Title: Synthesis of potent and selective HDAC6 inhibitors bearing a cyclohexane- or cycloheptane-annulated 1,5-benzothiazepine scaffold
Authors: De Vreese, Rob ×
Galle, Lisa
Depetter, Yves
Franceus, Jorick
Desmet, Tom
Van Hecke, Kristof
Benoy, Veronick
Van Den Bosch, Ludo
D'hooghe, Matthias #
Issue Date: Oct-2016
Publisher: VCH Verlagsgesellschaft
Series Title: Chemistry - a European Journal vol:Ahead of print
Article number: 10.1002/chem.201604167
Abstract: 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.
ISSN: 0947-6539
Publication status: accepted
KU Leuven publication type: IT
Appears in Collections:Laboratory for Neurobiology (Vesalius Research Center)
× corresponding author
# (joint) last author

Files in This Item:
File Description Status SizeFormat
Vreese_et_al-2016-Chemistry_-_A_European_Journal.pdf Submitted 2262KbAdobe PDFView/Open Request a copy

These files are only available to some KU Leuven Association staff members


All items in Lirias are protected by copyright, with all rights reserved.