Synthesis of Potent and Selective HDAC6 Inhibitors Bearing a Cyclohexane- or Cycloheptane-Annulated 1,5-Benzothiazepine Scaffold

Article abstract of DOI:10.1002/chem.201604167

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 benzohydro

Full text of DOI:10.1002/chem.201604167

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Accepted Article
Title: Synthesis of potent and selective HDAC6 inhibitors bearing a
cyclohexane- or cycloheptane-annulated 1,5-benzothiazepine
scaffold
Authors: Rob De Vreese, Lisa Galle, Yves Depetter, Jorick Franceus,
Tom Desmet, Kristof Van Hecke, Veronick Benoy, Ludo Van
Den Bosch, and Matthias D'hooghe
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10.1002/chem.201604167
Chemistry - A European Journal
Synthesis of potent and selective HDAC6 inhibitors bearing a cyclohexane- or
cycloheptane-annulated 1,5-benzothiazepine scaffold
Rob De Vreese,[a] Lisa Galle,[a] Yves Depetter,[a] Jorick Franceus,[b] Tom Desmet,[b] Kristof Van Hecke,[c]
Veronick Benoy,[d] Ludo Van Den Bosch[d] and Matthias D’hooghe*[a]
[a] R. De Vreese, L. Galle, Y. Depetter, Prof. Dr. M. D’hooghe. SynBioC Research Group, Faculty of Bioscience Engineering,
Ghent University, Coupure Links 653, B-9000 Ghent, Belgium. E-mail: matthias.dhooghe@UGent.be
[b] J. Franceus, Prof. Dr. T. Desmet. Centre for Industrial Biotechnology and Biocatalysis, Faculty of Bioscience Engineering,
Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
[c] Prof. Dr. K. Van Hecke. Xstruct, Department of Inorganic and Physical Chemistry, Faculty of Sciences, Ghent University,
Krijgslaan 281-S3, B-9000 Ghent, Belgium
[d] Dr. V. Benoy, Prof. Dr. L. Van Den Bosch. KU Leuven - University of Leuven, Department of Neurosciences, Experimental
Neurology; VIB - Vesalius Research Center, Laboratory of Neurobiology, B-3000 Leuven, Belgium
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-benzocycloheptathiazepines 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.
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10.1002/chem.201604167
Chemistry - A European Journal
Introduction
Histone deacetylases (HDACs), together with histone acetyltransferases (HATs), regulate the
acetylation status of histones and other proteins through lysine acetylation and deacetylation.[1] This
property to modify the -amino tail of lysine residues provides the ability to change the net charge of
proteins, which makes HDACs valuable regulatory enzymes and explains the broad biological
relevance of HDAC inhibitors (with potential applications in the treatment of cancer,
neurodegenerative diseases, depression, inflammatory diseases,…).[2] Unfortunately, commercially
available pan-HDAC inhibitors, known to inhibit multiple classes of zinc-dependent HDACs (class I:
HDAC1, 2, 3 and 8, class IIa: HDAC4, 5, 7 and 9, class IIb: HDAC6 and 10, class IV: HDAC11), have been
reported to demonstrate toxic side effects as well, hampering their broad clinical usability.[3]
Therefore, many efforts are now devoted to the design and discovery of isozyme-selective HDAC
inhibitors, with possibly less toxic side effects while maintaining a pronounced specific activity. In
that regard, HDAC6 (belonging to HDAC class IIb) has been identified as an interesting
pharmaceutical target since its activity is associated with biological pathways operating in
neurodegenerative diseases, cancer and immunology.[4] Because of its cytoplasmic location, HDAC6
has several non-histone substrates (α-tubulin, cortactin,…), and this feature renders it an interesting
protein to study the acetylation status of proteins in cells. Several research groups have thus
embarked on a journey to discover selective HDAC6 inhibitors, which resulted in a variety of new
compounds with promising potencies, as exemplified by inhibitors 1-8 (Figure 1).[5]
Figure 1. A selection of selective HDAC6 inhibitors reported in the literature.[5a-h]
From this list of compounds, our attention was initially drawn by Tubastatin A (1), a highly potent and
selective HDAC6 inhibitor accommodating a tricyclic protein surface recognition group (cap group)
and a benzohydroxamic acid linker/zinc binding group.
2
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10.1002/chem.201604167
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In our first attempts to pursue novel potent and selective HDAC6 inhibitors, the nitrogen-containing
tricyclic pyridoindole group in Tubastatin A (1) was replaced by a sulfur-containing thiopyranoindole
framework in compounds 9 (Figure 2), culminating in several S-oxidized analogs (denoted as
Tubathians) demonstrating excellent in vitro potency, selectivity and pharmacokinetics.[6] The higher
potency demonstrated by these S-oxidized analogs with respect to HDAC6 was rationalized in silico
through ligand docking studies, showing that sulfoxides (x = 1) 9 and sulfones (x = 2) 9 can establish
an additional hydrogen bond with the surface of HDAC6. Inspired by these interesting findings, the
present work aimed at expanding our thiaheterocyclic library of HDAC6 inhibitors through the design
of new structures bearing a benzohydroxamic acid functionality and an unprecedented sulfur-
containing tricyclic cap group. In that respect, 1,5-benzothiazepine was identified and selected as a
suitable privileged scaffold for elaboration into a new class of HDAC6 inhibitors. Indeed, 1,5-
benzothiazepine is a well-known pharmacophore exhibiting a broad range of biological activities
(Ca2+ channel blockers, CNS acting agents, anti-platelet aggregation, anti-HIV, angiotensin converting
enzyme inhibitors, antimicrobial, antifungal, calmodulin antagonist, bradykinin receptor agonist,
anticancer) and is present in several FDA-approved drugs (diltiazem, clentiazem, thiazesim,
quetiapine hemifumaraat and clothiapine).[7] Moreover, 1,5-benzothiazepine contains a secondary
amino group and an oxidizable sulfur atom, which makes it an ideal building block for further
synthetic elaboration into functionalized target structures. Considering the fact that the cap group in
previously developed HDAC6 inhibitors consist of a tricyclic structure bearing an aromatic A ring, an
azaheterocyclic B ring and a saturated C ring, the main objective of the present study involved the
development of a new tricyclic scaffold based on the annulation of a cyclohexane or cycloheptane
ring to the celebrated 1,5-benzothiazepine unit en route to the synthesis of a novel series of
octahydrodibenzo- (n = 1) or octahydro-6H-benzocycloheptathiazepine- (n = 2) based HDAC6
inhibitors 10.
Figure 2. Synthesis rationale for the present study.
3
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