Design, synthesis, and biological activity of NCC149 derivatives as histone deacetylasea 8-selective inhibitors

Article abstract of DOI:10.1002/cmdc.201300414

We recently discovered N-hydroxy-3-[1-(phenylthio)methyl-1H-1,2,3-triazol- 4-yl]benzamide (NCC149) as a potent and selective histone deacetylasea 8 (HDAC8) inhibitor from a 151-member triazole compound library using a click chemistry approach. In this wor

Full text of DOI:10.1002/cmdc.201300414

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DOI: 10.1002/cmdc.201300414
Design, Synthesis, and Biological Activity of NCC149
Derivatives as Histone Deacetylase 8-Selective Inhibitors
Takayoshi Suzuki,*[a, b] Nobusuke Muto,[c] Masashige Bando,[d] Yukihiro Itoh,[a] Ayako Masaki,[e]
Masaki Ri,[e] Yosuke Ota,[a] Hidehiko Nakagawa,[c] Shinsuke Iida,[e] Katsuhiko Shirahige,[d] and
Naoki Miyata*[c]
We recently discovered N-hydroxy-3-[1-(phenylthio)methyl-1H-
1,2,3-triazol-4-yl]benzamide (NCC149) as a potent and selective
histone deacetylase 8 (HDAC8) inhibitor from a 151-member
triazole compound library using a click chemistry approach. In
this work, we present a series of NCC149 derivatives bearing
various aromatic linkers that were designed and synthesized as
HDAC8-selective inhibitors. A series of in vitro assays were
used to evaluate the newly synthesized compounds, four of
which showed HDAC8 inhibitory activity similar to that of
NCC149, and one of which displayed HDAC8 selectivity superi-
or to that of NCC149. In addition, these top four compounds
induced the increase of acetylated cohesin (an HDAC8 sub-
strate) in HeLa cells in a dose-dependent manner, indicating in-
hibition of HDAC8 in the cells. While none of these compounds
enhanced the acetylation of H3K9 (a substrate of HDAC1 and
2), only one compound refrained from increasing a-tubulin
acetylation, a substrate of HDAC6, indicating that this com-
pound is more selective for HDAC8 than the other derivatives.
Furthermore, this HDAC8-selective inhibitor suppressed the
growth of T-cell lymphoma cells more potently than did
NCC149. These findings are useful for the further development
of HDAC8-selective inhibitors.
Introduction
Post-translational e-acetylation and methylation of lysine resi-
dues on histones and non-histone proteins is important for the
regulation of fundamental life processes, including gene ex-
pression and cell cycle progression.[1] The lysine acetylation
state of cellular proteins is determined by the activities of his-
tone acetyltransferases and histone deacetylases (HDACs).[1a,b]
Eighteen HDAC subtypes have been identified so far, and they
are subdivided into two families: zinc-dependent HDACs
(HDAC1–11) and NAD+-dependent HDACs (SIRT1–7).[2] Among
these, HDAC8 is unique in that it deacetylates non-histone pro-
teins, such as cohesin,[3] estrogen-related receptor a,[4] and
HSP20,[5] and is involved in genetic repression[6] and the actin
cytoskeleton.[7] Recent studies have indicated that HDAC8 is as-
sociated with several disease states, particularly T-cell lympho-
ma[8] and neuroblastoma.[9] Therefore, HDAC8-selective inhibi-
tors are of great interest, not only as tools for probing the bio-
logical functions of HDAC8, but also as candidate anticancer
agents with potentially few side effects.
Several classes of HDAC8-selective inhibitors have been
identified so far (Figure 1). These include SB-379278A (1),[10]
“linkerless” hydroxamic acid 2,[11] PCI-34051 (3),[8] azetidinone
4,[12] A8B4 (5),[13] and ortho-aryl N-hydroxycinnamide 6.[14] We
recently discovered NCC149 (7) (Figure 1) as a potent and se-
lective HDAC8 inhibitor from a 151-member triazole com-
pound library using a click chemistry approach.[15] Here we
report the design, synthesis, in vitro HDAC inhibitory activity,
cohesin acetylation activity, and T-cell lymphoma cell growth
inhibitory activity of NCC149 derivatives.
[a] Prof. T. Suzuki, Dr. Y. Itoh, Y. Ota
Graduate School of Medical Science
Kyoto Prefectural University of Medicine
13 Taishogun, Nishitakatsukasa-cho, Kita-ku, Kyoto 603-8334 (Japan)
E-mail: suzukit@koto.kpu-m.ac.jp
Results and Discussion
Design
[b] Prof. T. Suzuki
PRESTO (Japan) Science and Technology Agency (JST)
4-1-8 Honcho, Kawaguchi, Saitama 332-0012 (Japan)
The molecular model of NCC149 (7) docked into the HDAC8
catalytic core suggested that the triazole ring interacts with
the methylene group of HDAC8 Phe152 through CH-p or hy-
drophobic interactions[15b] (Figure 2). The triazole ring is also
considered to be important in fixing the orientation of the
zinc-binding hydroxamate and the hydrophobic pocket-bind-
ing phenylthiomethyl group appropriately, thereby contribu-
ting to the potent HDAC8 inhibitory activity and HDAC8 selec-
tivity of NCC149. On the basis of the simulated HDAC8/
NCC149 (7) complex, we designed compounds 8–12 (Figure 3),
[c] N. Muto, Prof. H. Nakagawa, Prof. N. Miyata
Graduate School of Pharmaceutical Sciences, Nagoya City University
3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603 (Japan)
E-mail: miyata-n@phar.nagoya-cu.ac.jp
[d] Dr. M. Bando, Prof. K. Shirahige
Institute of Molecular and Cellular Biosciences
University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032 (Japan)
[e] A. Masaki, Dr. M. Ri, Prof. S. Iida
Graduate School of Medical Sciences, Nagoya City University
1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601 (Japan)
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(methoxycarbonyl)phenylboronic acid 14 provided
biphenyl derivative 15. Bromination of the hydroxy
group in 15 and coupling with thiophenol gave sul-
fide compound 17. Hydrolysis of the methyl ester of
17 afforded carboxylic acid 18, which was then treat-
ed with O-THP hydroxylamine in the presence of
EDCI and HOBt to give O-THP hydroxyamide 19, after
which removal of the THP group under acidic condi-
tions yielded desired compound 8.
Thiazole 9 was synthesized from 3-acetylbenzoic
acid 20, as shown in Scheme 2. Methyl esterification
of 20 and subsequent bromination gave a-bromo-3-
acetylbenzoic acid methyl ester 22. Alternatively, phe-
nylthioacetic acid 23 was converted into amide 24,
and subsequent treatment with Lawesson’s reagent
afforded thioacetamide 25. a-Keto compound 22
Figure 1. Reported HDAC8-selective inhibitors.
Figure 3. Conversion of the triazole ring of NCC149.
Figure 2. Schematic view of the conformation of NCC149 (7) docked into
the HDAC8 catalytic core.
was then reacted with thioacetamide 25 in EtOH at 708C to
give thiazole 26. Hydrolysis of the methyl ester of 26, O-THP
hydroxyamide formation, and deprotection of the THP group
gave thiazole 9.
in which the triazole ring of NCC149 (7) was converted into
various aromatic rings. We antici-
pated that these aromatic rings
would interact with Phe152 of
HDAC8 more efficiently, thereby
leading to more potent and se-
lective inhibition of HDAC8.
Synthesis
A series of compounds (8–12)
modeled after NCC149 were syn-
thesized,
as
shown
in
Schemes 1–5 below. The syn-
thetic route for compound 8, in
which the triazole ring of
NCC149 (7) is replaced with
a benzene ring, is described in
Scheme 1. Suzuki coupling[16] of
Scheme 1. Synthesis of 8. Reagents and conditions: a) Pd(OAc)2, Na2CO3, DMF, H2O, 558C, 1.5 h, (quant.); b) PBr3,
1,4-dioxane, 08C, 1.5 h, 83%; c) PhSNa, Et3N, acetone, H2O, RT, 19.5 h, 50%; d) NaOH, MeOH, H2O, THF, RT, 5 h,
3-iodobenzyl alcohol 13 with 3- 50%; e) NH2OTHP, EDCI, HOBt, DMF, RT, 30 h, 84%; f) TsOH, MeOH, RT, 5.5 h, 40%.
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fide 36. Compound 36 was con-
verted into hydroxamate 12 in
three steps using the procedure
described above.
Biological evaluation
Enzyme assays
The synthesized compounds
were examined for inhibitory
effects toward total HDACs,
HDAC1, HDAC2, HDAC3, HDAC4,
HDAC6, and HDAC8. The results
of the enzyme assays are shown
in Table 1. NCC149 (7) showed
Scheme 2. Synthesis of 9. Reagents and conditions: a) H2SO4, MeOH, reflux, 26.5 h, 97%; b) Br2, HBr, AcOH, CHCl3,
RT, 2 h, (quant.); c) 1. (COCl)2, DMF, THF, 08C 0.5 h, 2. NH3, H2O, THF, 08C, 1.5 h, 83%; d) Lawesson’s reagent, tolu-
ene, 808C, 3.5 h, 21%; e) MS (4 ꢁ), EtOH, 708C, 3 h, 78%; f) NaOH, MeOH, H2O, THF, RT, 5 h, 68%; g) NH2OTHP,
EDCI, HOBt, DMF, RT, 30 h, 96%; h) TsOH, MeOH, RT, 5.5 h, 73%.
potent and selective inhibition of HDAC8 (IC50 for HDAC8=
0.070 mm; IC50 for HDACs=54 mm; IC50 for HDAC1=38 mm; IC50
for HDAC2>100 mm; IC50 for HDAC3=68 mm; IC50 for
HDAC4=44 mm; IC50 for HDAC6=2.4 mm) as compared with
vorinostat, a pan-HDAC inhibitor.[17] Compound 8, in which the
triazole ring of NCC149 (7) is replaced with a phenyl ring, dis-
played 20-fold less potent HDAC8 inhibition, although it
showed HDAC8-selective inhibition. On the other hand, com-
Scheme 3. Synthesis of 10. Reagents and conditions: a) NH2OH, KOH, MeOH,
RT, 20 h, 43%; b) 1. monomethyl isophthalate, CDI, DMF, RT, overnight; 2. mi-
crowave, 1408C, 2 min, 33%; c) NaOH, MeOH, H2O, THF, RT, 5 h, 86%;
d) NH2OTHP, EDCI, HOBt, DMF, RT, 30 h, 99%; e) TsOH, MeOH, RT, 5.5 h, 20%.
The preparation of oxadiazole 10 was achieved via key inter-
mediate 28 (Scheme 3). (Phenylthio)acetonitrile 27 was con-
verted into hydroxyamidine 28 by reaction with hydroxylamine
in the presence of KOH. Compound 28 was allowed to react
with monomethyl isophthalate in the presence of CDI to give
an O-acyl hydroxyamidine intermediate. Ring closure of the in-
termediate to oxadiazole 29 was effected under microwave ir-
radiation at 1408C. Compound 29 was converted into hydroxa-
mate 10 in three steps using the same procedure as
described for compound 8.
Scheme 4. Synthesis of 11. Reagents and conditions: a) 1. NaNO2, H2O, TFA,
08C, 1.5 h; 2. NaN3, H2O, RT, 2.5 h, 94%; b) phenyl propargyl sulfide, CuSO4,
Na ascorbate, MeOH, H2O, RT, 21 h, 67%; c) NaOH, MeOH, H2O, THF, RT, 5 h,
(quant.); d) NH2OTHP, EDCI, HOBt, DMF, RT, 30 h, 58%; e) TsOH, MeOH, RT,
5.5 h, 83%.
Scheme 4 illustrates the synthesis of reversed tria-
zole 11. Treatment of aniline 30 with NaNO2 under
acidic conditions, followed by addition of NaN3, yield-
ed azide 31. The copper-catalyzed coupling of
phenyl propargyl sulfide with azide 31 provided re-
versed triazole 32. Compound 32 was converted into
compound 11 using the procedure described above.
The preparation of thiophene 12 is shown in
Scheme 5. Suzuki coupling of 2-iodo-3-methylthio-
phene 33 with 3-(methoxycarbonyl)phenylboronic
acid 14 gave thiophenylbenzene compound 34. Bro-
Scheme 5. Synthesis of 12. Reagents and conditions: a) Pd(OAc)2, Na2CO3, DMF, H2O,
608C, 1.5 h, 69%; b) AIBN, NBS, CCl4, reflux, 1 h, (quant.); c) PhSH, Et3N, DMF, RT, 19.5 h,
73%; d) NaOH, MeOH, H2O, THF, RT, 5 h, (quant.); e) NH2OTHP, EDCI, HOBt, DMF, RT, 30 h,
mination of the 2-methyl group of 34 with N-bromo-
succinimide in the presence of AIBN afforded bro-
mide 35. Coupling of 35 and thiophenol yielded sul- 79%; f) TsOH, MeOH, RT, 5.5 h, 63%.
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Because it has been reported
that HDAC8 inhibitors including
PCI-34051 (3), NCC149 (7), and
NCC149 derivatives exhibit T-cell
lymphoma cell growth inhibitory
activity without affecting other
Table 1. HDAC inhibitory activities of vorinostat, NCC149 (7), and compounds 8–12.[a]
Compd
IC50 [mm]
Class I
Nuclear
Extract
Class IIa
HDAC4
Class IIb
HDAC6
HDAC1
HDAC2
HDAC3
HDAC8
vorinostat
NCC149 (7)
8
9
10
11
12
0.17
54
0.27
38
0.78
>100
>100
>100
>100
>100
>100
0.68
68
65
1.5
0.070
1.4
0.15
0.12
0.053
0.22
28
44
>100
>100
40
0.21
2.4
31
cancer
cells
and
normal
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
cells,[8,15b] compounds 7, 9, 10,
and 11 were tested in cell
growth inhibition assays using
human T-cell lymphoma cell
lines. Results are shown in
Table 2. All of the tested HDAC8-
selective inhibitors had clear
12
14
>100
>100
84
7.8
2.2
7.2
>100
>100
[a] Values are the mean of at least two experiments; in all cases data varied by 10% or less.
pounds 9–12 potently inhibited HDAC8. These results suggest
that the five-membered ring of compounds 9–12 is important
to fix the orientation of the zinc-binding hydroxamate and the
hydrophobic pocket-binding phenylthiomethyl group appro-
priately, thereby contributing to the potent HDAC8 inhibitory
activity. Among compounds 9–12, reversed triazole analogue
11 showed slightly more potent HDAC8 inhibitory activity than
NCC149 (7) (IC50 of 11 =0.053 mm; IC50 of 7=0.070 mm). More-
over, compounds 9–12 selectively inhibited HDAC8. In particu-
lar, compound 11 displayed greater HDAC8 selectivity than
NCC149 (7) (11: HDAC1 IC50/HDAC8 IC50 >1900; HDAC4 IC50/
HDAC8 IC50 >1900; HDAC6 IC50/HDAC8 IC50 =42. 7: HDAC1
IC50/HDAC8 IC50 =540; HDAC4 IC50/HDAC8 IC50 =630; HDAC6
IC50/HDAC8 IC50 =34). These data suggest that small geometric
differences in five-membered heteroaryl rings have an effect
on not only HDAC8 inhibitory activity but also HDAC8 selectivi-
ty. As a result of these enzyme assays, compound 11 was
found to be a more potent and selective inhibitor of HDAC8
than NCC149 (7).
growth inhibitory effects on T-cell lymphoma cell lines, includ-
ing Jurkat, HH, MT4, and HUT78. Although compound 11
showed the highest HDAC8 inhibitory activity in enzyme
assays (Table 1), it did not show strong T-cell lymphoma cell
growth inhibitory activity as compared with compounds 7, 9,
and 10 (Table 2). The reason for this weak T-cell lymphoma cell
Cell-based assays
To examine HDAC8 selectivity in cells of compounds 7, 9, 10,
and 11, which were potent HDAC8-selective inhibitors in the
enzyme assays (Table 1), we performed a cellular assay using
Western blot analysis. As HDAC8 is a deacetylase of cohesin,[3]
HDAC8 inhibition was initially assessed by evaluating the accu-
mulation of acetylated cohesin in HeLa cells. As shown in
Figure 4, the test compounds induced an increase of acetylat-
ed cohesin in a dose-dependent manner, suggesting strong
HDAC8 inhibition in the cells. Although it has been reported
that trichostatin A, a representative pan-HDAC inhibitor, signifi-
cantly increases acetylated H3K9 in HeLa cells,[18] compounds
7, 9, 10, and 11 did not enhance the acetylation of H3K9,
a major substrate of nuclear HDACs such as HDAC1 and
HDAC2. As for acetylated a-tubulin, a substrate of HDAC6,[19]
NCC149 (7) and compounds 10 and 11 induced acetylation of
a-tubulin at a concentration of >10 mm, whereas compound 9
did not display a major increase in acetylated a-tubulin. These
results indicate that compound 9 selectively inhibits HDAC8
over other HDACs in cells, in contrast to NCC149 (7) and com-
pounds 10 and 11.
Figure 4. Western blot analysis of acetylated structural maintenance of chro-
mosome 3 (SMC3, a subunit of cohesion), H3K9, and a-tubulin levels in HeLa
cells after 4 h treatment with compounds 7, 9, 10, and 11.
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Flash column chromatography was performed using silica gel 60
(particle size: 0.046–0.063 mm) from Merck.
Table 2. Growth inhibition of T-cell lymphoma cells by NCC149 (7) and
compounds 9–11.[a]
3-(3-Hydroxymethylphenyl)benzoic acid methyl ester (15): A
mixture of 3-iodobenzyl alcohol (13) (2.72 g, 11.6 mmol), 3-(me-
thoxycarbonyl)phenylboronic acid (14) (2.00 g, 11.1 mmol), and
Pd(OAc)2 (56.2 mg, 0.250 mmol) in DMF (7 mL) and 1 m aqueous
Na2CO3 (34 mL) was heated at 558C for 1.5 h. The reaction mixture
was diluted with CHCl3 and filtered. The CHCl3 layer was separated,
washed with H2O and brine, and dried over Na2SO4. Filtration, con-
centration in vacuo, and purification by silica gel flash column
chromatography (eluting with a 0–80% EtOAc/n-hexane gradient)
Cell Line
GI50 [mm]
7
9
10
11
Jurkat
HH
MT4
2.8
21
22
32
2.0
7.4
5.8
2.1
12
12
35
24
40
43
50
HUT78
27
[a] Values are the mean of at least two experiments; in all cases data
varied by 30% or less.
1
gave 3.85 g (quant.) of 15 as a light brown oil: H NMR (500 MHz,
CDCl3): d=8.27 (t, J=1.7 Hz, 1H), 8.00 (dt, J=1.5, 7.5 Hz, 1H), 7.78
(dt, J=1.6, 7.8 Hz, 1H), 7.63 (s, 1H), 7.57–7.48 (m, 2H), 7.43 (t, J=
7.7 Hz, 1H), 7.37 (d, J=7.0 Hz, 1H), 4.76 (d, J=6.0 Hz, 2H),
3.94 ppm (s, 3H); EIMS: m/z 242 [M+].
growth inhibitory activity of compound 11 is unclear, but it
can be assumed that compound 11 has problems with plasma
protein binding affinity, cell membrane permeability, metabolic
stability, localization, and/or off-target effects in T-cell lympho-
ma cells. Among compounds 7, 9, 10, and 11, compound 9
showed greater growth inhibitory activity than NCC149 (7)
against T-cell lymphoma cells. The results shown in Table 2
suggest that our HDAC8-selective inhibitors are useful for the
treatment of T-cell lymphoma.
3-(3-Bromomethylphenyl)benzoic acid methyl ester (16): PBr3
(0.6 mL, 6.38 mmol) was added dropwise to a solution of alcohol
15 (3.85 g, 15.9 mmol) in 10 mL of anhydrous dioxane at 08C
under N2 atmosphere. The reaction mixture was stirred for 1.5 h at
08C. The mixture was poured into a mixture of ice and saturated
NaHCO3. The mixture was then extracted with Et2O, and the Et2O
layer was separated, washed with sat. NaHCO3 and brine, and
dried over Na2SO4. Filtration and concentration in vacuo gave
1
4.01 g (83%) of 16 as a yellow oil: H NMR (500 MHz, CDCl3): d=
8.26 (s, 1H), 8.02 (d, J=7.5 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.63 (s,
1H), 7.56–7.47 (m, 2H), 7.44–7.38 (m, 2H), 4.55 (s, 2H), 3.94 ppm (s,
3H); EIMS: m/z 304, 306 [M+].
Conclusions
We have identified novel, potent, HDAC8-selective inhibitors.
Although in general, these inhibitors displayed a relatively
small improvement in in vitro HDAC8 selectivity over HDAC6,
compound 11 showed the most potent HDAC8 inhibitory ac-
tivity. In vitro evaluation showed that, of the test compounds,
only compound 9 increased cohesion (HDAC8 substrate) acety-
lation without also significantly enhancing acetylation of other
HDAC substrates such as H3K9 and a-tubulin in a dose-depen-
dent manner, indicating that this compound was the most
highly HDAC8-selective. Compound 9 also exhibited more
potent T-cell lymphoma cell growth inhibitory activity than
NCC149. These findings should pave the way for the develop-
ment of new anticancer drugs. Detailed studies of these
HDAC8-selective inhibitors and further analogues are under-
way.
3-(3-Phenylthiomethylphenyl)benzoic acid methyl ester (17):
Sodium thiophenol (2.07 g, 15.7 mmol) in H2O (15 mL) and Et3N
(5 mL) was added to a solution of bromide 16 (3.70 g, 12.1 mmol)
in acetone (35 mL). The mixture was stirred for 19.5 h at room tem-
perature. After removal of the solvent, the residue was poured into
H2O and extracted with CHCl3. The organic layer was washed with
H2O and brine and dried over Na2SO4. Filtration, concentration in
vacuo, and purification by silica gel flash column chromatography
(eluting with a 0–30% EtOAc/n-hexane gradient) gave 2.02 g
1
(50%) of 17 as a colorless oil: H NMR (500 MHz, CDCl3): d=8.20 (t,
J=1.7 Hz, 1H), 7.99 (dt, J=1.4, 7.7 Hz, 1H), 7.68 (dt, J=1.2, 7.2 Hz,
1H), 7.47–7.44 (m, 3H), 7.35–7.18 (m, 7H), 4.14 (s, 2H), 3.92 ppm (s,
3H); EIMS: m/z 334 [M+].
3-(3-Phenylthiomethylphenyl)benzoic acid (18): Aqueous NaOH
(2 N, 12 mL, 24.0 mmol) was added to a solution of methyl ester
17 (2.02 g, 6.04 mmol) in MeOH (20 mL), THF (10 mL) and CHCl3
(10 mL). The reaction mixture was stirred for 5 h at room tempera-
ture. After removal of the solvent, the residue was poured into 2 N
aqueous NaOH and extracted with CHCl3. The aqueous layer was
neutralized by 2 N aqueous HCl and extracted with CHCl3. The or-
ganic layer was separated, washed with brine, and dried over
Na2SO4. Filtration, concentration in vacuo, and purification by silica
gel flash column chromatography (eluting with a 10–40% EtOAc/
n-hexane gradient, then a 10–40% MeOH/CHCl3 gradient) gave
Experimental Section
Chemistry
General: Melting points were determined using a Yanagimoto
micro melting point apparatus or a Bꢂchi 545 melting point appa-
ratus. Proton nuclear magnetic resonance spectra (1H NMR) and
carbon nuclear magnetic resonance spectra (13C NMR) were record-
ed using a JEOL JNM-LA500 or a JEOL JNM-A500 spectrometer in
solvent as indicated. Chemical shifts (d) are reported in parts per
million relative to the internal standard tetramethylsilane. Elemen-
tal analysis was performed with a Yanaco CHN CORDER NT-5 ana-
lyzer, and all values were within Æ0.4% of the calculated values,
confirming >95% purity. EIMS analyses were performed on a JEOL
JMS-SX102A mass spectrometer. FTIR spectra were measured on
a Shimadzu FTIR-8400S spectrometer. Reagents and solvents were
purchased from Aldrich, Tokyo Kasei Kogyo, Wako Pure Chemical
Industries, and Kanto Kagaku and were used without purification.
1
957 mg (50%) of 19 as a white solid: H NMR (500 MHz, CDCl3): d=
8.26 (s, 1H), 8.07 (d, J=7.5 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.53–
7.21 (m, 10H), 4.18 ppm (s, 2H); EIMS: m/z 320 [M+].
3-(3-Phenylthiomethylphenyl)-N-(tetrahydropyran-2-yloxy)ben-
zamide (19): NH2OTHP (1.00 g, 8.55 mmol) was added to a solution
of acid 18 (0.957 g, 2.99 mmol), EDCI·HCl (1.70 g, 8.85 mmol), and
HOBt·H2O (1.39 g, 9.08 mmol) in DMF (25 mL), and the mixture was
stirred for 30 h at room temperature. The mixture was poured into
aqueous saturated NaHCO3 and extracted with Et2O. The organic
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layer was washed with aqueous saturated NaHCO3 and brine and
dried over Na2SO4. Filtration, concentration in vacuo, and purifica-
tion by silica gel flash column chromatography (eluting with a 10–
50% EtOAc/n-hexane gradient) gave 1.06 g (84%) of 19 as a light
residue was purified by silica gel flash column chromatography
(eluting with a 15–50% EtOAc/n-hexane gradient) to give 554 mg
(21%) of 25 as a crude white solid: EIMS: m/z 183 [M+].
3-[2-(Phenylthiomethyl)thiazol-4-yl]benzoic acid methyl ester
(26): A solution of thioamide 25 (555 mg, 2.16 mmol) in EtOH
(10 mL) was added to a mixture of bromide 22 (1.52 g, 8.31 mmol)
and activated 3 ꢁ molecular sieves in EtOH (10 mL) and CHCl3
(10 mL) under N2 atmosphere. The mixture was stirred for 3 h at
708C. After filtration, the solvent was removed, and the residue
was poured into aqueous saturated NaHCO3 and extracted with
EtOAc. The organic layer was separated, washed with aqueous sa-
turated NaHCO3 and brine, and dried over Na2SO4. Filtration, con-
centration in vacuo, and purification by silica gel flash column
chromatography (eluting with a 0–30% EtOAc/n-hexane gradient)
gave 636 mg (78%) of 26 as a white solid: 1H NMR (500 MHz,
CDCl3): d=8.45 (s, 2H), 8.11 (d, J=7.5 Hz, 1H), 7.63–7.61 (m, 2H),
7.48 (d, J=7.5 Hz, 2H), 7.34 (t, J=7.0 Hz, 2H), 7.29–7.28 (m, 1H),
6.92 (s, 1H), 4.97 (s, 2H), 3.97 ppm (s, 3H); EIMS: m/z 341 [M+].
1
yellow amorphous solid: H NMR (500 MHz, CDCl3): d=8.90 (s, 1H),
7.88 (s, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.49–
7.45 (m, 3H), 7.37–7.27 (m, 6H), 7.21 (m, 1H), 5.11 (s, 1H), 4.16 (s,
2H), 4.02 (t, J=10.2 Hz, 1H), 3.68–3.66 (m, 1H), 1.91–1.86 (m, 3H)
1.87–1.59 ppm (m, 3H); EIMS: m/z 419 [M+].
3-(3-Phenylthiomethylphenyl)-N-hydroxybenzamide
(8):
TsOH·H2O (12.0 mg, 63 mmol) was added to a solution of com-
pound 19 (264 mg, 0.630 mmol) in MeOH (30 mL), and the mixture
was stirred for 5.5 h at room temperature. After removal of the sol-
vent, the solid was suspended in EtOAc and collected by filtration
to give 85.1 mg (40%) of 8 as a white solid. The solid was recrystal-
lized from THF to give 51 mg of 8 as a colorless crystals: mp: 167–
1688C; 1H NMR (500 MHz, [D6]DMSO): d=11.33 (s, 1H), 9.12 (s,
1H), 7.98 (s, 1H), 7.76–7.73 (m, 2H), 7.69 (s, 1H), 7.59–7.53 (m, 2H),
7.44–7.37 (m, 4H), 7.31 (t, J=7.7 Hz, 2H), 7.19 (t, J=7.2 Hz, 1H),
4.33 ppm (s, 2H); 13C NMR (125 MHz, [D6]DMSO): d=164.1, 140.0,
139.5, 138.4, 136.0, 133.5, 129.3, 129.2, 129.1, 129.0, 128.5, 128.3,
127.4, 126.1, 126.0, 125.6, 125.1, 36.7 ppm; EIMS: m/z 335 [M+];
Anal: calcd for C20H17NO2S·0.5H2O: C 69.74, H 5.27, N 4.07, found: C
69.72, H 5.12, N 4.17.
3-[2-(phenylthiomethyl)thiazol-4-yl]-N-hydroxybenzamide
(9):
Compound 9 (48% yield) was prepared from compound 26 ac-
cording to the procedure for the preparation of compound 8: mp:
1
56–608C; H NMR (500 MHz, CD3OD): d=8.25 (s, 1H), 8.02 (d, J=
8.0 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.50 (t, J=7.7 Hz,
1H), 7.41 (d, J=8.0 Hz, 2H), 7.28 (t, J=7.5 Hz, 2H), 7.21 (t, J=
8.0 Hz, 1H), 4.53 ppm (s, 2H); 13C NMR (125 MHz, CD3OD): d=
171.1, 168.0, 155.2, 136.1, 135.9, 134.2, 131.3, 130.4, 130.2, 130.1,
128.2, 127.6, 126.0, 116.3, 36.5 ppm; EIMS: m/z 343 [M+]; Anal:
calcd for C17H14N2O2S2·H2O: C 56.65, H 4.47, N 7.77, found: C 56.65,
H 4.42, N 7.76.
3-Acetylbenzoic acid methyl ester (21): Concentrated H2SO4
(4 mL) was added to a solution of 3-acetylbenzoic acid (20) (2.02 g,
12.3 mmol) in MeOH (60 mL). The reaction mixture stirred at reflux
for 26.5 h. After removal of the solvent, the residue was poured
into H2O and extracted with EtOAc. The organic layer was washed
with H2O and brine and dried over Na2SO4. Filtration and concen-
2-(Phenylthio)-N-hydroxyethanimidamide (28):
A mixture of
1
tration in vacuo gave 2.12 g (97%) of 20 as a white solid: H NMR
NH2OH·HCl (3.70 g, 53.3 mmol) and KOH (3.00 g, 53.5 mmol) in
MeOH (10 mL) was stirred for 30 min at room temperature. A solu-
tion of (phenylthio)acetonitrile 27 (2.00 g, 13.4 mmol) in MeOH
(14 mL) was added, and the reaction mixture was stirred for an ad-
ditional 20 h at room temperature. The mixture was filtered, and
the filtrate was concentrated in vacuo. The residue was purified by
silica gel flash column chromatography (eluting with a 30–50%
EtOAc/n-hexane gradient) to give 1.04 g (43%) of 28 as a brown
oil: 1H NMR (500 MHz, [D6]DMSO): d=9.18 (s, 1H), 7.39 (d, J=
8.5 Hz, 2H), 7.29 (t, J=7.7 Hz, 2H), 7.17 (t, J=6.7 Hz, 1H), 5.50 (s,
2H), 3.56 ppm (s, 2H); EIMS: m/z 182 [M+].
(500 MHz, CDCl3): d=8.60 (s, 1H), 8.24 (t, J=7.5 Hz, 1H), 8.17 (d,
J=7.5 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 3.96 (s, 3H), 2.66 ppm (s,
3H); EIMS: m/z 178 [M+].
a-Bromo-3-acetylbenzoic acid methyl ester (22): Br2 (0.3 mL,
5.82 mmol) and a catalytic amount of 25%HBr-AcOH were added
to a solution of compound 21 (1.11 g, 6.24 mmol) in CHCl3 (5 mL)
at 08C. The reaction mixture was stirred at room temperature for
2 h. The mixture was poured into aqueous saturated NaHCO3 and
extracted with CHCl3. The organic layer was washed with brine and
dried over Na2SO4. Filtration and concentration in vacuo gave
1.48 g (quant.) of 22 as a crude white solid: EIMS: m/z 256, 258
[M+].
3-[3-(phenylthiomethyl)-1,2,4-oxadiazol-5-yl]benzoic acid methyl
ester (29): A solution of CDI (0.871 g, 5.37 mmol) in DMF (3 mL)
was added to a solution of monomethyl isophthalate (0.937 g,
5.26 mmol) in DMF (4 mL). The mixture was stirred at room tem-
perature for 30 min, and then a solution of 28 (0.979 g, 5.37 mmol)
in DMF (7 mL) was added, and the mixture was stirred at room
temperature overnight. The mixture was then heated in a micro-
wave oven (1408C, 2 min, 450 W). The mixture was poured into
H2O and extracted with Et2O. The organic layer was washed with
H2O and brine and dried over Na2SO4. Filtration, concentration in
vacuo, and purification by silica gel flash column chromatography
(eluting with a 5–50% EtOAc/n-hexane gradient) gave 557 mg
(33%) of 29 as a yellow solid:1H NMR (500 MHz, CDCl3): d=8.79 (s,
1H), 8.30 (d, J=7.5 Hz, 1H), 8.26 (d, J=7.0 Hz, 1H), 7.62 (t, J=
8.0 Hz, 1H), 7.45 (d, J=7.5 Hz, 2H), 7.31 (t, J=7.7 Hz, 2H), 7.26–
7.24 (m, 1H), 4.22 (s, 2H), 3.97 ppm (s, 3H); EIMS: m/z 326 [M+].
2-(Phenylthio)acetamide (24): A catalytic amount of DMF was
added to
a solution of phenylthioacetic acid (23) (3.01 g,
17.9 mmol) and oxalyl chloride (4 mL, 46.6 mmol) in 20 mL of dry
THF at 08C. The mixture was stirred at 08C for 0.5 h, then the sol-
vent was removed in vacuo to give the corresponding acid chlo-
ride as a yellow solid. Aqueous 25% NH3 (20 mL) was added drop-
wise to a solution of the acid chloride in 40 mL of THF at 08C.
After 1.5 h, the reaction mixture was poured into aqueous saturat-
ed NaHCO3 and extracted with EtOAc. The organic layer was sepa-
rated, washed with aqueous saturatedNaHCO3 and brine, and dried
over Na2SO4. Filtration and concentration in vacuo gave 2.46 g
1
(83%) of 24 as a white solid: H NMR (500 MHz, CDCl3): d=7.34–
7.30 (m, 3H), 7.25–7.21 (m, 2H), 6.69 (broad s, 1H), 5.45 (broad s,
1H), 3.63 ppm (s, 2H); EIMS: m/z 167 [M+].
2-(Phenylthio)ethanethioamide (25): Lawesson’s reagent (2.84 g,
3-[3-(Phenylthiomethyl)-1,2,4-oxadiazol-5-yl]-N-hydroxybenza-
mide (10): Compound 10 (17% yield) was prepared from com-
pound 29 according to the procedure for the preparation of com-
pound 8: mp: 157–1588C: 1H NMR (500 MHz, CDCl3): d=8.48 (t,
7.02 mmol) was added to
a solution of amide 24 (2.46 g,
14.7 mmol) in dry toluene (100 mL) under N2 atmosphere. The mix-
ture was stirred for 3.5 h at 808C. After removal of the solvent, the
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J=1.5 Hz, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.01 (dt, J=1.5, 8.0 Hz, 1H),
7.69 (t, J=8.0 Hz, 1H), 7.44 (d, J=7.0 Hz, 2H), 7.30 (t, J=7.5 Hz,
2H), 7.23 (t, J=7.5 Hz, 1H), 4.26 ppm (s, 2H); 13C NMR (125 MHz,
CD3OD): d=176.6, 170.3, 166.6, 135.8, 135.0, 132.5, 131.9, 131.8,
130.9, 130.2, 128.3, 127.7, 125.7, 29.8 ppm; EIMS: m/z 327 [M+];
Anal: calcd for C16H13N3O3S: C 58.70, H 4.00, N 12.84, found: C
58.31, H 4.14, N 12.53.
tration in vacuo gave 811 mg (quant.) of 35 as a brown oil:
1H NMR (500 MHz, CDCl3): d=8.24 (s, 1H), 7.96 (dt, J=1.4, 7.7 Hz,
1H), 7.74 (ddd, J=1.2, 2.0, 6.1 Hz, 1H), 7.21 (d, J=4.0 Hz, 1H), 7.10
(d, J=3.5 Hz, 1H), 4.75 (s, 2H), 3.95 ppm (s, 3H); EIMS: m/z 310,
312 [M+].
3-(5-Phenylthiomethylthiophen-2-yl)-N-hydroxybenzamide (12):
Compound 12 (36% yield) was prepared from compound 35 ac-
cording to the procedure for the preparation of compound 8: mp:
3-Azido benzoic acid ethyl ester (31): An aqueous solution
(30 mL) of NaNO2 (3.69 g, 53.4 mmol) was added to a solution of 3-
amino benzoic acid ethyl ester 30 (2.02 g, 12.2 mmol) in TFA
(17 mL) at 08C. The mixture was stirred at 08C for 1.5 h, then an
aqueous solution (14 mL) of NaN3 (4.05 g, 62.3 mmol) was added.
The solution was stirred at room temperature for 2.5 h. The mix-
ture was poured into 2 N aqueous HCl and extracted with EtOAc.
The organic layer was washed with brine and dried over Na2SO4.
Filtration, concentration in vacuo, and purification by silica gel
flash column chromatography (eluting with a 2–20% EtOAc/n-
1
154–1558C: H NMR (500 MHz, [D6]DMSO): d=11.32 (s, 1H), 7.92 (s,
1H), 7.72 (d, J=7.5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.47 (t, J=
7.5 Hz, 1H), 7.40–7.36 (m, 3H), 7.32 (t, J=7.7 Hz, 2H), 7.21 (t, J=
7.2 Hz, 1H), 7.01 (d, J=3.5 Hz, 1H), 4.51 ppm (s, 2H); 13C NMR
(125 MHz, CDCl3): d=163.6, 141.5, 141.5, 135.2, 133.7, 133.4, 129.2,
128.9, 128.6, 127.9, 127.5, 126.2, 125.8, 123.7, 123.2, 31.6 ppm;
EIMS: m/z 341 [M+]; Anal: calcd for C18H15NO2S2·0.5H2O: C 61.19, H
4.60, N 4.00, found: C 61.77, H 4.76, N 4.10.
1
hexane gradient) gave 2.20 g (94%) of 31 as a yellow oil: H NMR
(500 MHz, CDCl3): d=7.82 (dt, J=1.0, 8.5 Hz, 1H), 7.70 (t, J=1.7 Hz,
1H), 7.68 (d, J=8.0 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.19 (ddd, J=
0.9, 2.4, 6.4 Hz, 1H), 4.39 (q, J=7.3 Hz, 2H), 1.40 ppm (t, J=7.0 Hz,
3H); FTIR (neat): n˜ =2102 cmÀ1
.
Biology
Enzyme assays: HDAC activity assays were performed using an
HDACs/HDAC8 deacetylase fluorimetric assay kit (CY-1150/CY-1158,
Cyclex Company Limited), an HDAC1/HDAC6 fluorescent activity
drug discovery kit (AK-511/AK-516, BIOMOL Research Laboratories),
a Fluorescent SIRT1 Activity Assay/Drug Discovery Kit (AK-555,
3-[4-(Phenylthiomethyl)-1H-1,2,3-triazol-1-yl]benzoic acid ethyl
ester (32): An aqueous solution (10 mL) of CuSO4 (83.7 mg,
523 mmol) and sodium ascorbate (0.585 g, 2.95 mmol) was added
to a solution of phenyl propargyl sulfide (0.775 g, 5.23 mmol) and
azide 31 (0.980 g, 5.12 mmol) in MeOH (10 mL). The reaction mix-
ture was stirred for 21 h at room temperature, then filtered
through Celite. After removal of the solvent, the residue was puri-
fied by silica gel flash column chromatography (eluting with a 5–
40% EtOAc/n-hexane gradient) to give 1.17 g (67%) of 32 as
BIOMOL Research Laboratories) or and
a Fluorogenic HDAC
Class2a Assay Kit (BPS Bioscience Incorporated), with total HDACs
(CY-1150, Cyclex Company Limited), HDAC1 (SE-456, BIOMOL Re-
search Laboratories), HDAC2 (SE-500, BIOMOL Research Laborato-
ries), HDAC3/NCOR1 complex (SE-515, BIOMOL Research Laborato-
ries), HDAC4 (BPS Bioscience Incorporated), HDAC6 (SE-508,
BIOMOL Research Laboratories), and HDAC8 (CY-1158, Cyclex Com-
pany Limited), according to the supplier’s instructions. Fluores-
cence of the wells was measured on a fluorimetric reader with ex-
citation set at 360 nm and emission detection set at 460 nm, and
the percent inhibition was calculated from the fluorescence read-
ings of inhibited wells relative to those of control wells. The con-
centration of a compound that results in 50% inhibition (IC50) was
determined by plotting log[inhibitor] versus the log function of
percent inhibition.
1
a white solid: H NMR (500 MHz, CDCl3): d=8.27 (t, J=1.7 Hz, 1H),
8.10 (dt, J=1.2, 8.0 Hz, 1H), 7.95 (ddd, J=1.0, 2.2, 6.2 Hz, 1H), 7.84
(s, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.38 (d, J=7.5 Hz, 2H),7.30 (t, J=
7.7 Hz, 2H), 7.22 (t, J=7.5 Hz, 1H), 4.43 (q, J=7.3 Hz, 2H), 4.33 (s,
2H), 1.43 ppm (t, J=7.2 Hz, 3H); EIMS: m/z 339 [M+].
3-[4-(Phenylthiomethyl)-1H-1,2,3-triazol-1-yl]-N-hydroxybenza-
mide (11): Compound 11 (48% yield) was prepared from com-
pound 32 according to the procedure for the preparation of com-
1
pound 8: mp: 179–1808C: H NMR (500 MHz, [D6]DMSO): d=11.40
(s, 1H), 9.22 (s, 1H), 8.74 (s, 1H), 8.22 (s, 1H), 8.01 (d, J=8.0 Hz,
1H), 7.84 (d, J=7.5 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.41 (d, J=
8.0 Hz, 2H), 7.33 (t, J=7.7 Hz, 2H), 7.20 (t, J=7.2 Hz, 1H), 4.39 ppm
(s, 2H); 13C NMR (125 MHz, [D6]DMSO): d=162.8, 144.9, 136.4,
135.5, 134.3, 130.1, 129.0, 128.2, 126.8, 126.0, 122.4, 121.5, 118.3,
27.1 ppm; EIMS: m/z 326 [M+]; Anal: calcd for C16H14N4O2S: C
58.88, H 4.32, N 17.17, found: C 58.69, H 4.54, N 17.00.
Western blot analysis: The cohesin, a-tubulin, or H3K9 acetylating
activities of the test compounds were assayed according to pub-
lished methods.[3,19]
.
Cell growth inhibition assay: Cells were plated at an initial density
of 2ꢃ105 cells per well (50 mL per well) in 96-well plates in RPMI
1640 medium with 10% fetal bovine serum, and were exposed to
inhibitors for 72 h at 378C in a 5% CO2 incubator. A solution of 3-
(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfo-
phenyl)-2H-tetrazolium inner salt (MTS) was then added (20 mL per
well), and incubation was continued for 2 h. The solubilized dye
was quantified by colorimetric reading at 490 nm using a reference
wavelength of 650 nm. The absorbance values of control wells (C)
and test wells (T) were measured. The absorbance of the test wells
was also measured at time 0 (T0, addition of compounds). Using
these measurements, cell growth inhibition (percentage of growth)
by a test inhibitor at each concentration used was calculated as:
%growth=100ꢃ[(TÀT0)/(CÀT0)], when T>T0 and %growth=100ꢃ
[(TÀT0)/T], when T<T0. Computer analysis of the percent growth
values afforded a 50% growth inhibition parameter (GI50). The GI50
was calculated as 100ꢃ[(TÀT0)/(CÀT0)]=50.
3-(5-Methylthiophen-2-yl)benzoic acid methyl ester (34): Com-
pound 34 (69% yield) was prepared from 3-(methoxycarbonyl)phe-
nylboronic acid (14) and 2-iodo-3-methylthiophene (33) according
to the procedure for the preparation of compound 15: 1H NMR
(500 MHz, CDCl3): d=8.22 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.72 (d,
J=7.5 Hz, 1H), 7.42 (t, J=7.7 Hz, 1H), 7.18 (d, J=3.5 Hz, 1H), 6.75–
6.74 (m, 1H), 3.94 (s, 3H), 2.52 ppm (s, 3H); EIMS: m/z 232 [M+].
3-(5-Bromomethylthiophen-2-yl)benzoic acid methyl ester (35):
NBS (0.554 g, 3.11 mmol) and AIBN (19.2 mg, 0.116 mmol) were
added to a solution of compound 34 (0.601 g, 2.61 mmol) in CCl4
(20 mL). The mixture was stirred at reflux for 1 h, then diluted with
CCl4 and filtered. The filtrate was evaporated, poured into H2O, and
extracted with EtOAc. The organic layer was separated, washed
with H2O and brine, and dried over Na2SO4. Filtration and concen-
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ChemMedChem 2014, 9, 657 – 664 663

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This work was supported in part by the Japan Science and Tech-
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Published online on January 8, 2014
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