Design, Synthesis, and Pharmacological Evaluation of Novel N-Acylhydrazone Derivatives as Potent Histone Deacetylase 6/8 Dual Inhibitors
| Autor: | Ana Carolina dos Santos Ferreira, Carlos A. M. Fraga, Jolie K. Kwee, Guilherme Álvaro Ferreira-Silva, Marisa Ionta, Daniel Alencar Rodrigues, Renan Amphilophio Fernandes, Carlos Mauricio R. Sant'Anna |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Models Molecular Cell cycle checkpoint Stereochemistry Antineoplastic Agents Apoptosis Histone Deacetylase 6 Histone Deacetylases 03 medical and health sciences Enzyme activator Structure-Activity Relationship 0302 clinical medicine Cell Movement Tubulin Cell Line Tumor Drug Discovery medicine Structure–activity relationship Animals Humans Cell Proliferation Chemistry Cell growth Cell Cycle Hydrazones Acetylation HDAC6 Rats Enzyme Activation Histone Deacetylase Inhibitors Repressor Proteins 030104 developmental biology Trichostatin A 030220 oncology & carcinogenesis Caspases Drug Design Molecular Medicine Histone deacetylase medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 59(2) |
| ISSN: | 1520-4804 |
| Popis: | 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: | OpenAIRE |
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