Design and synthesis of a potent histone deacetylase inhibitor

Article abstract of DOI:10.1021/jm061082q

Histone deacetylase (HDAC) inhibitors have potential for cancer therapy. An HDAC inhibitor based on a cyclic peptide mimic of known structure, linked by an aliphatic chain to a hydroxamic acid, was designed and synthesized. The chimeric compound showed potent competitive inhibition of nuclear HDACs, with an IC₅₀ value of 46 nM and a K_i value of 13.7 nM. The designed inhibitor showed 4-fold selectivity for HDAC1 (57 nM) over HDAC8 (231 nM).

Full text of DOI:10.1021/jm061082q

J. Med. Chem. 2007, 50, 2003-2006
2003
Design and Synthesis of a Potent Histone
Deacetylase Inhibitor
Tao Liu, Galina Kapustin, and Felicia A. Etzkorn*
Virginia Tech, Department of Chemistry MC 0212,
Blacksburg, Virginia 24061-0212
ReceiVed September 14, 2006
Abstract: Histone deacetylase (HDAC) inhibitors have potential for
cancer therapy. An HDAC inhibitor based on a cyclic peptide mimic
of known structure, linked by an aliphatic chain to a hydroxamic acid,
was designed and synthesized. The chimeric compound showed potent
competitive inhibition of nuclear HDACs, with an IC50 value of 46
nM and a Ki value of 13.7 nM. The designed inhibitor showed 4-fold
selectivity for HDAC1 (57 nM) over HDAC8 (231 nM).
DNA is assembled into nucleosomes, which are the funda-
mental repeating subunits of all eukaryotic chromatin. Nucleo-
somes are made up of DNA (146 base pairs) wrapped around
an octamer of histones.1 Post-translational modification of the
N-terminal tails of the histones, including acetylation, phos-
phorylation, and methylation, alter the chromatin structure and
regulate gene transcription.2 Histones can exist in two forms,
acetylated and deacetylated, which are controlled by histone
acetyltransferases (HATsa) and histone deacetylases (HDACs).
HDACs are divided into three classes based on mechanism,3
of which classes I and II are therapeutic targets for the treatment
of leukemia4 and solid tumors.5,6 Recent studies have shown
that inhibition of HDACs silences the growth of tumor cells
by introducing terminal differentiation, growth arrest, and
apoptosis.7,8 Quite a few inhibitors are in phase I or II clinical
trials:9 suberoylanilide hydroxamic acid (SAHA),10 butyrate,11
4-(acetylamino)-N-(2-aminophenyl) benzamide (CI-994),12,13
and cyclo[(2Z)-2-amino-2-butenoyl-L-valyl-(3S,4E)-3-hydroxy-
7-mercapto-4-heptenoyl-D-valyl-D-cysteinyl], cyclic (3f5)-di-
sulfide (FK228).14
Many HDAC inhibitors have been reported, both naturally
occurring, such as trichostatin A (TSA),15 apicidin,16 and
trapoxin,17 and synthetic, such as SAHA18 (Figure 1). These
HDAC inhibitors can be divided into categories according to
their structural characteristics, such as hydroxamates, carbox-
ylates, benzamides, and cyclic peptides, though most are
hydroxamic acid derivatives.19 We have shown that charged
phosphorus-based compounds are poor inhibitors of HDACs,20
which may distinguish the mechanism of HDAC-catalyzed
deacetylation from that of zinc protease amide hydrolysis.21
Based on SAR studies, efficient HDAC inhibitors should have
three features: (1) a hydrophobic region that binds the rim of
the active site and blocks the entrance, (2) a coordinating group
Figure 1. Naturally occurring and synthetic HDAC inhibitors, of which
the hydroxamic acid derivatives (TSA15 and SAHA18) are the most
common. Cyclic peptides, such as apicidin,16 and cyclic peptide mimic
1 are another class of potent HDAC inhibitors.
to chelate to Zn2+ at the bottom of the tubular pocket, and (3)
a five- to seven-atom linker from the hydrophobic region to
the coordinating group.19 The linker helps insert the hydroxamic
acid into the bottom of the tubular active site.
Most inhibitors exhibit IC50 values against HDACs in the
micromolar range.19 However, some inhibitors containing a large
active site rim recognition element, such as trapoxin, apicidin,16
and cyclic tetrapeptides,22-24 give nanomolar IC50 values against
HDACs. The high potency of these tetrapeptides suggested that
introduction of a macrocycle into an HDAC inhibitor would be
promising.
HDAC inhibitor (HDI) 1 was designed based on a cyclic
peptide mimic previously synthesized in our lab.25 We have
investigated alternative phosphorus-containing head groups for
HDAC inhibitors and found them deficient, so we chose the
hydroxamic acid head group.20 Combining the cyclic peptide
mimic with the hydroxamic acid functionality not only retained
the hydrophobic property of the cyclic peptide mimic, but also
introduced the linker and zinc-binding functional group into the
targeted molecule 1. The three-dimensional structure of the
cyclic peptide mimic was determined by NMR in previous
work.26 In the molecular modeling, the known 3-D structure of
the cyclic peptide mimic26 was attached to the linker and
hydroxamic acid of SAHA from the cocrystal structure with
the bacterial histone deacetylase-like protein (HDLP),27 which
is similar to class I HDACs.28 Compound 1 was docked
manually by superposition onto SAHA in the HDLP active site.
Several conformers around the CR-Câ torsion were minimized
in the active site using Sybyl 7.1 (Tripos Associates, see
Supporting Information).
Molecular visualization shows that there are several pockets
on the HDLP surface (Figure 2). The surface around the entrance
to the active site is mostly nonpolar. The aromatic group and
the 12-membered ring of compound 1 were predicted to make
good contacts with the enzyme surface recognition site, and the
hydroxamic acid group is known to bind tightly to Zn2+. The
results of the computational study indicated that the designed
peptide mimic would be an efficient HDAC inhibitor. Because
* To whom correspondence should be addressed. Phone: 540-231-2235.
Fax: 540-231-3255. E-mail: fetzkorn@vt.edu.
a Abbreviations: DPPA, diphenylphosphoryl azide; FDDP, pentafluoro-
phenyl diphenyl phosphate; HAT, histone acetyl transferase; HATU, O-(7-
azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate;
HBTU, O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophos-
phate; HDAC, histone deacetylase; HDI, histone deacetylase inhibitor;
HDLP, histone deacetylase like protein; HOAt, 1-hydroxy-7-azabenzotri-
azole; HOBt, hydroxybenzotriazole; PyAOP, (7-azabenzotriazol-1-yloxy)
tripyrrolidino-phosphonium hexafluorophosphate; SAHA, suberoylanilide
hydroxamic acid; TBAF, 1-tetra-n-butyl ammonium fluoride; TBS, t-
butyldimethylsilyl; TES, triethylsilane; TFFH, N,N,N′,N′-tetramethylfluoro-
formamidinium hexafluorophosphate; TMSE, trimethylsilylethyl; TSA,
trichostatin A.
10.1021/jm061082q CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/10/2007

2004 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 9
Letters
Scheme 2
Figure 2. Molecular model of the rim and the active site of the complex
of compound 1 (ball and stick with translucent red-orange surface) and
HDLP (lipophilic potential surface with scale at left). Created with
Sybyl 7.1.
Scheme 1
which could be cleaved if TFA was used to remove Boc
(Scheme 2).32 The amine was blocked with acetyl, as in the
modeled inhibitor, to give 8. Liberation of the amine by
hydrogenolysis of the Cbz group of 8 furnished the free amine.
Condensation with 6 to give 9 was accomplished using (7-
azabenzotriazol-1-yloxy) 1-tripyrrolidino-phosphonium hexa-
fluorophosphate (PyAOP) as the coupling reagent. PyAOP,
which suppresses racemization, is suitable for the coupling of
hindered amino acids, difficult short sequences, and cyclic
systems.33,34 We encountered unexpected difficulty in the
deprotection of the TMSE ester. Various fluoride ion sources
were used to attempt cleavage of the TMSE group, but none of
these reactions afforded the desired intermediate. TMSE esters
are known to be labile to strong acid, so the TMSE of 9 was
cleaved by TFA with triethylsilane (TES) as a scavenger, which
simultaneously deprotected Boc.35-37 Exchange of the TFA salt
using HCl in ether did not improve cyclization results in the
next step.
Many attempts were made to produce cyclic intermediate 10,
employing different classes of coupling reagents, including the
phosphates diphenylphosphoryl azide (DPPA) and pentafluoro-
phenyl diphenyl phosphate (FDDP), the phosphonium salts
PyAOP, the uronium salts O-benzotriazol-1-yl-N,N,N′,N′-tetra-
methyluronium hexafluorophosphate (HBTU) and O-(7-aza-
benzo-triazol-1-yl)-N,N,N′,N′-tetramethyluronium hexa-fluoro-
phosphate (HATU), and the acid fluorides formed using cyanuric
fluoride or N,N,N′,N′-tetramethyl-fluoroformamidinium hexa-
fluorophosphate (TFFH).38 However, only DPPA or HATU
coupling produced macrocycle 10. DPPA is a widely used
coupling reagent in peptide cyclizations,39 however, in our case,
the highest yield of cyclized 10 using DPPA was only 10%.
Comparable yields were obtained with HATU; the best result
was achieved with a 1 h HATU coupling. Long coupling times
using HATU or PyAOP produced no product. Steric hindrance
was not a problem in previous cyclizations with Ala in the
position of the R-aminosuberic acid.26 The instability of the
hydroxamic acid functionality may have contributed to the low
yield of 10. Hydrogenolysis of 10 to expose the key hydroxamic
compound 1 does not contain natural R-amino acids, it may be
less susceptible to biodegradation than the cyclic peptide
inhibitors. We now present the synthesis of compound 1 and
describe its inhibitory activity against HDACs.
The amine group of R-(S)-aminosuberic acid 2 was protected
by treatment with Boc2O in dioxane-water (Scheme 1). The
formation of oxazolidinone 4 was successfully carried out by
treatment with paraformaldehyde and TsOH.29,30 The Boc group
was stable in the presence of TsOH with heating.
The best solvent for the reaction was 1,1,3-trichloroethane,
in which 3 was soluble, and with which water forms an
azeotrope.29 Oxazolidinone 4 was coupled with benzyloxy-
hydroxylamine to give protected hydroxamate 5. The oxazoli-
dinone of 5 was saponified with LiOH.29
The stereoselective synthesis of intermediate 7 was reported
previously by Travins and Etzkorn.25 From our modeling, the
size of the Boc group might have hindered efficient binding of
the cyclic peptide mimic into the surface site of the enzyme.
The Boc group of 7 was deprotected with 4 M HCl31 because
of its compatibility with the trimethylsilylethyl (TMSE) group,

Letters
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 9 2005
Table 1. In Vitro Inhibition (IC50) of HeLa Nuclear Extract HDACs,
HDAC1, and HDAC8 Activity
Thus, the designed inhibitor showed 4-fold selectivity for
HDAC1 over HDAC8. All of the IC50 values for the designed
inhibitor 1 and controls 11 and 12 reported in Table 1 were
measured under the same conditions.
HDI
HDACs (nM)
HDAC1 (nM)
HDAC8 (nM)
1
12
11
TSA
SAHA
46 ( 8
57 ( 10
231 ( 30
NDa
167 ( 20
8100 ( 2100
41 ( 5
174 ( 28
40 000 ( 7400
60 ( 223
11243
In conclusion, we have designed and synthesized a potent
HDAC inhibitor based on our own cyclic peptide mimic.25 The
key steps of the synthesis included 12-membered ring cyclization
and hydroxamic acid deprotection. The new inhibitor exhibited
4-fold selectivity for HDAC1 over HDAC8. The potency of
the HDAC inhibitor demonstrated that the surface recognition
region plays an important role in the design of new HDAC
inhibitors.
NDa
4042
11020
27020
a Not determined.
acid functionality using the mild catalysts, 5% Pd(OH)2/C40 or
5% Pd/BaSO4,41 produced the target HDAC inhibitor 1.
Inhibition of HDAC activity in HeLa nuclear extracts by
compound 1 was measured using a fluorescence-based assay.
The IC50 value of 1 was 46 ( 8 nM (Table 1). The IC50 value
for TSA measured in this assay system was 20-fold less potent
than that reported in radioactively-labeled histones HDAC
assays.24 This may indicate that our inhibitor may be more potent
than we report. The Ki value was measured in the same system
to be 13.7 ( 4.1 nM, and the data fit best to a tight-binding
competitive inhibition model (see Supporting Information). The
Ki value is more robust and may be compared across assay
systems because both the inhibitor and the substrate concentra-
tions are varied. The high efficiency of the designed synthetic
HDAC inhibitor 1 indicates that the hydrophobicity and the
shape of the surface recognition element play an important role
in the formation of the enzyme-inhibitor complex.
Acknowledgment. We thank Professor Daniel Rich (Uni-
versity of Wisconsin) and Dr. Jeremy M. Travins (Wyeth
Pharmaceuticals) for the helpful suggestions. We thank the NIH
for Grant GM52516 and Virginia Tech for financial support.
Supporting Information Available: Computational and ex-
1
perimental procedures, H and 13C NMR spectra of compounds
1-12, HPLC chromatograms of 1, 11, and 12, and COSY, HMQC
for 1. This material is available free of charge via the Internet at
http://pubs.acs.org.
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2006 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 9
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