Macrocyclic peptoid-peptide hybrids as inhibitors of class I histone deacetylases

Article abstract of DOI:10.1021/ml300162r

We report the design, synthesis, and biological evaluation of the first macrocyclic peptoid-containing histone deacetylase (HDAC) inhibitors. The compounds selectively inhibit human class I HDAC isoforms in vitro, with no inhibition of the tubulin deacetylase activity associated with class IIb HDAC6 in cultured Jurkat cells. Compared to the natural product apicidin (1), one inhibitor (compound 10) showed equivalent potency against K-562 cells, but was more cytoselective across a panel of cancer cell lines.

Full text of DOI:10.1021/ml300162r

Letter
pubs.acs.org/acsmedchemlett
Macrocyclic Peptoid−Peptide Hybrids as Inhibitors of Class I Histone
Deacetylases
Christian A. Olsen,† Ana Montero, Luke J. Leman, and M. Reza Ghadiri*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: We report the design, synthesis, and biological evaluation of the first
macrocyclic peptoid-containing histone deacetylase (HDAC) inhibitors. The
compounds selectively inhibit human class I HDAC isoforms in vitro, with no
inhibition of the tubulin deacetylase activity associated with class IIb HDAC6 in
cultured Jurkat cells. Compared to the natural product apicidin (1), one inhibitor
(compound 10) showed equivalent potency against K-562 cells, but was more
cytoselective across a panel of cancer cell lines.
KEYWORDS: HDAC inhibitors, peptides, peptoids, macrocycles, apicidin
e have recently described the design of conformationally
homogeneous macrocyclic tetrapeptides as scaffolds to
cyclic tetrapeptides would provide access to distinct conforma-
tional space compared to traditional α- or β-peptides. For
instance, mixing peptide and peptoid residues affords the
opportunity to vary the number of backbone bonds between
side chains, and thereby change their relative distances. Further,
the secondary amides found in peptides are overwhelmingly
populated by the trans conformation, whereas both the cis and
trans conformers are generally accessible in the tertiary amides
found in peptoids.32−35 Indeed, a force field based conforma-
tional search of a peptoid−peptide hybrid (vide infra) indicated
that its lowest energy conformation would contain a cis amide
but would nevertheless closely match the pharmacophoric
model for compounds containing all trans amide bonds
determined in our previous studies (Figure 1).
By applying a combination of standard Fmoc solid-phase
synthesis and peptoid subunit synthesis (Figure S1, Supporting
Information), we initially prepared analogs 3−6, in which the
amino acids of our parent compound 21 (Figure 2) were
gradually substituted with peptoid units (Figure 2b). In contrast
to the low yields obtained in the macrolactamization of 12-
membered ring peptides,36 the efficiency of the ring-closure was
generally good as judged by LC-MS analysis, similar to that
observed for 13-membered ring α3β peptides (typical overall
isolated yields were 10−18%, Table S1).1−6
W
display four amino acid side chain functionalities in predictable
three-dimensional arrangements (Figure 1).1−6 The structure-
guided studies relied on peptide backbone modifications, such
as the incorporation of beta amino acids or triazole moieties, to
simultaneously promote conformational homogeneity and
provide efficient synthetic routes to the macrocycles. Our
studies included systematic investigations of the importance of
stereochemical changes and N-methylation of backbone
amides, as well as the effect of various side chains.1−6 With
the goal of further expanding the repertoire of unique side
chain spatial arrangements and backbone conformations
beyond those that are available with simple α- or β-peptides,
here we incorporate peptoid (N-alkylglycine) residues into
cyclic tetrapeptide histone deacetylase (HDAC) inhibitors. In
addition to accessing unique structure space, we anticipated
that the inclusion of peptoid residues could impart useful
biological properties such as proteolytic resistance or improved
cell permeability.
HDAC inhibitors are promising agents for anticancer
chemotherapy,7−9 with several candidates in clinical trials,7
and vorinostat (SAHA)10 and romidepsin (FK-228)11 approved
to treat cutaneous T-cell lymphoma. A notable group of HDAC
inhibitors are macrocyclic compounds, such as apicidin (1),12
bearing an extended Zn2+-coordinating unit that interacts with
the active site zinc ion of the class I, II, and IV HDAC
enzymes.13,14
HDAC inhibitory activity was initially assessed using HeLa
cell nuclear extract.37 Compound 5 showed modest inhibition
of HDAC activity (∼1 μM), whereas the other three
compounds were inactive. Based on the structure of 5, we
prepared analogs 7a−e to probe the tryptamine subunit more
carefully (Figure 2b); unfortunately, compound 7a showed a
decrease in potency and 7b−e were inactive. We also prepared
Peptoid residues15,16 offer the potential for extensive modular
diversification of ligands due to the ready availability of the
synthetic subunits.17 Peptoid-based peptidomimetics have
found utility in various biological applications,18−26 and N-
alkyl-β-alanine residues (“β-peptoids”) have also been success-
fully incorporated into biologically active oligomers.27−31 We
envisioned that installing peptoid or β-peptoid residues in our
Received: June 20, 2012
Accepted: August 7, 2012
Published: August 10, 2012
© 2012 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
Figure 1. Peptoid moieties provide access to conformational space not
available to α- or β-peptides, so they complement efforts in designing
conformationally distinct macrocyclic HDAC inhibitors. The structure
overlay highlights the overlap of pharmacophoric side chains between
the global minimum energy molecular conformation of a peptoid−
peptide hybrid obtained in a conformational search (green) with the
NMR structures of apicidin (white),38 a 1,4-disubstituted triazole
peptide (yellow),3 a 1,5-disubstituted triazole peptide (gray),3 and a
peptide containing a β-amino acid (magenta).1 Aoda, (S)-2-amino-8-
oxodecanoic acid.
Figure 2. Compound structures and their corresponding IC50 values
measured against the HDAC activity in HeLa cell extract. (a) Parent
compounds 1 and 2. (b) Structures of analogs 3−11. Peptoid residues
are highlighted in blue, and β-peptoid residues are highlighted in
green.
analog 8, in which the number of bonds between the aromatic
group and the 1- and 3-position side chains, respectively, is the
same as in compound 2 and apicidin. This analog did not
inhibit HDAC activity in the tested concentration range.
Next, we constructed compounds 9 and 10, in which amino
acid positions 1−3 of the macrocycle were kept as present in
compound 5, while the N-Me-Ala residue was substituted with
arginine (9) or ε-N-acetyl-lysine (10) (Figures 2 and S1). We
had previously identified these substitutions as being beneficial
for HDAC inhibition in a library screen of α3β-peptides.2 In the
present context, these substitutions gave rise to nanomolar
inhibition of the HeLa cell HDAC activity, with the potency
measured for 9 being close to that observed for parent
compound 2 (58 nM and 40 nM, respectively). Finally,
position three was probed by preparing the more sterically
demanding N-dimethylallyl analog 11 (Figures S2 and S3),
which turned out to be less potent than 9 or 10 (Figure 2).
1
The H NMR spectra of compounds 9 and 10 recorded in
DMSO-d6 at 295 K revealed a single set of signals (Figures S8
and S9). In contrast, both N-Me-Ala analogs 21 and 5, like
apicidin,3,38 exhibited multiple conformations by NMR
(Figures S6 and S7). The multiple conformations of apicidin
are known to stem from cis/trans isomerization of the pipecolic
acid residue (position 4);3,38 by analogy, compound 2 also
presumably isomerizes at the alkylated amide at position 4.
Likewise, considering that compounds 5, 9, and 10 all contain
peptoid moieties at residues 2 and 3, but only compound 5 is
alkylated at position 4, it appears that the multiple
conformations observed for 5 are due to isomerization at the
alkylated position 4 amide.
To further explore the possible conformations of compounds
9 and 10, we carried out a force field based conformational
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search of a representative structure having an Ala residue at
position 4. The ten lowest energy conformations (Figure S4,
Table S2) contained a cis amide at the tryptamine subunit; the
rest of the amides were in the trans configuration (Figure 3).
apicidin and 2, with the most potent candidates (9 and 10)
being ∼6-fold less potent than 2 against HDAC1. Because
ethylketone-containing apicidin analogs do not appear to
inhibit class IIa HDACs,39,40 we excluded enzymes of this
class in the present investigation. As expected based on
inhibition profiles of other ligands containing the ethylketone
Zn2+-coordinating amino acid,1−3 all the compounds were
inactive against HDAC6, a representative member of the
HDAC class IIb (Table 1). HDAC8 is a class I HDAC but
diverges significantly from the other class I isoforms41 and was
recently shown to be similar to class IIa isoforms in terms of
inhibitor specificity.39 It was therefore not surprising that
compound 9 was 4-fold less potent against HDAC8 as
compared to HDAC1. In contrast, compound 9 was ∼3-fold
more potent than parent compound 2 against HDAC8, which
corresponds with a possible interaction of arginine residues
with HDAC8 previously proposed by Mrksich and co-workers
based on experiments with histone substrates.42
To confirm that compound 9 could inhibit HDACs in a
cellular context, we treated cultured Jurkat cells with various
concentrations of 9 for 24 h. Western blot analysis of the cell
lysates showed high levels of acetylated-histone H3 (K9Ac
+K14Ac) when compound 9 was present at 2 μM or 20 μM,
which indicates that 9 inhibited class I HDACs in the cells
(Figure S5). On the other hand, the level of acetylated α-
tubulin (substrate for HDAC6) was not elevated by any tested
concentration of compound 9, indicating that HDAC6 was not
inhibited. These results are in agreement with the recombinant
enzyme assays (Table 1).
Figure 3. Comparison of the NMR structure of apicidin (left) with
one of the low energy calculated structures of compounds 9/10
(right). Side chain atoms have been removed for clarity. Even though
the amide bond between positions 1 and 2 adopts a different cis/trans
configuration, the distances and vectors between pharmacophoric side
chains are nearly identical.
Finally, we investigated the ability of the peptoid−peptide
hybrids to inhibit growth of selected cancer cell lines (Table 2).
The moderate potencies observed for 5 correlate well with its
lower potencies against the various HDACs as compared to
apicidin and 2. Compounds 9 and 11 showed no activity in the
tested concentration range, possibly due to poor cell
permeability caused by the cationic guanidinium functionality
in arginine. Compound 10 showed moderate activity against
HeLa and Hct-116 cells but intermediate and good activities
against the leukemic cell lines KYO-1 and K-562, respectively.
Interestingly, when comparing the activities to those of apicidin
(1), the less potent HDAC inhibitor 10 is equipotent against K-
562 cells but shows a much higher degree of cytoselectivity,
which may be desirable with respect to the future development
of therapeutic agents.
An inspection of these low energy structures suggests that
adoption of the cis configuration reduces unfavorable steric
interactions between the indole group and the side chains at
positions 1 and 3. Interestingly, there is good overlap of this
backbone conformer with the NMR structure of apicidin in the
pharmacophoric region (rmsd of 0.4 Å, Figures 3 and S4),
suggesting a basis for the observed potencies of compounds 9
and 10. Due to the additional methylene unit between the
backbone and the indole functionality as compared to the
natural product, the active peptoid−peptide compounds are
more flexible in this important region of the pharmacophore,
which may explain the somewhat lower potencies observed.
Some higher-energy modeled conformations contained all-trans
amide configurations; while the cis-trans-trans-trans conforma-
tions overlay well with the pharmacophoric region of apicidin
(Figure S4), the all-trans conformations do not.
In summary, we have successfully constructed cyclic peptoid-
containing ligands with potent HDAC inhibitory activity in
HeLa cell extract, comparable to the parent compound. The
choice of an ethyl ketone Zn2+-coordinating amino acid enabled
high class I selectivity against recombinant enzyme isoforms 1−
Selected compounds were further tested against several
recombinant human HDACs in a standard trypsin-coupled
fluorogenic assay (Table 1). The potencies recorded against the
class I HDACs 1−3 generally followed the trends observed for
a
Table 1. IC50 Values (nM) for Selected Compounds against Recombinant Human HDACs 1−3 and 6
class I
class IIb
HDAC6
b
compd
HDAC1
HDAC2
HDAC3
HDAC8
apicidin
11
30
3
5
34
2
13
30
5
7
750
>10000
>10000
>10000
>10000
>10000
>10000
2
70 24
2200
N.D.
750
5
540 60
180 16
200 72
700 160
2000 500
300 16
370 48
1200 140
650 140
100 14
320 21
9
10
11
N.D.
N.D.
270
4
a
b
IC50 values are means of at least two assays performed in duplicate. In complex with nuclear receptor corepressor 2 (NCoR-2). N.D. = not
determined.
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a
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Table 2. Growth Inhibition of Selected Cancer Cell Lines
cell growth inhibition, GI50 (μM)
compd
HeLa
2
Hct-116
MCF-7
5
KYO-1
2.7
K-562
apicidin
1
1.5
b
b
b
b
2
4
N.D.
28
18
7.5
7
5
30
>50
>50
>50
>50
18
15
9
>50
38
>50
50
>50
10
>50
1.5
10
11
>50
>50
N.D.
N.D.
a
GI50 values are based on at least two assays performed in triplicate.
b
N.D. = not determined. From a previous report.1
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, compound characterization data,
supplementary figures, PDB structures of the 25 lowest energy
modeled conformations, and selected NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ghadiri@scripps.edu. Telephone: (+1) 858 784 2700.
Fax: (+1) 858 784 2798.
■
Present Address
†Department of Chemistry, The Technical University of
Denmark, Kemitorvet 207, DK-2800 Kgs. Lyngby, Denmark.
Funding
This work was supported by the Benzon Foundation (C.A.O.),
the Lundbeck Foundation (C.A.O.), the Danish Council for
Independent Research | Natural Sciences Grant 10-080907
(C.A.O.), and the Skaggs Institute for Chemical Biology
(M.R.G).
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
■
We thank the laboratories of Prof. P. S. Baran and Prof. D. L.
Boger for use of their microwave reactors, Prof. J. M. Gottesfeld
and Dr. D. Herman for discussions and assistance with the
Western blot development, and Dr. B. E. Maryanoff for valuable
comments on the manuscript. Dr. P. Fristrup (Technical
University of Denmark) is thanked for performing the force
field calculations.
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