Design, synthesis and evaluation of novel HDAC inhibitors as potential antitumor agents

Article abstract of DOI:10.1016/j.bmcl.2014.06.080

Phenyl imidazolidin-2-one was introduced as the linker for novel HDAC inhibitors. A focused library of 20 compounds was designed and synthesized, among which eight compounds showed equivalent or higher potencies against HDAC1 as compared to vorinostat. In vitro antitumor activity assays in HCT-116, PC-3 and HL-60 cancer cells revealed six compounds with potent antitumor activities, and compound 1o showed 6- to 9-fold higher potencies compared to vorinostat. In an HCT-116 nude mice xenograft model, compound 1o displayed significant antitumor activity in both continuous and intermittent dosing schedules.

Full text of DOI:10.1016/j.bmcl.2014.06.080

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and evaluation of novel HDAC inhibitors
as potential antitumor agents
⇑
Jianjun Cheng , Jihong Qin, Sihua Guo, Hangdeng Qiu, Yun Zhong
Shanghai Huilun Life Sciences & Technology Co. Ltd, Shanghai 201108, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Phenyl imidazolidin-2-one was introduced as the linker for novel HDAC inhibitors. A focused library of 20
compounds was designed and synthesized, among which eight compounds showed equivalent or higher
potencies against HDAC1 as compared to vorinostat. In vitro antitumor activity assays in HCT-116, PC-3
and HL-60 cancer cells revealed six compounds with potent antitumor activities, and compound 1o
showed 6- to 9-fold higher potencies compared to vorinostat. In an HCT-116 nude mice xenograft model,
compound 1o displayed significant antitumor activity in both continuous and intermittent dosing
schedules.
Received 9 February 2014
Revised 21 June 2014
Accepted 27 June 2014
Available online xxxx
Keywords:
Histone deacetylases
Hydroxamate
Antitumor
Ó 2014 Elsevier Ltd. All rights reserved.
Vorinostat
Histone acetylation and deacetylation plays an important role
in the regulation of gene expression, influencing the transcription
of many genes, including tumor suppressor genes.1 This reversible
process is catalyzed by histone acetyl tranferases (HATs) and his-
tone deacetylases (HDACs).2,3 To date, 18 human HDACs have been
identified and grouped into four classes: class I (HDAC1, 2, 3 and 8),
class II (HDAC4, 5, 6, 7, 9 and 10), class III enzymes (also known as
sirtuins, SIRT 1–7) and class IV (HDAC11).4,5 Class I, II and IV HDACs
are also referred to as ‘classical’ HDACs and are Zn2+-dependent
enzymes whereas sirtuins require NAD+ as a cofactor. Altered
HDAC activity has been identified in various types of cancer,6 and
developing HDAC inhibitors as novel therapeutics has been vali-
dated in both preclinical and clinical studies, in both solid and hae-
matological cancers.7,8 Efforts from the scientific community have
led to the discovery of a number of isoform selective HDAC inhib-
itors,9 which would be very good pharmacological tools to study
the different roles each of these HDAC isoforms plays. But there
is still a large medical need for pan inhibitors as candidates for
cancer therapy, since it has been demonstrated that the various
cancer types do not involve the same HDAC isoforms.
the therapy of cutaneous T-cell lymphoma.11 The structure of vori-
nostat represents the common structure of HDAC inhibitors, which
constitutes a ‘CAP’ moiety, a linker and the zinc-binding group
(ZBG) (Fig. 1). The binding mode of hydroxamates to HDACs was
confirmed with the structure of a histone deacetylase homologue
bound to vorinostat.12 Several other clinical HDAC inhibitors, such
as panobinostat (LBH-589),13 belinostat (PXD-101),14 resminostat
(4SC-201), pracinostat (SB-939),15 givinostat (ITF-2357) and qui-
sinostat (JNJ-26481585)16 all contain hydroxamates as their ZBGs
and share the same canonical scaffold with vorinostat. In this
Letter, we report novel HDAC inhibitors characterized by phenyl
imidazolidin-2-one moiety as a new linker and their use as
potential antitumor agents (Fig. 1).
A focused library was designed based on general structure 1,
and a simple and convenient route was applied for the synthesis
of compounds 1a–1t (Scheme 1). Commercially available ethyl
4-aminobenzoate was treated with 1-chloro-2-isocyanatoethane
to afford the urea intermediate 3, which underwent an intra-
molecular cyclization to give the phenyl imidazolidin-2-one 4 in
good yield.17 Introduction of the R substitution was accomplished
via Buchwald coupling of 4 with aryl bromides or alkylation reac-
tions with alkylating agents listed in Scheme 1 (for detailed infor-
mation on the preparation of intermediates 6a–6t, see Supporting
information, Table S1). Most of the intermediates 5a–5t were com-
mercially available or could be prepared according to reported
methods,18 and preparations of some of them were depicted in
Schemes 2–6. When hydrochloride salts of the reagents were used,
the equivalence of base was increased in the alkylating reaction.
Most HDAC inhibitors reported so far can be grouped into four
chemical families (hydroxamates, benzamides, short-chain fatty
acids and macrocyclic peptides),10 and hydroxamates have been
proven to be most potent and the major class in clinical trials.
Among them, vorinostat was approved by the FDA in 2006 for
⇑
Corresponding author. Tel./fax: +86 21 34304236.
E-mail address: chengjianjun83@163.com (J. Cheng).
http://dx.doi.org/10.1016/j.bmcl.2014.06.080
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Cheng, J.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.06.080

2
J. Cheng et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Figure 1. Representative HDAC inhibitors in clinical trials and novel scaffold design.
Scheme 1. Reagents and conditions: (a) 2-chloroethyl isocyanate, toluene, 0–40 °C, 62%; (b) K2CO3, DMF, rt, overnight, 78%; (c) Buchwald coupling with 5a or 5b, or alkylating
with 5c–5t; (d) NH2OH, MeOH, 0 °C–rt.
with poor prognosis.19–21 We screened compounds 1a–1t for their
IC50s on HDAC1 and the result was listed in Table 1.22 A direct sub-
stitution of the imidazolidin-2-one with pyridine (compound 1a)
or quinoline (compound 1b) showed poor HDAC1 inhibitory activ-
ities, as compared to vorinostat. However, aryl substitution with a
methylene spacer displayed much better potencies, as shown by a
benzyl substitution in compound 1c, which showed equivalent
potency with vorinostat (IC50 = 17 nM for 1c vs 13 nM for vorino-
stat). Substitution with a fluorine atom (compound 1d) or methoxy
group (compound 1e) on the benzene ring slightly altered the
activities, but an electron-withdrawing trifluoromethyl group
(compound 1f) reduced the potency significantly. In order to
explore heteroaryl substitutions at this position, pyridine was
introduced to replace the benzene ring, however both 4-pyridine
Scheme 2. Reagents and conditions: (a) LiAlH4, THF, 0 °C–rt, 1 h, 78%; (b) SOCl2,
toluene, rt, 1 h, 98%.
The esters 6a–6t were converted to the corresponding hydroxamic
acids by treating with methanol solution of hydroxylamine.
Among the various isoforms, overexpression of HDAC1 has been
found in gastric, breast, pancreatic, hepatocellular, lung and pros-
tate carcinomas and in most cases HDAC1 up-regulation associates
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J. Cheng et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
Scheme 3. Reagents and conditions: (a) Me2NH in water (33%, w/w), THF, rt, overnight, quantitative; (b) MeOH, SOCl2, 70 °C, overnight, 94–97%; (c) LiAlH4, THF, 0 °C–rt, 1 h,
64–93%; (d) SOCl2, toluene, rt, 1 h, 75–99%.
substitutions without an aromatic ring showed much less activity,
and compounds 1r, 1s and 1t displayed poor HDAC1 inhibition.
The eight compounds with equivalent or higher potencies com-
pared to vorinostat in Table 1 were elevated for in vitro antitumor
activity.23 Growth inhibition assays in HCT-116 cells were run
firstly, and most of the compounds showed potent inhibition of cell
proliferation, with GI50 values below 1 lM (Table 2). Five most
Scheme 4. Reagents and conditions: (a) LiAlH4, THF, 0 °C–rt, 1 h, 51%; (b) SOCl2,
toluene, rt, 1 h, 98%.
potent compounds 1i, 1m, 1n, 1o and 1q were further evaluated
for their inhibition of PC-3 and HL-60 cell proliferation. All these
five compounds showed at least 2-fold higher inhibitory potencies
on all the 3 cell lines and compound 1o showed 6 to 9-fold poten-
and 3-pyridine substitutions (compounds 1g and 1h) reduced
enzyme inhibition slightly.
We predicted that an electron-donating substitution might be
favored for the benzyl group, and substitutions with amino groups
were introduced. Compound 1i with a dimethylamino substitution
showed an enhanced activity (IC50 = 9.5 nM), but an introduction
of methylene link between dimethylamino group and the benzene
reduced the inhibitory activity more than 2-fold (compounds 1j
and 1k). Bicyclic substitutions were also introduced to explore
the SAR of the CAP group. To our delight, single digit nanomolar
potencies were observed for both naphthyl (compounds 1l and
1m) and quinolone (compound 1n) groups. And compound 1o,
with a further introduction of diethylamino methylene group to
the naphthyl ring (the same CAP group as givinostat), displayed
the most potent HDAC1 inhibition in this series, with a 5-fold more
potency compared to vorinostat (IC50 = 2.7 nM for 1o vs 13 nM for
vorinostat). Elongation of the linker between the aromatic ring and
imidazolidin-2-one, from one carbon to two carbons, also dis-
played potent activities, as represented by compound 1p and 1q,
which showed 13 nM and 4.0 nM IC50 values respectively. Alkyl
cies compared to vorinostat, with GI50 values around 0.1
against all 3 cell lines.
lM
As many HDAC inhibitors from diverse structural classes have
been reported to be associated with QT prolongation in
humans,24,25 we tested compound 1o for hERG inhibition, which
would indicate potential influence on K+ ion channel.26 Compound
1o displayed hERG inhibition of 27% at a concentration of 10 lM
(n = 3), which predicted a very low risk of inducing QT prolonga-
tion. Furthermore, compound 1o showed excellent physiochemical
properties, with a molecular weight of 446.5, ClogP value of 3.3
(calculated with Chemdraw) and high water solubility (data not
shown). Based on its potent in vitro activity and favorable drug-
like profile, compound 1o was then chosen for further in vivo
evaluation.27
The HCT-116 xenograft model in nude mice was selected for
preliminary in vivo anticancer activity test of 1o.28 Because most
HDAC inhibitors that are currently in the clinical trial can only be
given intermittently due to the side effect of fatigue, which is
Scheme 5. Reagents and conditions: (a) DMF, Et2NH, HATU, DIPEA, rt, overnight, 73%; (b) MeOH, SOCl2, 70 °C, overnight, 83%; (c) BH3–SMe2 (2 M in THF), THF, 50 °C,
overnight; then 2 M HCl, 70 °C, 1 h, 90%; (d) SOCl2, toluene, rt, 1 h, 87%.
Scheme 6. Reagents and conditions: (a) LiAlH4, THF, rt, overnight, 85%; (b) TBSCl, CH2Cl2, imidazole, Et3N, overnight, 78%; (c) DMF, NaH, MeI, rt, 2 h, 83%; (d) THF, TBAF, rt,
overnight, 78%; (e) MeCN/Et2O, imidazole, Ph3P, I2, rt, 0.5 h, 87%.
Please cite this article in press as: Cheng, J.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.06.080

4
J. Cheng et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Table 1
Table 2
HDAC1 inhibitory activities of compounds 1a–1t
GI50s of selected compounds (‘—’, not tested).
Compound
R
IC50 (nM)
182
Compound
GI50 (lM)
HCT-116
PC-3
HL-60
1a
1c
1e
1i
1m
1n
1o
1p
1q
0.85
0.47
0.33
0.21
0.27
0.11
0.65
0.24
0.65
—
—
—
—
N
0.43
0.38
0.34
0.10
—
0.44
0.36
0.25
0.086
—
1b
152
N
1c
1d
1e
1f
17
21
12
80
41
0.21
0.96
0.48
0.75
Voninostat
F
O
F3C
N
1g
1h
1i
42
N
N
9.5
N
1j
23
25
N
1k
Figure 2. Antitumor activity of compound 1o in HCT-116 xenograft model.
1l
9.5
5.4
for 3 weeks resulted in 54% TGI (Fig. 2).29 Doses in both groups
were well tolerated and body weight losses of animals were within
15% (data not shown). The intermittent dosing schedule showed a
similar antitumor effect with a total drug dosing amount less than
the continuous dosing schedule.
In summary, a focused library of HDAC inhibitors with phenyl
imidazolidin-2-one as the new linker was designed and synthe-
sized. Several compounds displayed potent HDAC1 inhibition and
tumor cell growth inhibition in vitro. Compound 1o was evaluated
in an HCT-116 xenograft model in vivo and showed significant
tumor growth inhibition in both continuous and intermittent dos-
ing schedules. Further evaluation of compound 1o is ongoing and
will be reported in due time.
1m
1n
5.4
N
N
1o
1p
2.7
13
1q
4.0
Acknowledgment
N
We are grateful to Dr. Joel A. Bergman for helpful discussions
and valuable suggestions.
1r
1s
250
125
O
Supplementary data
N
1t
114
13
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.
06.080. These data include MOL files and InChiKeys of the most
important compounds described in this article.
N
Voninostat
—
considered to be a class effect, we tested the efficacy of 1o using
both continuous and intermittent dosing schedules. Daily oral
administration of 1o at 50 mg/kg for 3 weeks resulted in 45%
tumor growth inhibition (TGI) when compared to the vehicle con-
trol; intermittent dosing schedule with 3 days on plus 3 days off
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52.Vorinostat at
water (V/V)) was used as the positive control group for the in vivo test of
compound 1o, but it displayed significant toxicity and this group was
a dose of 200 mg/kg, qd (formulated in 50% PEG400 in
17. Saha, A.; Yu, X. Y.; Lobera, M.; Lin, J.; Cheruku, S. R.; Becker, O.M.; Marantz, Y.;
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a
terminated after 10 days dosing, with about 50% TGI at that time point.
29. Compound 1o was formulated in 50% PEG400 in water (V/V), vehicle control
group was dosed with 50% PEG400 in water, and dosing volume was 10 mL/kg;
Tumor volume (mm3) = (w2 Â l)/2, in which w is the width and l is the length
of the tumor in mm; TGI was calculated using the following formula:
18. 5a–5f, 5l, 5m, 5p, 5r, 5s, 5t are commercially available; preparation of some of
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(Barlin, G. B.; Davies, L. P.; Ireland, S. J.; Ngu, M. M. L. Aust. J. Chem. 1989, 42,
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7177.).
%TGI = (Tday 21 À Tday 0)/(Cday 21 À Cday 0) Â 100 [in which Tday
is the median
21
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tumor volume for treatment group on day 21; Tday is the median tumor
0
volume for treatment group on day 0; Cday is the median tumor volume for
21
20. Minamiya, Y.; Ono, T.; Saito, H.; Takahashi, N.; Ito, M.; Mitsui, M.; Motoyama,
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control group (vehicle) on day 21; Cday is the median tumor volume for
control group (vehicle) on day 0].
0
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