Synthesis of potent and selective HDAC6 inhibitors bearing a cyclohexane- or cycloheptane-annulated 1,5-benzothiazepine scaffold
| Autor: | Tom Desmet, Matthias D'hooghe, Jorick Franceus, Kristof Van Hecke, Yves Depetter, Lisa Galle, Veronick Benoy, Rob De Vreese, Ludo Van Den Bosch |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Scaffold Cyclohexane polycycles Thiazepines Stereochemistry Molecular Dynamics Simulation MUTAGENICITY Histone Deacetylase 6 01 natural sciences Histone Deacetylases Catalysis HDAC6-SELECTIVE INHIBITORS DISEASE Inhibitory Concentration 50 03 medical and health sciences chemistry.chemical_compound Isomerism Cyclohexanes HISTONE DEACETYLASE 6 inhibitors LYSINE ACETYLATION Humans RATIONAL DESIGN Cycloheptanes HYDROXAMIC ACIDS chemistry.chemical_classification heterocycles Binding Sites IDENTIFICATION 010405 organic chemistry Organic Chemistry General Chemistry HDAC6 Combinatorial chemistry CANCER 0104 chemical sciences Histone Deacetylase Inhibitors Chemistry 030104 developmental biology Enzyme TUBASTATIN chemistry synthetic methods Cycloheptane Selectivity benzothiazepines |
| Zdroj: | CHEMISTRY-A EUROPEAN JOURNAL |
| ISSN: | 0947-6539 |
| Popis: | Selective inhibitors of histone deacetylase 6 (HDAC6) are an emerging class of pharmaceuticals due to the involvement of HDAC6 in different pathways related to neurodegenerative diseases, cancer, and immunology. Herein, the synthesis of ten new benzohydroxamic acids, constructed by employing the tetrahydrobenzothiazepine core as a privileged pharmacophoric unit, is described. This is the first report on the synthesis and isolation of octahydrodibenzothiazepines and octahydro-6H-benzocycloheptathiazepines, which were then used to develop a new class of HDAC6 inhibitors. Evaluations of their HDAC-inhibiting activity resulted in the identification of cis-N-(4-hydroxycarbamoyl-benzyl)-1,2,3,4,4a, 5,11,11a-octahydrodibenzo[b, e] [1,4]thiazepine-10,10-dioxide and cis-N-(4-hydroxycarbamoyl-benzyl)-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, which also show excellent selectivity on the enzymatic and cellular levels. Furthermore, four promising inhibitors were subjected to an Ames fluctuation assay, which revealed no mutagenic effects associated with these structures. |
| Databáze: | OpenAIRE |
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