Potent non-hydroxamate inhibitors of histone deacetylase-8: Role and scope of an isoindolin-2-yl linker with an α-amino amide as the zinc-binding unit

Article abstract of DOI:10.1016/j.bmcl.2019.126926

A series of potent inhibitors of histone deacetylase-8 (HDAC8) is described that contains an α-amino amide zinc-binding unit and a substituted isoindolinyl capping group. The presence of a 2,4-dichlorophenyl unit located in the acetate-release cavity was

Full text of DOI:10.1016/j.bmcl.2019.126926

Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Potent non-hydroxamate inhibitors of histone deacetylase-8: Role and scope
of an isoindolin-2-yl linker with an α-amino amide as the zinc-binding unit
⁎
Simon O.R. Greenwooda,b, A.W. Edith Chanc, D. Flemming Hansenb, Charles M. Marsona,
a Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London WC1H OAJ, UK
b Division of Biosciences, Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK
c Wolfson Institute of Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK
A R T I C L E I N F O
A B S T R A C T
Keywords:
A series of potent inhibitors of histone deacetylase-8 (HDAC8) is described that contains an α-amino amide zinc-
binding unit and a substituted isoindolinyl capping group. The presence of a 2,4-dichlorophenyl unit located in
the acetate-release cavity was shown to confer a gain of approx. 4.3 kJ mol−1 in binding energy compared to a
phenyl group, and the isoindoline linker has approx. 5.8 kJ mol−1 greater binding energy than the corre-
sponding tetrahydroisoquinoline ring system. In a series of 5-substituted isoindolin-2-yl inhibitors, a 5-acet-
ylamino derivative was found to be more potent than the 5-unsubstituted lead HDAC8 inhibitor (increase in
binding energy of 2.0 kJ mol−1, ascribed to additional binding interactions within the Nε-acetyl-L-lysine binding
tunnel in HDAC8, including hydrogen bonding to Asp101. Tolerance of a 5-substituent (capping group) on the
isoindoline ring has been demonstrated, and which in some cases confers improved enzyme inhibition, the
HDAC8 substrate-binding region providing a platform for additional interactions.
Synthesis of isoindoline derivatives
α-Amido amide inhibitors
Histone deactylase-8
Ligand binding energies
Once considered as a post-translational modification unique to
histones, lysine acetylation is now accepted as a common modification
across the proteome.1 Histone deacetylases (HDACs) catalyse deacety-
lation of lysine residues, resulting in chromatin compaction and tran-
scriptional repression2–4 where the substrates are histones. Increased
levels of HDAC activity have been associated with precancerous or
malignant states. Epigenetic mechanisms5 are increasingly implicated
in cancer, heart disease and neurological disorders, and some inhibitors
of histone deacetylase (HDAC) are used in cancer therapy,6,7 their relief
of transcriptional repression8,9 playing an important role in the treat-
ment of certain leukaemias. Of the Class I HDACs, HDAC1, HDAC2 and
HDAC3 have been the main focus as targets for cancer treatment;
however, upregulation of HDAC8 strongly correlates with the pro-
gression and prognosis of juvenile neuroblastoma10 which accounts for
15% of all pediatric deaths.11,12 HDAC8 also plays a crucial role in the
induction of the tumour suppressor p53, mutations of which are present
in over 50% of all cancers.13 In a variety of cancer cell lines only
knockdown of HDAC8, not knockdown of HDAC1, HDAC2 or HDAC3,
led to decreased mutant and wild-type p53 expression; furthermore,
disruption of HDAC8 function triggered defects in proliferation for cells
with mutant but not wild-type p53.14 Thus, targeting HDAC8 selec-
tively could provide a personalised therapy specifically for patients
with cancers involving mutant p53. Consequently, structurally novel,
specific inhibitors of HDAC8 are a priority.
Most Class I HDAC inhibitors used as anti-cancer agents6,7 are either
hydroxamic acids such as 1, and include Vorinostat (suberoylanilide
hydroxamic acid),20 or are aminoanilides such as Mocetinosat.21,22 The
nonselective metal-chelating properties of hydroxamic acids confer
limitations of efficacy and toxicity which restrict the scope of current
HDAC inhibitors. Additionally, such inhibitors bind significantly in only
three major regions: by coordination to zinc, by occupancy of the cat-
alytic tunnel (that otherwise contains the lysine chain of the natural
substrate), and through binding to the protein periphery (the Zn binder-
linker-capping group assembly). Consequently, the report by a Novartis
group of the α-amino amide HDAC8 inhibitor 2 (Fig. 1)19 that binds in
the acetate-release channel (located deeper within the protein, beyond
the zinc-binding region) is an unusual feature that characterises this
class of HDAC inhibitor, and has important implications for research
programs on the discovery novel HDAC inhibitors, including our own
research program that also aims to understand their mode of ac-
tion.23,24 Herein are described the synthesis and preliminary evaluation
of a new series of α-amino amide HDAC8 inhibitors and a rationale for
the structure-activity relationships observed.
HDAC8 inhibitor 2 is one of only two α-amino amide HDAC in-
hibitors previously described,19 and to the best of our knowledge SAR
studies have not been reported. To establish the SAR and gain greater
⁎ Corresponding author.
E-mail address: c.m.marson@ucl.ac.uk (C.M. Marson).
https://doi.org/10.1016/j.bmcl.2019.126926
Received 26 September 2019; Received in revised form 18 December 2019; Accepted 19 December 2019
0960-894X/©2019PublishedbyElsevierLtd.
Pleasecitethisarticleas:SimonO.R.Greenwood,etal.,Bioorganic&MedicinalChemistryLetters,
https://doi.org/10.1016/j.bmcl.2019.126926

S.O.R. Greenwood, et al.
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Scheme 2.
2,4-dichlorophenylmethyl unit. One of the analogs 5l had an IC50 close
to 1 µM for inhibition of HDAC8, but none had improved potency
compared to 5q. Overall, compounds containing an isoindoline ring in
the series 8 were more potent than others that did not, and phenyl
derivatives were more potent than 4-hydroxyphenyl derivatives.
With indications of 2,4-dichlorophenylmethyl unit being a preferred
structural motif, the second series of compounds focused on the in-
troduction of a 5-substituent on the isoindoline ring (Schemes 3 and 4).
(Ligand docking suggested that a 4-substituent would not be tolerated).
Reduction of 925 (Scheme 3) furnished amine 10 from which three 5-
(acylamino)isoindolines were synthesised by a sequence of acylation of
the 5-amino group, hydrogenolytic N-debenzylation, acylation at the 2-
position, and Boc deprotection of the primary amino group to give the
α-amino amides 14b-14d (Scheme 3). The parent amine 14a was
synthesised by hydrogenolysis of 10 to give (12a)25 (51%) which un-
derwent acylation with 3 to give 13a (44%); subsequent deprotection
gave 14a.
Fig. 1. Examples of HDAC8-selective inhibitors.15–19
understanding of such α-amino amide ligands, the first series of com-
pounds designed for synthesis and evaluation in the present work re-
tained the isoindolin-2-yl linker, thereby permitting the energies of
binding of various units in the acetate-release channel to be de-
termined. Other initial aims were to establish whether replacements for
the 2,4-(dichlorophenyl)methyl unit of 2 could be identified that in-
creased the potency, and also to understand the unit’s role and relative
importance. In later series of α-amino amides, we show here that
whereas the isoindoline unit comprises part of the linker region, that a
polar 5-substituent on that ring system can act as a capping group,
engaging in hydrogen bonding with Asp101, as suggested by molecular
docking.
In order to maximise opportunities for hydrogen bonding of the 5-
substituent on the isoindoline ring with HDAC8 residues, a route to the
reverse amides was also devised and the representative N-methyl car-
boxamide 21 synthesised (Scheme 4). Reaction of bromoisoindoline-
1,3-dione26,27 with benzylamine in acetic acid (1 h reflux) afforded 2-
benzyl-5-bromoisoindoline-1,3-dione27 (90%) which underwent re-
duction with NaBH4 in the presence of Et2O·BF3 to give 16 82%). This
reagent was found here to be generally satisfactory for the reduction of
phthalimide derivatives to isoindoline derivatives; isoindoline itself has
been prepared by the reduction of phthalimide with THF.BH3.28 Me-
talation followed by carboxylation afforded the acid 17 which was
converted into amide 18 and hence the α-amino diamide 21.
To explore the scope of inhibitor structure binding in the acetyl-
lysine region, analogs of 2 were prepared. In this work, the hydro-
chloride salts were synthesised and evaluated, and compared to in-
hibitor 5q (Scheme 1), the hydrochloride salt of 2. Coupling of car-
boxylic acid 3 with a variety of amines (aliphatic, benzylic, aromatic)
all proceeded satisfactorily, giving the amides 4; Boc deprotection then
gave the corresponding α-amino amides 5 (Scheme 1).
Using the above route, a set of phenyl and 4-hydroxyphenyl deri-
vatives was prepared (Scheme 2), mainly to determine the efficacy of
the 2,4-dichloro groups in 5q. Compounds 8c and 8e are direct analogs
of 5q, having respectively no substituent and a 4-hydroxy group on the
phenyl ring. However, in vitro assays of compounds 8a-8f showed lower
inhibition of HDAC8 compared to 5q, confirming the importance of the
Synthesis of 26, the amine analog of 21, required careful handling
of disparate nitrogen functionality (Scheme 5). Reduction of amide 18
followed by N-Boc protection and debenzylation afforded the key
Scheme 1.
2

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Scheme 3.
Scheme 4.
protected amine 24. Acylation at the 2-position followed by con-
comitant deprotection of both Boc groups afforded the desired amine
salt 26.
from the planarity of the isoindoline ring which is evidently well ac-
commodated in the acetyl-lysine binding tunnel. The efficacy of the 2,4-
dichloro unit is shown in 5r being fivefold more potent than 8d (un-
substituted phenyl group) which in turn is twice as potent as 8f that
contains a 4-hydroxy substituent. The same pattern was observed for
the isoindoline series, 5q being fivefold more potent than 8c which in
turn is more than three times as potent as 8e that contains a 4-hydroxy
substituent. The fused aromatic ring of the tetrahydroisoquinoline
series was evidently an indispensable feature since the N-methylpiper-
azine analog 8a was less potent than 5r, and the N-methylpiperazine
analog 8b showed no measurable activity.
In order to probe HDAC8 inhibition, structural analysis and ligand
binding, the initial set of compounds (Table 1) was designed to probe
the binding energy of the isoindoline ring and the 2,4-dichlorophenyl
unit, compared to other similar units. Since a diverse array of tetra-
hydroisoquinoline derivatives are straightforward to prepare, and are
usually less prone to decomposition than isoindoline derivatives, the
tetrahydroisoquinoline compounds 5r, 8d and 8f were synthesised and
evaluated for in vitro inhibition of HDAC8. The homolog of 5q, com-
pound 5r, was tenfold less potent, showing that ring size and planarity
are crucial to activity, probably in part because the larger ring departs
Since the results from the first series (Table 1) had not identified an
improvement upon the 2,4-dichlorophenyl unit for binding, that unit
Scheme 5.
3

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Table 1
In Vitro Inhibition of Histone Deacetylase 8 by Substituted α-Amino Amides.
was retained in the second series of compounds (Table 2) which probed
interactions within the acetyl-lysine binding tunnel, a region associated
with conformational flexibility, especially the ability of Phe152 to
adopt a variety of orientations in order to accommodate different li-
gands.19 The Phe152 sidechain can rotate to reveal a pocket thought to
be unique to HDAC8.19 The parent amino acid (Table 2, first entry) and
the methyl carboxamide 5a, compounds lacking a region that could
bind in the acetyl-lysine binding tunnel, were some of the least potent
inhibitors of HDAC8. Chain extension, either as an aryl ring (5b) or as a
benzyl substituent (5c) restored potency to low micromolar levels. The
bond) appear to be the main factors that confer greater potency of
isoindolin-2-yl derivatives compared to other systems. Compared to 5q,
the greater number of rotatable bonds in 5c, 5h and 5n conferred much
lower binding to HDAC8 (Table 2).
Inhibitory values of HDAC8 for previous compounds, especially
those in Table 2, confirmed a strong preference for an isoindolin-2-yl
unit to be present in the linker unit. Accordingly, this ring system was
studied in the final series of compounds synthesised (Table 3). Lateral
substitution (4- or 4,7-positions) was not considered since preference
for a relatively linear and planar ring system in the catalytic tunnel was
strongly indicated by molecular docking (discussed below) and also
supported by the above in vitro HDAC8 inhibition assay data. Since the
synthesis of substituted isoindolines can pose considerable challenges,
efforts were focused on preparing 5-acylamino and 5-aminoacyl deri-
vatives, potentially conferring hydrogen-bond donor or acceptor prop-
erties, or even both, to provide additional interactions with the enzyme.
Encouragingly, HDAC8 inhibition compared to 5q was greater for the
parent 5-aminoisoindoline 14a and for the corresponding N-acetyl de-
rivative 14b, and was comparable or better for all other compounds
synthesised in this series (Table 3). The amides containing pheny-
lethanoyl and 3-phenylpropanoyl N-substituents (14c and 14d respec-
tively), of comparable potency to 5q, show potential for further opti-
misation through the incorporation of substituents on the aryl rings.
Reversal of the amide linkage in 14b still retained the high level of
potency, although HDAC8 inhibition of amide 21 was about one-half
that of 14b. The N-methylaminomethyl derivative 26 showed com-
parable or improved potency compared to amide 21 and all other
compounds in the series.
loss of 7.5
1.7 kJ mol−1 binding energy (see Supplementary
Material) on going from the conformationally constrained ring in 2 to
the unrestricted benzyl group in 5c corresponds to the expected in-
crease in entropy of 2.5–4.2 kJ mol−1 per rotatable bond gained,29 and
suggests that any additional poses of the non-fused benzene ring offer
no advantage in binding. An α-methylbenzyl group attached to the
terminal nitrogen atom was not well tolerated, although the (R)-en-
antiomer 5d was threefold more potent than the (S)-enantiomer 5e. A p-
methoxy group had an adverse effect upon HDAC inhibition (compare
5f to 5c). A 2-thienyl group (5g) showed a small increase in potency
compared to the benzyl analog (5c). The phenylethyl series 5h-5j ex-
hibited low micromolar potency, the 4-hydroxy group being well tol-
erated, and possibly conferring some potency. A 3-phenylpropyl unit
(5n) also showed low micromolar potency, but a 2-indanyl N-sub-
stituent (5p, an analog of 5h constrained to form a ring), was less
beneficial than any of the linear analogs. The presence of nitrogen
within the N-substituent was advantageous in the case of indolylethyl
analogs (5l and 5m), the parent compounds showing potency close to
1 µM. However, a 3-carbazolyl substituent conferred lower potency
than an aromatic analog (compare 5p to 5b), probably because of steric
bulk. Overall, while some benzylic and N-substituents were well toler-
ated, no improvement was identified as superior to the 2-isoindolin-2-yl
unit.
Interpretation of the above results in terms of both HDAC8-ligand
crystallography and molecular docking is insightful. For all the α-amino
amides herein discussed, including 2 (apparently of the same con-
stitution as 5q), binding in the acetate-release channel (located deeper
in the protein, beyond the zinc-binding region; Fig. 2) is an unusual
feature that characterises this class of HDAC inhibitor. Among the 11
Rigidity and a planar ring system linked linearly (w.r.t. the N-CO
4

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Table 2
In Vitro Inhibition of Histone Deacetylase 8 by Varied-Linker α-Amino Amides.
human HDAC isoforms, Trp at position 141 is unique to HDAC8, and
being present within the acetate-release channel, is thought to play a
major role in the selectivity of inhibitor binding to HDAC8,30 involving
aromatic stacking, as confirmed by crystallography of amide 2 in
HDAC8 (Fig. 2a). Off-centre parallel aromatic stacking occurs between
the 2,4-dichlorophenyl unit of inhibitor 2 and Trp141. Interactions of
5

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Table 3
not resolved, suggesting that it does not bind to 2. Given that amides 5i
and 5l (containing polar OH and NH groups respectively that could
engage in hydrogen bonding) were the most potent in the series shown
in Table 2 (IC50 values close to 1 µM) in which the isoindoline ring is
absent, this supported examining the effect of the introduction of a 5-
substituent in an isoindoline series that might also engage in hydrogen
bonding with Asp101.
In Vitro Inhibition of HDAC8 by Substituted Isoindolinyl α-Amino Amides.
The 5-substituted isoindoline series (Table 3) provided further evi-
dence of effectiveness in exploiting ligand binding to Asp101; for the
most potent compounds, amine 14a (IC50 = 0.13 µM) and amide 14b
(IC50 = 0.10 µM), molecular docking poses (Figs. 2b and 2c) clearly
identified distances consistent with hydrogen bonding to Asp101 (ap-
proximately 2.75 Å in both cases) as well as an aromatic edge-to-face
interaction with Phe152. The NH groups of the 5-NHR substituent act as
hydrogen bond donors to the Asp101 sidechain (Fig. 2). However,
translocation of the nitrogen atom to the β-position of the 5-substituent,
as in the reversed amide 21 and the aminomethyl derivative 26 lowers
the ligand binding energy. In amide 21, the amide is more than 4 Å
from Asp101 and the orientation of the NeH bond departs from the
ideal linear hydrogen-bonded assembly.36
As shown in the crystal structure (PDB: 3SFH),19 the aromatic ring
of isoindoline in 2 is well positioned for edge-to-face interactions with
Phe152 of HDAC8, but that is not the case for the corresponding tet-
rahydroisoquinolinyl analog 5r, being more remote from Phe152
(Fig. 2d); additionally, the different topology of a larger and a non-
planar isoquinoline ring would lead to altered interactions with back-
bone amide residues. Such factors would contribute to the lower
binding energy compared to the isoindoline ring system in 2, as re-
flected by a difference of 5.8 kJ mol−1 estimated from IC50 values. The
lack of aromatic interactions and a relatively planar but non-aromatic
ring also account for the weak binding of the piperazine derivatives 8a
and 8b.
In conclusion, general routes to 5-substituted isoindolines have been
developed, and their conversion into the corresponding α-amino
amides has furnished potent HDAC8 inhibitors. Amide 14b was found
to be highly selective for HDAC8 (IC50 = 0.10 µM), compared to
HDAC1 (IC50 = 8.8 µM), HDAC2 (IC50
> 30 µM), and HDAC6
(IC50 > 30 µM). The presence of the 2,4-dichloro substitution at the
phenyl ring of the α-amino amides was shown to confer a gain of ap-
prox. 4.3 kJ mol−1 in binding energy, being an essential unit in this
series of HDAC8 inhibitors, for binding within the acetate-release
channel.19 The need for a linear, planar and rigid ring system, as in-
dicated by the efficacy of a isoindolin-2-yl linker, was underscored by
its replacement with tetrahydroisoquinoline ring system (approx.
5.8 kJ mol−1 lower binding energy than the isoindoline ring system)
which invariably conferred poorer in vitro inhibition of HDAC8. A final
series of α-amino amides was synthesised and shown to give potent in
vitro inhibition of HDAC8, compounds 14a and 14b being somewhat
more potent than the lead HDAC8 inhibitor 5q in the assay used, with
improved binding energy of about 2.0 kJ mol−1 arising from additional
binding interactions within the acetyl-lysine binding tunnel, including
π-π interactions, particularly involving Phe152, and hydrogen bonding
of a 5-isoindoline substituent to Asp101. The importance of Asp101 in
HDAC8 activity and its inhibition has been previously empha-
sised;30,34,35 mutations of Asp101 led to loss of inhibitor binding in
studies of hydroxamic acid inhibitors of HDAC8.30
Fig. 2. (a) Conformation of α-amino amide 2 in HDAC8 (PDB: 3SFH).19 (b)-(d)
Poses of α-amino amides 14a, 14b and 5r respectively docked into HDAC8
(PDB: 3SFH, see Supplementary Material). In addition to edge-to-face interac-
tions of the aromatic ring of isoindoline, (b) and (c) also indicate hydrogen
bonding to Asp101 of the amine substituent in 14b (in magenta), and the amide
substituent 14c (in pink) respectively. Figure (d) shows the markedly different
pose of 5r (brown) containing a fused piperidine ring compared to 2 (overlaid
in green).
the 2-chloro substituent with Gly140, and of the 4-chloro substituent
with Arg37 also contribute to binding in the acetate-release channel
(Fig. 2a). Arg37 has been shown to regulate the release of acetate.31,32
The 4-chloro substituent interacts side-on to Arg37, a standard mode for
a Lewis base. In contrast, the 2-chloro substituent is end-on to the
backbone carbonyl oxygen atom of Gly140, and is engaged in halogen
bonding.33
This study has evaluated the scope and limitations of indolin-2-yl α-
amino amides as HDAC8 inhibitors, and has provided an analysis of
binding energies of the various structural features along with rationales
for the binding of each major structural subunit. Appropriately sub-
stituted isoindolinyl inhibitors have been shown to confer additional
binding of the HDAC8 inhibitor to the acetyl-lysine binding tunnel, the
substituent acting as a capping group that offers additional molecular
diversity. Consequently, there is scope for the development of more
potent and isoform-selective inhibitors of HDACs containing an α-
amino amide as the zinc-coordinating unit within the active site.
For all the α-amino amides in Table 3, the similar or improved
potency of the 5-substituted isoindoline derivatives can be accounted
for as follows. In many HDAC isoforms other than HDAC8 a capping
group that binds to the protein periphery is required for potent in-
hibition. The potential for improved binding by adding a capping group
to 2 is also supported by previous findings that Asp101 is essential for
substrate binding in HDAC8 via the formation of a hydrogen bond.34,35
Such hydrogen bonding involving Asp101 is shown in Figs. 2b and 2c,
whereas in the crystal structure of 2 the flexible location of Asp101 is
6

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Declaration of Competing Interest
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[15]. KrennHrubec K, Marshall BL, Hedglin M, Verdin E, Ulrich SM. Bioorg Med Chem
Lett. 2007;17:2874.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
[16]. Tang W, Luo T, Greenberg EF, Bradner JE, Schreiber SL. Bioorg Med Chem Lett.
2011;21:2601.
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Financial support from the BBSRC for a studentship (to S. O. R. G.) is
gratefully acknowledged. D. F. H. acknowledges the BBSRC for financial
support (BB/H022570/1). We are grateful to Dr Christopher Matthews
for providing the MAL substrate and to Drs Nicolas D. Werbeck and
Micha B. A. Kunze for assistance with in vitro assays and dockings, and
for helpful discussions.
(b) Kelly WK, O’Connor OA, Krug ML, et al. J Clin Oncol. 2005;23:3923.
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