Histone deacetylase inhibitors derived from 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine and related heterocycles selective for the HDAC6 isoform

Article abstract of DOI:10.1016/j.bmcl.2014.10.022

Acyl derivatives of 4-(aminomethyl)-N-hydroxybenzamide are potent sub-type selective HDAC6 inhibitors. Constrained heterocyclic analogs based on 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine show further enhanced HDAC6 selectivity and inhibitory activity in ce

Full text of DOI:10.1016/j.bmcl.2014.10.022

Bioorganic & Medicinal Chemistry Letters 24 (2014) 5450–5454
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Histone deacetylase inhibitors derived from
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine and related
heterocycles selective for the HDAC6 isoform
⇑
Christopher Blackburn , Cynthia Barrett, Mable Brunson, Janice Chin, Dylan England, Kris Garcia,
Kenneth Gigstad, Alexandra Gould, Juan Gutierrez, Kara Hoar, R. Scott Rowland, Christopher Tsu,
John Ringeling, Krista Wager, He Xu
Discovery, Takeda Pharmaceuticals International Co., 40 Landsdowne Street, Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Acyl derivatives of 4-(aminomethyl)-N-hydroxybenzamide are potent sub-type selective HDAC6 inhibi-
tors. Constrained heterocyclic analogs based on 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine show further
enhanced HDAC6 selectivity and inhibitory activity in cells. Homology models suggest that the heterocy-
clic spacer can more effectively access the wider catalytic channel of HDAC6 compared to other HDAC
sub-types.
Received 5 September 2014
Revised 2 October 2014
Accepted 6 October 2014
Available online 13 October 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Histone deacetylase
HDAC6 selective
Hydroxamic acid
Acetyl tubulin
Histone deacetylase (HDAC) enzymes catalyze the hydrolysis of
acetyl groups from the -amino group of lysine residues of protein
hypothesis, the HDAC6 selective inhibitor Tubacin is reported to
e
induce hyper-acetylation of a-tubulin but not histones in multiple
substrates. The HDACs are sub-divided into classes I (types 1, 2, 3,
8), IIa (4, 5, 7, 9), IIb (6, 10), III and IV (11) of which the class I, II and
IV enzymes are Zn2+ dependent metalloamidases.1 HDAC6 resides
predominantly in the cytosol and has two functional catalytic
domains as well as a carboxy-terminal zinc-finger domain that
myeloma cells13–15 and to potentiate proteasome inhibitor-
induced apoptosis.16
Many HDAC inhibitors have been reported17 comprising a Zn2+
complexing agent, usually a hydroxamic acid, spacer, and capping
group (Fig. 1). Pan HDAC or class I selective HDAC inhibitors are
most common, such as suberoylanilide hydroxamic acid (SAHA),
or vorinostat, which has been shown to have therapeutic bene-
fits.18–21 In order to investigate synergistic effects of HDAC6 and
proteasome inhibitors, we required inhibitors with at least compa-
rable potency and selectivity to Tubacin and with improved physi-
cal properties. Despite their metabolic liabilities, hydroxamic acids
exhibit unique binding energetics.22 Thus, the uncharged form pre-
dominates in aqueous solution and the conjugate base is formed in
the active site of the enzyme resulting in a much smaller desolva-
tion penalty on binding than species that are already ionized in
the aqueous phase. In terms of HDAC6 inhibitory activity, the highly
potent inhibitor NOC-7 with moderate sub-type selectivity23 and
Tubastatin A24 with high HDAC6 selectivity are notable. We
screened several hundred hydroxamic acids in our collection for
inhibitory activity of HDAC6 and those enzymes present in HeLa
nuclear extract, predominantly the class I HDACs 1 and 2 and iden-
tified a derivative of 4-aminomethylbenzoic acid (compound 1) as a
selective inhibitor of HDAC6.25 Optimization of this hit in the case
binds ubiquitinated proteins.2 Substrates for HDAC6 including
a-
tubulin, cortactin, and Hsp903,4 mediate a wide range of cellular
functions which are important in tumorigenesis, tumor growth
and metastasis.5–8 HDAC6 has also been linked to autophagy, a
pathway for protein degradation that compensates for reductions
in the activity of the ubiquitin proteasome system arising from
treatment with a proteasome inhibitor.9–12 In this process, HDAC6
binds ubiquitin, or ubiquitin-like conjugated proteins which would
otherwise induce proteotoxic stress and transports them as ternary
complexes with dynein to the microtubule organizing center
where they are incorporated into the aggresome6 and degraded
by fusion with lysosomes. Simultaneously targeting the protea-
some and aggresome pathways in tumor cells would therefore be
expected to cause greater accumulation of polyubiquitinated
proteins leading to cell stress and apoptosis. In support of this
⇑
Corresponding author. Tel.: +1 617 761 6811.
E-mail address: chris.blackburn@takeda.com (C. Blackburn).
http://dx.doi.org/10.1016/j.bmcl.2014.10.022
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

C. Blackburn et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5450–5454
5451
O
H
O
N
OH
H
N
N
H
HN
OH
5
O
5
O
Zolinza/Vorinostat/SAHA
O
O
O
NHOH
O
S
H
N
Ph
Ph
R
N
HO
O
1
R =
Tubacin
N
O
NHOH
NHOH
N
O
N
R
OH
N
H
O
2
N
O
H
N
Tubastatin A
Ph
O
3
Figure 1. Examples of hydroxamic acid inhibitors of Histone deacetylases.
of fused ring heterocyclic analogs led to highly selective nanomolar
HDAC6 inhibitors with cellular activity such as 2 (Fig. 1).25 Similar
observations on the HDAC6 selectivity of C-aryl hydroxamic acids,
exemplified by compound 3, have been made recently by Holson
and co-workers.26 Using homology modeling, we showed that the
selectivity of compounds 1 and 2 may arise from the differing
‘width’ of the (benzylic) spacer as compared to long chain aliphatic
series.25 In order to investigate cyclic analogs further we designed
three additional series based on 1,2,3,4-tetrahydropyrrolo[1,2-
a]pyrazine, 4,5,6,7-tetrahydropyrazolopyrazine and 5,6,7,8-tetra-
hydroimidazo[1,2-a]pyrazines and report here their synthesis and
biochemical characterization.
1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines were prepared start-
ing with the condensation of ethylpropiolate with ethyl iso-
cyanoacetate in the presence of strong base to give pyrrole ester
4.27 which was alkylated with dibromopropane to give 5 and fur-
ther transformed to the azide 6 (Scheme 1). Hydrogenation of azide
6 effected reductive ring closure to lactam 7 which was further
reduced using diborane affording tetrahydropyrrolopyrazine ethyl
ester (8). Acylation of 8 with a range of capping groups was fol-
lowed by transformation to the corresponding hydroxamic acids
9 by reaction with hydroxylamine hydrochloride in the presence
of base.
afforded compounds 13. Representative examples of the isomeric
5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine series 15 were obtained
by acylation of commercially available ester 14 followed by trans-
formation to the corresponding hydroxamic acids 15 (Scheme 2).
The inhibitory activities of hydroxamic acids in series 9, 13 and
15 on the rate of deacylation of the substrate Ac-Arg-Gly-Lys(Ac)-
AMC (where AMC denotes 7-aminocoumarin) catalyzed by HDAC6
were measured and selectivity was assessed with respect to inhibi-
tion of the enzymes present in HeLa nuclear extract (NucEx), pre-
dominantly HDACs 1 and 2. In addition, compounds with an
appropriate combination of inhibitory potency and selectivity were
assayed in cells for their ability to induce hyperacetylation of tubu-
lin (Table 1) and of nuclear histones.
We previously observed that C-arylhydroxamic acids are potent
HDAC6 inhibitors with high selectivity with respect to inhibition of
the other sub-types. For example, hydroxamic acid 1, with an
N-methylpyrrole carboxylate capping group, exhibited an IC50
value of 19 nM for HDAC6 inhibition as compared with 2.2 lM
inhibition of the class I enzymes present in nuclear extract enzyme
(Table 1). Cyclic analog 2 showed slightly reduced HDAC6 inhibi-
tory activity but improved selectivity with respect to inhibition
of nuclear extract enzymes.25 Similarly, tetrahydropyrrolo[1,2-
a]pyrazine 9a has comparable potency to cyclic compound 2
though in this case the selectivity was somewhat more modest
(190-fold). The cellular activity (Ac-Tub assay) of 9a (IC50 = 69 nM)
is, however, a marked improvement over both compounds 1 and 2.
In addition, 9a and all other compounds tested in cellular assays
(Table 1) showed selectivity with respect to inducing acetyl lysine
The tetrahydropyrazolopyrazines were accessed as shown in
Scheme 2.28 Thus, the nosyl derivative of propargylamine was
alkylated with 1-bromo-2-chloroethane to give 10. Cycloaddition
of 10 with ethyldiazoacetate and ring closure in situ onto the chlo-
roethyl group afforded 11 which was deprotected to give amine 12.
Reaction of 12 with a series of carboxylic acid capping groups fol-
lowed by displacement of the ethoxy group by hydroxylamine
accumulation in nuclear histones (<20% inhibition @ 20 lM). While
other small aryl residues as capping groups led to potent and
X
O
i.
ii.
OEt
N
OEt
HN
5; X = Br
6: X = N3
NC
O
EtO
iii.
O
O
O
OEt
OEt
4
OEt
O
HN OH
O
OEt
O
N
9
iv.
N
vi.
v.
N
R
N
HN
HN
O
O
8
7
Scheme 1. Reagents and conditions: (i) ethyl propioloate, KH, MTBE; (ii) 1,2-dibromoethane, K2CO3, MeCN; (iii) NaN3, DMF; (iv) Pd-C, H2, MeOH; (v) BH3, Me2S, THF; (vi)
(a) RCOOH, HATU, TEA; (b) NH2OHÁHCl, KOH, MeOH.

5452
C. Blackburn et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5450–5454
O
N
N
Cl
OEt
O
O
N
S
ii.
S
i.
N
O
N
O
O
N
S
H
NO2
10
O
NO2
NO2
11
O
HN
O
OH
iv.
N
N
iii.
N
OEt
R
N
HN
HN
O
12
13
O
OMe
O
N
HN
O
N
OH
iv.
R
N
N
N
14
15
Scheme 2. Reagents and conditions: (i), Cs2CO3, acetone; (ii) ethyldiazoacetate, toluene, 140 °C; (iii) PhSH, Cs2CO3; (iv). (a) RCOOH, HATU, TEA; (b) NH2OHÁHCl, KOH, MeOH.
Table 1
HDAC6 inhibitory activity and selectivity of fused ring hydroxamic acids
Capping Groups
Cl
MeO
Cl
S
N
a
S
N
b
d
f
e
c
Ph
N
N
N
H
N
k
g
h
j
i
Compd
HDAC6 IC50/nMa
Selectivity NucExb/HDAC6
Ac-Tub IC50 /nMc
Compd
HDAC6 IC50/nMa
Selectivity NucExb/HDAC6
Ac-Tub IC50 /nMc
9a
9b
9c
9d
9e
9f
9h
9i
9j
33
33
110
39
43
100
280
190
85
190
100
150
14
130
250
24
69
9k
32
44
ND
2200
ND
3500
ND
ND
2100
460
210
150
ND
ND
100
730
ND
ND
140
13a
13e
13g
15a
15d
15k
1
350
810
76
130
64
87
19
36
220
120
66
770
52
70
115
500
6.3
35
2
a
Enzymatic data obtained with recombinant HDAC6 or HeLa nuclear extracts using Ac-Arg-Gly-Lys(Ac)-AMC as substrate with subsequent release of AMC by treatment
with trypsin. IC50 values are means of two or more determinations. Standard deviation is within 20% of the IC50
.
b
Nuclear extract (NucEx) expresses predominantly HDACs 1 and 2.
Cellular data: Ac-tubulin accumulation was determined by immunofluorescence with an anti-Ac-tubulin antibody in cytosol. Ac-Lys accumulation in nuclear histones
M. ND not determined.
c
was measured by immunofluorescence in HeLa cells with all compounds showing <20% inh @ 20
l
selective compounds, larger groups gave more variable results.
Thus, comparable potency was maintained for analogs 9b, 9d, 9e,
and 9k but selectivity was adversely affected. The enzymatic
HDAC6 inhibitory activities of pyrazolopyrazine analogs 13a, 13e
and 13g as well as tetrahydroimidazo[1,2-a]pyrazines 15a, 15d,
and 15k were invariably lower than for series 9 and could not be
compensated by further changes to the capping groups.
In order to probe sub-type selectivity in more detail, the inhib-
itory activity of compound 9a was assessed across the full panel of
individual HDACs. These data are compared with previously
reported HDAC6 selective compounds in Table 2 and confirm the
significant improvement in selectivity of 9a as compared to the
acyclic analog 1 observed in the nuclear extract assay. Moreover,
compound 9a shows a better selectivity profile than those of
vorinostat21 and Tubacin16,24 and comparable to that of Tubasta-
tin,24 with HDAC8 the only isoform for which any significant inhib-
itory activity was observed (ca. 100-fold selectivity). Significantly,
9a is the most potent compound in the cellular acetyl tubulin
assay. Other properties of compound 9a appropriate for a biologi-
cal probe and for potential further optimization include high aque-
ous solubility (>200 lM at pH 6.8), moderate Caco-2 permeability
(4.2 Â 10À6 cm sÀ1 at pH 7.4 with efflux ratio = 1.9) and relatively
low in vitro clearance (human microsomal, Eh < 0.2; rat S9 Eh = 0.3).
Although the crystal structure of HDAC6 has not been reported,
homology models of HDAC6 and HDAC1 have been developed to
explain the selectivity of Tubastatin A24 and tubacin29 in terms of
the interactions of capping groups with the rim of the catalytic
channels. Our own homology models25 of HDAC6 and HDAC7

C. Blackburn et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5450–5454
5453
M)
Table 2
Comparison of HDAC isoform inhibitory activity of benzylic spacer derived inhibitors with reference compounds
a
Compd
IC50
5
(l
M) isoform
Ac-Tubb IC50
(l
1
2
3
4
6
7
8
10
11
Vorinostatc
0.119
1.40
16.4
5.80
45.0
15
0.164
6.27
>30
16.0
>50
39
0.106
1.27
>30
4.50
46.0
8.5
NR
NR
3.35
>30
3.30
>50
29
0.090
0.004
0.015
0.019
0.036
0.033
NR
1.50
1.27
0.854
0.69
2.10
3.3
0.072
3.71
>30
3.70
>50
41
NR
NR
2.9
ca. 2.5
0.460
0.21
0.069
Tubacind,e
17.3
>30
15.0
>50
>50
9.70
>30
4.60
>50
35
3.79
>30
ND
>50
29
Tubastatine
1
2
9a
NR not reported. ND not determined.
a
Enzymatic data obtained with recombinant HDAC6 using Ac-Arg-Gly-Lys(Ac)-AMC as substrate with subsequent release of AMC by treatment with trypsin. See
Supplementary information for details of assays for the other sub-types.
b
Cellular data: Ac-tubulin accumulation was determined by immunofluorescence with an anti-Ac-tubulin antibody in cytosol.
c
Data from Yannini et al.21 and Kozikowski et al.23
d
Data from Schrieber et al.16
Data from Kozikowski et al.24
e
Figure 2. Compounds 2 (blue) and 9a (grey) docked into the active site of HDAC6 from a homology model; side view (left) showing interaction with the catalytic zinc; top
view (right) looking down the 11 Angstrom tunnel. Figure constructed using Moe pocket; color coding is purple polar and green hydrophobic.
(obtained from the published crystal structure)30 focused on differ-
ences in the dimensions of the channels of the HDAC sub-types.
Thus, while the HDACs are highly conserved,29 differences in the
loop regions31 cause the channel of HDAC6 leading to the catalytic
Zn2+ to be wider and shallower than that of the other sub-types.
This is illustrated in Fig. 2 in which hydroxamates 2 and 9a are
docked into the active site where they bind to zinc in a bidentate
fashion, with two Asp and one His residue completing the primary
coordination sphere. The spacers project along the 11 Angstrom
deep channel32 with the pyrrole capping groups participating in
additional binding interactions with the rim of the active site of
the protein. While HDAC6 can readily accommodate hydroxamic
acids with heterocyclic spacers such as compounds 2 and 9a, sig-
nificant steric clashes are expected with the narrower channels
of the other sub-types as shown by docking into the crystal struc-
ture of HDAC7.25,33 In contrast, the flexibility of hydroxamic acids
derived from long chain aliphatic spacers facilitates access to the
active site channels of all the sub-types potentially accounting
for the pan HDAC inhibitory activity of vorinostat and related
compounds.
biological tools are of interest for studying the function of HDAC6
in proteotoxic stress and its interactions between the ubiquitin
proteasome system and aggresome pathways for protein
degradation.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.10.
022.
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