Synthesis of N′-propylhydrazide analogs of hydroxamic inhibitors of histone deacetylases (HDACs) and evaluation of their impact on activities of HDACs and replication of hepatitis C virus (HCV)

Article abstract of DOI:10.1016/j.bmcl.2019.06.006

N′-Propylhydrazide analogs of hydroxamic inhibitors of histone deacetylases (HDACs), including tubastatin A, vorinostat and belinostat, were synthesized. All prepared compounds inhibited HDAC1/2/3, but not HDAC6, except for one hydrazide analog of HDAC4/5/7 inhibitor that was completely inactive. A novel 4-substituted derivative of N′-propylbenzohydrazide with extremely high anti-HCV activity was discovered.

Full text of DOI:10.1016/j.bmcl.2019.06.006

Accepted Manuscript
Synthesis of N'-propylhydrazide analogs of hydroxamic inhibitors of histone
deacetylases (HDACs) and evaluation of their impact on activities of HDACs
and replication of hepatitis C virus (HCV)
Maxim V. Kozlov, Konstantin A. Konduktorov, Anastasia S. Shcherbakova,
Sergey N. Kochetkov
PII:
S0960-894X(19)30373-7
https://doi.org/10.1016/j.bmcl.2019.06.006
BMCL 26484
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 March 2019
24 May 2019
5 June 2019
Please cite this article as: Kozlov, M.V., Konduktorov, K.A., Shcherbakova, A.S., Kochetkov, S.N., Synthesis of
N'-propylhydrazide analogs of hydroxamic inhibitors of histone deacetylases (HDACs) and evaluation of their
impact on activities of HDACs and replication of hepatitis C virus (HCV), Bioorganic & Medicinal Chemistry
Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.06.006
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Synthesis of N'-propylhydrazide analogs of hydroxamic inhibitors of histone
deacetylases (HDACs) and evaluation of their impact on activities of HDACs and
replication of hepatitis C virus (HCV).
Maxim V. Kozlov*, Konstantin A. Konduktorov, Anastasia S. Shcherbakova, Sergey N.
Kochetkov
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991 Russia
ABSTRACT
N'-Propylhydrazide analogs of hydroxamic inhibitors of histone deacetylases (HDACs),
including tubastatin A, vorinostat and belinostat, were synthesized. All prepared compounds
inhibited HDAC1/2/3, but not HDAC6, except for one hydrazide analog of HDAC4/5/7 inhibitor
that was completely inactive. A novel 4-substituted derivative of N'-propylbenzohydrazide with
extremely high anti-HCV activity was discovered.
Key words: HDAC; HCV; Inhibitor; Pharmacophore; Hydroxamic Acid; N'-Propylhydrazide
*Corresponding author.
E-mail address: kozlovmavi@gmail.com
Histone acetyltransferases (HATs) transfer the acetyl group of acetyl coenzyme A to lysine
residues of protein substrates, while histone deacetylases (HDACs) catalyze the reverse process.
Together, both groups of enzymes support the necessary level of acetylation of histones,
transcription factors, and other nuclear and cytoplasmic proteins.
Zinc-dependent HDACs of class I, IIb and IV catalyze the hydrolysis of the acetamide
bond in the ε-N-acetyl lysine residues of protein substrates, coordinating the oxygen atom of the
carbonyl group by the zinc ion that is a part of the enzyme active site.1 Histone deacetylases of
these classes can be localized either only in nucleus (HDAC1/2/3 class I), or in the nucleus and
cytoplasm (HDAC8 class I), or only in the cytoplasm (HDAC6/10 class IIb and HDAC11 class
IV).2 Note in particular that HDAC4/5/7/9 comprising class IIa do not have deacetylating
activity but are capable of catalyzing detrifluoroacetylation of artificial substrates.3
The structure of the classic hydroxamic multipotent inhibitor of HDACs – vorinostat –
contains a sequence of three main elements that form the pharmacophore: cap, linker and zinc
binding group (ZBG) (Fig. 1). On the one hand, the linker is associated with ZBG and facilitates
its penetration into the hydrophobic “tunnel” of the active site of HDACs, at the bottom of which
chelation of the catalytic zinc ion takes place. On the other hand, the linker is associated with the

cap structure, most often aryl or heteroaryl radical which additionally interacts with the protein
substrate binding cavity, affecting the strength and selectivity of inhibition.4
However, in the non-hydroxamic inhibitors of HDACs class I, one more element of the
pharmacophore can be distinguished – the leader that is preceding ZBG and is the first to enter
the hydrophobic “tunnel”. Penetrating further into the acetate release channel, the leader ensures
the necessary positioning of the ZBG relative to the catalytic zinc ion (Fig. 1). Choosing the right
combination of linker-ZBG-leader makes it possible to control the selectivity of inhibition of
isoform HDACs class I even in the case of minimum sizes of cap, as demonstrated for UFO10
and Cmpd4 or Cmpd60 (Fig. 1).
Catalytic
center
Acetyl-lysine
binding tunnel
Protein substrate
binding cavity
Acetate release
channel
Cap
Linker
ZBG
Leader
Zn2+
HDAC1 IC50: 0.06 M
HDAC2 IC50: 0.3 M
HDAC3 IC50: 0.02 M
HDAC8 IC50: 0.8 M
HDAC6 IC50: 0.009 M
O
H
N
OH
N
H
HDAC4/5/7/9 IC50
:
O
> 10 M
Vorinostat
O
HDAC1 IC50: 0.5 M
HDAC2 IC50: 0.1 M
HDAC3 IC50: 0.06 M
HDAC8 IC50: 1.5 M
HDAC6 IC50: 9.1 M
H
N
N
H
HDAC4/5/7/9 IC50
:
Br
> 100 M
UFO10
O
NH2
HDAC1 IC50: 1.7 M
HDAC2 IC50: 3.9 M
HDAC8 IC50: 0.09 M
HDAC6 IC50: 30 M
N
Cmpd4
Cl
Cl
H2N
O
O
HDAC1 IC50: 0.007 M
HDAC2 IC50: 0.049 M
HDAC3 IC50: 10 M
N
N
H
H
HDACs 4-8 IC50: >10 M
S
Cmpd60
Fig. 1. Pharmacophore 2D model for HDAC inhibitors carrying different zinc binding groups (ZBG): Vorinostat
(hydroxamate),5 UFO10 (N'-butylhydrazide),5 Cmpd4 (chiral α-amino-ketone)6 and Cmpd60 (α-
aminobenzamide).7,8

Hydroxamic inhibitors of histone deacetylases block the replication of the hepatitis C virus
(HCV), however, whether it happens by HDACs-dependent mechanism or not is still not quite
clear.9-13 We conducted a comparative study of hydroxamic inhibitors of HDACs and their
hydrazide analogues (Fig. 2) in order to find out how the introduction of a ZBG-leader fragment
in the form of the N'-propylhydrazide residue will affect (i) the selectivity of the inhibition of
HDACs, (ii) blocking of HCV replication, and (iii) how these processes are associated with each
other.
CONHX
CONHX
BHA (X=OH)
3-PHA (X=OH)
3-PPH (X=NHPr)
BMH (X=NHMe)
BEH (X=NHEt)
BPH (X=NHPr)
H
N
CONHX
O
CONHX
Vorinostat
(X=OH)
Vorinostat-PH (X=NHPr)
4-BHA (X=OH)
4-BPH (X=NHPr)
CONHX
CHA (X=OH)
CPH (X=NHPr)
CONHX
CONHX
N
Cmpd12a
(X=OH)
Cmpd12a-PH (X=NHPr)
O
N
S
Belinostat
(X=OH)
NH
O
Belinostat-PH (X=NHPr)
CONHX
CONHX
O
N
Tubastatin A
(X=OH)
Cmpd13
(X=OH)
Tubastatin-PH (X=NHPr)
Cmpd13-PH (X=NHPr)
N
Fig. 2. Structures of tested hydroxamic acids (HA) and N'-propylhydrazide analogs (PH).
The synthesis of compounds tested in this study is presented in Scheme 1. All N'-
propylhydrazide analogs were obtained by reductive alkylation method, while N'-methyl- and N'-
ethylbenzohydrazide (BMH and BEH) were synthesized by alkylation of benzohydrazide with
the appropriate dialkyl sulfate with the subsequent product isolation through the carbamate
derivative. Cinnamic acid hydrazides were prepared by hydrazinolysis of their NHS esters at
room temperature to prevent the formation of pyrazolidin-3-one cycle.14 Hydroxamates – 4-
phenylbenzohydroxamic acid (4-BHA), 3-phenylpropanhydroxamic acid (3-PHA) and

Cmpd13 – were synthesized by activation of the corresponding carboxylic acid with
carbonyldiimidazole and subsequent hydroxyaminolysis, as described earlier.15
The antiviral effect of the compounds was determined in a test system of a full-length
replicon in cells of the Huh7 luc/neo line, whereas the efficiency of inhibition of HDAC1/2/3
(nuclear localization) and HDAC6 (cytoplasmic localization) was assessed using the Western
blot analysis for the content of the acetylated forms of the corresponding substrate proteins – Ac-
K9/K14 of histone H3 and Ac-K40 of α-tubulin in cell lysates.16
O
(a)
NHR
NR2
O
O
O
Ph
Ph
N
H
NHR
NRBoc
NH2
(ii)
(i)
(iii)
BMH (R=Me )
BEH (R=Et )
Ph
N
Ph
N
H
Ph
N
H
H
O
N
H
(b)
O
O
O
BPH (vii)*
Tubastatin-PH
CPH
R
(iv)
(v)
R
O N
OH
O
O
Belinostat-PH
(vii)
O
R
R
4-BPH, 3-PPH
Cmpd12a-PH
Vorinostat-PH
Cmpd13-PH
HN NHPr
HN NH2
(vi)
O
R
O CH3
* - first step in
preparation
Scheme 1. Reagents and conditions: (a) (i) (MeO)2SO4 or (EtO)2SO4, 18h; (ii) Boc2O, 1,2-DCE, 18h; (iii) TFA,
0.5h. (b) (iv) NHS, DCC, DMSO/CH2Cl2, 1h [Tubastatin-PH] or NHS, DCC, MeCN/THF, 1.5h [CPH and
Belinostat-PH]; (v) NH2NH2•H2O, DMSO/CH2Cl2/MeOH, 1h [Tubastatin-PH] or NH2NH2•H2O, MeOH, 0.5h [CPH
and Belinostat-PH]; (vi) NH2NH2•H2O, EtOH, 3h [3-PPH and Vorinostat-PH] or NH2NH2•H2O, MeOH/EtOH, 70
°C, 5h [4-BPH, Cmpd12a-PH and Cmpd13-PH]; (vii) CH3CH2CHO, MeOH, 4h, vacuum evaporation, NaBH4, i-
PrOH, 85 °C, 1.5h.
Properties of benzoic acid derivatives as anti-HCV agents are summarized in Table 1,
whereas the results of the Western blot analysis are presented in Fig. 3. In agreement with
previous data, BHA demonstrated selective inhibition of HDAC6 and moderate anti-HCV
activity.15,16 The lower analogues, BMH and BEH, were inactive in both tests. In contrast, BPH
effectively inhibited HDAC1/2/3, but not HDAC6, and had antiviral activity even stronger than
that of BHA.
Thus, among N'-alkyl-substituted benzohydrazide (alkyl = Me, Et and Pr), the inhibition of
HDAC1/2/3 and the suppression of HCV replication were tightly associated with each other. It
should be noted that BMH, BEH, and BPH are the closest homologues, and it is difficult to
expect the existence of any additional antiviral target with the same profile of sensitivity to the

elongation of the alkyl radical. As previously shown, selective inhibition of HDAC3 with N-
(ortho-aminophenyl)carboxamide derivative, RGFP966, led to the suppression of HCV
replication.17 The authors attributed the antiviral effect of RGFP966 to changes in the expression
of LEAP-1 and Apo-A1 genes as a result of the hyperacetylation of histone H3 and transcription
factors HIF1a and STAT3. It cannot be excluded that BPH blocks HCV replication in a similar
way.
The benzohydroxamates that we tested – 4-ВНА, Cmpd12a and tubastatin A – have an
aromatic or heterocyclic cap at the 4-position of linker’s benzene ring. In accordance with data
from literature, Cmpd12a and tubastatin A demonstrated highly selective inhibition of HDAC6,
which was ensured by their heterocyclic caps.18,19 However, the hydrazide analogues – 4-ВРН,
Cmpd12a-РН and tubastatin-РН – did not inhibit HDAC6, but only HDAC1/2/3. Thus, the N'-
propylhydrazide ZBG-leader fragment completely changed the selectivity of inhibition, and the
caps that were responsible for the selective inhibition of HDAC6 by hydroxamic precursors did
not prevent this.
Fig. 3. Accumulation of acetylated α-tubulin and histone H3 in Huh7-luc/neo cells treated with benzohydroxamic
acids and their N'-propylbenzohydrazide analogs for 24 h.
The approximately equal antiviral potency of benzohydroxamates – 4-ВНА, Cmpd12a
and tubastatin A – changed in opposite directions upon the transition to benzohydrazide
analogues – 4-BHP, Cmpd12a-PH or tubastatin-PH. Accordingly, the value of EC50 either
increased 3-fold or fell 11-fold, or remained almost unchanged. Interestingly, Cmpd12a-РН

showed an excellent antiviral activity with an EC50 value of 0.025 μM, but only slightly inhibited
HDAC1/2/3 at a concentration of 0.1 μM. It is very likely that the suppression of HCV
replication by this compound occurred via the HDAC-independent mechanism.
Table 1
SAR studies of benzohydroxamic acids and their N'-propylbenzohydrazide analogs
Inhibition
of HDACs
6>>1/2/3
EC50
(µM)
15a
CC50
(µM)
210a
Compound
BHA
Cap
Linker
ZBG
HA
MH
EH
Leader
none
Me
TI
14a
−
BMH
BEH
BPH
NA
NA
NA
NA
5.5
>1000
>1000
120
none
Et
−
PH
Pr
1/2/3
22
4-BHA
4-BPH
HA
PH
none
Pr
6>>1/2/3
1/2/3
0.40
1.5
30
75
5.9
3.9
HA
none
6
0.27
7.9
9.9
29
Cmpd12a
N
N
PH
HA
PH
Pr
none
Pr
1/2/3
6
0.025
400
Cmpd12a-PH
Tubastatin A
Tubastatin-PH
0.30b
0.24
11b
5.3
37b
22
N
1/2/3>>6
N
a See Ref. 15
b See Ref. 10
In the literature, the hydrazide-based class I selective HDAC inhibitors are described, with
linker structure in the form of a -(CH2)n- fragment of ε-amino carboxylic acids (n=6-8) or in the
form of a residue of para-substituted cinnamic acid.20 The potent inhibitors of HDACs –
vorinostat and belinostat – possess almost identical linker structures (Fig. 1 and 2). According to
the literature, both of these compounds suppressed HCV replication in the subgenomic replicon
system, however, with low values of therapeutic index.11 We thought it interesting to compare
vorinostat and belinostat with their N'-propylhydrazide analogs, both as inhibitors of HDACs and
as anti-HCV agents. In this series of experiments, hydroxamic and N'-propylhydrazide
derivatives of 3-phenylpropanoic acid (3-PHA and 3-PPH) and cinnamic acid (CHA and
CPH) played the role of reference compounds that do not possess a cap structure.

Fig. 4. Accumulation of acetylated α-tubulin and histone H3 in Huh7-luc/neo cells treated with aliphatic and
cinnamic hydroxamic acids and their N'-propylbenzohydrazide analogs for 24 h.
As can be seen from the results presented in Fig. 4, all four of the tested hydroxamic
inhibitors of HDACs had a multipotent effect, while all four of their hydrazide analogs inhibited
only HDAC1/2/3. Thus, “fixation” of the new selectivity with the help of the N'-propylhydrazide
ZBG-leader fragment occurred both in the absence and in the presence of cap structures, in full
agreement with the results obtained for benzohydrazide inhibitors (Fig. 3).
Antiviral properties of hydroxamates and hydrazides of aliphatic and cinnamic acids are
summarized in Table 2. Note that the obtained EC50 and CC50 values for vorinostat and CHA
were slightly different from those previously published, however, in the case of belinostat, the
discrepancies were minimal.11 The loss of inhibitory effect on HDAC6 by the hydrazides 3-
PPH и vorinostat-PH was accompanied by a change in antiviral activity in opposite directions –
for instance, the EC50 value decreased by a factor of 1.4 or increased by a factor of 2.3 when
compared with the corresponding values for 3-PНА and vorinostat. Suddenly, vorinostat-PH
was 11 times less cytotoxic than its hydroxamic precursor. Interestingly, cinnamic acid
hydrazides – CPH and belinostat-PH – lost antiviral activity compared to CHA and belinostat,
but retained the strength of the cytotoxic effect. In the case of belinostat-PH, this meant a
complete loss of selective suppression of HCV replication.

Table 2
SAR studies of aliphatic, cinnamic and hydroxamic acids and their N'-propylbenzohydrazide analogs and TMP269
Kind of
inhibited
HDACs
EC50
(µM)
CC50
(µM)
Compound
3-PHA
Cap
Linker
ZBG
Leader
TI
HA
PH
none
Pr
1/2/3/6
1/2/3
5.2
3.8
110
96
21
25
none
3-PPH
0.56
0.64
1.1
H
N
HA
PH
HA
PH
HA
none
Pr
1/2/3/6
1/2/3
Vorinostat
0.36a
1.9a
5.3a
-(CH2)6-
O
O
1.3
7.0
5.4
Vorinostat-PH
CHA
2.0
20
10
none
Pr
1/2/3/6
1/2/3
0.86a
39a
45a
none
5.4
18
3.3
CPH
0.19
0.65
3.4
S
none
1/2/3/6
Belinostat
HN
0.12a
0.68a
5.7a
O
PH
Pr
1/2/3
0.55
0.68
1.2
Belinostat-PH
HA
PH
none
Pr
3/5/7b
none
0.75
NA
300
400
Cmpd13
>300
−
Cmpd13-PH
O
F
F
F
O
3/5/7/9c
4.5
83
18
TMP269
none
N
N
N
O
O
O
NH
a See Ref. 11
b See Ref. 22
c See Ref. 23
As previously shown, HCV infection enhanced the expression of HDAC9, which in turn
led to an increase in the expression of gluconeogenic genes via deacetylation of the transcription
factor FoxO1 together with HDAC3.21 The properties of two selective inhibitors of HDACs class
IIa, TMP269 and Cmpd13, as anti-HCV agents are listed in Table 2. Although both compounds
according to the literature had a similar profile of inhibition of HDACs,22,23 Cmpd13 was many
times more efficient than TMP269 both in antiviral activity and in selectivity of action. So, we
demonstrated for the first time effective suppression of HCV replication with selective HDAC
class IIa inhibitors and their potential usefulness for treating HCV-induced abnormal glucose
homeostasis.21
The hydrazide analog Cmpd13-PH was inactive in both luciferase and MTT tests and did
not inhibit either HDAC1/2/3 or HDAC6 (Table 2). To explain the resistance of HDAC1/2/3 to
the N'-propylhydrazide ZBG-leader fragment of Cmpd13-PH, it should be recalled that the
catalytic pocket of HDACs class IIa is capable of accommodating more bulky molecules than
other HDACs.3 It appears that the 9H-xanthene group of Cmpd13-PH simply cannot be correctly

oriented inside the active site of HDAC1/2/3. In addition, for some unknown reason, Cmpd13-
PH probably does not inhibit HDAC4/5/7/9, as indicated by the complete absence of antiviral
activity of this compound.
In conclusion, a comparative study of the hydroxamic inhibitors of HDACs and their
hydrazide analogues demonstrated that the N'-propylhydrazide ZBG-leader fragment ensured a
selective effect on HDAC1/2/3 regardless of the structure of the cap-linker fragment of its
precursor, a hydroxamic inhibitor. An important exception to this rule was the complete
inactivity of the hydrazide analog of HDACs class IIa hydroxamic inhibitor carrying a bulky
cap-linker group. No consistent patterns in antiviral activity changes during the transition from
hydroxamic inhibitors of HDACs of class I and IIb to their hydrazide analogs were found,
however, among N'-alkyl-substituted benzohydrazides, the suppression of HCV replication was
associated with the inhibition of HDAC1/2/3. Our results clearly demonstrated that different
HDAC inhibitors targeting HDACs class I, IIa and IIb effectively suppress HCV replication.
Therefore, the use of broad-spectrum inhibitors of HDACs for the treatment of HCV infection
deserves closer consideration.
Acknowledgments
The work was supported by the Russian Foundation for Basic Research (Grant # 17-04-
00175) and by the Program of Fundamental Research of the State Academies of Sciences (Grant
# 01201363818).
References
1. Lombardi PM, Cole KE, Dowling DP, et al. Structure, mechanism, and inhibition of
histone deacetylases and related metalloenzymes. Curr Opin Struc Biol. 2011;21:735–
743.
2. Witt O, Deubzer HE, Milde T, et al. HDAC family: What are the cancer relevant targets?
Cancer Lett. 2009;277:8–21.
3. Lahm A, Paolini C, Pallaoro M, et al. Unraveling the hidden catalytic activity of
vertebrate class IIa histone deacetylases. Proc Natl Acad Sci USA. 2007;104:17335–
17340.
4. Melesina J, Praetorius L, Simoben CV, et al. Design of selective histone deacetylase
inhibitors: rethinking classical pharmacophore. Future Med Chem. 2018;10:1537–1540.
5. Whitehead L, Dobler MR, Radetich B, et al. Human HDAC isoform selectivity achieved
via exploitation of the acetate release channel with structurally unique small molecule
inhibitors. Bioorg Med Chem. 2011;19:4626–4634.

6. Wang Y, Stowe RL, Pinello CE, et al. Identification of histone deacetylase inhibitors
with benzoylhydrazide scaffold that selectively inhibit class I histone deacetylases. Chem
Biol. 2015;22:273–284.
7. Methot JL, Chakravarty PK, Chenard M, et al. Exploration of the internal cavity of
histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2). Bioorg
Med Chem Lett. 2008;18:973–978.
8. Wambua MK, Nalawansha DA, Negmeldin AT, et al. Mutagenesis studies of the 14 Å
internal cavity of histone deacetylase 1: insights toward the acetate-escape hypothesis and
selective inhibitor design. J Med Chem. 2014;57:642−650.
9. Sato A, Saito Y, Sugiyama K, et al. Suppressive effect of the histone deacetylase
inhibitor suberoylanilide hydroxamic acid (SAHA) on hepatitis C virus replication. J Cell
Biochem. 2013;114:1987–1996.
10. Kozlov MV, Kleymenova AA, Konduktorov KA, et al. Selective inhibitor of histone
deacetylase 6 (Tubastatin A) suppresses proliferation of hepatitis C virus replicon in
culture of human hepatocytes. Biochemistry Moscow. 2014;79:637–642.
11. Ai T, Xu Y, Qiu L, et al. Hydroxamic Acids Block Replication of Hepatitis C Virus. J
Med Chem. 2015;58:785–800.
12. Kozlov MV, Malikova AZ, Kamarova KA, et al. Synthesis of pyridyl-4-oxy-substituted
N-hydroxy amides of cinnamic acid as new inhibitors of histone deacetylase activity and
hepatitis C virus replication. Russ J Bioorg Chem. 2018;44:453–460.
13. Zhao F, Liu N, Zhan P, Liu X. Repurposing of HDAC inhibitors toward anti-hepatitis C
virus drug discovery: teaching an old dog new tricks. Future Med Chem. 2015;7:1367-
1371.
14. Harada R, Kondo H. Synthesis of α,β-unsaturated carboxylic hydrazides. Bull Chem Soc
Jpn. 1968;41:2521–2523.
15. Kozlov MV, Kleymenova AA, Romanova LI, et al. Benzohydroxamic acids as potent
and selective anti-HCV agents. Bioorg Med Chem Lett. 2013;23:5936–5940.
16. Kozlov MV, Kleymenova AA, Romanova LI, et al. Pyridine hydroxamic acids are
specific anti-HCV agents affecting HDAC6. Bioorg Med Chem Lett. 2015;25:2382–
2385.
17. Zhou Y, Wang Q, Yang Q, et al. Histone deacetylase 3 Inhibitor suppresses hepatitis C
virus replication by regulating Apo-A1 and LEAP-1 expression. Virol Sin. 2018;33:418–
428.

18. Shen S, Benoy V, Bergman JA, et al. Bicyclic-capped histone deacetylase 6 inhibitors
with improved activity in a model of axonal Charcot-Marie-Tooth disease. ACS Chem
Neurosci. 2016;7:240−258.
19. Butler KV, Kalin J, Brochier C, et al. Rational design and simple chemistry yield a
superior, neuroprotective HDAC6 inhibitor, Tubastatin A. J Am Chem Soc.
2010;132:10842–10846.
20. Li X, Peterson YK, Inks ES, et al. Class I HDAC inhibitors display different antitumor
mechanism in leukemia and prostatic cancer cells depending on their p53 status. J Med
Chem. 2018;61:2589−2603.
21. Chen J, Wang N, Dong M, et al. The metabolic regulator histone deacetylase 9
contributes to glucose homeostasis abnormality induced by hepatitis C virus infection.
Diabetes 2015;64:4088–4098.
22. Tessier P, Smil DV, Wahhab A, et al. Diphenylmethylene hydroxamic acids as selective
class IIa histone deacetylase inhibitors. Bioorg Med Chem Lett. 2009;19:5684–5688.
23. Lobera M, Madauss KP, Pohlhaus DT, et al. Selective class IIa histone deacetylase
inhibition via a nonchelating zinc-binding group. Nat Chem Biol. 2013;9:319–325.