Design and Synthesis of Mercaptoacetamides as Potent, Selective, and Brain Permeable Histone Deacetylase 6 Inhibitors

Article abstract of DOI:10.1021/acsmedchemlett.7b00012

A series of nonhydroxamate HDAC6 inhibitors were prepared in our effort to develop potent and selective compounds for possible use in central nervous system (CNS) disorders, thus obviating the genotoxicity often associated with the hydroxamates. Halogens are incorporated in the cap groups of the designed mercaptoacetamides in order to increase brain accessibility. The indole analogue 7e and quinoline analogue 13a displayed potent HDAC6 inhibitory activity (IC₅₀, 11 and 2.8 nM) and excellent selectivity against HDAC1. Both 7e and 13a together with their ester prodrug 14 and disulfide prodrugs 15 and 16 were found to be effective in promoting tubulin acetylation in HEK cells. The disulfide prodrugs 15 and 16 also released a stable concentration of 7e and 13a upon microsomal incubation. Administration of 15 and 16 in vivo was found to trigger an increase of tubulin acetylation in mouse cortex. These results suggest that further exploration of these compounds for the treatment of CNS disorders is warranted.

Full text of DOI:10.1021/acsmedchemlett.7b00012

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Letter
Design and Synthesis of Mercaptoacetamides as Potent,
Selective, and Brain Permeable Histone Deacetylase 6 Inhibitors
Wei Lv, Guangming Zhang, Cyril Barinka, James H. Eubanks, and Alan P. Kozikowski
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00012 • Publication Date (Web): 07 Apr 2017
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Design and Synthesis of Mercaptoacetamides as Potent, Selective,
and Brain Permeable Histone Deacetylase 6 Inhibitors
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Wei Lv,† Guangming Zhang,‡ Cyril Barinka,§ James H. Eubanks,‡ and Alan P. Kozikowski†*
†Department of Medicinal Chemistry and Pharmacognosy, Drug Discovery Program, University of Illinois at Chicago, Chiꢀ
cago, Illinois 60612, United States
‡Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
§Laboratory of Structural Biology, Institute of Biotechnology, Czech Academy of Science, Vestec, Czech Republic
KEYWORDS: HDAC6 inhibitors, Mercaptoacetamides, brain permeable, CNS disorders
ABSTRACT: A series of nonꢀhydroxamate HDAC6 inhibitors were prepared in our effort to develop potent and selective comꢀ
pounds for possible use in Central Nervous System (CNS) disorders, thus obviating the genotoxicity often associated with the hyꢀ
droxamates. Halogens are incorporated in the cap groups of the designed mercaptoacetamides in order to increase brain accessibilꢀ
ity. The indole analogue 7e and quinoline analogue 13a displayed potent HDAC6 inhibitory activity (IC50 11 nM and 2.8 nM) and
excellent selectivity against HDAC1. Both 7e and 13a together with their ester prodrug 14 and disulfide prodrugs 15 and 16 were
found to be effective in promoting tubulin acetylation in HEK cells. The disulfide prodrugs 15 and 16 also released a stable concenꢀ
tration of 7e and 13a upon microsomal incubation. Administration of 15 and 16 in vivo was found to trigger an increase of tubulin
acetylation in mouse cortex. These results suggest that further exploration of these compounds for the treatment of CNS disorders is
warranted.
Histone deacetylases (HDACs) are a family of zincꢀ
dependent enzymes that specifically remove the acetyl groups
from lysine residues on target proteins, including nuclear hisꢀ
tones, transcription factors, HSP90, cortactin, and αꢀtubulin.1,2
The HDACs together with the histone acetyltransferases
(HATs) regulate the acetylation state of lysine residues present
in the histone tails and thus the condensation status of chromaꢀ
tin, therefore modulating patterns of gene expression.3 Beꢀ
cause of their important role in epigenetic regulation, HDACs
have been identified as therapeutic targets for the treatment of
a wide range of diseases, including cancer, neurodegenerative
diseases, arthritis, and others.4,5
ty as has been observed with inhibition of the class I isoforms,
making it a presumably a safer drug target.13
Currently, 4 HDACIs have been approved by the FDA, inꢀ
cluding suberoylanilide hydroxamic acid (Vorinostat), FK228
(Romidepsin), LBHꢀ589 (Panobinostat), and PXD101 (Beliꢀ
nostat).14 All of these compounds are panꢀinhibitors (low
HDAC isoform selectivity), and they are used exclusively for
the treatment of various types of cancer. Many HDAC6 selecꢀ
tive inhibitors have been developed, including ACYꢀ1215,
Tubacin, Tubastatin A, etc., and some of them are being evalꢀ
uated in clinical trials (ACYꢀ1215 and ACYꢀ241).14,15,16 Howꢀ
ever, a majority of currently reported HDAC6 selective inhibiꢀ
tors bear a hydroxamic acid moiety as the zinc binding group
(ZBG). The hydroxamic acid group has in many cases proven
to be genotoxic, thus leading to chromosomal aberrations, and
as such represents a major hindrance for clinic development
beyond oncology, especially for long term treatments.17 To
identify more promising HDAC6 inhibitors, our group has
initiated studies to develop HDAC6 selective inhibitors with a
mercaptoacetamide group as the ZBG. Our previous efforts
led to the discovery of MFꢀ2ꢀ30, which is a potent and selecꢀ
tive HDAC6 inhibitor (Figure 1).18 Compared to the hydroxꢀ
amic acid inhibitors, the mercaptoacetamides are less likely to
be genotoxic. Moreover, the mercaptoacetamides have also
been reported to exhibit superior neuroprotective effects in
cortical neurons compared to hydroxamates.19 For these reaꢀ
sons, the mercaptoacetamides may represent possible candiꢀ
dates in the quest for HDAC6 inhibitors for treatment of neuꢀ
rological disorders.
The HDAC family includes 11 zincꢀcontaining members,
which are classified into 4 groups, class I (including HDACs 1,
2, 3, and 8), class IIa (including HDACs 4, 5, 7, and 9), class
IIb (including HDACs 6 and 10), and class IV (including
HDAC 11).6,7,8 In these isozymes, HDAC6 has emerged as an
attractive target for drug development due to its unique bioloꢀ
gy. Unlike other HDAC family members, HDAC6 primarily
resides within the cytosol and is responsible for regulating the
acetylation status of specific cytosolic proteins, such as αꢀ
tubulin, HSP90, cortactin, etc.9 HDAC6 is relatively highly
expressed in the central nervous system (CNS), and aberrant
expression of HDAC6 has been linked to the pathological
development of a host of CNS disorders.10 Selective inhibition
of HDAC6 by small molecules promotes survival and reꢀ
growth of neurons following injury, and HDAC6 inhibition
thus holds promise for the treatment of spinal cord injury,
depression, and neurodegenerative diseases such as Alzꢀ
heimer’s, Parkingson’s, and Hutington’s disease.11,12 Moreover,
selective inhibition of HDAC6 does not lead to serious toxiciꢀ
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MFꢀ2ꢀ30 has a negative LogBB value (ꢀ0.27), and as such reaction with the amines 10a-b to provide 11a-b in good yield.
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this compound is predicted to have poor brain penetration
properties, thus limiting its use in the treatment of CNS disꢀ
eases. In this report, we explore modifications of the quinoline
cap group of MFꢀ2ꢀ30 by incorporating halogen atoms to inꢀ
crease the compounds’ lipophilicity and thus brain accessibilꢀ
ity. We have also designed a series of halogenatedꢀindole
based mercaptoacetamides which have been little explored in
the prior literature. The results of these studies will facilitate
the development of potent, selective HDAC6 inhibitors with
appropriate physicochemical properties for treatment of CNS
diseases.
The Boc protecting groups of 11a-b were cleaved under acidic
conditions followed by coupling with 2ꢀ(tritylthio)acetic acid
(5) in the presence of HBTU to afford 12a-b. Finally, the trityl
groups were removed to provide the final products 13a-b.
To synthesize the quinolineꢀbased mercaptoacetamides 13c,
the hydroxyquinoline 8 was first reacted with the alcohol 1b
under Mitsunobu conditions to afford 11c (Scheme 3). Then,
the Boc group of 11c was cleaved under acidic conditions
followed by coupling with 2ꢀ(tritylthio)acetic acid (5) to afford
12c. Finally, the trityl protecting group of 12c was hydrolyzed
to afford the product 13c in good yield.
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Scheme 2. Synthesis of quinolineꢀbased mercaptoacetamides
13a-b.a
Figure 1. The structure of MFꢀ2ꢀ30 and strategy of optimization.
The indoleꢀbased mercaptoacetamides (7a-e) were syntheꢀ
sized starting from NꢀBoc protected amino alcohols with varyꢀ
ing chain lengths (1a-d, Scheme 1). The alcohols 1a-d were
first converted to the bromides 2a-d with carbon tetrabromide
and triphenylphosphine in good yields. Then, the bromides 2a-
d were used to alkylate various substituted indoles 3a-d in the
presence of sodium hydride to afford 4a-e. The Boc protecting
groups of 4a-e were subsequently cleaved under acidic condiꢀ
tions, and the products were reacted with 2ꢀ(tritylthio)acetic
acid (5) with the aid of 2ꢀ(1Hꢀbenzotriazolꢀ1ꢀyl)ꢀ1,1,3,3ꢀ
tetramethyluronium hexafluorophosphate (HBTU) to provide
6a-e. Finally, the trityl groups of 6a-e were removed with triꢀ
fluoroacetic acid and triethylsilane to afford the final products
7a-e.
aReagents and conditions: (a) Tf2O, TEA, DCM, 84%; (b)
Pd(OAc)2, BINAP, Cs2CO3, DCM, 87ꢀ88%; (c) MeOH, HCl; (d)
5, HBTU, DIPEA, DMF, 36ꢀ40%; (e) TFA, Et3SiH, DCM, 50ꢀ
55%.
Scheme 3. Synthesis of quinolineꢀbased mercaptoacetamides
13c.a
Scheme 1. Synthesis of indoleꢀbased mercaptoacetamides 7aꢀ
e.a
o
aReagents and conditions: (a) Ph3P, DEAD, THF, mw, 60 C, 40
min, 80%; (b) TFA, DCM; (c) EDC, DMAP, TEA, DMF, 36% in
two steps; (d) TFA, Et3SiH, DCM, 86%.
The sulfhydryl group of mercaptoacetamide is known to be
unstable and can easily be oxidized. Thioester and disulfide
prodrugs, in which the sulfhydryl group was transiently
masked, are reported to have improved activity in cells and
also in vivo studies.20,21,22 Thus, prodrugs of 7e and 13a were
prepared. For preparation of the indole bearing thioester 14,
compound 6e was treated with trifluoroacetic acid and triꢀ
ethylsilane to cleave the trityl protecting group, followed by
reaction with isobutyric anhydride in the presence of potassiꢀ
um carbonate to provide the ester 14 in good yield (Scheme 4).
The disulfides 15-16 were prepared by oxidizing the correꢀ
sponding thiols (7e and 13a) with iodine in the presence of
triethylamine (Scheme 5).
aReagents and conditions: (a) CBr4, PPh3, THF, 83ꢀ100%; (b) 3a-
d, NaH, DMF, 60ꢀ88%; (c) HCl, MeOH; (d) 5, HBTU, DIPEA,
DMF, 22ꢀ38% over two steps; (e) TFA, Et3SiH, DCM, 50ꢀ77%.
The quinolineꢀbased mercaptoacetamides 13a-b were preꢀ
pared from the hydroxyquinoline 8, which was first treated
with trifluoromethanesulfonic anhydride in the presence of
triethylamine to afford the triflate 9 (Scheme 2). Then, the
triflate 9 was subjected to a BuchwaldꢀHartwig cross coupling
In an effort to synthesize the cyclic disulfide 25, the starting
material, 5ꢀbromoꢀ1ꢀpentene (17), was first oxidized with mꢀ
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CPBA to afford the oxirane (18, Scheme 6). Without purificaꢀ shortening the linker length (from 5 carbons to 4 carbons)
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tion, the crude product of 18 was reacted with 5,6ꢀ
dichloroindole (3a) in the presence potassium hydroxide to
provide 19 in good yield. The oxirane ring was opened by
heating 19 with ammonium hydroxide in a sealed tube at 120
oC, and the product 20 was reacted with 21 in hot acetonitrile
to give compound 22 in excellent yield. Compound 22 underꢀ
went Mitsunobu reaction with thioacetic acid to afford the
thioester 23, which was hydrolyzed with sodium hydroxide
and subsequently treated with TFA/triethylsilane to provide
the dithiol 24. In the last step, the cyclization of 24 to form 25
could not be achieved. Most likely, this is due to conformaꢀ
tional reasons since cyclization requires the amide bond of 24
to adopt a cis conformation, which is known to exist in relaꢀ
tively low abundance (0.07ꢀ0.12%) in typical secondary amꢀ
ides.23 Nonetheless, this attempted synthesis provided a unique
bisꢀthiol for the HDAC6 assay.
boosted the HDAC6 inhibitory activity, and the resulting
compound 13a displayed excellent potency (IC50 2.79 nM) and
selectivity (2470 fold over HDAC1) toward HDAC6. This
SAR diverges from our previous observations on quinoline
based mercaptoacetamides, in which analogues containing
fiveꢀcarbon linkers proved more potent than those with fourꢀ
carbon linkers.6
Similar to quinoline, the indole caps also afforded potent
and selective HDAC6 inhibitors, namely 7a, 7d, and 7e. Genꢀ
erally, the SAR indicates that substituents (isopropyl, chlorine)
at the 3ꢀposition of the indole ring are not favorable for
HDAC6 inhibition, as compounds 7b and 7c were much less
potent than 7a. Replacing the chlorine atom in the indole’s 5ꢀ
position with fluorine (7d) had little effect on HDAC6 inhibiꢀ
tion. In line with our observations for the quinoline analogues,
shortening the linker from 6 carbon atoms to 5 carbon atoms
increased HDAC6 inhibitory activities (7a vs 7e). Introduction
of the second thiol group in the linker region (compound 24)
resulted in a compound with relatively poor HDAC6 inhibition.
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Scheme 4. Synthesis of thiol ester prodrug 14.a
Among the quinoline and indole based mercaptoacetamides,
compounds 7e and 13a are the most potent HDAC6 inhibitors
in each series. Both 7e and 13a displayed excellent potency at
and selectivity for HDAC6 against HDAC1 and HDAC8 (data
in Table S2). Moreover, both compounds also have signifiꢀ
cantly better LogBB values (0.37 and 0.17, respectively) than
MFꢀ2ꢀ30 (LogBB ꢀ0.27). Thus these two compounds 7e and
13a represent candidates for further investigation.
aReagents and conditions: (a) TFA, Et3SiH, DCM; (d) (iꢀ
PrCO)2O, K2CO3, EtOAc, 79% over two steps.
Scheme 5. Synthesis of disulfide prodrugs 15-16.a
Table 1. HDAC Inhibitory Activity of Mercaptoacetamides
7a-e, 13a-c, and 24.a
Selectivity
HDAC6
Log-
BBb
HDAC1
(IC50, nM)
Compound
HDAC1/
HDAC6
(IC50 nM)
aReagents and conditions: (a) TEA, I2, CHCl3, 73ꢀ79%.
Scheme 6. Synthesis of dithiol 24.a
Trichostatin
A
N.T. c
7.7±1.3
> 30000
2.3±1.2
3.3
7a
7b
7c
7d
7e
0.49
0.66
0.50
0.30
0.37
63.9±8.0 > 470
28700±1900 1570±42 18
> 30000 241±81 > 124
29300±1100 65.1±6.9 450
7490±318
11.4±0.9 657
2.79±0.1
2470
2
13a
0.17
6880±650
13b
13c
24
0.38
0.16
0.20
6570±820
> 30000
N.T.c
14.8±5.2 444
33.3±2.5 > 901
534±3.5
N.T.c
aResults were determined by Reaction Biology Corp. (Malvern,
PA, USA); IC50 values displayed are the mean of two experiꢀ
ments. LogBB values were calculated using ACD software. Not
tested.
aReagents and conditions: (a) mꢀCPBA, DCM, 87%; (b) 3a, KOH,
o
o
DMF, 80 C, 77%; (c) NH4OH, CH3CN, 120 C; (d) 21, DMAP,
CH3CN, 60 oC, 92% over two steps; (e) AcSH, DIAD, PPh3, THF,
82%; (f) NaOH, MeOH; (g) Et3SiH, TFA, DCM, 62% over two
steps; (h) I2, TEA, CHCl3.
b
c
To assess the cellular activities of these two HDAC6 inhibiꢀ
tors, HEK 293 cells were treated with mercaptoacetamides 7e
and 13a, the ester prodrug 14, and disulfide prodrugs 15 and
16, and the acetylation of tubulin (the major substrate of
HDAC6) and H3 (the substrate of HDAC1) was monitored
(Figure 2 and Figure S1). The results indicate that both 7e and
13a induce tubulin acetylation in a doseꢀdependent manner.
13a appears to be more potent than 7e in cells, as a clear inꢀ
The HDAC1 and 6 inhibitory activities of mercaptoacetamꢀ
ides 7a-e, 13a-c, and 24 are summarized in Table 1. Incorpoꢀ
ration of two chlorine atoms into the quinoline ring (comꢀ
pound 13b) decreased HDAC6 inhibition (IC50 14.8 nM) when
compared with MFꢀ2ꢀ30 (1.3 nM). Replacing the secondary
amine linker with an ether (compound 13c) further reduced the
HDAC6 inhibitory activity to an IC50 of 33.3 nM. Interestingly,
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duction of tubulin acetylation was observed with 10 ꢁM of crosomes is short. Compound 13b has a halfꢀlife comparable
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13a. This is consistent with their HDAC6 inhibitory activities
(IC50 2.8 nM compared to 11 nM). Interestingly, the ester proꢀ
drug 14 showed improved cellular activity compared to 7e,
possibly due to its increased cell penetration. In addition, both
disulfide prodrugs 15 and 16 displayed comparable efficacy to
the corresponding mercaptoacetamides 7e and 13a. Consistent
with HDAC6 selective inhibition, 7e, 13a, 14 and 15 displayed
only a modest increase in H3 acetylation, which was similar in
magnitude to that seen with Tubastatin A (Figure S1). The
disulfide prodrug 16 did display a moderate effect on H3 acetꢀ
ylation, but this effect remained well below what was obꢀ
served for acetylꢀtubulin at the same dose (Figure S1).
to that of 7e in both human and mouse liver microsomes.
The ester prodrug 14 was found to be very unstable towards
hydrolysis and almost quantitatively converted to 7e when
exposed to microsomes. This result is consistent with the preꢀ
vious reports that thioesters are usually metabolically unstable
in microsomes (t1/2 < 3 min).22 The disulfide prodrugs 15 and
16 afforded compounds with better stability than the ester,
having halfꢀlives (20.7~49.5 min) slightly shorter than or
comparable to those of the corresponding mercaptoacetamides.
In fact, we observed that the disulfides 15 and 16 are readily
converted to the corresponding mercaptoacetamides in microꢀ
somes. As shown in Figure 3 and Figure S2, the incubation of
disulfide 15 or 16 with both human and mouse liver microꢀ
somes resulted in the release of 7e or 13a, which reached a
stable concentration after 15 min.
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Figure 2. Western blots showing acetylated tubulin levels in
HEKꢀ293 cells following 24 hour treatment with selected mercapꢀ
toacetamides at the indicated concentrations. Tubastatin at 10 ꢁM
is included on each blot as a positive control. The negative control
lane on each blot is DMSO (left blot) or medium (right blot).
GAPDH immunoreactivity is shown for each blot to normalize for
lane loading, and no significant differences in unmodified total
tubulin were observed between samples (data not shown).
Figure 3. The metabolism of disulfide prodrug 16 in pooled huꢀ
man (HLM) and mouse liver microsomes (MLM), with the reꢀ
lease of mercaptoacetamides 13a. The percentage of released 13a
was calculated as (Actual concentration of 13a)/(2*Initial concenꢀ
tration of 16).
Table 3. Metabolic Stabilities of Mercaptoacetamides 7b,
7e, 13a, and 13b, and Prodrugs 14-16 in Pooled Human
and Mouse Liver Microsomesa
Since both disulfide prodrugs 15 and 16 effectively induce
tubulin acetylation in cells and are capable of releasing a staꢀ
ble concentration of corresponding mercaptoacetamides (7e
and 13a) in microsomes, they were selected for further studies
in vivo. Mice were treated with 15 or 16 at doses of 20 mg/kg,
and the relative tubulin acetylation levels in the cerebral cortex
were monitored (Figure 4). Both 15 and 16 significantly inꢀ
creased tubulin acetylation levels in the cortex (40% increase
for 15 vs 30% for 16). These results demonstrate that adminꢀ
istration of either disulfide prodrug effectively delivers the
corresponding mercaptoacetamide to the brain at concentraꢀ
tions sufficient to elicit changes in acetylꢀtubulin levels.
Whether these changes capture the peak effect in the brain, or
their respective duration of effect in vivo, will require further
investigation.
Human Liver Microꢀ Male Mouse Liver
somes
Microsomes
Compound
%
Remainꢀ
% Remainꢀ
ing at 60
min
t1/2
(min)
t1/2
(min)
ing at 60
min
7b
33.3%
25.3%
22.3%
32.1%
< 1%
48.8
35.2
32.2
42.5
< 1
44.3%
29.5%
61.7%
39.6%
< 1%
70.0
41.3
91.2
51.0
< 1
7e
13a
13b
14
15
40.5%
8.5%
49.5
20.7
18.2%
18.2%
24.8
25.9
In this report, we have identified several improved mercapꢀ
toacetamides that were designed for possible use in the treatꢀ
ment of CNS disorders. Halogens were incorporated into the
cap group in order to increase lipophilicity and brain accessiꢀ
bility. Several of the prepared analogues, in particular 7e and
13a, displayed potent HDAC6 inhibitory activity and excellent
selectivity against HDAC1. Prodrugs (an ester and disulfides)
were also prepared from 7e and 13a. The disulfide prodrugs
15 and 16 were found to release a stable concentration of the
active mercaptoacetamides 7e and 13a upon incubation with
microsomes. Both mercaptoacetamides 7e and 13a and their
prodrugs 14, 15, and 16, induced a doseꢀdependent increase in
acetylated tubulin in HEK293 cells in vitro. Administration of
the disulfide prodrugs 15 and 16 in vivo also triggered a clear
16
a All tests were performed in duplicate with NADPH.
To investigate the compounds’ metabolic stabilities in vivo,
microsomal stabilities were measured for selected mercaptoaꢀ
cetamides and also the prodrugs, and the results are summaꢀ
rized in Table 3. The indole 7e showed limited stability in both
human and mouse liver microsomes (t1/2 35.2 min and 41.3
min, respectively). Compound 7b offered slightly improved
metabolic stability compared to 7e, likely due to the incorporaꢀ
tion of an isopropyl group in the metabolically active site of
the indole ring. The quinoline 13a showed good stability in
mouse liver microsomes, but the halfꢀlife in human liver miꢀ
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(3) Minucci, S.; Pelicci, P. G. Histone deacetylase inhibitors and
the promise of epigenetic (and more) treatments for cancer. Nat Rev
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increase of acetylated tubulin in mouse cortex. Since these
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mercaptoacetamides are less likely to be burdened with the
genotoxicity associated with hydroxamates (a consequence of
their ability to undergo the Lossen rearrangement to afford an
electrophilic isocyanate), the present results suggest that these
compounds are possible candidates for further studies in aniꢀ
mal models of CNS disorders.
(4) Marks, P. A.; Dokmanovic, M. Histone deacetylase inhibitors:
Discovery and development as anticancer agents. Expert Opin Invest
Drugs 2005, 14, 1497–1511.
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Figure 4. Left: Western blot illustrating tubulin acetylation levels
in mouse cortex following treatment with 15 and 16. For this asꢀ
say, mice (n=3) were injected at 18:00 with 20 mg/kg drug IP,
then given a second 20 mg/kg dose in the morning at 10:00. Mice
were sacrificed, and tissues harvested 6 hours later. GAPDH imꢀ
munoreactivity is shown to normalize for protein loading per lane.
Right: histogram showing the cumulative results expressed as the
densitometric ratio of acetyltubulin to GAPDH per lane, normalꢀ
ized as a percentage of vehicle treated mice. * denotes a signifiꢀ
cant difference from vehicle levels (p<0.05; oneꢀway ANOVA
with Bonferroni postꢀhoc test).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental Details for Chemistry and Biological Assays (PDF)
AUTHOR INFORMATION
Corresponding Author
Alan P. Kozikowski, Phone: +1 312ꢀ996ꢀ7577. Eꢀmail:
kozikowa@uic.edu
Funding Sources
This work was supported by the NIH (NS079183, to APK) and
the EpLink program of the Ontario Brain Institute, and the Canaꢀ
dian Institutes of Health Research (grant MOPꢀ125909 to JHE).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The author gratefully acknowledges Dr. Werner Tuechmantel and
Dr. Sida Shen for reviewing the article and providing comments.
ABBREVIATIONS
(19) Kozikowski, A. P.; Chen, Y.; Gaysin, A.; Chen, B.; D'Anniꢀ
bale, M. A.; Suto, C. M.; Langley, B. C. Functional differences in
epigenetic modulatorsꢀsuperiority of mercaptoacetamideꢀbased hisꢀ
tone deacetylase inhibitors relative to hydroxamates in cortical neuron
neuroprotection studies. J Med Chem 2007, 50, 3054–61.
(20) Itoh, Y.; Suzuki, T.; Kouketsu, A.; Suzuki, N.; Maeda, S.; Yoꢀ
shida, M.; Nakagawa, H.; Miyata, N. Design, synthesis, structureꢀꢀ
selectivity relationship, and effect on human cancer cells of a novel
series of histone deacetylase 6ꢀselective inhibitors. J Med Chem.
2007, 50, 5425ꢀ38.
CNS, Central Nervous System; HDAC, Histone Deacetylase;
HAT, Histone acetyltransferase; HLM, human liver microsome;
MLM, mouse liver microsome.
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Design and Synthesis of Mercaptoacetamides as Potent, Selective,
and Brain Permeable Histone Deacetylase 6 Inhibitors
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Wei Lv, Guangming Zhang, Cyril Barinka, James H. Eubanks, and Alan P. Kozikowski
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