title: Synthesis of Potent and Selective HDAC6 Inhibitors Bearing a Cyclohexane- or Cycloheptane-Annulated 1,5-Benzothiazepine Scaffold.
abstract: 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-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, 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.
authors.affiliation: SynBioC Research Group, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium.
authors.forename: Rob
authors.initials: R
authors.lastname: De Vreese
authors.affiliation: SynBioC Research Group, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium.
authors.forename: Lisa
authors.initials: L
authors.lastname: Galle
authors.affiliation: SynBioC Research Group, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Depetter
authors.affiliation: Centre for Industrial Biotechnology and Biocatalysis, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium.
authors.forename: Jorick
authors.initials: J
authors.lastname: Franceus
authors.affiliation: Centre for Industrial Biotechnology and Biocatalysis, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Desmet
authors.affiliation: XStruct, Department of Inorganic and Physical Chemistry, Faculty of Sciences, Ghent University, Krijgslaan 281-S3, 9000, Ghent, Belgium.
authors.forename: Kristof
authors.initials: K
authors.lastname: Van Hecke
authors.affiliation: University of Leuven, Department of Neurosciences, Experimental Neurology, VIB-Vesalius Research Center, Laboratory of Neurobiology, 3000, Leuven, Belgium.
authors.forename: Veronick
authors.initials: V
authors.lastname: Benoy
authors.affiliation: University of Leuven, Department of Neurosciences, Experimental Neurology, VIB-Vesalius Research Center, Laboratory of Neurobiology, 3000, Leuven, Belgium.
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.affiliation: SynBioC Research Group, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium.
authors.forename: Matthias
authors.initials: M
authors.lastname: D'hooghe
mesh_terms: D001665:Binding Sites; D003508:Cycloheptanes / Q000737:chemistry; D003510:Cyclohexanes / Q000737:chemistry; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D007536:Isomerism; D056004:Molecular Dynamics Simulation; D013841:Thiazepines / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: C106746:1,5-benzothiazepine; D003508:Cycloheptanes; D003510:Cyclohexanes; D056572:Histone Deacetylase Inhibitors; D013841:Thiazepines; C506365:Cyclohexane; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: benzothiazepines; heterocycles; inhibitors; polycycles; synthetic methods