Design and synthesis of aryl ether and sulfone hydroxamic acids as potent histone deacetylase (HDAC) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.11.006

A series of novel hydroxamic acid based histone deacetylases (HDAC) inhibitors with aryl ether and aryl sulfone residues at the terminus of a substituted, unsaturated 5-carbon spacer moiety have been synthesized for the first time and evaluated. Compounds with meta- and para-substitution on the aryl ring of ether hydroxamic acids 19c, 20c, 19e, 19f and 19g are potent HDAC inhibitors with activities at low nanomolar levels.

Full text of DOI:10.1016/j.bmcl.2010.11.006

Bioorganic & Medicinal Chemistry Letters 21 (2011) 324–328
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of aryl ether and sulfone hydroxamic acids as potent
histone deacetylase (HDAC) inhibitors
Chittari Pabba a, , Brian T. Gregg a, , Douglas B. Kitchen b, Zhen Jia Chen a, Angela Judkins a
⇑
⇑
a AMRI, Medicinal Chemistry Department, 30 Corporate Circle, PO Box 15098, Albany, NY 12212, USA
b AMRI, CADD Department, 30 Corporate Circle, PO Box 15098, Albany, NY 12212, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel hydroxamic acid based histone deacetylases (HDAC) inhibitors with aryl ether and aryl
sulfone residues at the terminus of a substituted, unsaturated 5-carbon spacer moiety have been synthe-
sized for the first time and evaluated. Compounds with meta- and para-substitution on the aryl ring of
ether hydroxamic acids 19c, 20c, 19e, 19f and 19g are potent HDAC inhibitors with activities at low
nanomolar levels.
Received 21 September 2010
Revised 29 October 2010
Accepted 1 November 2010
Available online 5 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
HDAC
Histone deacetylase
HDAC-inhibitors
Molecular modeling
Hydroxamic acids
Cell-cycle arrest
Anticancer agents
Histone deacetylase (HDAC) enzymes are critically important in
the functional regulation of gene transcription as well as chromatin
structure remodeling and have become an emerging target in the
search for new anticancer drugs.1 Currently, there are 18 HDAC
known in humans which are classified into four main phylogenetic
classes. Of these known HDAC enzymes, it is commonly accepted
that class I HDAC1, HDAC2, HDAC3 and HDAC8 serve a critical
function in cell proliferation and survival. The primary function
of HDAC’s is the deacetylation of terminal amines present in the
lysine residues found in the core of histones. This deacetylation re-
sults in free amino groups which are capable of strongly binding
with DNA and results in the formation of chromatin structures
which effectively block gene transcription. The antibiotic trichosta-
tin A, (TSA), is a potent inhibitor of HDACs and is postulated to re-
sult in the induction of p21, a cyclin-dependent kinase inhibitor,
which is responsible for cell cycle arrest, differentiation, and apop-
tosis in several types of cancer cells.2 Several natural products
including trapoxin, herbimycin, depudecin, apicidin, FR 901228
and a few synthetic congeners such as suberoylanilide hydroxamic
acid (SAHA), MS-275, VX-563, Scriptaid and Oxamflatin have been
identified as HDAC inhibitors (Fig. 1) and are reported to revert the
morphological changes following the transformation of cells in cul-
ture.3,4 While the hydroxamic acid containing compounds have
been shown to have better activity in comparison to their
O
O
O
O
NHOH
NHOH
NHOH
H3C
N
H
CH3 CH3
N
O
SAHA
CH3
Trichostatin A
2
1
H
N
O
Ar
NHOH
S
O
X
O
X = O, CH2, NOH
Oxamflatin
3
4
metal
binding
cap
O
X
NHOH
R
CH3
spacer
R2
X = SO2 or O
5
Figure 1.
non-hydroxamic analogs, they typically have poor metabolic sta-
bility.5 It is promising to develop potentially superior HDAC inhib-
itors based on TSA or SAHA since detailed crystallographic data of
their binding interactions with the active binding site of a bacterial
HDAC homologue (HDLP) have been reported.6a Furthermore, both
⇑
Corresponding author.
E-mail address: brian.gregg@amriglobal.com (B.T. Gregg).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.11.006

C. Pabba et al. / Bioorg. Med. Chem. Lett. 21 (2011) 324–328
325
O
O
O
CH3
a
Br
ArO
a
OAc
OEt
OEt
OEt
O
75%
64-85%
OAc CH3
O
R
CH3
R
CH3
13:
14: R = CH3
6
7
11/12
R = H
b
HO
c
O
OEt
c
b
82%
ArO
OH
CH3
8
61-82%
75-92%
O
R
CH3
88%
O
15: R = H
OEt
16:
R = CH3
CH3
9
e
78%
O
O
d
ArO
R
ArO
d
95%
NHOH
NHOTHP
62-75%
O
O
CH3
R
CH3
17: R = H
18: R = CH3
e
Br
HO
OEt
OEt
19:
20:
R = H
R= CH3
84%
R
CH3
: R = H
12 : R = CH3
CH3 CH3
11
10
Scheme 2. Reagents and conditions: (a) ArOH, Cs2CO3, THF; (b) LiOH, EtOH, H2O, rt,
8 h; (c) NH2OTHP, EDCI, HOBt, THF, rt, 8 h; (d) MP-SO3H, MeOH, rt, 3 h.
Scheme 1. Reagents and conditions: (a) NaH, THF, (EtO)2P(O)CH2CO2Et; (b) K2CO3,
EtOH; (c) MnO2, CH2Cl2, 10 h, reflux; (d) 3.0 M CH3MgBr in Et2O, 4 h, 0 °C; (e) PBr3,
THF.
were directly saponified with lithium hydroxide giving carboxylic
acids 15 and 16 in moderate yields. Subsequent coupling with
THP-protected hydroxylamine (NH2OTHP) in the presence of EDCI
and HOBT gave protected hydroxamic acids 17 and 18. THP depro-
tection using solid phase macroporous sulfonic acid resin (MP-
TsOH) in methanol provided the aryl ether hydroxamic acids 19
and 20 in good yields.7a,9 The HDAC inhibition activity of the com-
pounds reported herein were assayed using a peptide substrate
and mixture of HDACs, predominantly HDAC1 and HDAC210 and
the in vitro IC50 values of the various derivatives were obtained.
Bioassay results for aryl ethers 15/16 (carboxylic acids) and 19/20
(hydroxamic acids) with various ‘cap’ substitution are presented in
Table 1. The first notable observation is the lack of inhibition activ-
ity for all of the carboxylic acid derivatives (15/16) tested; all
TSA and SAHA have been identified as potent and specific HDAC
inhibitors and specifically SAHA has been approved by the FDA
for the treatment of cutaneous T-cell lymphoma (CTCL).
The active site of an HDAC enzyme consists of a tubular pocket
leading to a zinc(II) and two aspargine–histidine charge relay sys-
tems; class I and II HDACs share this common feature of a zinc(II)
speciespresentat the enzymatic catalyticsite. Consequently, revers-
ible HDAC inhibitors reported to date have a chelating group that
forms a complex with the zinc(II) and a hydrophobic spacer that fits
into the tubular pocket. Therefore, options for the structural modifi-
cation of the chelating group and the hydrophobic spacer are lim-
ited.6 Several groups have reported the synthesis and bioassay of
novel HDAC inhibitors based on TSA with varying chain length, aryl
substitution, and aryl-chain connection with functionality that in-
cludes ketones, alkenes and oximes, etc. Of these analogs, those
which possess a hydroxamic acid metal binding group have shown
HDAC inhibition IC50 in the low nanomolar range.7
These studies led us to initiate structural modifications of the
terminal residue (‘cap’) while retaining the hydroxamic acid group.
It is postulated that structural features of the molecule in the ‘cap’
region interact at the entrance of the HDAC pocket and provides
opportunities to discover potent and possibly even selective HDAC
inhibitors.
exhibiting greater than >1 lm HDAC IC50 activity; conversely,
nearly all hydroxamic acid derivatives (19/20) showed promising
inhibition results. Incorporation of m-substituted aryloxy moieties
proved successful in achieving activity for a number of analogs pre-
sumably thru interactions at the hydrophobic region of the HDAC
pocket (Fig. 1). Our initial lead compound, 3-chlorophenyl 19a,
showed moderate HDAC inhibitory activity (IC50 = 188 nM). Fur-
ther probing of the hydrophobic pocket interaction with 3-phenyl-
aryloxy 19c gave a fivefold increase in activity (IC50 = 41 nM), and a
further threefold increase in activity was obtained with the 7-
methoxynaphthyl analog 19g (IC50 = 20 nM). Activity was retained
for 20c which incorporated a second methyl group on the diene
spacer portion of the molecule (IC50 = 55 nM). The most potent
compound tested in this series of analogs incorporated a 3-trifluo-
romethylphenoxy group 19f, displaying an HDAC inhibitory activ-
ity of IC50 = 18 nM.
We now report our results on the design, synthesis and HDAC
inhibitory data for a series of the TSA analogs which contain either
an aryl ether or sulfone functionality as the ‘capping’ group, a
branched chain diene spacer linker and carboxylic or hydroxamic
acid terminal group capable of binding to the zinc residue con-
tained within the active site of HDAC enzymes.
Substitution of the aryloxy group in the para position reduced
activity; 4-bromophenyl-4-phenoxy 20i showed a fourfold de-
crease in activity (IC50 = 162 nM) compared with the similar 3-phe-
nyl analog 19c. Both 2,4-dibromoaryloxy 19b and 4-n-
hexylaryloxy 20h analogs significantly lost activity with nearly
micromolar activity IC50 = 890 nM and 1100 nM, respectively.
HDAC inhibition was mostly dependent on the substitution on
the aryl ring and it changed only minimally with methyl substitu-
tion on diene chain as demonstrated for the 3-biphenyl analogs
19c and 20c both showing similar inhibitory activity for the methyl
and unsubstituted diene chain (19c, 41 nM; 20c, 55 nM). These re-
sults indicated that for this series of compounds, arene substitution
at the meta- and/or para-positions is preferred for good inhibition
activity. Similar results have previously been reported that support
the observation for the preference of para-substituted aryl ‘cap’
groups.11
Synthesis of analogs started from commercially available (E)-3-
methyl-4-oxobut-2-enyl acetate 6 and the preparation of alcohols
88 and 103a is illustrated in Scheme 1. Specifically, aldehyde 6
undergoes a Horner–Wadsworth–Emmons olefination with tri-
ethyl phosphoroacetate and NaH in THF to give trans-diene 7 in
moderate yield. Acetate deprotection cleanly gave primary alcohol
8. Incorporation of the second branched methyl to the diene back-
bone was achieved by a two-step process; oxidization with manga-
nese dioxide to give aldehyde 9 followed by methylmagnesium
bromide addition afforded secondary alcohol 10. Both alcohols 8
and 10 were treated with PBr3 to yield bromides 11 and 12.
Aryl ethers 15/16, and 19/20 were prepared from bromides 11
and 12 in four steps by the procedure outlined in Scheme 2. Reac-
tion of 11 and 12 with substituted phenols in the presence of ce-
sium carbonate gave aryl ethers 13 and 14 in good yields. These

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C. Pabba et al. / Bioorg. Med. Chem. Lett. 21 (2011) 324–328
Table 1
O
O
In vitro inhibitory activities for aryloxy analogs at histone deacetylase10
S
Br
a
Ar
OEt
OEt
70-90%
CH3 CH3
CH3 CH3
O
Y
21
Ar
12
R
CH3
O
O
19
: Y = CO H, R = H
: Y = CO H, R = CH
: Y = CONHOH, R = H
O
15
16
2
b
c
S
20: Y = CONHOH, R = CH3
2
3
OEt
40-60%
Ar
CH3 CH3
10
HDAC Inhibition IC50 (M)
22
Y = CO2H
Ar
Y = CONHOH
O
S
O
O
R = H (15) R = CH3(16)
R = H (19) R = CH3 (20)
R
Ar
Cl
CH3 CH3
>1
>1
0.188
0.890
23: R = NHOH
24: R = OH
a
Scheme 3. Reagents and conditions: (a) ArSH, NaH, THF; (b) mCPBA, CH2Cl2, 0 °C,
8 h; (c) KOH, NH2OHÁHCl, rt, 8 h.
Br
Ph
Br
b
c
Table 2
Inhibitory activities for sulfone hydroxamic acid and sulfone carboxylic acids at
>1
>1
0.041
1.200
0.068
0.018
0.020
0.055
histone deacetylase10
O
O
S
R
Ar
Ph
>50
CH3 CH3
23: R = CO2H
d
24: R = CONHOH
10
HDAC Inhibition IC50 (M)
>1
H3CO
F3C
R = CO2H
23
Ar
R = CONHOH
24
e
R2
>50
>1.0
f
R1
R1 = Br, Cl, F; R2 = H
R1 = CH3; R2 = 3-CH3, 2-CH3
H3CO
R2
g
R1
>1.0
CH3(CH2)5O
h
>1
1.100
0.162
R1 = Br, CH3, OCH3, NAc; R2 = H
1 = H; R2 = OCH3
R1 = Cl; R2 = Cl
R
Br
i
>1.0
>1.0
H3C
N
N
H3C
>50
N
H3C
H3C
O
j
N
>1.0
N
>1
>1
>50
>50
CH3
k
H3C
H3C
l
capping group compared to the aryloxy group, we hoped that the
activity seen as a result of incorporating a hydroxamic acid metal
binding group would allow for some tractable SAR data. Specifi-
cally bromide 12 was used to incorporate the desired aryl diversity
elements by reaction with a variety of thiophenols to generate sul-
fides 21 that were converted to the target aryl sulfones by oxida-
tion using m-chloroperbenzoic acid (Scheme 3) giving esters 22.
Finally, one pot hydroxamination of the resultant esters afforded
the sulfone hydroxamic acids 23 in low to moderate yields along
with isolated acids 24 as by product. Unfortunately all of the aryl-
sulfonates 23 as well as the analogous carboxylic acid derivatives
Tricostatin A
0.003
1
Recently the Marson group12 reported SAR data for examples of
aryl sulfide and sulfoxide analogs at ‘cap’ region of the SAHA core 2
with both fully saturated and diene unsubstituted backbone
‘spacer’ linker, with interesting HDAC inhibition activity but did
not provide enough data to draw an accurate conclusion on
whether sulfones would be active. Having prepared the key inter-
mediate 12 we decided to further probe the ‘cap’ region of our core
molecule by replacement of the aryloxy group with a series of aryl-
sulfone derivatives. While the sulfone is a significantly different
24 had HDAC inhibitory activity IC50 >1 lm. (Table 2)
Molecular modeling: In order to better understand the results for
compounds 19/20 we built a model of TSA in HDAC-2. Recently, an

C. Pabba et al. / Bioorg. Med. Chem. Lett. 21 (2011) 324–328
327
tory effect on HDACs. We have shown that the potency depends on
the substitution pattern on the arene ring. We have also observed
the multifold increase in activity with the replacement of large
arylsulfone group with the corresponding aryl ether. SAR results
with the aryl ether hydroxamic acids are consistent with the
hypothesis that these HDAC inhibitors operate as mimetics of the
natural product TSA. These small molecule aryl ether hydroxamic
acids may be useful as tools for biological research and as orally
bioavailable anticancer drugs. Currently, further detailed SAR stud-
ies and the next stage of evaluation are underway.
Acknowledgments
We would like to thank Drs. David M. Vigushin, R. Charles
Coombes, Christophe Tratrat and Anthony G. M. Barrett of the
Departments of Chemistry and Cancer Medicine, Imperial College,
London and Drs. Bruce F. Molino, Cheryl Garr, and Barry Berkowitz
for their support on this project as well as Susan Mulligan and John
Dolan for their contributions.
References and notes
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the N-terminal of the released product ([3H]acetic acid) with ethyl acetate
quantification by liquid scintillation counting. Each test compound was
assayed in duplicate whilst positive control (trichostatin A) and negative
control samples were assayed in triplicate. Further details are provided in
reference: Marson, C. M.; Serradji, N.; Rioja, A. S.; Gastaud, S. P.; Alao, J. P.;
Coombes, R. C.; Vigushin, D. M. Bioorg. Med. Chem. Lett. 2004, 14, 2477.
12. Marson, M. C.; Savy, P.; Rioja, A. P.; Mahadevan, T.; Miko, C.; Veerupalli, A.;
Nsubuga, E.; Chahwan, A.; Joel, S. P. J. Med. Chem. 2006, 49, 800.
13. The starting structure of TSA was obtained from HDAC-8 (pdbcode: 3f0r15) and
aligning its C
a atoms to those of HDAC-2 based on sequence similarity. The
coordinates of TSA were then used to place it in HDAC-2 and a series of
molecular dynamics simulations (200 ps with a temperature bath of 298 K
applied) were used to adjust the protein structure and position of TSA. Initially
the entire protein was fixed in place except of residues within 4 Å of the TSA
molecule. Additional simulations relaxed the constraints in 1 Å increments
until
a sphere of 8 Å was obtained. The same procedure was used for
11. Histone deacetylase activity was measured by incubation of HeLa cell nuclear
extract (a source of histone deacetylase enzymes) prepared according to
Dingam, J. D.; Lebovitz, R. M.; Roeder, R. G. Nucleic Acids Res. 1983, 11, 1475,
with a [3H]acetate-radiolabled peptide substrate followed by extraction with
[3H]acetate-radiolabled peptide substrate and subsequent extraction of the
released product ([3H]acetic acid) with ethyl acetate and quantification by
scintillation counting. The substrate was a synthetic peptide corresponding to
compound 19f. The starting structure for 19f was obtained by modifying the
16
structure of TSA. All simulations were performed using the program, BMIN
.
14. Molecular Operating Environment (MOE), Chemical Computing Group, Inc.,
Montreal, ON.
15. Dowling, D. P.; Gantt, S. L.; Gattis, S. G.; Fierke, C. A.; Christianson, D. W.
Biochemistry 2008, 47, 13554.
16. BMIN, version 9.7.110, Schrodinger, Inc.: NY, NY.