The effect of various zinc binding groups on inhibition of histone deacetylases 1-11

Article abstract of DOI:10.1002/cmdc.201300433

Histone deacetylases (HDACs) have the ability to cleave the acetyl groups of ε-N-acetylated lysine residues in a variety of proteins. Given that human cells contain thousands of different acetylated lysine residues, HDACS may regulate a wide variety of processes including some implicated in conditions such as cancer and neurodegenerative disorders. Herein we report the synthesis and ina vitro biochemical profiling of a series of compounds, including known inhibitors as well as novel chemotypes, that incorporate putative new zinc binding domains. By evaluating the compound collection against all 11 recombinant human HDACs, we found that the trifluoromethyl ketone functionality provides potent inhibition of all four subclasses of the Zn²⁺- dependent HDACs. Potent inhibition was observed with two different scaffolds, demonstrating the efficiency of the trifluoromethyl ketone moiety as a zinc binding motif. Interestingly, we also identified silanediol as a zinc binding group with potential for future development of non-hydroxamate classa I and classa IIb HDAC inhibitors.

Full text of DOI:10.1002/cmdc.201300433

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DOI: 10.1002/cmdc.201300433
The Effect of Various Zinc Binding Groups on Inhibition of
Histone Deacetylases 1–11
Andreas S. Madsen, Helle M. E. Kristensen, Gyrithe Lanz, and Christian A. Olsen*[a]
Histone deacetylases (HDACs) have the ability to cleave the
acetyl groups of e-N-acetylated lysine residues in a variety of
proteins. Given that human cells contain thousands of different
acetylated lysine residues, HDACS may regulate a wide variety
of processes including some implicated in conditions such as
cancer and neurodegenerative disorders. Herein we report the
synthesis and in vitro biochemical profiling of a series of com-
pounds, including known inhibitors as well as novel chemo-
types, that incorporate putative new zinc binding domains. By
evaluating the compound collection against all 11 recombinant
human HDACs, we found that the trifluoromethyl ketone func-
tionality provides potent inhibition of all four subclasses of the
Zn2+-dependent HDACs. Potent inhibition was observed with
two different scaffolds, demonstrating the efficiency of the tri-
fluoromethyl ketone moiety as a zinc binding motif. Interest-
ingly, we also identified silanediol as a zinc binding group with
potential for future development of non-hydroxamate class I
and class IIb HDAC inhibitors.
Introduction
Histone deacetylases (HDACs) are Zn2+-dependent hydrolytic
enzymes with the ability to cleave acetyl groups of e-N-acety-
lated lysine residues in a variety of proteins.[1] Humans have 11
isoforms (HDACs 1–11), which are classified according to se-
quence. Thus, HDACs 1–3 and 8 are referred to as class I en-
zymes, HDACs 4, 5, 7, and 9 are class IIa, HDACs 6 and 10
belong to class IIb, and HDAC11 is the sole member of clas-
s IV.[2] The HDACs localize to different subcellular compart-
ments, appear in a variety of multiprotein complexes,[3] and
have varying intrinsic deacetylase capacities.[4] Furthermore,
their individual substrate specificities are not yet well under-
stood, and the recent realization that thousands of different
lysine residues are acetylated in our cells[5] may indicate that
a wide variety of processes are regulated by HDACs in addition
to epigenetic chromatin-related actions.[6] The recent realiza-
tion that lysine side chains may also be post-translationally
functionalized with other acyl groups with regulatory function
adds yet another degree of complexity.[7] Thus far, very few
studies of HDAC activity against these e-N-acyl lysine residues
have appeared,[8] whereas members of the class III HDACs, the
sirtuins, have shown promising activities against some of these
e-N-acyl lysine residues.[9] However, due to the fundamentally
different mechanism of action of the sirtuins (NAD+ co-factor
dependent), the chemotypes known to inhibit class III HDAC
enzymes are structurally different from those that inhibit other
HDAC classes. It was therefore decided to focus on the Zn2+
-dependent HDACs in the present study.
Inhibitors of HDACs have received considerable attention, in
particular due to their potential as anticancer agents, and two
HDAC-targeting compounds have been approved by the US
Food and Drug Administration for treatment of cutaneous T-
cell lymphoma (vorinostat (3) and romidepsin (6), Figure 1).[10]
Figure 1. Examples of known HDAC inhibitors.
[a] Dr. A. S. Madsen, H. M. E. Kristensen, G. Lanz, Prof. C. A. Olsen+
Department of Chemistry, Technical University of Denmark
Kemitorvet 207, Kongens Lyngby, 2800 (Denmark)
E-mail: cao@kemi.dtu.dk
[+] Note: Prof. Olsen’s laboratory is moving to the Faculty of Health and Medi-
cal Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copen-
hagen (Denmark); future correspondence should be directed there.
However, a wide variety of conditions have been related to
HDAC dysfunction, including neurodegenerative disorders,[11]
memory loss,[12] and cystic fibrosis.[13] The potential of reversing
aberrant epigenetic states associated with a disease by target-
ing HDAC enzymes with small molecules is attractive. This has
therefore resulted in the development of numerous HDAC in-
hibitors,[14] of which several have entered clinical trials for anti-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201300433.
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cancer activity and other indications.[15] As HDAC enzymes
bind to and process acetylated lysine side chains, mimicry of
this functionality has emerged as a general principle for design
of HDAC inhibitors. As such, most HDAC inhibitors contain
a linker moiety (mimicking the lysine side chain), which proj-
ects a zinc binding group into the position of the active site,
where the substrate acetamide (e-N-acetyl) would interact with
the metal ion. At the opposite end of the linker, the inhibitors
generally have a functionality referred to as the “cap” group. A
selection of well-known HDAC inhibitors of varying complexity,
potency, and selectivity is shown in Figure 1. However, on
closer inspection, these all adhere to this general design al-
though they have varying linkers, zinc binding groups such as
carboxylate (1 and 2), hydroxamate (3 and 4), ethyl ketone (5),
and thiol (6), as well as “cap” groups ranging from 4-heptyl (2)
to tetrapeptide (5) or depsi-pentapeptide as realized by intra-
cellular reduction of the disulfide in compound 6. Since the
discovery of SAHA (vorinostat),[10a,16] the strongly zinc chelating
hydroxamic acid functionality has been incorporated into
a wide variety of chemically diverse scaffolds.[14a] However, due
to drawbacks associated with hydroxamates such as weak
binding to class IIa isozymes and otherwise poor selectivity, in-
cluding possible binding to different classes of metallopro-
teins,[17] alternative functionalities and inhibitor design strat-
egies are of interest.
One such approach has been to rely on a strong contribu-
tion to the overall binding affinity through the “cap” group in
combination with a zinc binding element of intermediate
strength,[18] such as the ketone found in apicidin (5),[19] or in
a few recent cases no zinc binding group at all.[20] Alternatively,
based on the series of o-aminoanilides reported to inhibit pri-
marily HDAC1, 2, and 3,[21] the discovery of diverse functionali-
ties that interact with the bottom of the active site around the
zinc-containing pocket has been pursued.[21a,22] Stronger zinc
binding elements, including thiols,[10b,23] electron deficient tri-
fluoromethyl ketones,[24] and a-ketoamides[25] have also been
described as HDAC inhibitors. In this work, we have synthe-
sized and profiled a number of new potential zinc binding
groups on different scaffolds and directly compared their activ-
ities to a series of known inhibitors (including 1–5).
Figure 2. Tested phenylbutyrate, valproate, and vorinostat analogues.
mediate strength Zn2+ coordinators thus compounds 8 and 18
were included as intermediate strength Zn2+ coordinators.[26]
a-Fluorinated ketones are considerably more electrophilic due
to the strong electron withdrawing effect of fluoride, and tri-
fluoromethyl ketones are therefore readily hydrated in aque-
ous media at physiological pH. The resulting geminal diol can
then serve as a transition-state mimic, which has been specu-
lated to be the reason for the previously reported potency of
compound 20.[24a] In agreement with this, a crystal structure of
compound 20 in complex with a class-IIa-like bacterial HDAH
(HDAC-like amidohydrolase) consistent with bidentate com-
plexation of the hydrate to the active site Zn2+ ion has also
been reported.[27] Furthermore, trifluoromethyl ketones con-
taining thiophene linkers have been reported as class IIa selec-
tive HDAC inhibitors,[24c–f] so the trifluoromethyl ketone func-
tionality was included in compounds 9, 10, and 20 of our ini-
tial series. Furthermore, we explored the effect of linker length
on inhibitory activity by synthesizing longer and shorter var-
iants of compound 20 (compounds 29a, b, d, and, e). Silane-
diols have been extensively studied embedded in peptidomi-
metic protease inhibitors, where the silanediol moiety serves
as an isostere of the tetrahedral intermediate of the hydrolyzed
peptide bond.[28] Furthermore, a recent theoretical study
showed that silanediols may coordinate zinc with an affinity
similar to that of hydroxamic acids,[29] and we therefore includ-
ed compound 19 in our screening library. We also speculated
that sulfonamides might be able to mimic this hydrated state
as well, although the geometry is distorted relative to the tet-
Results and Discussion
Chemistry
To probe the potential of various zinc binding groups we de-
vised a series of potential inhibitors incorporating various non-
hydrolyzable functional groups potentially mimicking either
the substrate acetamide moiety of an e-N-acetylated lysine res-
idue or the corresponding hydrated tetrahedral intermediate.
The structurally simple HDAC inhibitors 4-phenylbutyric acid
(1), valproic acid (2), and vorinostat (3) served as scaffolds for
our compound collection. Along with the native carboxylate
(weak Zn2+ coordinator) and hydroxamate (strong Zn2+ coor-
dinator) functionalities, a selection of other known and puta-
tive new zinc binding groups were included (Figure 2). As
mentioned, ketones such as apicidin (5) are known as inter-
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rahedral state of the native hydrate. This led to the inclusion of
compounds 11, 14, and 21 containing a methyl group as well
as compounds 12, 15, and 22 containing a trifluoromethyl
group.
4-Phenylbutyric acid (1), valproic acid (2), trichostatin A (TSA;
4), apicidin (5), and 5-phenylpentan-2-one (8) were obtained
from commercial sources. 4-Phenylbutanohydroxamic acid (7)
and valprohydroxamic acid (13) were synthesized from the cor-
responding carboxylic acids via esterification with methanol
and subsequent reaction with hydroxylamine, as previously de-
scribed.[30]
N-(2-phenethyl)trifluoromethanesulfonamide (11),[31] N-(2-
phenethyl)methanesulfonamide (12),[32] N,N-dipropyltrifluoro-
methanesulfonamide (14),[33] and N,N-dipropylmethanesulfona-
mide (15)[34] were synthesized by sulfonylation of the corre-
sponding amines. Similarly, sulfonylation of 6-amino-N-phenyl-
hexanamide hydrochloride (24)[35] afforded N-phenyl-6-(trifluor-
omethylsulfonylamino)hexanamide (21) and 6-methylsulfona-
Scheme 2. Synthesis of Weinreb amide 17 and methyl ketone 18. Reagents
and conditions: a) HOBt, EDC·HCl, MeNHOMe·HCl, CH2Cl2, 08C!RT, 21 h
(44%); b) MeMgBr, THF, ꢀ708C!RT, 20 h (45%).
mino-N-phenylhexanamide
(22),[36]
whereas
DIC/HOBt
mediated coupling with crotonic acid afforded 6-trans-crotony-
lamino-N-phenylhexanamide (23) (Scheme 1). 8-Oxo-8-(phenyl-
Scheme 3. Synthesis of silanediol 19. Reagents and conditions: a) oxalyl chlo-
ride, CH2Cl2, RT, 3 h; b) aniline, pyridine, CH2Cl2, RT, 18 h (93%);
c) 1,1,1,3,5,5,5-heptamethyltrisiloxane, Karstedt’s catalyst, toluene, reflux,
20 h (84%); d) NaOD, [D3]MeCN/D2O 50:50 (v/v), RT, 4 h (quant. according to
LC–MS).
Scheme 1. Synthesis of sulfonamides 21, 22, and amide 23. Reagents and
conditions: a) Tf2O, Et3N, CH2Cl2, ꢀ708C, 2 h (49%); b) MsCl, Et3N, CH2Cl2,
ꢀ708C, 2 h (63%); c) trans-crotonic acid, HOBt, DIC, iPr2NEt, CH2Cl2, RT, 20 h
(71%).
polymerization the reaction mixture was used directly in the
enzymatic assay (Scheme 3).
amino)octanoic acid (16)[37] was coupled to N,O-dimethylhy-
droxylamine hydrochloride using EDC/HOBt as coupling re-
agents to give the corresponding Weinreb amide (17),[38] which
upon treatment with methyl magnesium bromide gave 8-oxo-
N-phenylnonanamide (18) (Scheme 2).
Conversion of a carboxylic acid to the corresponding trifluor-
omethyl ketone, under modified Dakin-West conditions using
either acid chloride or mixed trifluoroacetic anhydride with tri-
fluoroacetic anhydride and pyridine,[43] suffered from very low
yields and poor reproducibility in our hands. Instead, direct
conversion of dicarboxylic acids [hexanedioic through decane-
dioic acid (27a–e)] to the corresponding trifluorooxocarboxylic
acids 28a–e was achieved in acceptable yields (21–29%;
Scheme 4), via enediolate formation by treatment with LDA,
followed by trifluoroacetylation with either ethyl trifluoroace-
tate or N-methoxy-N-methyltrifluoroacetamide and decarboxy-
lation.[44] The relatively low yields probably reflect some degree
of conversion into 1,1,1,w,w,w-hexafluorodiketones, whereas
the choice of trifluoroacyl donor seemingly did not affect the
yield. The following amidation with aniline proceeded smooth-
ly, after conversion into the corresponding acid chlorides with
oxalyl chloride and pyridine, to afford desired anilides 20 and
29a, b, d, and e in good yields (37–78%; Scheme 4). Using the
same trifluoroacetylation–decarboxylation method, 1,1,1-tri-
fluoro-4-(4-methylphenyl)butan-2-one (10) was prepared from
Internal silanediols in peptidomimetic protease inhibitors
have typically been synthesized from the corresponding diphe-
nylsilanes, which are converted into either the trimethylsilyl-
(TMS)-protected silanediol or difluorosilane, which is then hy-
drolyzed by aqueous base to afford the desired silanediol.
However, simple methylsilanediols can be accessed in
a straightforward manner from terminal alkenes.[39] Hydrosilyla-
tion of N-phenylhept-6-enamide (25)[40] with 1,1,1,3,5,5,5-hepta-
methyltrisiloxane using Karstedt’s catalyst (Platinum(0)-1,3-di-
vinyl-1,1,3,3-tetramethyldisiloxane complex)[41] afforded TMS-
protected silanediol 26 in good yield (84%). The following hy-
drolysis, to afford silanediol 19, was carried out using NaOD in
[D3]MeCN/D2O, to enable monitoring of the reaction and char-
1
acterization of the product by H NMR. Unencumbered silane-
diols are at risk of polymerization;[39,42] to decrease the risk of
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Scheme 4. Synthesis of trifluoromethyl ketones 9, 10, 20, and 29a,b,d, and e. Reagents and conditions: a) LDA, THF, ꢀ788C, 10 min, then RT, 45 min, then
ethyl trifluoroacetate, ꢀ788C, 100 min (10: 30%, 28a: 26%, 28b: 24%, 28c: 21%); b) LDA, THF, ꢀ788C, 15 min, then RT, 60 min, then N-methoxy-N-methyltri-
fluoroacetamide, ꢀ788C, 120 min (28d: 29%, 28e: 24%); c) oxalyl chloride, CH2Cl2, RT, 1 h; d) aniline, pyridine, CH2Cl2, 08C, 4 h (20: 69%, 29a: 45%, 29b:
78%, 29d: 66%, 29e: 37%); e) NaI, acetone, reflux, 18 h; f) tBuLi, Et2O, pentane, ꢀ788C, 15 min, then RT, 1 h, then N-methoxy-N-methyltrifluoroacetamide,
ꢀ788C, 75 min, then RT, 1 h (72%).
3-(4-methylphenyl)propanoic acid (30); however, the yield was
moderate (30%), despite the lack of other reactive functional
groups (Scheme 4). The low yields prompted us to look for al-
ternative reaction conditions. Trifluoromethyl ketone formation
by reaction of magnesium bromide trifluoroacetate,[45] ethyl tri-
fluoroacetate,[46] or N,N-dimethyl trifluoroacetamide[47] with aro-
matic Grignard reagents is known. Furthermore, the Weinreb
amide of trifluoroacetic acid (N-methoxy-N-methyltrifluoroace-
tamide) has been used as an electrophilic trifluoromethyl
ketone donor by reaction with lithioaryls generated either by
direct deprotonation,[24c,48] via halogen–lithium exchange,[24c,49]
or by reaction with aromatic Grignard reagents.[24c,50] The Wein-
reb amide has also been used in a few reactions with a vinyl
Grignard,[51] alkynyllithium,[52] or even 2-lithio-1,3-dithiane,[53]
but only a few examples of reaction with aliphatic Grignard
species have been reported.[54] However, Finkelstein conversion
of 3-phenylpropylbromide (31) to the corresponding iodide,
iodine–lithium exchange with tBuLi followed by addition to
a solution of N-methoxy-N-methyltrifluoroacetamide easily af-
forded 1,1,1-trifluoro-5-phenylpentan-2-one (9) in 72% yield,
thereby suggesting alkyllithium-Weinreb amides as an alterna-
tive route to trifluoromethyl ketones (Scheme 4).
In 19F NMR, three peaks could be detected for all the investi-
gated trifluoromethyl ketones when using [D6]DMSO as solvent
(for example, compound 20: d=ꢀ71.3, ꢀ78.4, and
ꢀ84.0 ppm). The three peaks are assigned to the trifluoro-
methyl ketone (d=ꢀ78.4 ppm, COCF3), hydrate (d=
ꢀ84.0 ppm, C(OD)2CF3) and DMSO-adduct (d=ꢀ71.3 ppm,
C(Oꢀ)OS+(CD3)2). In [D6]DMSO/D2O (80:20 (v/v)) the compound
is fully converted into the hydrate, as evident from the
19F NMR spectrum (single peak (d=ꢀ84.0 ppm)) and the
1H NMR spectrum where the triplet assigned to CH2COCF3 (d=
2.86 ppm, t, J=7.0 Hz, 2H) is replaced by a multiplet assigned
to the corresponding protons of the hydrate (CH2C(OD)2CF3,
d=1.29–1.44 ppm, m, 2H). With this compound collection, we
performed a screen using two compound concentrations to
obtain an overview of the inhibitor potencies.
nant human Zn2+-dependent HDACs at 100 mm and 10 mm in-
hibitor concentrations (Figures 3 and 4). All assays were carried
out using 7-amino-4-methylcoumarin-labeled peptides in
a trypsin-coupled functional assay. Protocols for HDACs 1–9
were adapted from Bradner, Mazitschek, and co-workers,[4a]
using Ac-Leu-Gly-Lys(Ac)-AMC as substrate for HDACs 1–3 and
6 and Ac-Leu-Gly-Lys(Tfa)-AMC as substrate for HDACs 4, 5,
and 7–9. HDAC10 was tested using Ac-Arg-His-Lys(Ac)-Lys(Ac)-
AMC as previously described,[8b,55] and HDAC11 was tested
using Ac-Leu-Gly-Lys(Ac)-AMC, as we found this enzyme-sub-
strate combination to perform better than the corresponding
trifluoroacetylated peptide.[8b] The screening was carried out
using substrate concentrations at or above reported KM
values.[4a,8b,55]
The full profiling data set is presented as bar graphs in
Figure 3, and the data points obtained from the screening at
10 mm compound concentrations are shown as a heat map
representation in Figure 4. Generally, this reveals strong all-
around potency of trifluoromethyl ketones (9, 10, and 20), in-
hibition of class I, IIb, and IV by hydroxamic acids (vorinostat
(3), TSA (4), and 7) as well as by apicidin and interestingly sila-
nediol 19. Notably, both valproate (2) and its hydroxamic acid
analogue 13 are generally poor inhibitors (Figure 4).[30]
Based on the initial screening results, six compounds [vori-
nostat (3), 7, 9, and 19–21] were then selected for a full dose–
response evaluation. The seemingly potent compound 10 was
not included due to the close resemblance to compound 9,
and compound 21 was included despite unimpressive poten-
cies to glean knowledge about this novel zinc binding group
(Figure 4). Apicidin (5) and trichostatin A (4) were not included,
as these have been profiled in detail before.[4a] Thus, the com-
pound selection represents both 4-phenylbutyric acid and vori-
nostat scaffolds in combination with hydroxamic acid, trifluoro-
methyl ketone, trifluoromethyl sulfonamide, and silanediol as
chelating motifs. With this selection of compounds, we then
performed dose–response experiments for all compound–
HDAC combinations, except for silanediol 19 against HDAC9
(Figure 5d). The obtained IC50 values were converted into Ki
values by use of the Cheng–Prusoff equation [Ki =IC50/(1+[S]/
KM)] with the assumption of a standard fast-on–fast-off mecha-
nism of inhibition (Table 1).
Biochemical profiling
Initially, HDAC inhibitory potencies—including those of 4-phe-
nylbutyric acid (1), valproic acid (2), vorinostat (3), TSA (4), and
apicidin (5)—were screened against the full family of recombi-
As exemplified by the dose–response curve obtained for
compound 7 against HDAC5 (Figure 5b), this enzyme generally
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Figure 3. HDAC inhibitory screening. Assays were performed at 100 mm (dark blue) and 10 mm (light blue). All inhibitor–enzyme combinations were tested in
at least two individual assays performed in duplicate. Error bars represent standard deviation. (*)GST-tagged HDAC3 in complex with the deacetylase activa-
tion domain (DAD) of nuclear receptor co-repressor (NCoR1).
gave rise to somewhat low maximum enzyme activity (80–
90%) relative to control wells. In light of this, we interpret the
apparent high HDAC5 inhibitory activity of most inhibitors in
the screening (Figure 4) as questionable. The Ki value of vorino-
stat (3) against HDAC5 (17 mm) supports this, as it does not
correlate with the high potency indicated in the single dose
experiments. This highlights the importance of full dose–re-
sponse experiments and determination of kinetic constants for
the characterization of enzyme–inhibitor interactions.
phenylbutyrate analogue 9. Thus, the full evaluation of com-
pound 20 performed herein, revealed it to be a remarkably
potent pan-HDAC inhibitor. Though this molecule is known
and has been tested for HDAC inhibitory activity previously,[24a]
this is the first demonstration of its relatively nonselective ac-
tivity across all the human Zn2+-dependent HDACs. Whereas
compounds with potent and selective activities are highly de-
sirable, pan-specific inhibitors may also become very useful
tool compounds.[4a] A comparison of the ranges in Ki values ex-
hibited by compound 20 (0.02–2.7 mm) and the previously de-
veloped nonselective HDAC inhibitor “pandacostat” (0.032–
1.4 mm)[4a] against HDAC1–9, turned out to be similar. For com-
pound 20 this range is expanded to 15 mm if the HDAC11 data
point is included; however, we do not have a value for panda-
costat for comparison against this enzyme.
The dose–response curves, and more accurately, the Ki
values thus confirmed the high general potency of the trifluor-
omethyl ketone-containing inhibitors against all enzyme iso-
forms (Table 1, Figure 5c, e). This is not too surprising, as its
structure was derived from the optimized HDAC inhibitor vori-
nostat, compound 20 was generally more potent than the 4-
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Table 1. Further evaluation of selected compounds against a panel of eleven recombinant human HDAC isoforms.
Isoform
Vorinostat
IC50 [mm][a]
Compd 7
IC50 [mm][a]
Compd 9
Compd 19
Compd 20
Ki [mm][b]
Ki [mm][b]
IC50 [mm][a]
Ki [mm][b]
IC50 [mm][a]
Ki [mm][b]
IC50 [mm][a]
Ki [mm][b]
HDAC1
HDAC2
HDAC3[c]
HDAC4
HDAC5
HDAC6
HDAC7
HDAC8
HDAC9
HDAC10
HDAC11
0.021ꢁ0.0002
0.032ꢁ0.008
0.028ꢁ0.001
24ꢁ1
0.008
0.007
0.011
12
17
0.023
35
1.5
–
0.025
0.011
26ꢁ2
9.8
1.0
1.2
4.1
0.9
0.4
–
3.9
–
1.7
5.3
8ꢁ0.2
4ꢁ0.8
3.0
0.8
0.8
0.08
0.04
8.7
9.5
0.3
17
2.7ꢁ0.7
6.0ꢁ1.3
0.6ꢁ0.005
1.0
1.4
0.2
–
–
8
7.8ꢁ1.0
1.4ꢁ0.09
0.30ꢁ0.04
0.04ꢁ0.009
0.9ꢁ0.04
2.2ꢁ0.3
2.9
0.32
0.11
0.02
0.4
0.98
0.3
0.81
1.9
5ꢁ1.5
3ꢁ0.3
8ꢁ7.4
3ꢁ1.5
0.9ꢁ0.03
2ꢁ1.6
0.16ꢁ0.03
0.1ꢁ0.05
20ꢁ6
>100
>100
18ꢁ0.9
>100
50ꢁ22
0.051ꢁ0.007
70ꢁ19
>100
8ꢁ4
>100
19ꢁ8
–
0.6ꢁ0.03
1.7ꢁ1.0
3ꢁ0.4
0.7ꢁ0.2
54ꢁ3
27ꢁ7.8
13
NT[d]
1.2
33
>100
NT[d]
5.9ꢁ2.8
0.11ꢁ0.01
7ꢁ0.6
15ꢁ7
32ꢁ10
45ꢁ26
7.4
16
5ꢁ0.34
57ꢁ38
19ꢁ5.9
4.4
36
0.03ꢁ0.0005
100ꢁ32
[a] Data represent the mean ꢁ standard deviation (SD) of at least two independent experiments performed in duplicate. [b] Calculated from IC50 data
using the Cheng–Prusoff equation. [c] GST-tagged HDAC3 in complex with the deacetylase activation domain (DAD) of nuclear receptor co-repressor
(NCoR1). [d] Not tested.
In addition to the interesting activities revealed for the tri-
fluoromethyl ketone compounds, our investigation showed
that both of our selected sulfonamides are poor zinc binding
moieties for development of HDAC inhibitors. In contrast, the
silanediol-containing compound 19 exhibited promising inhibi-
tory potencies, and may constitute a useful addition to the
current arsenal of design elements for HDAC inhibitors. In
combination with more complex scaffolds than the one tested
herein, we envision that this functionality could furnish potent
non-hydroxamate-containing chemotypes for inhibition of
these enzymes.
Figure 4. Single-dose HDAC inhibitory screening, weighted by inhibitory ac-
tivity (% inhibition). Assays were performed at 10 mm. All inhibitor–enzyme
combinations were tested in at least two individual assays performed in du-
Linker-length investigation
plicate. (*)GST-tagged HDAC3 in complex with the deacetylase activation
As the trifluoromethyl ketone zinc binding group proved to
domain (DAD) of nuclear receptor co-repressor (NCoR1).
afford potent pan-inhibitors of the selection of HDAC enzymes,
Figure 5. Dose–response curves for HDAC inhibitory activity of selected compounds against HDAC1–11. All inhibitor–enzyme combinations were tested in at
least two individual assays performed in duplicate. (*)GST-tagged HDAC3 in complex with the deacetylase activation domain (DAD) of nuclear receptor co-re-
pressor (NCoR1).
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we used compound 20 as a scaffold to investigate whether se-
lectivity for individual enzyme classes could be achieved by
changing the linker length instead. Varying the linker in HDAC
inhibitors has been evaluated in several studies before, but the
ability of the trifluoromethyl ketone functionality to potently
inhibit all isoforms as opposed to for example the hydroxa-
mate-containing vorinostat (Figure 5a) rendered this investiga-
tion unique. To address the effect of the linker, compounds
29a–e were prepared and tested for inhibition of a member of
each of the enzyme classes I, IIa, and IIb (Figure 6). Not surpris-
Conclusions
In the present investigation we have used state-of-the-art bio-
chemical profiling protocols for determination of the HDAC se-
lectivities of a collection of compounds comprising diverse
zinc binding groups. We have used commercially available
HDAC isoforms 1–11 and determined inhibition constants (Ki
values) rather than IC50 values to be able to compare our com-
pound potencies across the full panel of enzymes as well as to
published data. It is important to note, however, that to ad-
dress the intrinsically low deacetylase activities of class IIa en-
zymes, we have used e-N-trifluoroacetylated lysine-containing
substrates, which are not physiologically relevant. It is there-
fore not clear, at this point, how these inhibition constants
should be correlated with in vivo enzyme activity, or in what
context class IIa HDAC inhibitors may be useful. With the grow-
ing knowledge of how class IIa HDAC isoforms may be target-
ed by inhibitors,[56,24c–f] it will be interesting to determine what
their native substrates are in our cells. Adding to the current
knowledge on HDAC inhibitors, we reveal that a trifluoromethyl
ketone moiety serves as a potent zinc binding group, resulting
in pan-inhibitors on two different scaffolds and demonstrate
that a silanediol may serve as a novel useful zinc binding
group.
Experimental Section
Chemistry
General: All reagents and solvents were of analytical grade and
used without further purification as obtained from commercial
suppliers. Anhydrous solvents were obtained from a PureSolv
system. Reactions were conducted under an atmosphere of argon
or nitrogen whenever anhydrous solvents were used. Reactions
were monitored by thin-layer chromatography (TLC) using silica
gel coated plates (analytical SiO2-60, F-254), visualized under UV
light, or by UPLC–MS. Dry column vacuum chromatography
(DCVC) was performed with silica gel 60 (particle size 15–40 mm).
After column chromatography, appropriate fractions were pooled
and dried at high vacuum for at least 12 h to give the obtained
products in high purity (>95%). Evaporation of solvents was car-
Figure 6. Dose–response curves for HDAC inhibitory activity of trifluoro-
methyl ketones of varying linker length, against HDAC3, 4, and 6. All inhibi-
tor–enzyme combinations were tested in at least two individual assays per-
formed in duplicate.
1
ried out under reduced pressure at a temperature <408C. H NMR
and 13C NMR were recorded on a Bruker Ascend 400 spectrometer
at 400 MHz and 101 MHz, respectively or on a Varian Mercury 300
spectrometer at 300 MHz and 75 MHz, respectively. 19F NMR were
recorded on a Varian Mercury 300 spectrometer at 282 MHz. Chem-
ical shifts are reported in ppm relative to residual solvent peaks as
internal standard (dH: CDCl3 d=7.26 ppm, [D6]DMSO 2.50 ppm,
[D3]MeCN d=1.94 ppm; dC: CDCl3 d=77.16 ppm, [D6]DMSO d=
39.52 ppm) or external standard (dF). Assignments of NMR spectra
are based on correlation spectroscopy (COSY, HSQC, HMQC, and/or
HMBC spectra). Accurate mass verification measurements (HRMS)
were performed on a maXis G3 quadrupole time-of-flight (TOF)
mass spectrometer (Bruker Daltonics, Bremen, Germany) equipped
with an electrospray (ESI) source or on an Agilent 1290 UHPLC
equipped with a diode array detector and coupled to Agilent 6550
QTOF mass spectrometer operated in positive electrospray.[57]
ingly, as the length of compound 20 is modeled from the
structure of vorinostat (3), which is designed to inhibit class I
HDACs, compounds 20, 29b, and 29d were the most potent
against HDAC3. Interestingly however, both elongation (29e)
and truncation (29a) by two methylene groups had only
a minor effect (Figure 6a). This was also the case when tested
against HDAC4 except for the most truncated compound 29a,
which was ~35-fold less potent than 20 (Figure 6b). Finally,
class IIb enzyme, HDAC6, revealed the lowest degree of sensi-
tivity to linker length, and at the same time the representation
in Figure 6c clearly showed the significantly more potent in-
hibition of this enzyme by a hydroxamate relative to a trifluoro-
methyl ketone.
1,1,1-Trifluoro-5-phenylpentan-2-one
(9):[58]
NaI
(3.62 g,
24.1 mmol) was dissolved in acetone (40 mL) under a nitrogen at-
mosphere at room temperature. 1-Bromo-3-phenylpropane (31;
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ꢀ
2.44 g, 12.3 mmol) was added slowly, then the solution was heated
at reflux for 18 h. The reaction mixture was concentrated to ~5 mL,
then taken up in H2O (50 mL) and pentane (50 mL). The aqueous
phase was extracted with pentane (2ꢁ25 mL) and the combined
organic phase was washed with brine (25 mL), dried (MgSO4), fil-
tered, and evaporated to dryness, to afford a pale-red oil, which
was dissolved in Et2O (30 mL) and cooled to ꢀ708C under a nitro-
gen atmosphere. tBuLi (1.44m in pentane, 18 mL, 26 mmol) was
added over 5 min, the reaction was stirred for 10 min, then cooling
was removed and the reaction mixture was allowed to reach room
temperature over 2 h. N-Methoxy-N-methyltrifluoroacetamide
(773 mg, 4.92 mmol) was dissolved in Et2O (20 mL) under a nitrogen
atmosphere at ꢀ708C. The 1-lithio-3-phenylpropane solution
(22 mL, 6.0 mmol) prepared above was added over 10 min, and
the reaction mixture was stirred for 75 min, then cooling was re-
moved and the reaction mixture was allowed to reach room tem-
perature over 60 min. The reaction mixture was poured into H2O
(20 mL) and acidified by addition of aqueous HCl (0.5m, 15 mL).
The aqueous phase was extracted with Et2O (2ꢁ25 mL) and the or-
ganic phase washed with saturated aqueous NaHCO3 (20 mL),
dried (MgSO4), filtered, and evaporated to dryness. The resulting
residue was purified by DCVC (CH2Cl2/pentane 0:100–30:70 (v/v))
to afford the desired trifluoromethyl ketone 9 (762 mg, 72%) as
(CDCl3): d=ꢀ79.8 ppm (CF3); MS m/z 197.1 ([MꢀH]ꢀ, C7H8F3O3
calcd: 197.0).
8,8,8-Trifluoro-7-oxooctanoic acid (28b): General trifluoromethyl
ketone formation procedure A from pimelic acid (27b): Yield 24%;
Rf =0.3 (EtOAc/hexane/AcOH 50:50:0.25 (v/v/v); 1H NMR (CDCl3):
d=2.73 (t, J=7.2 Hz, 2H, CH2COCF3), 2.37 (t, J=7.3 Hz, 2H,
HO2CCH2), 1.76–1.61 (m, 4H, HO2CCH2CH2, CH2CH2COCF3), 1.46–
1.34 ppm (m, 2H, HO2CCH2CH2CH2); 13C NMR (CDCl3): d=191.5
(q, J=34.5 Hz, COCF3), 179.8 (HO2C), 115.7 (q, J=292.5 Hz,
CF3), 36.2 (CH2COCF3), 33.8 (HO2CCH2), 28.2 (HO2CCH2CH2CH2),
24.3
(HO2CCH2CH2/CH2CH2COCF3),
22.1 ppm
(HO2CCH2CH2/
CH2CH2COCF3); 19F NMR (CDCl3): d=ꢀ79.8 ppm (CF3); MS m/z 211.2
([MꢀH]ꢀ, C8H10F3O3 calcd: 211.1).
ꢀ
9,9,9-Trifluoro-8-oxononaoic acid (28c):[24a,60] General trifluoro-
methyl ketone procedure A from suberic acid (27c): Yield 21%;
1
Rf =0.3 (CH2Cl2/MeOH/AcOH 95:5:0.25 (v/v/v); H NMR (CDCl3): d=
2.71 (t, J=7.2 Hz, 2H, CH2COCF3), 2.36 (t, J=7.4 Hz, 2H, HO2CCH2),
1.58–1.75 (m, 4H, HO2CCH2CH2, CH2CH2COCF3), 1.31–1.44 ppm (m,
4H, HO2CCH2CH2CH2CH2); 13C NMR (CDCl3): d=191.7 (q, J=34.8 Hz,
COCF3), 180.1 (CO2H), 115.8 (q, J=290.6 Hz, CF3), 36.3 (CH2COCF3),
34.0 (HO2CCH2), 28.7 (HO2CCH2CH2CH2/HO2CCH2CH2CH2CH2), 28.4
(HO2CCH2CH2CH2/HO2CCH2CH2CH2CH2),
24.4
(HO2CCH2CH2/
1
CH2CH2COCF3), 22.2 ppm (HO2CCH2CH2/CH2CH2COCF3); 19F NMR
a colorless oil. Rf =0.3 (CH2Cl2/pentane 25:75 (v/v)); H NMR (CDCl3):
(CDCl3): d=ꢀ79.8 ppm (CF3); MS m/z 225.2 ([MꢀH]ꢀ, C9H12F3O3
ꢀ
d=7.06–7.27 (m, 5H, Ph), 2.63 (t, J=7.2 Hz, 2H, PhCH2/COCH2),
2.59 (t, J=7.5 Hz, 2H, PhCH2/COCH2), 1.93 ppm (dt, J=7.2 Hz, 7.5,
2H, CH2CH2CH2); 13C NMR (CDCl3): d=191.5 (q, J=34.9 Hz, CO),
140.7 (C1Ph), 128.7 (C2Ph, C6Ph/C3Ph, C5Ph), 128.5 (C2Ph, C6Ph/C3Ph,
C5Ph), 126.4 (C4Ph), 115.7 (q, J=292.1 Hz, CF3), 35.6 (PhCH2/COCH2),
34.6 (PhCH2/COCH2), 24.0 ppm (CH2CH2CH2); 19F NMR (CDCl3): d=
ꢀ79.7 ppm (CF3). Analytical data are in agreement with those pre-
viously reported.
calcd: 225.1).
Synthesis of trifluoromethyl ketones, general procedure B: The
carboxylic acid (5.3 mmol) was dissolved in anhydrous THF (40 mL)
at ꢀ788C. Under vigorous stirring, LDA (1.5m in THF-heptane-eth-
ylbenzene, 18.6 mmol) was added over 15 min resulting in
a brown suspension. The reaction mixture was stirred at ꢀ788C for
10 min, then allowed to warm to room temperature and stirred for
1 h. The reaction mixture was cooled to ꢀ788C and a solution of
N-methoxy-N-methyltrifluoroacetamide (8.0 mmol) in THF (2 mL)
was added followed by stirring for 2 h. If necessary, additional N-
methoxy-N-methyltrifluoroacetamide (2.7 mmol) was added and
the mixture was stirred for an additional 1 h. The mixture was
quenched with aqueous HCl (6m, 16 mL), followed by concentra-
tion to ~25 mL and partitioning between H2O (30 mL) and EtOAc
(70 mL). The aqueous phase was then extracted with EtOAc (3ꢁ
30 mL). The combined organic phase was dried (MgSO4), filtered,
and adsorbed onto silica gel, and then purified by DCVC (EtOAc/
hexane/AcOH 0:100:0.2!50:50:0.2 (v/v/v)).
10,10,10-Trifluoro-9-oxodecanoic acid (28d): General trifluoro-
methyl ketone formation procedure B from azelaic acid (27d):
Yield 29%; Rf =0.4 (EtOAc/hexane/AcOH 50:50:0.25 (v/v/v));
1H NMR (CDCl3): d=2.70 (t, J=7.2 Hz, 2H, CH2COCF3), 2.35 (t, J=
7.4 Hz, 2H, HO2CCH2), 1.73–1.57 (m, 4H HO2CCH2CH2,
CH2CH2COCF3), 1.34 ppm (s, 6H, HO2CCH2CH2CH2CH2CH2); 13C NMR
(CDCl3): d=191.7 (q, J=34.9 Hz, COCF3), 180.0 (HO2C), 115.7 (q, J=
292.3 Hz, CF3), 36.4 (CH2COCF3), 34.1 (HO2CCH2), 29.0, 28.9, 28.6,
Synthesis of trifluoromethyl ketones, general procedure A: The
carboxylic acid (6.2 mmol) was dissolved in anhydrous THF (45 mL)
at ꢀ788C. Under vigorous stirring, LDA (1.5m in THF/heptane/eth-
ylbenzene, 14.6 mL, 21.9 mmol) was added over 20 min, initially re-
sulting in a colorless gel, and then a brown suspension. The reac-
tion mixture was stirred at ꢀ788C for 10 min, then allowed to
reach room temperature and stirred for 45 min. After cooling to
ꢀ788C, a solution of ethyl trifluoroacetate (9.4 mmol) in THF
(2.0 mL) was added dropwise over 20 min. The reaction was then
stirred for 1 h. If necessary, additional ethyl trifluoroacetate
(3.1 mmol) was added and the mixture was stirred for an additional
1 h. Hereafter, aqueous HCl (6m, 20 mL, 120 mmol) was added,
and the mixture was concentrated to ~30 mL, then partitioned be-
tween H2O (30 mL) and EtOAc (70 mL). The aqueous phase was
then extracted with EtOAc (5ꢁ30 mL). The organic phase was
dried (MgSO4), filtered, and adsorbed onto silica gel, and then puri-
fied by DCVC (EtOAc/hexane/AcOH 10:90:0.2!50:50:0.2 (v/v/v)),
to afford the desired trifluoromethyl ketone.
1,1,1-Trifluoro-4-(4-methylphenyl)butan-2-one (10):[59] General tri-
fluoromethyl ketone formation procedure A from 3-(4-methylphe-
nyl)propanoic acid (30): Yield: 30%. Analytical data are in agree-
ment with those previously reported.
24.6
(HO2CCH2CH2/CH2CH2COCF3),
22.4 ppm
(HO2CCH2CH2/
CH2CH2COCF3); 19F NMR (CDCl3): d=ꢀ79.8 ppm (CF3); MS m/z 239.2
([MꢀH]ꢀ, C10H14F3O3 calcd: 239.1).
ꢀ
7,7,7-Trifluoro-6-oxoheptanoic acid (28a): General trifluoromethyl
ketone formation procedure A from adipic acid (27a): Yield 26%;
Rf =0.3 (EtOAc/hexane/AcOH 50:50:0.25 (v/v/v); 1H NMR (CDCl3):
d=2.75 (t, J=6.7 Hz, 2H, CH2COCF3), 2.40 (t, J=6.9 Hz, 2H,
HO2CCH2), 1.79–1.60 ppm (m, 4H, HO2CCH2CH2CH2); 13C NMR
(CDCl3): d=191.2 (q, J=35.1 Hz, COCF3), 179.6 (HO2C), 115.6 (q, J=
292.0 Hz, CF3), 36.1 (CH2COCF3), 33.7 (HO2CCH2), 23.7 (HO2CCH2CH2/
CH2CH2COCF3), 21.8 ppm (HO2CCH2CH2/CH2CH2COCF3); 19F NMR
11,11,11-Trifluoro-10-oxoundecanoic acid (28e): General trifluoro-
methyl ketone formation procedure B from decanedioic acid (27e):
Yield 24%; Rf =0.4 (EtOAc/hexane/AcOH 50:50:0.25 (v/v/v); H NMR
(CDCl3): d=2.70 (t, J=7.2 Hz, 2H), 2.34 (t, J=7.5 Hz, 2H), 1.72–1.56
(m, 4H), 1.32 ppm (s, 8H); 13C NMR (CDCl3): d=191.8 (q,
J=34.8 Hz, COCF3), 180.3 (HO2C), 115.7 (q, J=292.2 Hz, CF3),
36.5 (CH2COCF3), 34.1 (HO2CCH2), 29.09, 29.07, 29.0, 28.8, 24.7
1
(HO2CCH2CH2/CH2CH2COCF3),
22.5 ppm
(HO2CCH2CH2/
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CH2CH2COCF3); 19F NMR (CDCl3): d=ꢀ79.8 ppm (CF3); MS m/z 253.2
10,10,10-Trifluoro-9-oxo-N-phenyldecanamide (29d): General ani-
([MꢀH]ꢀ, C11H16F3O3ꢀ calcd: 253.1).
lide formation procedure from 10,10,10-trifluoro-9-oxodecanoic
1
acid (28d): Yield 66%; Rf =0.5 (EtOAc/hexane 50:50 (v/v); H NMR
Synthesis of anilides, general procedure: Carboxylic acid
(0.7 mmol) was dissolved in anhydrous CH2Cl2 (6 mL) at room tem-
perature, and then oxalyl chloride (0.85 mmol) was added. After
stirring for 1 h, the reaction mixture was evaporated to dryness.
The resulting brown oil was then dissolved in anhydrous CH2Cl2
(5 mL) and cooled to 08C. A solution of aniline (0.9 mmol) and an-
hydrous pyridine (1.8 mmol) in CH2Cl2 (1.0 mL) was added drop-
wise to the acid chloride solution. The reaction mixture was stirred
at 08C for 4 h, and then poured into ice-H2O (20 mL, 50:50 (v/v)).
The aqueous phase was extracted with CH2Cl2 (3ꢁ30 mL) and the
combined organic phase washed with aqueous HCl (1.0m, 2ꢁ
20 mL), saturated aqueous NaHCO3 (20 mL) and brine (40 mL),
back extracting each aqueous phase with CH2Cl2 (10 mL). The com-
bined organic phase was dried (MgSO4), filtered, and adsorbed di-
rectly onto silica gel, and then purified by DCVC (EtOAc/hexane
0:100–25:75 (v/v)).
([D6]DMSO): d=9.84 (s, 1H, NH), 7.55–7.60 (m, 2H, H2Ph,H6Ph), 7.23–
7.30 (m, 2H, H3Ph,H5Ph), 6.97–7.04 (m, 1H, H4Ph), 2.86 (t, J=7.1 Hz,
2H, CH2COCF3), 2.29 (t, J=7.4 Hz, 2H, HNCOCH2), 1.50–1.64 (m, 4H,
HNCOCH2CH2,
CH2CH2COCF3),
1.22–1.34 ppm
(m,
6H,
NHCOCH2CH2CH2CH2CH2); 13C NMR ([D6]DMSO): d=191.7 (q, J=
33.6 Hz), 171.1 (NHCO), 139.3 (C1Ph), 128.6 (C3Ph, C5Ph), 122.8 (C4Ph),
118.9 (C2Ph, C6Ph), 115.2 (q, J=293.4 Hz, CF3), 36.3 (NHCOCH2), 35.9
(CH2COCF3), 28.4, 27.8, 25.0 (NHCOCH2CH2/CH2CH2COCF3), 21.6 ppm
(NHCOCH2CH2/CH2CH2COCF3); 19F NMR ([D6]DMSO): d=ꢀ71.4
(C(OD)OS+(CD3)2), ꢀ78.5 (COCF3), ꢀ84.0 ppm (C(OD)2CF3); HRMS
m/z 316.1529 ([M+H]+, C16H21F3NO2 calcd: 316.1519).
+
11,11,11-Trifluoro-10-oxo-N-phenylundecanamide (29e): General
anilide formation procedure from 11,11,11-trifluoro-10-oxoundeca-
noic acid (28e): Yield 37%; Rf =0.6 (EtOAc/hexane 50:50 (v/v);
1H NMR ([D6]DMSO): d=9.84 (s, 1H, NH), 7.55–7.60 (m, 2H,
H2Ph,H6Ph), 7.23–7.31 (m, 2H, H3Ph,H5Ph), 6.97–7.04 (m, 1H, C4Ph),
2.85 (t, J=7.1 Hz, 2H, CH2COCF3), 2.28 (t, J=7.4 Hz, 2H, HNCOCH2),
1.64–1.50 (m, 4H, HNCOCH2CH2, CH2CH2COCF3), 1.24–1.32 ppm (m,
8H NHCOCH2CH2CH2CH2CH2CH2); 13C NMR ([D6]DMSO): d=191.8 (q,
J=33.3 Hz), 171.2 (NHCO), 139.4 (C1Ph), 128.6 (C3Ph, C5Ph), 122.9
(C4Ph), 119.0 (C2Ph, C6Ph), 115.3 (q, J=293.1 Hz, CF3), 36.4
(NHCOCH2), 36.0 (CH2COCF3), 28.62, 28.59, 28.0, 25.1 (NHCOCH2CH2/
CH2CH2COCF3), 21.7 ppm (NHCOCH2CH2/CH2CH2COCF3); 19F NMR
9,9,9-Trifluoro-8-oxo-N-phenylnonanamide (20):[24a,60,61] General
anilide formation procedure from 9,9,9-trifluoro-8-oxononaoic acid
(28c). Yield 69%; Rf =0.4 (EtOAc/heptane 50:50 (v/v)); 1H NMR
([D6]DMSO): d=9.85 (s, 1H, NH), 7.54–7.62 (m, 2H, H2Ph,H6Ph), 7.22–
7.32 (m, 2H, H3Ph,H5Ph), 6.97–7.06 (m, 1H, H4Ph), 2.86 (t, J=7.0 Hz,
2H, CH2COCF3), 2.29 (t, J=7.4 Hz, 2H, HNCOCH2), 1.49–1.67 (m, 4H,
HNCOCH2CH2,
CH2CH2COCF3),
1.25–1.38 ppm
(m,
4H,
NHCOCH2CH2CH2CH2); 13C NMR ([D6]DMSO): d=191.7 (q, J=
33.6 Hz, COCF3), 171.2 (CONH), 139.4 (C1Ph), 128.6 (C3Ph, C5Ph), 122.9
(C4Ph), 119.0 (C2Ph, C6Ph), 115.30 (q, J=294.3 Hz, CF3), 36.3
([D6]DMSO):
d=ꢀ71.4
(C(OD)OS+(CD3)2),
ꢀ78.5
(COCF3),
ꢀ84.0 ppm (C(OD)2CF3); HRMS m/z 330.1681 ([M+H]+,
+
C17H23F3NO2 calcd: 330.1675).
(NHCOCH2),
36.0
(CH2COCF3),
28.3
(NHCOCH2CH2CH2/
CH2CH2CH2COCF3), 27.8 (NHCOCH2CH2CH2/CH2CH2CH2COCF3), 24.9
Synthesis of sulfonamides, general procedure: Amine
(2.56 mmol) and Et3N (0.38 mL, 2.73 mmol) were dissolved in anhy-
drous CH2Cl2 (12 mL) and stirred at ꢀ708C. Trifluoromethanesulfon-
ic anhydride or methanesulfonic chloride (2.72 mmol) was dis-
solved in CH2Cl2 (3 mL), added dropwise, and the reaction mixture
was stirred at ꢀ708C for 2 h, after which H2O (10 mL) was added
and the reaction mixture heated at room temperature The aque-
ous phase was extracted with CH2Cl2 (2ꢁ10 mL), and the com-
bined organic phase washed with brine (10 mL), dried (MgSO4), fil-
tered, and evaporated to dryness. The resulting residue was puri-
fied by DCVC (EtOAc/hexane 10:90 (v/v)), to afford the desired sul-
fonamide.
(NHCOCH2CH2/CH2CH2COCF3),
21.6 ppm
(NHCOCH2CH2/
CH2CH2COCF3); 19F NMR ([D6]DMSO): d=ꢀ71.3 (C(OD)OS+(CD3)2),
ꢀ78.4 (COCF3), ꢀ84.0 ppm (C(OD)2CF3); HRMS m/z 302.1364 ([M+
H]+, C15H19F3NO2 calcd: 302.1362). Analytical data are in agree-
+
ment with those previously reported.
7,7,7-Trifluoro-6-oxo-N-phenylheptanamide (29a): General anilide
formation procedure from 7,7,7-trifluoro-6-oxoheptanioc acid
(28a): Yield 45%; Rf =0.5 (EtOAc/hexane 50:50 (v/v); 1H NMR
([D6]DMSO): d=9.89 (s, 1H, NH), 7.61–7.55 (m, 2H, H2Ph,H6Ph), 7.24–
7.32 (m, 2H, H3Ph,H5Ph), 6.97–7.05 (m, 1H, H4Ph), 2.91 (t, J=6.3 Hz,
2H, CH2COCF3), 2.37–2.27 (m, 2H, HNCOCH2), 1.67–1.56 ppm (m,
4H, HNCOCH2CH2CH2); 13C NMR ([D6]DMSO)[62] d=171.2 (NHCO),
139.4 (C1Ph), 128.7 (C3Ph, C5Ph), 124.3 (q, J=289.6 Hz, CF3), 123.0
(C4Ph), 119.0 (C2Ph, C6Ph), 92.7 (q, J=30.2 Hz, C(OD)2), 36.4, 34.9,
25.4, 21.3 ppm; 19F NMR ([D6]DMSO): d=ꢀ71.4 (C(OD)OS+(CD3)2),
ꢀ78.4 (COCF3), ꢀ84.0 ppm (C(OD)2CF3); HRMS m/z 274.1052 ([M+
N-(2-Phenethyl)methanesulfonamide (12):[32] General sulfonamide
formation procedure from 2-phenylethylamine. Yield 99%; Rf =0.4
(MeOH/CH2Cl2 2:98 (v/v)); 1H NMR (CDCl3): d=7.17–7.38(m, 5H),
4.45 (brt, 5.7, 1H, NH), 3.40 (td, J=6.9 Hz, 5.7, 2H, CH2NH), 2.87 (t,
J=6.9 Hz, 2H, PhCH2), 2.81 ppm (s, 3H, CH3); 13C NMR (CDCl3): d=
137.9 (C1Ph), 129.0 (C2Ph, C6Ph/C3Ph, C5Ph), 128.9 (C2Ph, C6Ph/C3Ph,
C5Ph), 127.0 (C4Ph), 44.6 (CH2NH), 40.4 (CH3), 36.6 ppm (PhCH2);
1H NMR ([D6]DMSO): d=7.17–7.36 (m, 5H, Ph), 7.09 (t, J=5.8 Hz,
1H, ex, NH), 3.17 (m, 2H, CH2NH), 2.82 (s, 3H, CH3), 2.77 ppm (m,
2H, PhCH2); 13C NMR ([D6]DMSO): d=139.0 (C1Ph), 128.8 (C2Ph, C6Ph/
C3Ph, C5Ph), 128.3 (C2Ph, C6Ph/C3Ph, C5Ph), 126.3 (C4Ph), 44.0 (CH2NH),
39.2 (CH3), 35.8 ppm (PhCH2); HRMS m/z 200.0745 ([M+H]+,
C9H15NO2S+ calcd: 200.0740). Analytical data are in agreement with
those previously reported.
+
H]+, C13H15F3NO2 calcd: 274.1049).
8,8,8-Trifluoro-7-oxo-N-phenyloctanamide (29b): General anilide
formation procedure from 8,8,8-trifluoro-7-oxooctanoic acid (28b):
1
Yield 78%; Rf =0.5 (EtOAc/hexane 50:50 (v/v); H NMR ([D6]DMSO):
d=9.86 (s, 1H, NH), 7.56–7.60 (m, 2H, H2Ph,H6Ph), 7.24–7.31 (m, 2H,
H3Ph,H5Ph), 6.98–7.04 (m, 1H, H4Ph), 2.88 (t, J=7.1 Hz, 2H,
CH2COCF3), 2.30 (t, J=7.4 Hz, 2H, HNCOCH2), 1.66–1.52 (m, 4H„
HNCOCH2CH2CH2CH2), 1.41–1.26 ppm (m, 2H, HNCOCH2CH2CH2);
13C NMR ([D6]DMSO)[63] d=191.8 (q, J=33.5 Hz, COCF3), 171.2
(NHCO), 171.1 (NHCO), 139.4 (C1Ph), 139.3 (C1Ph) 128.7 (C3Ph, C5Ph),
122.9 (C4Ph), 119.0 (C2Ph, C6Ph), 93.0 (q, J=30.0 Hz, C(OD)2CF3), 36.3,
36.1, 35.9, 35.0, 28.9, 27.6, 25.1, 24.8, 21.5, 21.4 ppm; 19F NMR
N,N-Dipropyltrifluoromethanesulfonamide (14):[33] General sulfo-
namide formation procedure from N,N-dipropylamine. Yield 94%;
Rf =0.5 (EtOAc/heptane 10:90 (v/v)). Analytical data are in agree-
ment with those previously reported.
([D6]DMSO):
d=ꢀ71.3
(C(OD)OS+(CD3)2),
ꢀ78.4
(COCF3),
ꢀ84.0 ppm (C(OD)2CF3); HRMS m/z 288.1213 ([M+H]+,
N,N-Dipropylmethanesulfonamide (15):[34] General sulfonamide
formation procedure from N,N-dipropylamine. Yield 64%; Rf =0.4
+
C14H17F3NO2 calcd: 288.1206).
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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(Et2O/pentane 50:50 (v/v)); 1H NMR (CDCl3): d=3.08–3.15 (m
(AA’XX’, JAX =9.4, JAX’ =6.0, JAA’ =JXX’ =11.5 Hz), 4H, CH2N), 2.81 (s,
3H, SO2CH3), 1.54–1.68 (m, 4H, CH2CH3), 0.91 ppm (t, J=7.4 Hz, 6H,
CH3); 13C NMR (CDCl3): d=49.7 (CH2N), 38.3 (SO2CH3), 22.1 (CH2CH3),
11.3 ppm (CH3); HRMS m/z 180.1052 ([M+H]+, C7H18NO2S+ calcd:
180.1053).
8-Oxo-N-phenylnonanamide (18): Weinreb amide 17 (131 mg,
0.448 mmol) was suspended in anhydrous THF (3 mL) and cooled
to ꢀ708C. Methyl magnesium bromide (3.0m in Et2O, 0.5 mL,
1.5 mmol) was added dropwise and the reaction mixture was
stirred for 105 min at ꢀ708C, before additional anhydrous THF
(2 mL) and methyl magnesium bromide (3.0m in Et2O, 0.5 mL,
1.5 mmol) was added, and the reaction mixture was stirred for
20 h, while allowing the reaction mixture to reach room tempera-
ture. Aqueous HCl (0.5m, 40 mL) was added, and the resulting so-
lution was extracted with EtOAc (3ꢁ30 mL). The combined organic
phase was washed with saturated aqueous NaHCO3 (25 mL) and
brine (25 mL), then dried (MgSO4), filtered, and evaporated to dry-
ness. The resulting residue was purified by DCVC (EtOAc/hexane
0:100–50:50 (v/v)) to afford desired ketone 18 (50 mg, 45%) and
Weinreb amide 17 (23 mg, 18%) as white solids. Rf =0.3 (EtOAc/
hexane 50:50 (v/v)); 1H NMR (CDCl3): d=7.52 (d, J=7.3, 3H, NH,
C2Ph, C6Ph), 7.29 (t, J=7.9, 2H, C3Ph, C5Ph), 7.08 (t, J=7.4 Hz, 1H,
C4Ph), 2.41 (t, J=7.3, 2H, CH2COCH3), 2.33 (t, J=7.5, 2H,
PhNHCOCH2), 2.12 (s, 3H, COCH3), 1.71 (p, J=7.4, 2H,
PhNHCOCH2CH2), 1.57 (p, J=7.4, 2H, CH2CH2COCH3), 1.42–
1.24 ppm (m, 4H, PhNHCOCH2CH2CH2CH2); 13C NMR (CDCl3): d=
209.5 (COCH3), 171.5 (CONH), 138.2 (C1Ph), 129.1 (C3Ph, C5Ph), 124.2
(C4Ph), 119.9 (C2Ph, C6Ph), 43.7 (CH2COCH3), 37.7 (PhNHCOCH2), 30.0
(CH3), 29.0 (PhNHCOCH2CH2CH2), 28.8 (CH2CH2CH2COCH3), 25.5
(PhNHCOCH2CH2), 23.6 ppm (CH2CH2COCH3); HRMS m/z 270.1462
([M+Na]+, C15H21NO2Na+ calcd: 270.1465).
N-Phenyl-6-(trifluoromethylsulfonylamino)hexanamide (21): Gen-
eral sulfonamide formation procedure from 6-amino-N-phenylhexa-
namide hydrochloride[35] (24). Yield 49%; Rf =0.3 (EtOAc/hexane
1
50:50 (v/v)); H NMR ([D6]DMSO): d=9.85 (s, 1H, ex, HNCO), 9.33 (t,
J=4.6 Hz, 1H, ex, NHSO2), 7.53–7.64 (m, 2H, H2Ph, H6Ph), 7.20–7.35
(m, 2H, H3Ph, H5Ph), 6.92–7.08 (m, 1H, H4Ph), 3.04–3.22 (m, 2H,
CH2NH), 2.30 (t, J=7.4 Hz, 2H, COCH2), 1.59 (p, J=7.4 Hz, 2H,
COCH2CH2), 1.52 (p, J=7.3 Hz, 2H, CH2CH2NH), 1.34 ppm (m, 2H,
COCH2CH2CH2); 13C NMR ([D6]DMSO): d=171.1 (CO), 139.3 (C1Ph),
128.6 (C3Ph, C5Ph), 122.9 (C4Ph), 119.7 (q, J=322.6 Hz, CF3) 119.0
(C2Ph, C6Ph), 43.4 (CH2NH), 36.2 (COCH2), 29.4 (CH2CH2NH), 25.4
(COCH2CH2CH2), 24.6 ppm (COCH2CH2); 19F NMR ([D6]DMSO): d=
ꢀ77.8 ppm (CF3); HRMS m/z 339.0985 ([M+H]+, C13H18F3N2O3S+
calcd: 339.0985).
N-Phenyl-6-methylsulfonylaminohexanamide (22):[36,61] General
sulfonamide formation procedure from 6-amino-N-phenylhexana-
mide hydrochloride[35] (24). Yield 63%; Rf =0.2 (MeOH/CH2Cl2 2:98
1
(v/v)); H NMR ([D6]DMSO): d=9.85 (s, 1H, ex, NHPh), 7.54–7.63 (m,
2H, H2Ph, H6Ph), 7.23–7.32 (m, 2H, H3Ph, H5Ph), 6.97–7.06 (m, 1H,
H4Ph), 6.94 (t, J=5.9 Hz, 1H, ex, NHSO2), 2.88–2.97 (m, 2H, CH2NH),
2.87 (s, 3H, CH3), 2.30 (t, J=7.4 Hz, 2H, COCH2), 1.53–1.67 (m, 2H,
COCH2CH2), 1.41–1.53 (m 2H, CH2CH2NH), 1.25–1.40 ppm (m, 2H,
COCH2CH2CH2); 13C NMR ([D6]DMSO): d=171.2 (CO), 139.3 (C1Ph),
128.6 (C3Ph, C5Ph), 122.9 (C4Ph), 119.0 (C2Ph, C6Ph), 42.4 (CH2NH), 39.2
(CH3), 36.3 (COCH2), 29.3 (CH2CH2NH), 25.9 (COCH2CH2CH2),
24.8 ppm (COCH2CH2); HRMS m/z 285.1268 ([M+H]+, C13H21N2O3S+
calcd: 285.1267). Analytical data are in agreement with those previ-
ously reported.
6-trans-Crotonylamino-N-phenylhexanamide (23): trans-Crotonic
acid (128 mg, 1.49 mmol) and HOBt (244 mg, 1.81 mmol) were sus-
pended in anhydrous CH2Cl2 (17 mL) at room temperature. DIC
(0.26 mL, 1.7 mmol) was added and the reaction mixture was
stirred for 5 min. 6-Amino-N-phenylhexanamide hydrochloride[35]
(24, 401 mg, 1.65 mmol) and iPr2NEt (0.67 mL, 3.8 mmol) were
added and the resulting suspension was stirred for 20 h. The reac-
tion mixture was partitioned between aqueous HCl (1.0m, 10 mL)
and MeOH/CH2Cl2 (10:90 (v/v), 25 mL). The aqueous phase was ex-
tracted with MeOH/CH2Cl2 (10:90 (v/v), 3ꢁ20 mL), and the com-
bined organic phase was washed with saturated aqueous NaHCO3
(10 mL) and the aqueous phase was back extracted with MeOH/
CH2Cl2 (10:90 (v/v), 3ꢁ20 mL). The combined organic phase was
then dried (MgSO4), filtered, concentrated, and purified by DCVC
(MeOH/CH2Cl2 0:100–4:96 (v/v)) to afford desired amide 23
(290 mg, 71%) as a white solid. Rf =0.4 (MeOH/CH2Cl2 5:95 (v/v));
1H NMR ([D6]DMSO): d=9.85 (s, 1H, ex, NHPh), 7.85 (t, J=5.6 Hz,
1H, ex, CH2NH), 7.55–7.61 (m, 2H, H2Ph, H6Ph), 7.23–7.32 (m, 2H,
H3Ph, H5Ph), 6.96–7.04 (m, 1H, H4Ph), 6.58 (dq, J=15.3 Hz, 6.8, 1H,
CH=CHCH3), 5.88 (dq, J=15.3 Hz, 1.6, 1H, CH=CHCH3), 3.09 (q,
J=6.5 Hz, 2H, CH2NH), 2.29 (t, J=7.4 Hz, 2H, COCH2), 1.76 (dd, J=
6.8, 1.6 Hz, 3H, CH3), 1.58 (p, J=7.5 Hz, 2H, COCH2CH2), 1.36–1.50
(m, 2H, CH2CH2NH), 1.21–1.36 ppm (m, 2H, COCH2CH2CH2);
13C NMR ([D6]DMSO): d=171.2 (COPh), 164.7 (COCH), 139.4 (C1Ph),
137.3 (CH=CHCH3), 128.7 (C3Ph, C5Ph), 126.0 (CH=CHCH3), 122.9
(C4Ph), 119.0 (C2Ph, C6Ph), 38.3 (CH2NH), 36.4 (COCH2), 29.1
(CH2CH2NH), 26.2 (COCH2CH2CH2), 24.9 (COCH2CH2), 17.3 ppm
N1-Methoxy-N1-methyl-N8-phenyloctanediamide (17):[38] 8-Oxo-8-
(phenylamino)octanoic acid (16, 427 mg, 1.71 mmol)[37] was dis-
solved in anhydrous CH2Cl2 (13 mL) at 08C, and HOBt (693 mg,
5.13 mmol) and then a solution of EDC·HCl (493 mg, 2.57 mmol) in
CH2Cl2 (4 mL) was added. After stirring for 15 min, a suspension of
N,O-dimethylhydroxylamine hydrochloride (250 mg, 2.56 mmol)
was added and the reaction mixture was stirred for 21 h, while al-
lowing it to warm to room temperature. The reaction mixture was
taken up in CH2Cl2 (10 mL) and the solution was washed with
NaOH (0.5m, 3ꢁ50 mL), HCl (0.5m, 3ꢁ50 mL), and brine (50 mL),
then dried (MgSO4), filtered, and evaporated to dryness. The result-
ing residue was purified by DCVC (EtOAc/hexane 0:100–50:50 (v/
v)), to afford desired Weinreb amide 17 (218 mg, 44%) as a white
1
solid. Rf =0.2 (EtOAc/hexane 50:50 (v/v)); H NMR (CDCl3): d=7.53
(d, J=7.9, 3H, NH, C2Ph, C6Ph), 7.30 (t, J=7.9, 2H, C3Ph, C5Ph), 7.08
(t, J=7.4, 1H, C4Ph), 3.67 (s, 3H, OCH3), 3.17 (s, 3H, NCH3), 2.42 (t,
J=7.4, 2H, CH2CONCH3), 2.35 (t, J=7.5, 2H, PhNHCOCH2), 1.73 (q,
J=6.9, 2H, PhNHCOCH2CH2), 1.69–1.60 (m, 2H, CH2CH2CONCH3),
1.45–1.33 ppm (m, 4H, PhNHCOCH2CH2CH2CH2); 13C NMR (CDCl3):
d=174.7 (CONCH3),[64] 171.6 (PhNHCO), 138.3 (C1Ph), 129.1 (C3Ph,
C5Ph), 124.2 (C4Ph), 119.9 (C2Ph, C6Ph), 61.4 (OCH3), 37.6
(PhNHCOCH2), 32.3 (NCH3),[64] 31.8 (CH2CONCH3),[64] 28.92
(CH3); HRMS m/z 275.1763 ([M+H]+, C16H22N2O2 calcd: 275.1754)
+
7-(1,1,1,3,5,5,5-Heptamethyltrisiloxan-3-yl)-N-phenylheptana-
mide (26): 6-Heptenoic acid (475 mg, 3.71 mmol) was dissolved in
anhydrous CH2Cl2 (5 mL) at room temperature. Oxalyl chloride
(0.39 mL, 4.5 mmol) was added, the reaction was stirred for 3 h,
and then evaporated to dryness to afford a colorless oil. The resi-
due was dissolved in anhydrous CH2Cl2 (10 mL) at room tempera-
ture. Anhydrous aniline (0.40 mL, 4.4 mmol) and anhydrous pyri-
dine (0.72 mL, 8.9 mmol) were dissolved in CH2Cl2 (4 mL) and
(PhNHCOCH2CH2CH2/PhNHCOCH2CH2CH2CH2),
(PhNHCOCH2CH2CH2/PhNHCOCH2CH2CH2CH2),
28.86
25.5
(PhNHCOCH2CH2), 24.4 ppm (CH2CH2CONCH3); HRMS m/z 315.1685
([M+Na]+, C16H24N2O3Na+ calcd: 315.1679).
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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added to the reaction mixture. After stirring the reaction mixture
at room temperature for 18 h, the reaction mixture was washed
with aqueous HCl (1m, 2ꢁ20 mL), and saturated aqueous NaHCO3
(20 mL). The acidic aqueous phase was back extracted with CH2Cl2
(3ꢁ10 mL) and the combined organic phase was dried (MgSO4), fil-
tered, and evaporated to dryness to afford desired amide 25
(697 mg, 93%) as a yellow solid. Rf =0.3 (EtOAc/heptane 25:75 (v/
v)); 1H NMR ([D6]DMSO): d=9.86 (s, 1H, NH), 7.55–7.62 (m, 2H,
H2Ph,H6Ph), 7.23–7.32 (m, 2H, H3Ph,H5Ph), 6.97–7.05 (m, 1H, H4Ph),
5.80 (ddt, J=17.0 Hz, 10.2, 6.7, 1H, CH=CH2), 4.97–5.05 (m, 1H,
CH=CH2, trans), 4.92–4.97 (m, 1H, CH=CH2, cis), 2.30 (t, J=7.4 Hz,
2H, COCH2), 1.99–2.11 (m, 2H, CH2CH=CH2), 1.53–1.67 (m, 2H,
COCH2CH2), 1.31–1.45 ppm (m, 2H, CH2CH2CH=CH2); 13C NMR
([D6]DMSO): d=171.2 (CO), 139.4 (C1Ph), 138.6 (CH=CH2), 128.6
(C3Ph, C5Ph), 122.9 (C4Ph), 119.0 (C2Ph, C6Ph), 114.9 (CH=CH2), 36.2
(COCH2), 33.0 (CH2CH=CH2), 27.9 (CH2CH2CH=CH2), 24.7 ppm
(COCH2CH2). UPLC–MS: tR =2.12 min, m/z 204.1 ([M+H]+,
C13H18NO+ calcd: 204.1); HRMS m/z 204.1383 ([M+H]+, C13H18NO+
calcd: 204.1383). Analytical data are in agreement with those previ-
ously reported.[40] Alkene 25 (202 mg, 1.00 mmol) was dissolved in
anhydrous toluene (10 mL) in a Schlenk tube. 1,1,1,3,5,5,5-Hepta-
methyltrisiloxane (0.32 mL, 1.2 mmol) was added followed by Kar-
sted’s catalyst (23 mg, 3 wt% Pt in xylenes, 3.5 mmol Pt) and the re-
action mixture was stirred at reflux for 2.5 h, after which additional
Karsted’s catalyst (24 mg, 3 wt% Pt in xylenes, 3.6 mmol Pt) was
added. After stirring at reflux for additional 17.5 h, the reaction
mixture was adsorbed on silica gel and purified by DCVC (EtOAc/
heptane 0:100–10:90 (v/v)) affording desired siloxane 26 (357 mg,
84%) as a colorless oil. Rf =0.5 (EtOAc/heptane 25:75 (v/v));
1H NMR ([D6]DMSO): d=9.83 (s, 1H, NH), 7.54–7.61 (m, 2H,
H2Ph,H6Ph), 7.22–7.31 (m, 2H, H3Ph,H5Ph), 6.96–7.05 (m, 1H, H4Ph),
2.28 (t, J=7.4 Hz, 2H, COCH2), 1.57 (p, J=7.3 Hz, 2H, COCH2CH2),
1.30 (m, 6H, COCH2CH2CH2CH2CH2), 0.43 (t, J=5.7 Hz, 2H, CH2Si),
0.07 (s, 18H, Si(CH3)3), ꢀ0.02 ppm (s, 3H, SiCH3); 13C NMR
([D6]DMSO): d=171.2 (CO), 139.4 (C1Ph), 128.6 (C3Ph, C5Ph), 122.9
(C4Ph), 119.0 (C2Ph, C6Ph), 36.4 (COCH2), 32.3 (CH2CH2CH2Si), 28.4
(COCH2CH2CH2), 25.1 (COCH2CH2), 22.5 (CH2CH2Si), 17.1 (CH2Si), 1.9
(Si(CH3)3), ꢀ0.2 ppm (SiCH3); UPLC–MS: tR =3.35 min, m/z 426.2
SDS-PAGE according to the supplier), and HDAC11 (purity >50%
by SDS-PAGE according to the supplier) were purchased from Enzo
Life Sciences (Postfach, Switzerland). HDAC4 (purity >90% by SDS-
PAGE according to the supplier) and HDAC7 (purity >90% by SDS-
PAGE according to the supplier) were purchased from Millipore (Te-
mecula, CA 92590). Trypsin (10000 Umgꢀ1, TPCK treated from
bovine pancreas) was from Sigma Aldrich (Steinheim, Germany).
In vitro HDAC inhibition assays: For inhibition of recombinant
human HDACs the dose–response experiments with internal con-
trols were performed in black low binding Corning half-area 96-
well microtiter plates. The 10-fold dilution series were prepared in
HDAC assay buffer (Tris/Cl (50 mm), NaCl (137 mm), KCl (2.7 mm),
MgCl2 (1 mm), bovine serum albumin (0.5 mgmLꢀ1), pH 8.0) from
10–100 mm DMSO stock solutions. The appropriate dilution of in-
hibitor (5 mL of 5ꢁ the desired final concentration) was added to
each well followed by substrate in HDAC assay buffer (10 mL). Ac-
Leu-Gly-Lys(Ac)-AMC was used at a final concentration of 10 mm for
HDAC1, 2, and 3 and 20 mm for HDAC6 and 11. Ac-Leu-Gly-Lys(Tfa)-
AMC was used at a final concentration of 10 mm for HDAC4,
120 mm for HDAC5, 20 mm for HDAC7, 200 mm for HDAC8, and
80 mm for HDAC9. Ac-Arg-His-Lys(Ac)-Lys(Ac)-AMC was used at
a final concentration of 5 mm for HDAC10. Finally, a freshly pre-
pared solution of the appropriate HDAC (10 mL) was added and
the plate was incubated at 378C for 30 min. The final concentra-
tions of enzyme were as follows; HDAC1: 6 ngmLꢀ1, HDAC2:
1 ngmLꢀ1
0.2 ngmLꢀ1
,
HDAC3: 0.2 ngmLꢀ1
HDAC6: 1.2 ngmLꢀ1
,
HDAC4: 0.04 ngmLꢀ1
HDAC5:
HDAC7: 0.04 ngmLꢀ1
, HDAC8:
,
,
,
0.2 ngmLꢀ1, HDAC9: 0.8 ngmLꢀ1, HDAC10: 10 ngmLꢀ1, and HDAC11:
10 ngmLꢀ1
. Then trypsin in the HDAC assay buffer (25 mL,
0.4 mgmLꢀ1) was added and the assay development was allowed
to proceed for 15–30 min at room temperature, before the plate
was read using a PerkinElmer Enspire plate reader with excitation
at 360 nm and detecting emission at 460 nm. Each assay included
two wells with the appropriate inhibitor concentration, substrate,
and HDAC and control wells containing substrate only. All assays
were performed at least in duplicate. The data were analyzed by
nonlinear regression using GraphPad Prism to afford IC50 values
from the dose-response experiments, and Ki values were deter-
mined from the Cheng–Prusoff equation [Ki =IC50/(1+[S]/KM)] as-
suming a standard fast-on–fast-off mechanism of inhibition.
([M+H]+, C20H40NO3Si3 calcd: 426.2); HRMS m/z 426.2314 ([M+
+
H]+, C20H40NO3Si3 calcd: 426.2311).
+
7-(Dihydroxy(methyl)silyl)-N-phenylheptanamide (19): Siloxane
26 (3.7 mg, 8.7 mmol) was dissolved in [D3]MeCN/D2O (800 mL,
50:50 (v/v)) followed by addition of NaOD in D2O (40% w/w,
10.2 mg, 100 mmol) and the reaction was agitated for 4 h. LC–MS
indicated complete conversion into the desired silanediol 19.
1H NMR ([D3]MeCN/D2O 50:50 (v/v)): d=7.47–7.41 (m, 2H,
H2Ph,H6Ph), 7.32–7.26 (m, 2H, H3Ph,H5Ph), 7.11–7.05 (m, 1H, H4Ph),
2.28 (t, J=7.5, 2H, COCH2), 1.58 (p, J=7.0, 2H, COCH2CH2), 1.32–
1.22 (m, 6H, COCH2CH2CH2CH2CH2), 0.38–0.29 (m, 2H, CH2Si), ꢀ0.04
(s, 18H, (CH3)3SiOH), ꢀ0.19 ppm (s, 3H, SiCH3); HRMS m/z 282.1526
([M+H]+, C14H24NO3Si+ calcd: 282.1520).
Acknowledgements
We thank Novo Nordisk A/S for a generous donation of peptide
coupling reagents, Ms. Tina Gustafsson (DTU Chemistry) for tech-
nical assistance, and Ms. Uraiwan N. Adamsen for assistance
with synthesis of compounds 16, 17, and 18. Dr. Kristian Fog
Nielsen (DTU Systems Biology) is thanked for assistance with
HRMS measurements. This work was supported by grants from
the Danish Independent Research Council–Technology and Pro-
duction Sciences (Sapere Aude Grant No. 12-132328; A.S.M.), the
Danish Independent Research Council–Natural Sciences (Steno
Grant No. 10-080907; C.A.O.), the Villum Foundation (C.A.O.), and
the Carlsberg Foundation (C.A.O.). C.A.O. is a Lundbeck Founda-
tion Fellow.
Biological evaluation
Assay materials: HDAC1 (Purity>62% by SDS-PAGE according to
the supplier), HDAC2 (full-length, purity ꢂ94% by SDS-PAGE ac-
cording to the supplier), HDAC5 (catalytic domain, purity ꢂ90%
by SDS-PAGE according to the supplier), HDAC8 (purity ꢂ90% by
SDS-PAGE according to the supplier), HDAC9 (purity>85% by SDS-
PAGE according to the supplier), and HDAC10 (purity >23% by
SDS-PAGE according to the supplier) were purchased from BPS Bio-
science (San Diego, CA 92121). HDAC3–NCoR1 complex (purity
90% by SDS-PAGE according to supplier), HDAC6 (purity >90% by
Keywords: epigenetics · histone deacetylases · inhibitors ·
silanediols · trifluoromethyl ketones · zinc
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Published online on && &&, 0000
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These are not the final page numbers!

FULL PAPERS
A. S. Madsen, H. M. E. Kristensen, G. Lanz,
C. A. Olsen*
Zinc about it: We synthesized a series
of compounds containing diverse zinc
binding motifs and profiled their inhibi-
tory activity against the 11 human his-
tone deacetylases (HDAC1–11). From
the results, we discovered silanediol to
be a novel functionality with potential
as a suitable design element in the
preparation of new HDAC inhibitors.
Compounds of this type show promise
as future drug leads.
&& – &&
The Effect of Various Zinc Binding
Groups on Inhibition of Histone
Deacetylases 1–11
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 0000, 00, 1 – 14
&14
&
ÞÞ
These are not the final page numbers!