PXD101 analogs with L-phenylglycine-containing branched cap as histone deacetylase inhibitors

Article abstract of DOI:10.1111/cbdd.12787

Histone deacetylases (HDACs) allow histones to wrap DNA more tightly and finally lead to the repression of some tumor suppressor genes. Histone deacetylase inhibitors (HDACIs) have been proved to have effects on tumorigenesis and tumor progression. In this study, we reported the design, synthesis, and in vitro activity evaluation of novel PXD101 analogs with L-phenylglycine-containing cap as HDACIs. Our results showed that HDACs inhibitory activities of compounds 10k, 10r, and 10s were not only superior to the first approved HDACI SAHA, but also comparable to their parent compound PXD101, a recently approved HDACI in 2014. However, all 6 selected PXD101 analogs exhibited moderate in vitro antiproliferative activities, less potent than PXD101 and SAHA. Representative compound 10s showed similar HDACs isoform selective profile to PXD101, which demonstrated that introduction of L-phenylglycine-containing branched cap group could not change the isoform selectivity of PXD101 dramatically.

Full text of DOI:10.1111/cbdd.12787

Received: 17 January 2016
DOI: 10.1111/cbdd.12787
Revised: 18 April 2016
Accepted: 25 April 2016
R E S E A R C H A R T I C L E
PXD101 analogs with L-phenylglycine-containing branched cap
as histone deacetylase inhibitors
Jingyao Li | Xiaoyang Li | Xue Wang | Jinning Hou | Jie Zang | Shuai Gao |
Wenfang Xu | Yingjie Zhang
Department of Medicinal Chemistry, School of
Histone deacetylases (HDACs) allow histones to wrap DNA more tightly and
finally lead to the repression of some tumor suppressor genes. Histone deacetylase
Pharmaceutical Sciences, Shandong University,
Ji’nan, Shandong, China
inhibitors (HDACIs) have been proved to have effects on tumorigenesis and
Correspondence
Yingjie Zhang
Email: zhangyingjie@sdu.edu.cn
tumor progression. In this study, we reported the design, synthesis, and in vitro
activity evaluation of novel PXD101 analogs with L-phenylglycine-containing cap
as HDACIs. Our results showed that HDACs inhibitory activities of compounds
10k, 10r, and 10s were not only superior to the first approved HDACI SAHA,
but also comparable to their parent compound PXD101, a recently approved
HDACI in 2014. However, all 6 selected PXD101 analogs exhibited moderate
in vitro antiproliferative activities, less potent than PXD101 and SAHA. Repre-
sentative compound 10s showed similar HDACs isoform selective profile to
PXD101, which demonstrated that introduction of L-phenylglycine-containing
branched cap group could not change the isoform selectivity of PXD101
dramatically.
K E Y W O R D S
antiproliferative activity, HDAC inhibitory activity, HDAC isoform selectivity,
HDACs, inhibitor
Epigenetic abnormality, caused by different modifications of
DNA and histones instead of changes of nucleotide sequence,
has been recognized to be widely implicated in tumor ini-
tiation and progression, and their manipulation holds great
promise for cancer prevention, detection, and therapy.[1] His-
tone deacetylases (HDACs), a histone modifier catalyzing
the removal of acetyl groups from N-acetyl lysine residues of
chromatin histones, allow histones to wrap DNA more tightly
and finally lead to the repression of some tumor suppressor
genes.[2,3]
So far, eighteen HDACs have been identified in humans,
which have been classified in four classes depending on
their sequence homology to the yeast original enzymes
and domain organization.[4] The class I HDACs (HDAC1,
2, 3, and 8) are generally nuclear, while class II HDACs
(IIa: HDAC4, 5, 7, and 9; IIb: HDAC6 and 10) can shuttle
between the nucleus and the cytoplasm.[5,6] HDAC 11, the
sole member of the class IV HDACs, is localized in both
nucleus and cytoplasm.[7] The class III HDACs (SIRT1-7)
are a set of NAD+-dependent enzymes, while the other
classes of HDACs are all Zn2+-dependent enzymes which
have been revealed to play a significant role in the process of
tumorigenesis and development.[3] HDAC inhibitors (HDA-
CIs) have been testified to cause tumor cell cycle arrest,
apoptosis, cell differentiation, and migration suppression by
blocking the act of HDACs.[8]
Up to now, dozens of structurally diverse HDACIs
have entered various stages of clinical trials. Among them,
4 HDACIs have been approved by the US Food and Drug
Administration (FDA) (Figure 1). Vorinostat (SAHA)[9] and
Chem Biol Drug Des 2016; 1–12
wileyonlinelibrary.com/cbdd
© 2016 John Wiley & Sons A/S.
1

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FIGURE 1 Pharmacophore model and structures
of representative HDACIs
romidepsin (FK228)[10] were approved for the treatment of
cutaneous T-cell lymphoma (CTCL), belinostat (PXD101)[11]
was for the treatment of peripheral T-cell lymphoma (PTCL),
and panobinostat (LBH589)[12] was for combination therapy
of recurrent multiple myeloma with bortezomib and dexa-
methasone. In addition, the class I selective HDACI chi-
damide (CS005)[13] was approved by the China Food and
Drug Administration (CFDA) for the treatment of relapsed
or refractory PTCL.
PXD101 is a broad-acting HDACI which shows stability
in diversified tumor types with low rates of adverse events,
especially for the treatment of hematological malignancies
indicated by a wide variety of clinical trials across a broad
range of tumors.[11] Clinical researches of PXD101 for the
treatment of ovary cancer, multiple myeloma, acute myeloid
leukemia, and myelodysplastic syndrome as a single drug or
combination drug therapy are still in progress. As most of
the HDACIs, PXD101 has three pharmacophore domains, a
Zn2+ binding group (ZBG), a hydrophobic cap group (Cap)
and a linker which concatenate the ZBG and the cap group[14]
(Figure 1).
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METHODS AND MATERIALS
1.1 | Chemistry
All commercially available starting materials, reagents,
and solvents were used without further purification unless
otherwise stated. All reactions were monitored by TLC
with 0.25 mm silica gel plates (60GF-254). UV light,
iodine stain, and ferric chloride were used to visualize
the spots. Silica gel was used for column chromatog-
raphy purification. H NMR and 13C NMR spectra were
1
recorded on a Bruker DRX spectrometer at 300, 400,
or 600 MHz, d in parts per million and J in hertz,
using TMS as an internal standard. High-resolution mass
spectra were conducted by Shandong Analysis and Test
Center in Ji’nan, China. ESI-MS spectra were recorded
on an API 4000 spectrometer. Melting points were
determined uncorrected on an electrothermal melting
point apparatus.
The compound sodium 3-formylbenzenesulfonate (2) was
synthesized following reported procedures.[23]
Many researches indicated that HDACIs with branched
cap seemed to be more potent and isoform selective due
to the additional hydrophobic interactions between the
branched cap group and the amino acid residues around
the entrance of the HDAC active site.[15–20] In our previous
study, two series of L-phenylglycine-containing cap HDAC
inhibitors were discovered to have good performance in
HDAC inhibition and antitumor evaluation.[21,22] Therefore,
to find HDACI with improved potency and isoform selec-
tivity, a novel series of PXD101 analogs were designed and
synthesized by replacing the simple aniline-based cap group
of PXD101 with L-phenylglycine-containing branched cap
(Figure 2).
1.2 | General procedure for the preparation
of 3
1.2.1 | Sodium (E)-3-(3-ethoxy-3-oxoprop-1-en-1-yl)
benzenesulfonate (3)
A mixture of 2 (0.50 g, 2.40 mmol), K2CO3 (0.66 g,
4.80 mmol), triethyl phosphonoacetate (0.65 g,
2.88 mmol), and H2O (5 mL) was stirred at room tem-
perature for 30 min. Precipitated solid was filtered off
and washed with MeOH. The filtrate was evaporated
and dried to obtained product compound 3, a pale

Li et aL.
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FIGURE 2 Design strategy of novel series of
HDACIs
yellow oil (0.32 g, 48%), which was directly used for
following reactions.
(3 × 50 mL), NaHCO3 (3 × 50 mL), and brine
(3 × 50 mL); dried over MgSO4 overnight; and evapo-
rated under vacuum. The desired compound 7a (1.44 g,
88% yield) was derived by crystallization in EtOAc as
white powder. Mp: 116–118 °C1H NMR (300 MHz,
DMSO-d6) δ 10.25 (s, 1H), 7.61–7.44 (m, 5H), 7.33
(ddd, J = 19.3, 11.4, 4.7 Hz, 5H), 7.04 (t, J = 7.4 Hz,
1H), 5.36 (d, J = 8.3 Hz, 1H), 1.39 (s, 8H), 1.31 (s,
1H). ESI-MS: m/z: 327.2 [M + H]+.
1.3 | General procedure for the preparation
of 4
1.3.1 | (E)-ethyl 3-(3-(chlorosulfonyl) phenyl)
acrylate (4)
A mixture of 3 (0.53 g, 2 mmol), SOCl2 (1.70 mL,
13.8 mmol), and DMF (2 drops) was stirred under reflux
for 5 h until the entire solid dissolved. The mixture was
evaporated, and the yellow residue was directly used for
following reactions.
The compound (S)-2-((tert-butoxycarbonyl) amino)-2-
phenylacetic acid (6) was synthesized according to the meth-
ods described in our previous study.[21]
The other compounds (7b–7t) were prepared using the
same procedure as described above.
1.5 | General procedure for the preparation
of 8a–8t
1.5.1 | (S)-2-amino-N,2-diphenylacetamide
hydrochloride (8a)
To a solution of compound 7a (3.3 g, 10 mmol) in EtOAc
(20 mL), a solution of EtOAc (40 mL) saturated by dry
HCl gas was added. The reaction solution was stirred at
room temperature for 5 h. Precipitates appeared and were
filtered, with the filter being washed with ether, to give
desired compound 8a (1.94 g, 74% yield). Title compound
was obtained as an amorphous white solid. Mp: 228–230 °C.
1H NMR (400 MHz, DMSO-d ) δ 11.25 (s, 1H), 8.94
(s, 3H), 7.71 (d, J = 6.9 Hz, 26H), 7.65 (d, J = 7.8 Hz,
2H), 7.49–7.39 (m, 3H), 7.32 (t, J = 7.9 Hz, 2H), 7.09
(t, J = 7.4 Hz, 1H), 5.33 (s, 1H). HRMS (AP-ESI) m/z
calcd [M + H]+ 227.1179.
1.4 | General procedure for the preparation
of 7a–7t
1.4.1 | (S)-tert-butyl (2-oxo-1-phenyl-2-
(phenylamino) ethyl) carbamate (7a)
To a solution of compound 6 (1.26 g, 5 mmol) in
DCM (50 mL), Et3N (0.61 g, 6 mmol) and TBTU
(1.93 g, 6 mmol) were added at 0 °C in turn. After
20 min, phenylamine (0.56 g, 6 mmol) was added in
the mixture. The reaction was stirred at room tempera-
ture for 8 h. Then, the solvent was evaporated with
the residue being taken up in EtOAc (100 mL). The
EtOAc solution was washed with saturated citric acid
The other compounds (8b–8t) were prepared using the
same procedure as described above.

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1.6 | General procedure for the preparation
1.7.2 | (S,E)-3-(3-(N-(2-(cyclohexylamino)-2-oxo-
of 9a–9t
1-phenylethyl)sulfamoyl)phenyl)-N-hydroxyacrylamide
(10b)
1.6.1 | (S,E)-ethyl3-(3-(N-(2-oxo-1-phenyl-
1
Pale yellow solid, 32% yield. Mp: 177–178 °C. H NMR
2(phenylamino)ethyl)sulfamoyl)phenyl)acrylate (9a)
(300 MHz, DMSO-d ) δ 10.85 (s, 1H), 9.10 (s, 1H), 8.59
(d, J = 8.6 Hz, 1H), 68.02 (d, J = 7.7 Hz, 1H), 7.86 (s, 1H),
7.76–7.64 (m, 2H), 7.47 (dd, J = 17.9, 11.7 Hz, 2H),
7.35–7.27 (m, 2H), 7.26–7.13 (m, 3H), 6.51 (d, J = 15.8 Hz,
1H), 5.01 (d, J = 8.4 Hz, 1H), 3.27–3.15 (m, 1H), 1.59–1.40
(m, 5H), 1.09–0.91 (m, 5H). HRMS (AP-ESI) m/z calcd for
C23H27N3O5S [M − H]− 456.1602, found 456.1599.
To a solution of compound 8a (0.58 g, 2.2 mmol) in
DCM (10 mL), Et3N (0.24 g, 2.4 mmol), a solution
of 4 (0.60 g, 2.2 mmol) in toluene (10 mL) was added
in turn. The reaction solution was stirred at room tem-
perature overnight. Then, the solvent was evaporated
with the residue being taken up in EtOAc (60 mL).
The EtOAc solution was washed with saturated citric
acid (3 × 20 mL), NaHCO3 (3 × 20 mL), and brine
(3 × 20 mL); dried over MgSO4; and evaporated under
vacuum. The desired compound 9a (0.82 g, 80% yield)
was derived by crystallization in EtOAc as white pow-
der. 1H NMR (300 MHz, DMSO-d ) δ 10.28 (s, 1H),
8.84 (d, J = 9.8 Hz, 1H), 8.006 (s, 1H), 7.76 (t,
J = 8.0 Hz, 2H), 7.56–7.42 (m, 2H), 7.41 (d, J = 1.7 Hz,
1H), 7.38 (d, J = 1.3 Hz, 1H), 7.36 (d, J = 1.1 Hz, 1H),
7.33 (s, 1H), 7.30–7.15 (m, 5H), 7.00 (t, J = 7.3 Hz,
1H), 6.55 (d, J = 16.1 Hz, 1H), 5.25 (d, J = 9.8 Hz, 1H),
4.21 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H).
ESI-MS: m/z: 465.3 [M + H]+.
1.7.3 | (S,E)-N-hydroxy-3-(3-(N-(2-oxo-1-phenyl-2-
(propylamino)ethyl)sulfamoyl)phenyl) acrylamide (10c)
1
Pale yellow solid, 32% yield. Mp: 172–174 °C. H NMR
(400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.13 (s, 1H), 8.60
(s, 1H), 8.15 (t, J = 5.3 Hz, 1H), 7.85 (s, 1H), 7.69 (t,
J = 7.6 Hz, 2H), 7.46 (dd, J = 20.3, 12.2 Hz, 2H), 7.30
(d, J = 6.9 Hz, 2H), 7.20 (dd, J = 15.6, 8.0 Hz, 3H),
6.50 (d, J = 15.8 Hz, 1H), 4.98 (d, J = 9.6 Hz, 1H),
2.85–2.68 (m, 2H), 1.28–1.12 (m, 3H), 0.66 (t, J = 7.4 Hz,
3H). HRMS (AP-ESI) m/z calcd for C20H23N3O5S
[M − H]− 416.1284, found 416.1286.
The other compounds (9b–9t) were prepared using the
same procedure as described above.
1.7.4 | (S,E)-N-hydroxy-3-(3-(N-(2-(isopropylamino)-
2-oxo-1-phenylethyl)sulfamoyl) phenyl)acrylamide (10d)
1.7 | General procedure for the preparation
Pale yellow solid, 27% yield. Mp: 174–175 °C. 1H
NMR (300 MHz, DMSO-d ) δ 10.84 (s, 1H), 9.10 (s,
1H), 8.58 (d, J = 9.7 Hz,61H), 8.02 (d, J = 7.4 Hz,
1H), 7.87 (s, 1H), 7.70 (dd, J = 8.1, 1.4 Hz, 2H),
7.53–7.40 (m, 2H), 7.30 (dd, J = 7.9, 1.5 Hz, 2H),
7.26–7.16 (m, 3H), 6.50 (d, J = 15.8 Hz, 1H), 4.96
(d, J = 9.7 Hz, 1H), 3.50 (dq, J = 13.3, 6.6 Hz, 1H),
0.83 (dd, J = 6.6, 1.6 Hz, 6H). HRMS (AP-ESI) m/z
calcd for C20H23N3O5S [M − H]− 416.1291, found
416.1286.
of 10a–10t
1.7.1 | (S,E)-N-hydroxy-3-(3-(N-(2-oxo-1-phenyl-2-
(phenylamino)ethyl)sulfamoyl)phenyl) acrylamide (10a)
Compound 9a (0.46 g, 1.0 mmol) was dissolved in 14 mL
of NH2OK (0.17 g, 2.4 mmol) methanol solution and
stirred for 3 h. After the reaction was complete, the
solvent was evaporated under vacuum. The residue was
acidified with saturated citric acid to a pH 3–4 and then
extracted with EtOAc (3 × 20 mL). The organic layers
were combined, washed with brine (3 × 20 mL), dried
over MgSO4, and evaporated under vacuum. The crude
material was purified via flash chromatography to afford
the desired compound 10a (0.19 g, 42% yield) as pale
yellow solid. Mp: 202–204 °C. 1H NMR (600 MHz,
DMSO-d6) δ 10.89 (s, 1H), 10.38 (s, 1H), 10.27 (s, 2H),
8.86 (d, J = 9.6 Hz, 1H), 7.90 (s, 1H), 7.71 (d, J = 7.9 Hz,
1H), 7.60 (d, J = 7.7 Hz, 1H), 7.43–7.37 (m, 6H),
7.25–7.19 (m, 5H), 7.01 (t, J = 7.4 Hz, 1H), 6.51 (d,
J = 15.8 Hz, 1H), 5.25 (d, J = 9.7 Hz, 1H). HRMS
(AP-ESI) m/z calcd for C23H21N3O5S [M − H]− 450.1131,
found 450.1129.
1.7.5 | (S,E)-3-(3-(N-(2-(butylamino)-2-oxo-1-
phenylethyl)sulfamoyl)phenyl)-N-hydroxyacrylamide (10e)
1
Pale yellow solid, 29% yield. Mp: 178–179 °C. H NMR
(300 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.10 (s, 1H), 8.59
(d, J = 9.6 Hz, 1H), 8.11 (t, J = 5.4 Hz, 1H), 7.86 (s,
1H), 7.74–7.65 (m, 2H), 7.53–7.40 (m, 2H), 7.30 (dd,
J = 7.9, 1.6 Hz, 2H), 7.26–7.16 (m, 3H), 6.50 (d,
J = 15.8 Hz, 1H), 4.97 (d, J = 9.6 Hz, 1H), 2.90–2.70
(m, 2H), 1.20–0.98 (m, 4H), 0.75 (t, J = 7.1 Hz, 3H).
HRMS (AP-ESI) m/z calcd for C21H25N3O5S [M − H]−
430.1445, found 430.1442.

Li et aL.
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1.7.6 | (S,E)-N-hydroxy-3-(3-(N-(2-(isobutylamino)-
1.7.10 | (S,E)-3-(3-(N-(2-((4-bromophenyl)
amino)-2-oxo-1-phenylethyl)sulfamoyl)phenyl)-N-
hydroxyacrylamide (10j)
2-oxo-1-phenylethyl)sulfamoyl)phenyl) acrylamide (10f)
1
Pale yellow solid, 25% yield. Mp: 174–176 °C. H NMR
(300 MHz, DMSO-d )
δ
10.83 (s, 1H), 9.10 (d,
Pale yellow solid, 31% yield. Mp: 223–225 °C. 1H
NMR (600 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.48
(s, 1H), 9.14 (s, 1H), 8.89 (d, J = 9.6 Hz, 1H), 7.89
(s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.7 Hz,
1H), 7.39 (ddd, J = 22.9, 16.2, 8.4 Hz, 8H), 7.23
(dt, J = 24.3, 7.1 Hz, 3H), 6.49 (d, J = 15.8 Hz,
1H), 5.21 (d, J = 9.4 Hz, 1H). HRMS (AP-ESI) m/z
calcd for C23H20BrN3O5S [M − H]− 528.0235, found
528.0234.
J = 1.3 Hz, 1H), 8.569 (d, J = 9.6 Hz, 1H), 8.12 (t,
J = 5.7 Hz, 1H), 7.85 (s, 1H), 7.73–7.65 (m, 2H),
7.52–7.39 (m, 2H), 7.31 (dd, J = 7.9, 1.5 Hz, 2H),
7.25–7.15 (m, 3H), 6.49 (d, J = 15.8 Hz, 1H), 5.02 (d,
J = 9.5 Hz, 1H), 2.66 (t, J = 6.3 Hz, 2H), 1.45 (dp,
J = 13.4, 6.8 Hz, 1H), 0.64 (d, J = 6.6 Hz, 6H). HRMS
(AP-ESI) m/z calcd for C21H25N3O5S [M − H]− 430.1446,
found 430.1442.
1.7.7 | (S,E)-3-(3-(N-(2-(tert-butylamino)-2-oxo-1-
phenylethyl)sulfamoyl)phenyl)-N-hydroxyacrylamide (10g)
1.7.11 | (S,E)-N-hydroxy-3-(3-(N-(2-((4-iodophenyl)
amino)-2-oxo-1-phenylethyl)sulfamoyl) phenyl)
acrylamide (10k)
Pale yellow solid, 28% yield. Mp: 182–184 °C. 1H
NMR (300 MHz, DMSO-d ) δ 10.84 (s, 1H), 8.49 (d,
J = 9.9 Hz, 1H), 7.91 (s, 61H), 7.75 (d, J = 4.7 Hz,
2H), 7.71 (d, J = 1.2 Hz, 1H), 7.57–7.46 (m, 2H),
7.44 (s, 1H), 7.32 (d, J = 6.7 Hz, 2H), 7.28–
7.18 (m, 3H), 6.52 (d, J = 15.8 Hz, 1H), 5.03 (d,
J = 9.8 Hz, 1H), 0.99 (s, 9H). HRMS (AP-ESI) m/z
calcd for C21H25N3O5S [M − H]− 430.1447, found
430.1442.
1
Pale yellow solid, 26% yield. Mp: 200–202 °C. H NMR
(600 MHz, DMSO-d ) δ 10.85 (s, 1H), 10.31 (d, J
= 68.5 Hz, 1H), 9.14 6(s, 1H), 8.86 (s, 1H), 7.89 (s, 1H),
7.69 (t, J = 7.8 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.57
(d, J = 8.7 Hz, 1H), 7.44–7.34 (m, 5H), 7.27–7.19 (m,
5H), 6.46 (dd, J = 15.8, 8.0 Hz, 1H), 5.20 (d, J = 16.7 Hz,
1H). HRMS (AP-ESI) m/z calcd for C23H20IN3O5S
[M − H]− 576.0101, found 576.0096.
1.7.8 | (S,E)-3-(3-(N-(2-((4-fluorophenyl)
amino)-2-oxo-1-phenylethyl)sulfamoyl)phenyl)-N-
hydroxyacrylamide(10h)
1.7.12 | (S,E)-N-hydroxy-3-(3-(N-(2-((4-
methoxyphenyl)amino)-2-oxo-1-phenylethyl) sulfamoyl)
phenyl)acrylamide (10l)
1
1
Pale yellow solid, 27% yield. Mp: 130–132 °C. H NMR
Pale yellow solid, 23% yield. Mp: 197–199 °C. H NMR
(600 MHz, DMSO-d6) δ 10.89 (s, 1H), 10.52 (s, 1H),
10.08 (s, 1H), 8.88 (d, J = 9.7 Hz, 1H), 7.90 (s, 1H),
7.71 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H),
7.44–7.36 (m, 6H), 7.25 (t, J = 7.3 Hz, 2H), 7.23–7.19
(m, 1H), 7.05 (t, J = 8.9 Hz, 2H), 6.52 (d, J = 15.8 Hz,
1H), 5.24 (d, J = 9.6 Hz, 1H). HRMS (AP-ESI) m/z
calcd for C23H20FN3O5S [M − H]− 468.1039, found
468.1035.
(600 MHz, DMSO-d6) δ 10.85 (s, 1H), 10.12 (s, 1H),
9.14 (s, 1H), 8.81 (d, J = 9.6 Hz, 1H), 7.88 (s, 1H),
7.70 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H),
7.45–7.33 (m, 4H), 7.25 (dd, J = 13.3, 8.3 Hz, 4H), 7.20
(t, J = 7.2 Hz, 1H), 6.80 (d, J = 9.0 Hz, 2H), 6.46 (d,
J = 15.8 Hz, 1H), 5.17 (d, J = 9.6 Hz, 1H), 3.69 (s,
3H). HRMS (AP-ESI) m/z calcd for C24H23N3O6S
[M − H]− 480.1234, found 480.1235.
1.7.9 | (S,E)-3-(3-(N-(2-((4-chlorophenyl)
amino)-2-oxo-1-phenylethyl)sulfamoyl)phenyl)-N-
hydroxyacrylamide (10i)
1.7.13 | (S,E)-N-hydroxy-3-(3-(N-(2-oxo-1-phenyl-2-
(o-tolylamino)ethyl)sulfamoyl)phenyl) acrylamide (10m)
1
Pale yellow solid, 28% yield. Mp: 161–163 °C. H NMR
1
Pale yellow solid, 24% yield. Mp: 204–206 °C. H NMR
(600 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.65 (s, 1H), 9.14
(s, 1H), 8.85 (d, J = 9.6 Hz, 1H), 7.93 (s, 1H), 7.76 (d,
J = 7.8 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.50 (t,
J = 7.8 Hz, 1H), 7.44 (t, J = 12.3 Hz, 3H), 7.27 (t,
J = 7.4 Hz, 2H), 7.23 (t, J = 7.2 Hz, 1H), 7.12 (d,
J = 7.3 Hz, 1H), 7.09–7.01 (m, 2H), 6.99 (d, J = 7.7 Hz,
1H), 6.51 (d, J = 15.8 Hz, 1H), 5.33 (d, J = 9.5 Hz,
(600 MHz, DMSO-d6) δ 10.88 (s, 1H), 10.54 (s, 1H),
9.14 (s, 1H), 8.89 (s, 1H), 7.90 (s, 1H), 7.70 (d, J = 7.8 Hz,
1H), 7.61 (d, J = 7.8 Hz, 1H), 7.43–7.35 (m, 6H), 7.29–
7.20 (m, 5H), 6.50 (d, J = 15.8 Hz, 1H), 5.23 (s, 1H).
HRMS (AP-ESI) m/z calcd for C23H20ClN3O5S [M − H]−
484.0738, found 484.0739.

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|
1H), 1.89 (s, 3H). HRMS (AP-ESI) m/z calcd for
1H), 7.70 (d, J = 7.8 Hz, 2H), 7.47 (t, J = 7.8 Hz, 1H),
7.43–7.38 (m, 1H), 7.37 (d, J = 1.1 Hz, 1H), 7.35 (d,
J = 2.1 Hz, 1H), 7.32 (d, J = 1.4 Hz, 1H), 7.24 (s, 1H),
7.23–7.18 (m, 3H), 7.14 (td, J = 7.5, 1.1 Hz, 1H), 6.92
(d, J = 7.5 Hz, 1H), 6.56 (d, J = 15.7 Hz, 1H), 5.13
(d, J = 9.4 Hz, 1H), 4.13 (d, J = 5.2 Hz, 2H). HRMS
(AP-ESI) m/z calcd for C25H24ClN3O5S [M − H]− 498.0901,
found 498.0896.
C24H23N3O5S [M − H]− 464.1292, found 464.1286.
1.7.14 | (S,E)-3-(3-(N-(2-((2-chlorophenyl)
amino)-2-oxo-1-phenylethyl)sulfamoyl)phenyl)-N-
hydroxyacrylamide (10n)
1
Pale yellow solid, 25% yield. Mp: 158–160 °C. H NMR
(600 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.89 (s, 1H), 9.13
(s, 1H), 8.88 (s, 1H), 7.93 (s, 1H), 7.76 (d, J = 7.8 Hz,
1H), 7.71 (d, J = 7.9 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H),
7.46–7.37 (m, 4H), 7.26 (ddd, J = 14.0, 13.0, 5.3 Hz,
5H), 7.16 (t, J = 6.9 Hz, 1H), 6.50 (d, J = 15.8 Hz,
1H), 5.45 (s, 1H). HRMS (AP-ESI) m/z calcd for
C23H20ClN3O5S [M − H]− 484.0745, found 484.0739.
1.7.18 | (S,E)-N-hydroxy-3-(3-(N-(2-oxo-2-
(phenethylamino)-1-phenylethyl)sulfamoyl) phenyl)
acrylamide (10r)
1
Pale yellow solid, 31% yield. Mp: 156–158 °C. H NMR
(600 MHz, DMSO-d ) δ 10.85 (s, 1H), 9.14 (s, 1H),
8.62 (s, 1H), 8.28 (t6, J = 5.4 Hz, 1H), 7.87 (s, 1H),
7.70 (dd, J = 13.6, 7.8 Hz, 2H), 7.49 (t, J = 7.8 Hz,
1H), 7.45 (d, J = 15.9 Hz, 1H), 7.26 (d, J = 6.5 Hz,
2H), 7.23–7.18 (m, 5H), 7.17–7.13 (m, 1H), 7.00 (d,
J = 7.0 Hz, 2H), 6.52 (d, J = 15.8 Hz, 1H), 4.97 (s,
1H), 3.07 (td, J = 13.1, 7.1 Hz, 1H), 3.01 (td, J = 13.0,
7.2 Hz, 1H), 2.48 (t, J = 7.4 Hz, 2H). HRMS (AP-ESI)
m/z calcd for C25H25N3O5S [M − H]− 478.144, found
478.1442.
1.7.15 | (S,E)-3-(3-(N-(2-((3-fluorophenyl)
amino)-2-oxo-1-phenylethyl)sulfamoyl)phenyl)-N-
hydroxyacrylamide (10o)
1
Pale yellow solid, 22% yield. Mp: 204–205 °C. H NMR
(600 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.48 (s, 1H),
9.13 (s, 1H), 8.89 (s, 1H), 7.88 (s, 1H), 7.70 (d, J = 7.8 Hz,
1H), 7.62 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H),
7.40–7.35 (m, 3H), 7.33 (d, J = 11.5 Hz, 1H), 7.30–7.24
(m, 3H), 7.24–7.19 (m, 1H), 7.09 (d, J = 8.1 Hz, 1H),
6.86 (dd, J = 8.3, 6.4 Hz, 1H), 6.45 (d, J = 15.8 Hz,
1H), 5.19 (d, J = 4.6 Hz, 1H). HRMS (AP-ESI) m/z calcd
for C23H20FN3O5S [M − H]− 468.104, found 468.1035.
1.7.19 | (S,E)-N-hydroxy-3-(3-(N-(2-(naphthalen-
1-ylamino)-2-oxo-1-phenylethyl)sulfamoyl)phenyl)
acrylamide (10s)
1
Pale yellow solid, 26% yield. Mp: 186–188 °C. H NMR
(300 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.24 (s, 1H),
9.11 (s, 1H), 8.89 (d, J = 9.5 Hz, 1H), 7.98 (s, 1H),
7.89 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H),
7.72 (t, J = 7.7 Hz, 2H), 7.60 (d, J = 8.1 Hz, 1H), 7.49
(t, J = 7.5 Hz, 4H), 7.45–7.36 (m, 2H), 7.30 (dt, J = 11.7,
6.8 Hz, 4H), 6.52 (d, J = 15.8 Hz, 1H), 5.50 (d, J = 9.5 Hz,
1H). HRMS (AP-ESI) m/z calcd for C27H23N3O5S
[M − H]− 500.1289, found 500.1286.
1.7.16 | (S,E)-N-hydroxy-3-(3-(N-(2-((3-
methoxyphenyl)amino)-2-oxo-1-phenylethyl) sulfamoyl)
phenyl)acrylamide (10p)
1
Pale yellow solid, 22% yield. Mp: 205–206 °C. H NMR
(600 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.24 (s, 1H),
9.13 (s, 1H), 8.85 (d, J = 9.5 Hz, 1H), 7.88 (s, 1H),
7.70 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H),
7.45–7.34 (m, 4H), 7.25 (t, J = 7.3 Hz, 2H), 7.20 (t,
J = 7.2 Hz, 1H), 7.13 (t, J = 8.1 Hz, 1H), 7.05 (s, 1H),
6.92 (d, J = 8.0 Hz, 1H), 6.60 (dd, J = 8.2, 1.8 Hz, 1H),
6.46 (d, J = 15.8 Hz, 1H), 5.19 (d, J = 9.5 Hz, 1H),
3.68 (s, 3H). HRMS (AP-ESI) m/z calcd for C24H23N3O6S
[M − H]− 480.1242, found 480.1235.
1.7.20 | (S,E)-N-hydroxy-3-(3-(N-(2-((naphthalen-1-
ylmethyl)amino)-2-oxo-1-phenylethyl)sulfamoyl)phenyl)
acrylamide (10t)
1
Pale yellow solid, 24% yield. Mp: 158–160 °C. H NMR
(300 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.11 (s, 1H), 8.71
(t, J = 5.2 Hz, 2H), 7.91 (d, J = 7.6 Hz, 1H), 7.87
(s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 7.8 Hz,
2H), 7.54 – 7.38 (m, 4H), 7.38–7.26 (m, 3H), 7.24–7.11
(m, 4H), 6.51 (d, J = 15.8 Hz, 1H), 5.10 (d, J = 8.4 Hz,
1H), 4.53 (qd, J = 15.2, 5.5 Hz, 2H). HRMS (AP-ESI)
m/z calcd for C28H25N3O5S [M − H]− 514.1443, found
514.1442.
1.7.17 | (S,E)-3-(3-(N-(2-((2-chlorophenethyl)
amino)-2-oxo-1-phenylethyl)sulfamoyl) phenyl)-N-
hydroxyacrylamide (10q)
1
Pale yellow solid, 30% yield. Mp: 122–124 °C. H NMR
(300 MHz, DMSO-d ) δ 10.90 (s, 1H), 9.11 (s, 1H), 8.78
(d, J = 5.8 Hz, 1H)6, 8.71 (d, J = 9.3 Hz, 1H), 7.88 (s,

Li et aL.
7
|
allowed to grow for 12 h ahead of addition of tested com-
pounds. These tested compounds were all dissolved in DMSO
and then diluted in culture medium maintaining the effective
DMSO concentration <0.2%. The plates were incubated for
an additional 48 h afterward, and then, a 0.5% MTT solu-
tion was added to each well. After incubation for another
4 h, formazan formed from MTT was extracted by adding
200 μL of DMSO for 15 min. Absorbance was then deter-
mined using an ELISA reader at 570 nm.
1.8 | In vitro HDACs inhibition fluorescence
assay
In vitro HDACs inhibition assays were conducted as previ-
ously described in our group.[24] In brief, 10 μL of enzyme
solution (HeLa nuclear extracts, HDAC1, HDAC4, HDAC6,
HDAC8, HDAC11) was mixed with various concentrations
of target compounds (50 μL), SAHA, and PXD101, using
100% and none HDACs groups as control group. After
incubation at 37 °C for 10 min, 40 μL of fluorogenic sub-
strate (Boc-Lys(Ac)-AMC for HeLa nuclear extracts; Ac-
Leu-GlyLyS(Ac)-AMC for HDAC1, HDAC6, and HDAC11;
Ac-Leu-GlyLyS(Tfa)-AMC for HDAC4 and HDAC8) was
added, and then, the mixture was incubated at 37 °C for
30 min. The mixture was stopped by addition of 100 μL
of developer containing trypsin and TSA afterward. Over
the next incubation at 37 °C for 20 min, fluorescence inten-
sity was measured using a microplate reader at excitation
and emission wavelengths of 390 and 460 nm, respectively.
The inhibition ratios were calculated from the fluorescence
intensity readings of tested wells relative to those of control
wells, and the IC50 values were calculated using a regres-
sion analysis of the concentration/inhibition data.
1.10 | Molecular docking studies
Compounds were docked into the active site of HDAC2 (PDB
entry: 4LXZ) using Tripos sybyL x 2.0 (Certara USA, Inc.,
Princeton, NJ, USA). Before the docking process, the protein
structure was treated by deleting water molecules, adding
hydrogen atoms, fixing atom types, and assigning AMBER7
FF99 charges. A 100-step minimization process was performed
to further optimize the protein structure. The molecular struc-
tures were generated with the Sybyl/Sketch module and opti-
mized using Powell’s method with the Tripos force field
with convergence criterion set at 0.05 kcal/(Å mol) and assigned
charges with the Gasteiger-Hückel method. Molecular docking
was carried out via the Sybyl/FlexX module. Other docking
parameters were kept to the default values.
1.9 | In vitro antiproliferative assay
In vitro antiproliferative assays were determined by the MTT
2
|
RESULTS AND DISCUSSION
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bro-
mide) method as previously described. Briefly, all cell lines
were maintained in RPMI1640 medium containing 10% FBS
at 37 °C in 5% CO2 humidified incubator. Cell proliferation
assay was determined by the MTT method. Cells were pas-
saged the day before dosing into a 96-well cell plate and
2.1 | Chemistry
The target compounds 10a–10t were synthesized fol-
lowing the procedures described in Scheme 1. Sulfonation
O
S
O
S
O
S
c
O
a
b
O
H
H
a
N
O
Cl
a
N
O
O
O
O
O
O
O
O
4
3
2
1
O
O
B
O
B
O
d
e
f
R
H
R
O
H
O
NH2
HN
HN
NH2
oc
oc
H
Cl
6
a- t
7
7
5
8a-8t
R
O
R
O
O
O
O
O
O
O
h
g
H
O
S
S
N
H
O
N
H
N
H
a-
10 10
t
a- t
9
9
SCHEME 1 Synthesis of target compounds 10a-10t. Reagents and conditions: (a) Oleum, 40 °C 10 h, room temperature overnight; (b) triethyl
phosphonoacetate, K2CO3, H2O; (c) SOCl2, DMF, 75 °C; (d) (Boc)2O, Et3N, MeOH/H2O; (e) TBTU, Et3N, THF; (f) HCl, anhydrous EtOAc; (g) PhMe;
(h) NH2OK, anhydrous MeOH

8
Li et aL.
|
TABLE 1 HDAC inhibitory activity of compounds 10a–10t
R
O
O
O
O
OH
S
N
H
N
H
IC50 of HeLa extracta
IC50 of HeLa extracta
Compound
10a
R
(nm)
Compound
10l
R
(nm)
H
N
H
N
136
4
114
1
9
9
O
H
N
H
N
10b
10c
327 13
238 13
10m
10n
125
126
H
N
Cl
H
N
H
N
H
N
10d
10e
10f
318
166
269
1
5
2
10o
10p
10q
133
178
159
6
7
8
F
H
N
H
N
O
H
N
Cl
N
H
H
N
H
N
10g
10h
428 17
281 10
10r
10s
83
88
1
1
H
H
N
N
F
H
10i
129
2
10t
N
H
101
5
N
Cl
H
N
10j
109
57
3
1
SAHA
114
51
1
2
r
B
H
10k
PXD101
N
I
aAssays were performed in replicate (n ≥ 2); values are shown as mean SD.
2.2 | HeLa cell extract inhibitory assay by
of the starting material benzaldehyde (compound 1) with
oleum gave compound 2. Under Horner–Wadsworth–
Emmons reaction, compound 2 was converted to 3,
which was treated with thionyl chloride to get sulfonyl
chlorides 4. Boc (tert-butoxycarbonyl) group protection
of another starting material L-phenylglycine (compound
5) led to compound 6, which reacted with appropriately
various amines by TBTU-mediated amide formation to
afford compound 7. Subsequent N-deprotection of 7
afforded compound 8. Compound 9 was prepared by
coupling 4 with 8 and then treated with NH2OK
in methanol to give corresponding hydroxamic acids
10.
the target compounds
To efficiently screen our synthesized compounds with dif-
ferent hydrophobic substituents in the phenylglycine group
of the cap, we conducted the enzymatic inhibitory assay
against HeLa cell nuclear extracts (primarily containing
HDAC1 and HDAC2) using SAHA and PXD101 as posi-
tive controls (Table 1). We first synthesized compounds
(10a–g) substituted by phenylamine (10a) and various ali-
phatic amines (10b–10g) to figure out the disparate effects
of aromatic and aliphatic substituents. Results indicated
that 10a with aromatic substituent was more potent than
10b–10g with various aliphatic substituents.

Li et aL.
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|
TABLE 3 In vitro antiproliferative activity of 10k, 10m, 10o, 10r, 10s,
and 10t
For the purpose of probing effects of diverse substit-
uents in the benzene ring of the R group in 10a, we syn-
thesized compounds with various para-substituent (10h–l),
ortho-substituent (10m–n) and meta-substituent (10o–p).
Results listed in Table 1 showed that most para-substituted
derivatives except 10h exhibited better HDAC inhibitory
activities than 10a. For para-substituted derivatives 10h–
10k, their inhibitory potency increased when the electron-
withdrawing abilities of the substituent decreased, the most
potent compound 10k was superior to SAHA and compa-
rable to PXD101. Compounds with ortho-substituent or
meta-substituent displayed comparable inhibitory potency
with 10a, which indicated ortho-substituent or meta-
substituent had no obvious effect on their HDAC inhibitory
activities.
IC50a (μm)
Compound HL60
U937
KG1
K562
U266
10k
2.1 0.4
4.6 0.1
5.0 0.2
5.9 0.1
6.1 0.1
5.6 0.1
6.3 0.2
5.9 0.9
5.6 0.2
5.8 0.9
0.7 0.2
0.7 0.3
10m
10o
2.6 0.1
4.0 0.2
3.9 0.1
2.5 0.2
4.9 0.1
0.8 0.1
0.2 0.1
2.9 0.1
4.8 0.4
4.8 0.5
7.5 0.1
6.9 1.4
1.2 0.1
0.6 0.1
4.2 0.3
5.0 0.2
5.1 0.1
4.8 0.1
4.4 0.3
1.4 0.1
0.8 0.1
5.5 0.1
7.4 0.2
5.7 0.1
6.0 0.6
7.1 0.1
1.6 0.1
0.7 0.1
10r
10s
10t
SAHA
PXD101
aAssays were performed in replicate (n ≥ 2); values are shown as mean SD.
Moreover, compounds with phenylethyl substituent (10r),
1-naphthyl substituent (10s), and 1-menaphthyl substituent
(10t) were synthesized to investigate the influence of volume
and length of R group on HDACs inhibition. Results showed
that 10r and 10s displayed better potency than SAHA.
activity of selected compounds was less potent than the
positive control SAHA and PXD101 despite their better
performance in the enzymatic inhibition assay.
2.4 | HDAC isoform selectivity of 10s
2.3 | In vitro antiproliferative assay by the
To explore the HDAC isoform selectivity profile of these
PXD101 analogs, the IC50 values of compound 10s for
class I representatives HDAC1 and HDAC8, class IIa
representative HDAC4, class IIb representative HDAC6,
and class IV isoform HDAC11 were determined with
PXD101 as positive control (Table 4). Results presented
in Table 4 demonstrated that 10s exhibited similar overall
selectivity profile with PXD101.
target compounds
For further investigation of the antiproliferative efficiency
of our novel compounds, we first tested the inhibitory
rate of all synthesized compounds at 5 μm against two
human leukemia cell lines (U937 and HEL).[25] According
to the preliminary results in Table 2, six compounds with
relatively higher inhibition (10k, 10m, 10o, 10r, 10s, 10t)
were selected for further antiproliferative evaluation against
5 types of hematological tumor cell lines (Table 3). It
was very disappointing that the overall antiproliferative
2.5 | Docking study
The proposed binding modes of compounds 10a and 10b
(Figure 3) in the active site of HDAC2 (PDB code 4LXZ)
were investigated by docking analysis. Figure 3A,B revealed
that benzene ring of the external motif of 10a could be
well accommodated in the S’ pocket of HDAC2, while
cyclohexyl group of 10b could hardly achieve the same
effect. Moreover, chelation geometry of catalytic zinc ion
demonstrated that although their hydroxamic acid group both
chelated the zinc ion, 10a (Figure 3C) displayed bidentate
chelation with shorter measured distance between carbonyl
and hydroxyl oxygens of hydroxamate and zinc ion, while
10b (Figure 3D) exhibited weaker monodentate chelation.
Furthermore, the H-bond interactions were detected in 10a
(Figure 3C) and 10b (Figure 3D) for enhancing the ligand–
receptor binding. The hydroxyl and carbonyl oxygens of 10a
have three H-bond interactions with His145, His146, and
Tyr308, respectively, while only two H-bong interactions of
10b with His145 and Gly154 were found. All the above
information could rationalize the inhibitory activity of 10a
than 10b.
TABLE 2 In vitro antiproliferative activity of compounds in U937 and
HEL cell line
U937
HEL
U937
HEL
Compoundd (inhib%)a,b (inhib%)a,b Compound (inhib%)a,b (inhib%)a,b
10a
48
18
10l
48
13
19
17
18
10
13
18
14
13
17
23
10b
10c
10d
10e
10f
10g
10h
10i
42
10
14
38
41
23
36
44
47
48
11
12
13
15
14
9
10m
10n
51
43
58
37
17
50
49
49
58
73
10o
10p
10q
10r
10
14
18
20
10s
10t
10j
10k
SAHA
PXD101
aAssays were performed in replicate (n ≥ 2); the SD values are <20% of the mean.
bThe activity was described as inhibition% at the concentration of 5 μm.

10
Li et aL.
|
TABLE 4 In vitro inhibition of HDACs isoforms of 10sa
IC50a (nm)
Although in vitro HeLa cell extract inhibitory fluores-
cence assay showed that compounds 10k, 10r, and 10s
displayed potent HDAC inhibitory activity compared with
approved drugs SAHA and PXD101, their antiprolifera-
tive potency was disappointing. 10s, one of the most
potent compounds, exhibited comparable similar overall
isoform selective profile with PXD101. Collectively, our
results showed that introduction of L-phenylglycine-
containing branched cap group to PXD101 could not
lead to analogs with improved potency or selectivity.
HDAC
10s
PXD101
Class I
HDAC 1
HDAC 8
93
3
34
353 49
4
659 50
23 000 2828
80 17
Class IIa
HDAC 4
9850 212
Class IIb
HDAC 6
27
2
Class IV
HDAC11
3850 212
25 000 8485
ACKNOWLEDGMENTS
aAssays were performed in replicate (n ≥ 2); values are shown as mean SD.
This work was supported by National High-Tech R&D
Program of China (863 Program) (Grant No.
2014AA020523), National Natural Science Foundation of
China (Grant Nos. 21302111, 81373282, 21172134), China
Postdoctoral Science Foundation funded project (Grant
Nos. 2013M540558 and 2014T70654), Major Project of
Science and Technology of Shandong Province
3
|
CONCLUSION
In this article, we described the design, synthesis, and
in vitro activity evaluation of a series of novel PXD101
analogs with L-phenylglycine-containing cap as HDACIs.
FIGURE 3 Proposed binding mode of compounds 10a (A, C), 10b (B, D) with HDAC2 (derived by modification of PDB code 4LXZ using Tripos
sybyL x 2.0). The zinc ion is shown as a green sphere. The H-bond is shown as dotted blue line (atom types: H, white; N, blue; O, red; S, yellow)

Li et aL.
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CONFLICT OF INTEREST
The authors confirm that this article content has no conflict
of interest.
ABBREVIATIONS
CTCL, cutaneous T-cell lymphoma HDACIs, histone dea-
cetylase inhibitors HDACs, histone deacetylases PTCL,
peripheral T-cell lymphoma ZBG, zinc binding group.
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