazone derivatives as potent histone deacetylase 6 inhibitors
1, 2 , 1, 3 , 4 , 1 , 1 , 5 , 6 , 6 , 6 , 1, 7 , 5 , * 1, 2, 3
1  Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, PO Box 68023, 21941-902, Rio de Janeiro, RJ, Brazil
2  Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, 21941-909, Rio de Janeiro, RJ, Brazil
3  Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil
4  Laboratório de Apoio ao Desenvolvimento Tecnológico (LADETEC), Instituto de Química, Avenida Horácio Macedo, 1281, Polo de Química, Bloco C, Cidade Universitária, Rio de Janeiro, RJ- CEP: 21941-598
5  Laboratório de Biologia Animal Integrativa, Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, 37130-000, Alfenas, MG, Brazil
6  Coordenação de Pesquisa, Instituto Nacional de Câncer, 20231-050, Rio de Janeiro, RJ, Brazil
7  Departamento de Química, Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro, 23970-000, Seropédica, RJ, Brazil

Published: 31 October 2018 by MDPI in 4th International Electronic Conference on Medicinal Chemistry session ECMC-4

Histone deacetylase 6 (HDAC6) catalyses the removal of acetyl groups from the lysine residues of a series of non-histone proteins, e.g., α-tubulin, Hsp90 and cortactin. The design of selective inhibitors of HDAC6 is related with important outcomes in the oncological, immunological and neurological fields. Herein, we describe the design, synthesis and pharmacological evaluation of a series of N-acylhydrazones (NAH) designed from the trichostatin A as HDAC6 inhibitors. The use of the phenyl linker in the design of the compounds led to HDAC6 selectivity among the HDAC family. Para-substituted phenyl-hydroxamic acids presented a more potent inhibition of HDAC6 than their meta-substituted analogs. The N- and C- methylation of the NAH framework attached to para-substituted phenyl-hydroxamic unit was evaluated and the compound LASSBio-1911 was identified as a potent and selective HDAC6 inhibitor (IC50 = 15 nM). In the next step, we evaluated the influence of the cap group. We found that the use of different aromatic and heteroaromatic rings did not influence the inhibition of HDAC6. Some of these compounds were able to reduce significantly cell migration, corroborating their inhibitory profile against HDAC6. On the other hand, an analysis of their antiproliferative activity against different tumor cell lines showed that they can induce cell cycle arrest or induce apoptosis through caspase 3/7 activation, with particular relevance for hepatocellular carcinoma (HepG2) cells.


Rodrigues, D. A.; Ferreira-Silva, G. A.; Ferreira, A. C.; Fernandes, R. A.; Kwee, J. K.; Sant'Anna, C. M.; Ionta, M.; Fraga, C. A. M. J. Med. Chem., 2016, 59, 655-706.

Rodrigues, D. A.; Thota, S.; Fraga, C. A. M. Mini-Rev. Med. Chem., 2016, 16, 1175-1184.

Pinheiro, P. S. M.; Rodrigues, D. A.; Sant'Anna, C. M. R.; Fraga, C. A. M. Int. J. Quantum Chem., 2018;e25720.

Keywords: N-acylhydrazone, Cancer, HDAC6, HDAC6 inhibitor