Design, synthesis, and biological evaluation of 2,4-imidazolinedione derivatives as hdac6 isoform-selective inhibitors

Article abstract of DOI:10.1021/acsmedchemlett.9b00084

Histone deacetylase 6 (HDAC6) has emerged as a promising drug target for various human diseases, including diverse neurodegenerative diseases and cancer. Herein, we reported a series of 2,4-imidazolinedione derivatives as novel HDAC6 isoform-selective inhibitors based on structure-based drug design. Most target compounds exhibit good profiles in a preliminary screening concerning HDAC6 inhibitory activities. Moreover, the most active compound 10c increases the acetylation level of α-tubulin with little effect on the acetylation of histone H3. Further biological evaluation suggested that potent compound 10c, which possesses good antiproliferative activity, could induce apoptosis in HL-60 cell by activating caspase 3.

Full text of DOI:10.1021/acsmedchemlett.9b00084

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Letter
Design, synthesis and biological evaluation of 2,4-
imidazolinedione derivatives as HDAC6 isoform-selective inhibitors
Tao Liang, Xuben Hou, Yi Zhou, Xinying Yang, and Hao Fang
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.9b00084 • Publication Date (Web): 05 Jul 2019
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Design, synthesis and biological evaluation of 2,4-imidazolinedione
derivatives as HDAC6 isoform-selective inhibitors
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Tao Liang, Xuben Hou, Yi Zhou, Xinying Yang, Hao Fang*
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of
Pharmaceutical Sciences, Shandong University, 44, Wenhuaxi Road, Jinan, Shandong, 250012, PR China.
KEYWORDS: HDAC6; Isoform-selective; 2,4-imidazolinedione; Anti-proliferative; Apoptosis
ABSTRACT: Histone deacetylase 6 (HDAC6) has emerged as a promising drug target for various human diseases, including
diverse neurodegenerative diseases and cancer. Herein, we reported a series of 2,4-imidazolinedione derivatives as novel HDAC6
isoform-selective inhibitors based on structure-based drug design. Most of target compounds exhibit good profiles in a preliminary
screening concerning HDAC6 inhibitory activities. Moreover, the most active compound 10c increases the acetylation level of α-
tubulin with little effect on the acetylation of Histone H3. Further biological evaluation suggested that potent compound 10c, which
possesses good anti-proliferative activity, could induce apoptosis in HL-60 cell by activating caspase 3.
Many human diseases which related to epigenetic etiology
have stimulated the development of 'epigenetic' therapies.1 As
epigenetic eraser, histone deacetylases (HDACs), together
with histone acetyltransferases (HATs), maintains the
homeostasis of the acetylation on histones and other proteins.2
However, the aberrant acetylated state of histone mediated by
HDACs overexpression is associated with many diseases
including cancer.3 Inhibition of HDACs could induce
apoptosis as well as anti-proliferation of diverse cancer cells in
vivo or in vitro, and HDACs have emerged as promising
targets for cancer treatment.4,5 Efforts of two decades have
developed five approved HDAC inhibitors (vorinostat,
romidepsin, panobinostat, belinostat and chidamide) for the
treatment of cutaneous T-cell lymphomas (CTCL), multiple
myeloma (MM) and peripheral T-cell lymphomas (PTCL).6-10
Despite the success of HDAC inhibitors in cancer therapy, the
indiscriminate inhibition on HDACs causes various side
effects, such as diarrhea, fatigue, neutropenia, and so on.11-14
HDAC isoform-selective inhibitors, which target specific
HDAC isoform, provide a blueprint for the development of
HDAC inhibitors with no or less side effect.15 As a member of
HDAC family, HDAC6 plays a pivotal role in myriad
eukaryotic biological processes.16,17 The overexpression of
HDAC6 has been confirmed in many tumor cell lines18,19 and
HDAC6 is required for efficient oncogenic cell
transformation.20 Although some HDAC6 selective inhibitors
exhibited good anti-proliferative activities,21,22 other HDAC6
inhibitors displayed minor anti-proliferative activities.23,24
Indiscriminate inhibition on HDACs or off-target effect may
be caused the controversy in the anti-proliferative activity of
HDAC6 selective inhibitors. Therefore, the anti-proliferative
activities remained to be explored. Here, we sought to develop
HDAC6 isoform-selective inhibitors and explore their anti-
proliferative activities.
HDAC inhibitors have the well accepted pharmacophore:
zinc binding group (ZBG), linker and cap group (SI Fig 1).
Modifying cap, altering the linker or varying ZBG have
become important strategies to develop HDAC isoform-
selective inhibitors.25 Recently, our group developed purine
derivatives as HDAC inhibitors which exhibit nanomolar
inhibitory activities against HDAC6, whereas the selectivity
remained to be improved.26
Fig 1. (A) Pocket analysis of HDAC6 was performed using
AlphaSpace;27 (B) Design of 2,4-imidazolinedione derivatives
as HDAC6 selective inhibitors.
It has been widely recognized that cap group plays an
important role in isoform selectivity of HDAC inhibitors.25 We
analyzed the binding pockets in HDAC6 using AlphaSpace27
and found several hydrophobic pockets in the rim of lysine
binding channel, including L1 loop pockets 1, 2 and 3 (Fig
1A). A recent study suggested that L1 loop pocket of HDAC6
provides a conserved binding site to achieve HDAC6 isoform
selectivity.28 Moreover, some 3-aryl-2,4-imidazolinedione
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derivatives were mentioned as HDAC inhibitors in 2015,29
In our ongoing study, we report the synthesis and biological
evaluation of the disubstituted (R1 and R2) 2,4-
imidazolinedione N-hydroxybenzamides derivatives as
HDAC6 selective inhibitors.
whereas these structures with only one aromatic substitution in
R1 position did not exhibit HDAC6 selective inhibition.
Molecular docking of 2,4-imidazolinedione-based lead
compound I (Fig 1A and Fig 1B), which possesses no
substituent at R1 and R2 positions, suggested that proper
modification of 2,4-imidazolinedione scaffold would be
helpful to accommodate unoccupied pocket spaces and
improve binding affinity to HDAC6. Considering the
hydrophobicity and size of these unoccupied pockets (Fig 1A),
different aromatic rings were introduced into 2,4-
imidazolinedione at R1 and R2 positions, which serves as cap
group in our newly designed HDAC6 inhibitors (Fig 1B). On
the other hand, bulky and aromatic linkers accommodate the
wide and shallow catalytic channel of HDAC6 well,30,31 which
indicated that N-hydroxybenzamide could be used as linker
and ZBG (Fig 1B).
The synthetic methods for compounds 10a-10p are shown
in Scheme 1. The amines listed were transformed into
isocyanates through triphosgene and intermediate urea (3a-3d)
were obtained from the isocyanates coupled with the amino
acid. The cyclization reactions were simply mediated by
concentrations of HCl to obtain intermediates 4a-4d. Then, the
key intermediates 6a-6i were prepared by N-alkylation at R2 of
2,4-imidazolinedione. Compounds 7a-7i were obtained by
deprotecting with LiOH and they were used to prepare 8a-8p
by amide coupling. After deprotecting, intermediates 9a-9p
were converted to target compounds 10a-10p according to
literature procedures32. It should be noted that intermediates
6a-6i, 7a-7i, 8a-8p and target compounds 10a-10p are
racemates.
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O
O
O
O
O
R1
R1
c
e
a
b
N
H
NH
R1
N
d
R1 NH2
N
R1
N C O
OH
O
NH
NH
HOOC
COOH
O
O
1a-1d
4a-4d
2a-2d
3a-3d
5a-5d
1a R1 = 4-Cl-Ph
1b R1 = Ph
3a R1 = 4-Cl-Ph
3b R1 = Ph
2a R1 = 4-Cl-Ph
2b R1 = Ph
4a R1 = 4-Cl-Ph
4b R1 = Ph
4c R1 = Bn
4d R1 = cyclohexyl
5a R1 = 4-Cl-Ph
5b R1 = Ph
5c R1 = Bn
5d R1 = cyclohexyl
1c R1 = Bn
1d R1 = cyclohexyl
3c R1 = Bn
3d R1 = cyclohexyl
2c R1 = Bn
2d R1 = cyclohexyl
O
O
O
O
O
O
g
f
R1
N
H
R1
R1
N
n
N
O
O
O
N
O
OH
N
N
N
O
R2
R2
O
R2
6a-6i
7a-7i
8a-8p
6a R1 = 4-Cl-Ph; R2 = 4-Br-Bn
6b R1 = 4-Cl-Ph; R2 = 4-CH3-Bn
6c R1 = 4-Cl-Ph; R2 = Bn
7a R1 = 4-Cl-Ph; R2 = 4-Br-Bn
7b R1 = 4-Cl-Ph; R2 = 4-CH3-Bn
7c R1 = 4-Cl-Ph; R2 = Bn
8a R1 = 4-Cl-Ph; R2 = 4-Br-Bn; n = 0; para 8i R1 = 4-Cl-Ph; R2 = n-propyl; n = 0; para
8b R1 = 4-Cl-Ph; R2 = 4-Br-Bn; n = 1; para 8j R1 = 4-Cl-Ph; R2 = Methy; n = 0; para
8c R1 = 4-Cl-Ph; R2 = 4-CH3-Bn; n = 0; para 8k R1 = 4-Cl-Ph; R2 = Methy; n = 1; para
8d R1 = 4-Cl-Ph; R2 = 4-CH3-Bn; n = 0; meta 8l R1 = Ph; R2 = 4-Br-Bn; n = 1; para
8e R1 = 4-Cl-Ph; R2 = 4-CH3-Bn; n = 1; para 8m R1 = Bn; R2 = 4-Br-Bn; n = 0; para
8f R1 = 4-Cl-Ph; R2 = Bn; n = 0; para
8g R1 = 4-Cl-Ph; R2 = Bn; n = 0; meta
8h R1 = 4-Cl-Ph; R2 = Bn; n = 1; para
6d R1 = 4-Cl-Ph; R2 = n-propyl
6e R1 = 4-Cl-Ph; R2 = Methyl
6f R1 = Ph; R2 = 4-Br-Bn
7d R1 = 4-Cl-Ph; R2 = n-propyl
7e R1 = 4-Cl-Ph; R2 = Methyl
7f R1 = Ph; R2 = 4-Br-Bn
8n R1 = cyclohexyl; R2 = 4-CH3-Bn; n = 0; para
8o R1 = cyclohexyl; R2 = 4-CH3-Bn; n = 1; para
8p R1 = cyclohexyl; R2 = n-propyl; n = 0; para
6g R1 = Bn; R2 = 4-Br-Bn
7g R1 = Bn; R2 = 4-Br-Bn
6h R1 = cyclohexyl; R2 = 4-CH3-Bn 7h R1 = cyclohexyl; R2 = 4-CH3-Bn
6i R1 = cyclohexyl; R2 = n-propyl
7i R1 = cyclohexyl; R2 = n-propyl
O
O
H
h, i
N
N
n
R1
N
OH
H
N
O
R2
O
10a-10p
10i R1 = 4-Cl-Ph; R2 = n-propyl; n = 0; para
10j R1 = 4-Cl-Ph; R2 = Methy; n = 0; para
10k R1 = 4-Cl-Ph; R2 = Methy; n = 1; para
10l R1 = Ph; R2 = 4-Br-Bn; n = 1; para
10m R1 = Bn; R2 = 4-Br-Bn; n = 0; para
10n R1 = cyclohexyl; R2 = 4-CH3-Bn; n = 0; para
10o R1 = cyclohexyl; R2 = 4-CH3-Bn; n = 1; para
10p R1 = cyclohexyl; R2 = n-propyl; n = 0; para
10a R1 = 4-Cl-Ph; R2 = 4-Br-Bn; n = 0; para
10b R1 = 4-Cl-Ph; R2 = 4-Br-Bn; n = 1; para
10c R1 = 4-Cl-Ph; R2 = 4-CH3-Bn; n = 0; para
10d R1 = 4-Cl-Ph; R2 = 4-CH3-Bn; n = 0; meta
10e R1 = 4-Cl-Ph; R2 = 4-CH3-Bn; n = 1; para
10f R1 = 4-Cl-Ph; R2 = Bn; n = 0; para
10g R1 = 4-Cl-Ph; R2 = Bn; n = 0; meta
10h R1 = 4-Cl-Ph; R2 = Bn; n = 1; para
Scheme 1. Reagents and conditions: (a)Triphosgene, NaHCO3, CH2Cl2; (b) (i) Toluene, 2 M NaOH, 0 ºC, 4 h, (ii) 6 M HCl, 44%-
72%; (c) Hydrochloric acid, reflux, 3 h, 88%-92%; (d) CH3COCl, MeOH, reflux, 5h, 95%-97%; (e) K2CO3, KI, DMF, overnight,
45%-93%; (f) LiOH•H2O, THF/H2O, rt, 6 h, 78%-97%; (g) HATU, DIPEA, CH2Cl2, rt, overnight, 40%-95%; (h) LiOH•H2O,
THF/H2O, rt, 6 h; (i) Isobutyl chlorocarbonate, 4-Methylmorpholine, THF, NH2OH•HCl, KOH, MeOH, rt, 6h, 17%-65%.
We evaluated HDAC6 inhibitory activities of all target
compounds with vorinostat (SAHA) as the positive control. As
the results summarized in Table 1, most target compounds
show good HDAC6 inhibitory activities. Structure and activity
relationships suggested that compounds with para-substituted
N-hydroxybenzamides exhibit good HDAC6 inhibitory
activities, whereas compounds with meta-substituted N-
hydroxybenzamides are less active. Molecule docking study of
compound 10c (SI Fig 15) indicated that the hydroxamic acid
of compound 10c chelated with zinc ion properly and formed a
series of hydrogen bond interactions with key residues (His
610, Tyr 782). This may help us to understand the reason why
para-substituted N-hydroxybenzamides are more active than
meta-substituted N-hydroxybenzamides (Table 1). As for the
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SAHA
39.9±9
linker, compounds without spacer (n=0) possess suitable
linkers and these linkers allow the cap groups to reach and
interact with L1 loop, while allowing the ZBG to chelate with
zinc ion properly (SI Fig 15). However, compounds 10b, 10e,
10h, 10k, 10l and 10o, which possess one methylene spacer
(n=1), exhibit lower inhibition against HDAC6 due to the
longer linkers. Moreover, docking study of compound 10c
suggested that the phenyl in the linker of (S)-10c formed π-π
interactions with Phe 680, whereas the phenyl in the linker of
(R)-10c formed π-π interactions with Phe 620. Specially, the
amide in the linkers of (S)-10c and (R)-10c both formed
hydrogen bond interaction with Ser 568, which may explain
the reason why compounds with no spacer (n=0) between
amide group and phenyl in the linker are more active than
those with one methylene spacer (n=1).
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9
a
All compounds were assayed at least two times, and the results are
expressed with standard deviations.
For potent compounds 10a, 10c and 10f, we subsequently
evaluated their HDACs inhibitory profile. IC50 values
calculated from the dose-effect curve (SI Fig 11) indicated
that all tested compounds exhibit good HDAC6 isoform
selectivity (Table 2). It is worth mentioning that compound
10c possesses better HDAC6 selectivity compared to the
positive control SAHA. Potent molecule 10c exhibits 218-fold
selectivity against HDAC1 and more than 53-fold selectivity
against HDAC2 and 3 as well as over 20000-fold selectivity
against HDAC4, 7, 8, 9 and 11.
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Table 2. HDACs inhibitory profiles of 10a, 10c and 10f
In our studies, different substituents attached to 2,4-
imidazolinedione in R1 and R2 position also show impacts on
HDAC6 inhibitory activities. Except compound 10j,
compounds with phenyl and substituted benzyl on cap region
show better HDAC6 inhibitory activities compared to other
compounds. Compound 10p, which possesses no aromatic
rings at R1 and R2 position, exhibit poor HDAC6 inhibitory
activity.
IC50 (nM) a
HDAC
Isoform
10a
10c
10f
SAHA
46±1
HDAC1
HDAC2
HDAC3
HDAC4
HDAC5
HDAC6
HDAC7
HDAC8
HDAC9
HDAC10
HDAC11
194±13
249±6
959±206
277±17
235±33
>100000
111±30
203±14
120±7
126±13
>100000
96±16
35±1
Table 1. HDAC6 inhibitory activities of target compounds
27000±6000
4600±600
7.6±0.8
>100000
41500±10000
39.9±9
O
O
O
4600±400 14900±1700
N
n
R1
N
H
N
OH
N
R2
H
O
9.7±0.6
6000±200
6700±700
9100±800
268±23
4.4±0.4
>100000
>100000
>100000
164±10
IC50 (nM) a
9.7±0.6
16.5±0.4
4.4±0.4
> 40
8800±1300
3600±100
15200±2900
114±26
41800±500
1800±300
64000±8100
80±8
Cpd
10a
10b
10c
10d
10e
10f
R1
R2
n
0
1
0
0
1
0
0
1
0
0
1
1
0
0
1
0
Position
para
para
para
meta
para
para
meta
para
para
para
para
para
para
para
para
para
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
Ph
4-Br-Bn
4-Br-Bn
4-CH3-Bn
4-CH3-Bn
4-CH3-Bn
Bn
>100000
>100000
>100000
40000±3000
a Assays were performed in replicate (n ≥ 2)
18.9±0.4
7.6±0.8
> 40
Research evidences revealed that HDAC6 inhibition
induces apoptosis and suppresses the growth of carcinoma
cells.23,24,33 Therefore, potent compounds (10a, 10c and 10f)
were chosen to evaluate their anti-proliferative activities. The
results (Table 3) suggested that compounds 10a, 10c and 10f
exhibit good anti-proliferative activities against several tumor
cell lines and molecule 10c possesses better anti-proliferative
activities against HL-60 cell (IC50 = 0.25 μM) as well as
RPMI-8226 cells (IC50 = 0.23 μM). Moreover, the anti-
proliferative activities of compound 10c against K562, HCT-
116 and A549 cell lines were approximately 3 times that of the
positive control SAHA.
10g
10h
10i
Bn
Bn
12.7±2.7
12.6±2.3
7.0±1.3
11.8±3.2
13.6±2.1
9.8±1.8
10.3±1.3
17.0±0.78
> 40
n-propyl
Methyl
Methyl
4-Br-Bn
4-Br-Bn
4-CH3-Bn
4-CH3-Bn
n-propyl
10j
10k
10l
10m
10n
10o
10p
Bn
Table 3. Anti-proliferative activities of 10a, 10c and 10f
cyclohexyl
cyclohexyl
cyclohexyl
IC50 (µM) a
Cpd
10a
K562
HL-60
RPMI-
8226
HCT-116
A549
0.69±0.21 0.34±0.05 0.36±0.06
1.25±0.07
5.86±0.34
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10c
10f
0.49±0.10 0.25±0.01 0.23±0.04
0.83±0.13 0.61±0.03 0.64±0.06
1.45±0.13 0.52±0.08 0.57±0.06
0.83±0.03
0.79±0.07
9.45±1.07
2.42±0.02
cell cycle arrest at G1 phase and subG1 phase compared to the
control (DMSO). Subsequently, caspase 3 activation assay
was performed to explore the mechanism of apoptosis
induction by potent compound 10c in HL-60 cell. After
incubating of HL-60 cells with various concentrations (0.25
μM, 0.45 μM and 0.75 μM) for 24 h and 48 h (Fig 2C), the
amount of activated caspase 3 is significantly increased
compared to control (untreated cells). Above research
evidences indicated that compound 10c could induce apoptosis
via activating caspase 3 in HL-60 cell.
2.25±0.12
1.81±0.17
SAHA
a IC50 values are expressed as the mean ± standard deviation of three
separate determinations.
To explore and verify the mechanism of the anti-
proliferative activity of target compounds, we further
performed apoptotic assay (AnnexinV/PI staining), cell cycle
analysis (PI staining) and caspase 3 activation in HL-60 cell.
As shown in Fig 2A, compounds 10a and 10c exhibit mild
apoptosis induction at 0.25 µM but exhibit strong apoptosis
induction at 0.45 µM, whereas the positive control SAHA
exhibits approximately no ability to induce apoptosis at
different concentrations (0.25 µM, 0.45 µM). Cell cycle
analysis (Fig 2B) showed that both 10a and 10c could induce
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To confirm whether potent molecule 10c targets HDAC6 to
exert antiproliferative activity, western blot was performed. As
shown in Fig 2D, SAHA increases the acetylation of α-tubulin,
(substrate for HDAC6) and the acetylation of H3 (a major
substrate of class I HDACs), whereas ACY-1215 and
compound 10c strongly increased the acetylation of α-tubulin
with slight effect on H3 at low concentrations.
Fig 2. (A) Inducing apoptosis of HL-60 by 10a, 10c and SAHA; (B) Cell cycle analysis for 10a, 10c and SAHA against HL-60; (C)
The fold increase of activated caspase 3 after treated with compound 10c for 24 h and 48h in HL-60 cell; Data are expressed as
mean ± SD of at least three independent experiments. Significant differences between treated cells with respect to control (untreated
cells) are indicated as p < 0.05; (D) The levels of the acetylation of α-tubulin and H3 after treated with compound 10c, ACY-1215
and SAHA in HL-60 cell at different concentrations for 24 h, respectively.
In summary,
a
series of 1,3-disubstituted 2,4-
needed in future work. In addition, compound 10c may be
used as a lead compound for the development of more potent
and selective HDAC6 inhibitors.
imidazolinedione derivatives were developed as HDAC6
selective inhibitors. Biological evaluations show that some
compounds (10a, 10c and 10f), especially compound 10c
exhibit good HDAC6 inhibitory activities, isoform-
selectivities and antiproliferative activities. Further studies
revealed that potent molecule 10c could induce apoptosis by
activating caspase 3 and significantly increase the acetylation
of α-tubulin with little effect on the acetylation of H3. It is
necessary to be noted that all target compounds are racemic
and developing method for the separation of enantiomers is
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on
the ACS Publications website at DOI:
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Approved HDAC inhibitors and the well accepted
pharmacophore of HDAC inhibitors; Experimental; Synthesis
and characterization of target compounds 10a-10p; H-NMR,
(3) Alessia Peserico, C. S. Physical and functional
HAT/HDAC interplay regulates protein acetylation balance. J.
Biomed. Biotechno. 2011, 2011, e371832.
1
13C-NMR, HRMS spectrum of representative compounds;
HPLC analysis; HDAC6 and HDAC isoform inhibitory assay;
In vitro antiproliferative assay (MTT assay); Apoptosis and
cell cycle analysis; Caspase 3 activation assay; Western blot
assay; Molecular docking.
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Yang, Y.L.; You, M.J.; Yu, B.H.; Li, X.Q.; Zhou, X.Y.
HDAC6 regulates microrna-27b that suppresses proliferation,
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AUTHOR INFORMATION
Corresponding Author
*Phone: +86-531-88382019; Fax: 86-531-88382548; E-mail:
haofangcn@sdu.edu.cn. Department of Medicinal Chemistry,
Key Laboratory of Chemical Biology (Ministry of Education),
School of Pharmaceutical Sciences, Shandong University, 44,
Wenhuaxi Road, Jinan, Shandong, 250012, PR China.
(6) Duvic, M.; Vu, J. Vorinostat: a new oral histone
deacetylase inhibitor approved for cutaneous T-cell lymphoma.
Expert. Opin. Inv. Drug. 2007, 16, 1111-1120.
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Final results from a multicenter, international, pivotal study of
romidepsin in refractory cutaneous T-cell lymphoma. J. Clin.
Oncol. 2010, 28, 4485-4491.
Funding Sources
This work was supported by National Natural Science
Foundation of China (Grant No. 81874288), Key Research and
Development Project of Shandong Province (Grant No.
2017CXGC1401), the Fundamental Research Funds of
Shandong University (Grant No. 2019GN045) and The Joint
Research Funds for Shandong University and Karolinska
Institute (SDU-KI-2019-06).
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2014, 74, 1543-1554.
(9) Garnockjones, K. P. Panobinostat: First Global
Approval, Drugs. 2015, 75, 695-704.
(10) Ning, Z.; Li, Z.; Newman, M. J.; Shan, S.; Wang, X.;
Pan, D.; Zhang, J.; Dong, M.; Du, X.; Lu, X. Chidamide
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Notes
The authors declare no competing financial interest.
ABBREVIATIONS
HDACs,
histone
deacetylase;
HATs,
histone
acetyltransferases; ZBG, zinc binding group; DMF, N,N-
Dimethylformamide; THF, tetrahydrofuran; HATU, 1-
(11) Richardson, P. G.; Harvey, R. D.; Laubach, J. P.;
Moreau, P.; Lonial, S.; San-Miguel, J. F. Panobinostat for the
treatment of relapsed or relapsed/refractory multiple myeloma:
pharmacology and clinical outcomes. Expert. Rev. Clin. Phar.
2016, 9, 35-48.
[Bis(dimethylamino)methylene]
-1H-1,2,3-triazolo[4,5-
b]pyridinium 3-oxid hexafluorophosphate; DIPEA, N,N-
Diisopropylethylamine; HeLa, human cervical cancer; SAHA
(vorinostat), suberanilohydroxamic acid; TSA, trichostatin A;
BSA, albumin from bovine serum; His, histidine; Tyr, tyrosine;
(12) Rivers, Z.T.; Oostra, D.R.; Westholder, J.S.; Vercellotti,
G.M. Romidepsin-associated cardiac toxicity and ecg changes:
a case report and review of the literature. J. Oncol. Pharm.
Pract. 2016, 24, 56-62.
Phe,
Phenylalanine;
Ser,
serine;
MTT,
methylthiazolyldiphenyl-tetrazolium bromide; K562, chronic
myelogenous leukemia cell; HL-60, human promyelocytic
leukemia cell; RPMI-8226, human multiple myeloma cell line;
HCT-116, human colon cancer cells; A549, human lung
cancer cells; PBS, phosphate-buffered saline; ACY-1215,
rocilinostat; PI, propidium iodide.
(13) Smith, N.; Nucera, C. Personalized therapy in patients
with anaplastic thyroid cancer: targeting genetic and
epigenetic alterations. J. Clin. Endocr. Metab. 2015, 100, 35-
42.
(14) Van, V.M.; Westerman, E.; Hamberg, P. Clinical
pharmacokinetics and pharmacodynamics of panobinostat.
Clin. Pharmacokinet. 2017, 57, 21-29.
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