Rodrigues Daniel A, Ferreira-Silva Guilherme À, Ferreira Ana C S, Fernandes Renan A, Kwee Jolie K, Sant'Anna Carlos M R, Ionta Marisa, Fraga Carlos A 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.
Coordenação de Pesquisa, Instituto Nacional de Câncer , 20231-050 Rio de Janeiro, Rio de Janeiro, Brazil.
J Med Chem. 2016 Jan 28;59(2):655-70. doi: 10.1021/acs.jmedchem.5b01525. Epub 2016 Jan 13.
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.
本手稿描述了一类新型的N-酰腙（NAH）衍生物，它们作为组蛋白脱乙酰酶（HDAC）6/8双重抑制剂，是从曲古抑菌素A（1）的结构设计而来。对位取代的苯基异羟肟酸对HDAC6/8的抑制作用比间位类似物更强。此外，化合物（E）-4-（（2-（4-（二甲基氨基）苯甲酰基）腙基）甲基）-N-羟基苯甲酰胺（3c）和（E）-4-（（2-（4-（二甲基氨基）苯甲酰基）-2-甲基腙基）甲基）-N-羟基苯甲酰胺（3f）对α-微管蛋白乙酰化的影响显示乙酰化水平升高。这两种化合物还影响细胞迁移，表明它们对HDAC6有抑制作用。对这些具有最强活性的化合物的抗增殖活性分析表明，化合物3c诱导细胞周期停滞，3g通过激活半胱天冬酶3/7诱导细胞凋亡。这些结果表明HDAC6/8是未来癌症分子治疗的潜在靶点。
