Science & Technology, Physical Sciences, Chemistry, Multidisciplinary, Chemistry, benzothiazepines, heterocycles, inhibitors, polycycles, synthetic methods, HISTONE DEACETYLASE 6, HYDROXAMIC ACIDS, HDAC6-SELECTIVE INHIBITORS, LYSINE ACETYLATION, RATIONAL DESIGN, DISEASE, CANCER, IDENTIFICATION, MUTAGENICITY, TUBASTATIN, Binding Sites, Cycloheptanes, Cyclohexanes, Histone Deacetylase 6, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Inhibitory Concentration 50, Isomerism, Molecular Dynamics Simulation, Thiazepines, General Chemistry, 03 Chemical Sciences
Histone deacetylase 6 (HDAC6) selective inhibitors represent an emerging class of pharmaceuticals due to the involvement of HDAC6 in different pathways related to neurodegenerative diseases, cancer and immunology. In this paper, the synthesis of a series of ten new benzohydroxamic acids, constructed employing the benzothiazepine core as a privileged pharmacophoric unit, is described. This is the first report on the synthesis and isolation of octahydrodibenzothiazepines and octahydro-6H-benzocyclo¬heptathiazepines as novel heterocyclic scaffolds, which were consecutively used to develop a new class of HDAC6 inhibitors. These compounds were then evaluated for their HDAC inhibitory activity, resulting in the identification of cis-N-(4-hydroxycarbamoylbenzyl)-1,2,3,4,4a,5,11,11a-octahydrodibenzo[b,e][1,4]thiazepine-10,10-dioxide and cis-N-(4-hydroxycarbamoylbenzyl)-7-trifluoromethyl-1,2,3,4,4a,5,11,11a-octahydrodibenzo¬[b,e][1,4]thiazepine-10,10-dioxide as highly potent and selective HDAC6 inhibitors with activity in the low nanomolar range, also displaying excellent selectivity on an enzymatic and a cellular level. Furthermore, four promising inhibitors were subjected to an Ames fluctuation assay, revealing no mutagenic effects associated with these structures.