Thiol-based SAHA analogues as potent histone deacetylase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2004.03.063

In order to find novel nonhydroxamate histone deacetylase (HDAC) inhibitors, a series of thiol-based compounds modeled after suberoylanilide hydroxamic acid (SAHA) was synthesized, and their inhibitory effect on HDACs was evaluated. Compound 6, in which t

Full text of DOI:10.1016/j.bmcl.2004.03.063

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3313–3317
Thiol-based SAHA analogues as potent histone deacetylase
inhibitors
Takayoshi Suzuki,a,* Akiyasu Kouketsu,a Azusa Matsuura,a Arihiro Kohara,b
Shin-ichi Ninomiya,b Kohfuku Kohdaa and Naoki Miyataa,*
aGraduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Aichi, Nagoya 467-8603, Japan
bDaiichi Pure Chemicals Co., Ltd, 2117 Muramatsu, Ibaraki, Tokai 319-1182, Japan
Received 21 February 2004; revised 22 March 2004; accepted 23 March 2004
Abstract—In order to find novel nonhydroxamate histone deacetylase (HDAC) inhibitors, a series of thiol-based compounds
modeled after suberoylanilide hydroxamic acid (SAHA) was synthesized, and their inhibitory effect on HDACs was evaluated.
Compound 6, in which the hydroxamic acid of SAHA was replaced by a thiol, was found to be as potent as SAHA, and opti-
mization of this series led to the identification of HDAC inhibitors more potent than SAHA.
Ó 2004 Elsevier Ltd. All rights reserved.
O
O
The reversible acetylation of the side chain of specific
histone lysine residues by histone deacetylases (HDACs)
and histone acetyl transferases (HATs) is an important
regulator of gene expression.1 Histone hyperacetylation
by HDAC inhibition neutralizes the positive charge of
the lysine side chain, and is thought to be associated
with change of the chromatin structure and the conse-
quential transcriptional activation of a number of gen-
es.2 One important outcome of histone hyperacetylation
is induction of the cyclin-dependent kinase inhibitory
protein p21Waf1=Cip1, which causes cell cycle arrest.3 In-
deed, HDAC inhibitors such as trichostatin A (TSA)
and suberoylanilide hydroxamic acid (SAHA) (Fig. 1)
have been reported to inhibit cell growth,4–6 induce
terminal differentiation in tumor cells,4;5 and prevent the
formation of tumors in mice.7 Therefore, HDACs have
been viewed as attractive targets for anticancer drug
development. A number of structurally diverse HDAC
inhibitors have been reported8 and most of them belong
to hydroxamic acid derivatives, typified by TSA and
SAHA, which chelate the zinc ion in the active site in a
bidentate fashion through its CO and OH groups.9 Al-
though hydroxamic acids are frequently employed as
zinc-binding groups (ZBGs), they often present meta-
bolic and pharmacokinetic problems such as glucuron-
O
H
N
OH
OH
N
H
N
H
O
Me 2N
TSA
SAHA
H
N
O
O
HN
O
N
O
H
S
O
HN
S
O
N
NH
O
H
OMe
S
O
N
O
O
S
N
FK228
1
Figure 1. HDAC inhibitors.
idation, sulfation, and enzymatic hydrolysis that result
in a short in vivo half-life.10;11 Because of such concerns
with the metabolic stability associated with hydroxamic
acids, it has become increasingly desirable to find
replacement groups that possess strong inhibitory action
against HDACs. Thus far, o-aminoanilides,12–14 elec-
trophilic ketones,15–17 bromoacetamides,18 semicarbaz-
ides18 (Fig. 2), and N-formyl hydroxylamines19 have
been reported as small molecule nonhydroxamate
HDAC inhibitors. However, they have reduced potency
as compared to hydroxamate inhibitors, and unfortu-
nately, electrophilic ketones have a metabolic disad-
vantage in that they are readily reduced to inactive
alcohols.15–17 We therefore initiated a search for
Keywords: HDAC; SAHA; Enzyme inhibitor; Zinc protein.
* Corresponding authors. Tel./fax: +81-52-836-3407; e-mail addresses:
suzuki@phar.nagoya-cu.ac.jp; miyata-n@phar.nagoya-cu.ac.jp
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.03.063

3314
T. Suzuki et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3313–3317
O
O
NH2
O
H
N
H
N
H
N
a
c
CF3
Ar
Br
n
Ar
SAc
n
Br
n
N
H
N
H
Cl
6
6
O
O
O
O
27a n = 7
27b n = 6
27c n = 5
27d n = 4
29a Ar = Ph, n = 7
29b Ar = Ph, n = 6
29c Ar = Ph, n = 5
29d Ar = Ph, n = 4
29e Ar = 4-NMe2-Ph, n = 6
29f Ar = 4-Br-Ph, n = 6
29g Ar = 4-biphenyl, n = 6
29h Ar = 3-biphenyl, n = 6
29i Ar = 4-OPh-Ph, n = 6
29j Ar = 3-OPh-Ph, n = 6
29k Ar = 3-Py, n = 6
7
Ar = Ph, n = 6
2
4
3
30a Ar = Ph, n = 7
30b Ar = Ph, n = 5
30c Ar = Ph, n = 4
30d Ar = 4-NMe2-Ph, n = 6
30e Ar = 4-biphenyl, n = 6
30f Ar = 3-biphenyl, n = 6
30g Ar = 4-OPh-Ph, n = 6
30h Ar = 3-OPh-Ph, n = 6
30i Ar = 3-Py, n = 6
O
O
H
N
H
N
Br
N
H
N
H
NHNH2
6
5
b
O
O
5
Figure 2. SAHA-based nonhydroxamate HDAC inhibitors.
30j Ar = 3-quinoline, n = 6
30k Ar = 4-Ph-2-thiazole, n = 6
29l Ar = 3-quinoline, n = 6
29m Ar = 4-Ph-2-thiazole, n = 6
replacement groups for hydroxamic acid with the goal
of drug discovery as well as finding new tools for bio-
logical research.
6 Ar = Ph, n = 6
10 Ar = Ph, n = 7
11 Ar = Ph, n = 5
12 Ar = Ph, n = 4
O
15 Ar = 4-NMe2-Ph, n = 6
In the search for a suitable hydroxamic acid replace-
ment, thiols seemed to be reasonable targets, because
they have been reported to inhibit zinc-dependent
enzymes such as angiotensin converting enzyme20 and
matrix metalloproteinase.21 Recently, Furumai et al.
demonstrated that the disulfide bond of FK228 (Fig. 1),
a cyclic peptide HDAC inhibitor, is reduced in the cel-
lular environment, releasing the free thiol analogue as
the active species,22 and Nishino et al. reported that
cyclic tetrapeptides bearing disulfide group such as 1
(Fig. 1) inhibit HDACs under reductive conditions.23
These reports prompted us to report on the synthesis
and HDAC inhibition of thiol-based small molecule
analogues.
d
Ar
SH
n
16 Ar = 4-biphenyl, n = 6
17 Ar = 3-biphenyl, n = 6
18 Ar = 4-OPh-Ph, n = 6
19 Ar = 3-OPh-Ph, n = 6
20 Ar = 3-Py, n = 6
N
H
21 Ar = 3-quinoline, n = 6
22 Ar = 4-Ph-2-thiazole, n = 6
O
e
29b
SMe
N
H
6
8
Scheme 1. Reagents and conditions: (a) ArNH2 (28), Et3N, CH2Cl2,
rt, 25–99%; (b) PhB(OH)2, Pd(PPh3)4, NaHCO3, 1-methyl-2-pyrro-
lidinone, H2O, 80 °C, 18%; (c) AcSK, EtOH, 60 °C, 84–99%; (d) 2 N aq
NaOH, EtOH, THF, rt, 47–99%; (e) 15% aq NaSMe, EtOH, rt, 99%.
The compounds prepared for this study are shown in
Tables 1–3. Syntheses were accomplished as illustrated
in Schemes 1–3. Compounds 6–8, 10–12, 15–21, and 22
were synthesized from the corresponding acid chlorides
27a–d by the route shown in Scheme 1. The amino group
of aromatic amines 28 was acylated with an appropriate
acid chloride 27 to give the amides 29a–f and 29h–m.
Suzuki coupling24 of bromobenzene 29f with phen-
ylboronic acid provided the biphenyl 29g. Bromides 29
were treated with potassium thioacetate to give com-
pounds 7 and 30a–k, after which hydrolysis of the thio-
acetates under alkaline conditions gave the desired
compounds 6, 10–12, 15–21, and 22. Sulfide 8 was
obtained by the alkylation of sodium methanethiolate
with bromide 29b.
ded amides 38b–f. Alcohols 38a–f were converted to
thiols 13, 14, 23–25, and 26 in a three-step sequence:
conversion of the alcohols to bromides, treatment of the
bromides with potassium thioacetate, and hydrolysis of
the resulting thioacetates.
The compounds synthesized in this study were tested
with an in vitro assay using a HeLa nuclear extract rich
in HDAC activity.26 The results are summarized in
Tables 1–3 as IC50 values.
O
HOOC
COOH
b
a
COOH
N
H
5
5
Synthesis of aminoethanethiol 9 was accomplished via
aldehyde 34 (Scheme 2). The condensation of dicar-
boxylic acid 31 with an equivalent amount of aniline
gave mono-anilide 32. The carboxylic acid 32 was con-
verted to Weinreb amide25 33 in the presence of EDCI
and HOBt. Compound 33 was allowed to react with
lithium aluminum hydride at 0 °C to give aldehyde 34
and subsequent reductive amination afforded amino-
ethanethiol 9.
31
32
O
O
O
O
c
OMe
N
H
N
N
H
H
5
5
Me
34
33
O
H
N
d - f
N
H
SH
6
9
Compounds 13, 14, 23–25, and 26 were prepared from
alcohol 35 or 36 by the procedure outlined in Scheme 3.
Treatment of bromide 35 with phenol in the presence of
K2CO3 gave ether 38a, and condensation of amine 36
with an appropriate aromatic carboxylic acid 37 affor-
Scheme 2. Reagents and conditions: (a) Aniline, 180 °C, 43%; (b) N,O-
dimethylhydroxylamine hydrochloride, Et3N, EDCI, HOBt, DMF, rt,
94%; (c) LiAlH4, THF, 0 °C, 72%; (d) 2-aminoethanol, NaBH(OAc)3,
THF, AcOH, rt; (e) (Boc)2O, Et3N, rt; (f) TFA, CH2Cl2, rt, 44% (three
steps).

T. Suzuki et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3313–3317
3315
Table 2. Effect of linker variation on HDAC inhibitory activity of
thiolsa
Br
OH
a
6
c - e
X
OH
35
36
Ar
b
6
H2N
OH
X
SH
38a Ar = Ph, X = -O-
38b Ar = Ph, X = -CONH-
n
6
Entry
Compd
X
n
IC50 (lM)
38c Ar = 4-NMe2-Ph, X = -CONH-
38d Ar = 2-naphthalene, X = -CONH-
38e Ar = 2-benzofuran, X = -CONH-
38f Ar = 2-indole, X = -CONH-
1
2
3
4
5
6
6
10
11
12
13
14
–NHCO–
–NHCO–
–NHCO–
–NHCO–
–O–
6
7
5
4
6
6
0.21
1.5
0.37
6.2
X
SH
Ar
6
11
13 Ar = Ph, X = -O-
14 Ar = Ph, X = -CONH-
23 Ar = 4-NMe2-Ph, X = -CONH-
24 Ar = 2-naphthalene, X = -CONH-
25 Ar = 2-benzofuran, X = -CONH-
26 Ar = 2-indole, X = -CONH-
–CONH–
0.36
a Values are means of at least three experiments.
inhibitor that was about 30-fold less potent and a
compound devoid of anti-HDAC activity, respectively
(entries 7 and 8). These results suggest that although the
inherent affinity of a monodentate thiol ZBG is less than
that of bidentate ZBGs such as hydroxamate and hy-
drated electrophilic ketone, its ease of ionization makes
thiol 6 as powerful as SAHA.27 In order to find more
potent ZBGs, we examined the activity of aminoetha-
nethiol 9, which was expected to coordinate zinc ion in a
bidentate fashion. Although aminoethanethiols have
been reported to inhibit zinc proteins,28 this functional
group led to a loss of HDAC inhibitory activity (entry
9).
Scheme 3. Reagents and conditions: (a) Phenol, K2CO3, DMF, 80 °C,
96%; (b) ArCOOH (37), EDCI, HOBt, DMF, rt, 61–96%; (c) CBr4,
PPh3, CH2Cl2, 0 °C, 25–99%; (d) AcSK, EtOH, 60 °C, 47–99%; (e) 2 N
aq NaOH, EtOH, THF, rt, 28–74%.
As seen in Table 1, the IC50 values of SAHA, o-am-
inoanilide 2, bromoacetamide 4, and semicarbazide 5
were 0.28, 120, 14, and 150 lM, respectively (entries 1, 2,
4, and 5). Trifluoromethyl ketone 3 was reported pre-
viously to inhibit HDACs with an IC50 of 6.7 lM (entry
3).15 In our study, changing the hydroxamic acid of
SAHA to thiol yielded fruitful results. A pronounced
inhibitory effect (IC50 ¼ 0.21 lM) was observed with
thiol 6, which was about 30–700-fold more active than
the previously reported nonhydroxamates, and as po-
tent as SAHA (entry 6). To confirm that the thiol group
plays an important role in anti-HDAC activity, thioac-
etate 7, and sulfide 8 were tested. As expected, thiol
transformation into thioacetate and sulfide led to an
We next examined the effect of linker parts of thiol 6.
The results are shown in Table 2. HDAC inhibition was
distinctly dependent on chain length, with n ¼ 7 (10)
and n ¼ 4 (12) resulting in less potent inhibitors. How-
ever, compound 11, in which n ¼ 5, proved to be equally
effective to 6, in which n ¼ 6 (entries 1–4). The similar
structure–activity relationship (SAR) between thiols and
hydroxamates, with n ¼ 6 optimal,29;30 indicates that
thiols inhibit HDACs in a binding mode similar to that
of hydroxamates. As for the group attaching the phenyl
moiety, ether 13 displayed a moderate activity, whereas
the activity of the reversed amide 14 was maintained
(entries 5 and 6).
Table 1. HDAC inhibition data for SAHA and SAHA-based non-
hydroxamatesa
H
N
R
n
O
Entry
1
Compd
SAHAb
n
R
IC50 (lM)
Having investigated the requirements for the ZBGs and
linker parts, we next turned our attention to aromatic
groups (Table 3). In the amide-linked series (entries 1–
9), 4-substituted phenyl compounds tended to reduce the
potency. Specifically, compounds 15 (Ar ¼ 4-NMe2-Ph),
16 (Ar ¼ 4-biphenyl), and 18 (Ar ¼ 4-PhO-Ph) showed
about a 3–10-fold decrease in potency when compared
to the parent thiol 6 (entries 2, 3, and 5). In contrast,
when a phenyl group was introduced at the 3-position of
the phenyl group of 6, the IC50 of compound 17 was
improved and reached 0.075 lM (entry 4). In addition,
3-phenoxy compound 19 was equipotent with com-
pound 6 (entry 6). Next, we investigated the effect of the
replacement of the phenyl group of compound 6 with
heteroaryl rings (entries 7–9). While pyridine 20 and
phenylthiazole 22 retained the potency of compound 6,
quinoline 21 was about 3-fold more active than com-
pound 6 (IC50 ¼ 0.072 lM). The reversed amide-linked
series (entries 11–14) exhibited potencies similar to or
6
–CONHOH
0.28
NH2
H
N
2
2c
6
120
O
3
4
5
6
7
8
9
3
6
6
5
6
6
6
6
–COCF3
6.7d
14
4e
5e
6
–NHCOCH2Br
–NHCONHNH2
–SH
150
0.21
7.1
7
–SAc
–SMe
–NHCH2CH2SH
8
9f
>100
>100
a Values are means of at least three experiments.
b Prepared as described in Ref. 31.
c Prepared as described in Ref. 13.
d Data taken from the literature (Ref. 15).
e Prepared as described in Ref. 18.
f Trifluoroacetic acid salt.

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T. Suzuki et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3313–3317
Table 3. Effect of aromatic group variation on HDAC inhibitory
activity of thiolsa
In summary, in order to find novel nonhydroxamate
HDAC inhibitors, we designed and prepared a series of
thiol-based SAHA analogues, and evaluated their
inhibitory effect on HDACs. Compound 6, in which the
hydroxamic acid of SAHA was replaced by a thiol, was
found to be as potent as SAHA. We have shown that the
potency is related to chain length, with n ¼ 6 optimal,
and the amide and reversed amide were preferred as the
group attaching the phenyl moiety. The conversion of
the phenyl group of compound 6 to other aromatic
groups led to the identification of inhibitors more potent
than SAHA. The SAR results within the thiol series
indicate that thiols inhibit HDACs in a manner similar
to that of hydroxamates. As far as we could determine,
this is the first report of nonmacrocyclic thiol inhibitors
of HDACs. These small molecule thiols may be useful as
tools for biological research and as orally bioavailable
anticancer drugs. Currently, further detailed SAR
studies and the next stage of evaluations are under way.
Ar
X
SH
6
Entry
1
Compd
Ar
X
IC50 (lM)
6
–Ph
–NHCO–
0.21
NMe2
Ph
2
3
15
16
–NHCO–
–NHCO–
1.2
1.1
4
5
17
18
–NHCO–
–NHCO–
0.075
0.62
Ph
OPh
6
7
19
20
–NHCO–
–NHCO–
0.21
0.11
OPh
Acknowledgements
This work was supported in part by grants from the
Health Sciences Foundation from the Ministry of
Health, Labor, and Welfare of Japan, and the Mochida
Memorial Foundation for Medical and Pharmaceutical
Research.
N
8
9
21
22
–NHCO–
0.072
0.17
N
N
–NHCO–
–CONH–
References and notes
S
10
11
14
23
–Ph
0.36
0.61
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