Biological evaluation of new largazole analogues: Alteration of macrocyclic scaffold with click chemistry

Article abstract of DOI:10.1021/ml300371t

We report the design, synthesis, and biological evaluation of a new series of largazole analogues in which a 4-methylthiazoline moiety was replaced with a triazole and tetrazole ring, respectively. Compound 7 bearing a tetrazole ring was identified to show much better selectivity for HDAC1 over HDAC9 than largazole (10-fold). This work could serve as a foundation for further exploration of selective HDAC inhibitors using a largazole molecular scaffold.

Full text of DOI:10.1021/ml300371t

Letter
pubs.acs.org/acsmedchemlett
Biological Evaluation of New Largazole Analogues: Alteration of
Macrocyclic Scaffold with Click Chemistry
Xianlin Li,† Zhenchao Tu,† Hua Li,† Chunping Liu,† Zheng Li,‡ Qiao Sun,† Yiwu Yao,† Jinsong Liu,†
and Sheng Jiang*,†
†Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou,
510530, China
‡The Methodist Hospital Research Institute, Houston, Texas, 77030, United States
S
* Supporting Information
ABSTRACT: We report the design, synthesis, and biological
evaluation of a new series of largazole analogues in which a 4-
methylthiazoline moiety was replaced with a triazole and
tetrazole ring, respectively. Compound 7 bearing a tetrazole
ring was identified to show much better selectivity for HDAC1
over HDAC9 than largazole (10-fold). This work could serve
as a foundation for further exploration of selective HDAC
inhibitors using a largazole molecular scaffold.
KEYWORDS: HDAC inhibitor, peptides, macrocycles, largazole, click chemistry
istone deacetylases (HDACs) are a family of enzymes
Hthat catalyze the deacetylation of lysine side chains in
chromatin, and thereby, these enzymes are involved in a wide
range of biological processes such as cell differentiation,
proliferation, angiogenesis, and apoptosis.1−4 Up to now, 18
members of the human HDAC family have been identified,
which are divided into four distinct classes on the basis of their
Figure 1. Structures of SAHA, romidepsin (FK228), and largazole.
size, number of catalytic active sites, subcellular localization,
and sequence homology to yeast counterparts.5−7 Class I
HDACs (1−3 and 8), class IIa HDACs (4, 5, 7, and 9), class
IIb HDACs (6 and 10), and class IV HDACs (11) are Zn2+-
dependent proteases, while class III HDACs (sirtuins 1−7) are
NAD+-dependent Sir2-like deacetylases.7 Among them, class I
HDAC isoforms have been intensively studied due to their
important role in tumorigenesis and development. It is highly
expressed in various cancers, including gastric cancer,
pancreatic cancer, colorectal cancer, prostate cancer, and
hepatocellular carcinoma8−11 but not resting endothelial cells
and normal organs. Therefore, selective targeting class I
HDACs by directly inhibiting its function has recently become
a major area of research in cancer chemotherapy.12−16
Thus far, over 12 HDACis are currently in clinical trials
against different cancers,17,18 and two of them, SAHA (Figure
1)19 and romidepsin (FK228) (Figure 1),20 have been
approved by the U.S. Food and Drug Administration (FDA)
for cutaneous T-cell lymphoma (CTCL). In most cases, the
reported HDAC inhibitors consist of three distinct structural
motifs: the Zn(II) binding moiety, a spacer moiety, and a
recognition cap group. It should be noted that the cap region is
a key factor in current HDACi design because topological
differences are observed in the corresponding “cap” regions of
HDAC isozymes.
Largazole 3 is a natural macrocyclic depsipeptide reported by
Luesch and co-workers in 2008, which show promising
HDAC1 inhibitory activity and selectivity.21 These excellent
properties of largazole have attracted significant attention and
make it a becoming lead molecule for further structural
optimization in pursuit of molecules of higher potency or
selectivity. Recently, several research groups have completed
total synthesis and structure−activity relationship (SAR)
studies of largazole.22−37 Among them, only two groups
focused mostly on the alteration or elimination of the methyl
group of 4-methylthiazoline moiety.35,36 On the basis of their
results, we envisioned that the 4-methylthiazoline moiety is not
essential for the potency of largazole, and modification of it is
tolerable. By analyzing molecular modeling of the largazole
complex with HDAC1 structure, we revealed that the 4-
methylthiazoline residue has hydrophobic interactions with the
side chains of Phe 150 of the HDAC1, and these interactions
may be crucial for HDAC class/isoform selectivity of largazole
(Figure 2). Click chemistry has been widely applied in organic
Received: November 1, 2012
Accepted: December 5, 2012
© XXXX American Chemical Society
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Scheme 1. Synthesis of the Key Fragments 17−19
Figure 2. Plausible binding mode of largazole to HDAC1 and
designed analogues.
ethylacetate at the N-1 position of the tetrazole isomer in 35%
yield. Then, the two alkylated products were subjected to basic
ester hydrolysis to generate the desired tetrazole acetic acids 18
and 19 in 90% yield, respectively, the structures of which were
confirmed by X-ray crystallographic analysis.45
The synthesis of the designed analogues 4−9 was prepared
as outlined in Scheme 2. Our synthesis started from the known
enantionpure allylic alcohol 25, which could be easily prepared
from commercially available (−)-malic acid 24 using our
previously reported method.32−37 Sequential coupling with
enantiomerically pure amino acid Fmoc-L-valine yielded the
depsipeptide, which was further subjected to remove the Fmoc
synthesis and drug discovery since Sharpless developed it for
synthesis of triazole moiety in 2001.38−44 We envisioned that
replacing the 4-methylthiazoline moiety of largazole with a
more hydrophobic ring, such as a triazole or tetrazole group,
would improve π−π stacking interactions and could increase
selectivity for HDAC1 over other isoforms. Herein, we report
our efforts to modify the structural scaffold of largazole through
click chemistry with the goal of further defining and expanding
structure−activity relationships within the family of macrocyclic
HDACis.
The synthesis of the key intermediates, 17−19, started with a
previously characterized thiazole-4-ester 12, which was
obtained from commercially available thioamide 10 using the
modified Hantzsch procedure (Scheme 1).32−37 Reduction of
12 with DIBAL-H afforded aldehyde 13 in 80% yield followed
by Corey−Fuchs reaction for the synthesis of the terminal
alkyne 14. The terminal alkyne 14 reacted smoothly with azide
15 at room temperature in the presence of catalytic amount of
copper sulfate and sodium ascorbate in DMF and water, giving
the triazole 16 in 90% yield. The ester group of 16 was
saponified with LiOH, which afforded an important inter-
mediate 17 in high yield. Subsequent transformation of
thiazole-4-ester 12 into nitrile 20 involved a three-step
sequence: (i) hydrolysis of ester 12, (ii) formation of amide
from acid and ammonia, and (iii) dehydration using trifluoro-
acetic anhydride and base (72% yield). The click reaction of
nitrile 20 with sodium azide furnished the tetrazole
intermediate 21 in 100% yield in the presence of zinc bromide.
Subsequent reaction of the tetrazole 21 with ethyl bromoace-
tate and triethyl amine generated two alkylated products. After
chromatographic separation of the two alkylated products, we
got the major one bearing the ethylacetate at the N-2 position
of the tetrazole in 58% yield and the minor one bearing the
Scheme 2. Synthesis of Lagazole's Analogues 4−9
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ACS Medicinal Chemistry Letters
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group to provide the amine 26. Treatment of the amine 26 with
the key intermediates 17−19 in different combinations in the
presence of HATU and HOAt at room temperature gave the
cyclization precursors 27−29, respectively. The formation of
the 17-membered cycloamide was achieved in a three-step
sequence involving TBAF and TFA-mediated removal of the 2-
(trimethylsilyl) ethanol and Boc groups, respectively, and
subsequent macrolactamization with HATU/DIPEA in anhy-
drous CH3CN to provide the intermediates 30−32 in 46%
yield, respectively (three steps). Removal of the S-trityl
protecting group was accomplished with i-Pr3SiH and TFA to
provide analogues 5, 7, and 9 in good yield, respectively.
Subsequently, acylation of 5, 7, and 9 with octanoyl chloride
under basic conditions afforded analogues 4, 6, and 8 in 78%
yield, respectively.
Figure 3. Plausible binding mode of compound 5 and 7 to HDAC1.
After completion of the synthesis of all six largazole
analogues 4−9, we evaluated their biochemical activity against
HDACs 1−3 and 9 using SAHA as the positive control. The
results are summarized in Table 1 and showed interesting
selectivity for HDAC1 over HDAC9 to that of largazole (10-
fold), which may be a benefit for the future development of
specific therapeutic agents. Molecular modeling reveals that the
distance between the tetrazole ring and Leu271 and Tyr204 is
in the range of van de Walls radius in figure 3B. Therefore, it is
not surprising that the tetrazole ring may result in favorable and
well-defined van der Waals interactions in comparison with the
triazole ring in Figure 3A. To evaluate the position of substitute
group on tetrazole ring influence activity or not, compound 8
was designed and synthesized, in which substitute group in the
N1 position on the tetrazole ring. As compared to compound 6,
the resulting compound 8 has lost the inhibitory activity against
HDAC1 and shows much less selectivity for HDAC1 over
HDAC9. It is apparent that its corresponding thiol analogue 9
shows much less selectivity for HDAC1 over HDAC9 than
other thiols 5 and 7. Molecular modeling found that the
binding conformation of compound 8 with HDAC1 has a big
difference in comparison with compound 6. Therefore, the
position of substitute in the tetrazole ring plays a significant role
in the selectivity for inhibition of HDAC1 over HDAC9.
In summary, a series of new largazole's analogues 4−9 have
been designed based on the molecular modeling of the complex
structure of HDAC1 with largazole. Nitrogen functionality was
employed as the replacement of 4-methylthiazoline moiety of
largazole under the concept of click chemistry. Biological results
demonstrate that 4-methylthiazoline moiety variations of
largazole have various effects to the selectivity toward
HDAC1 over HDAC9. For compound 6 with a tetrazole ring
(N-2 substitute), the selectivity between HDAC9 and HDAC1
is similar to that of largazole. Its free thiol 7 was identified to
show higher selectivity against HDAC1 over HDAC9 by
comparison with largazole. These results clearly indicate that
the introduction of appropriate aromatic groups into the
largazole skeleton is a useful optimizing tool for this unique
class of anticancer agents. Various biological studies including
inhibitory studies on different cancer cell lines, inhibitory
studies on metastatic tumors in animal models, and the
activities against the missing HDAC isoforms are currently in
progress in our laboratory.
Table 1. IC50 Values for HDAC1-1, HDAC2, HDAC3, and
a
HDAC9 Inhibition (μM)
IC50(μM)
selectivity
sample
HDAC1 HDAC2 HDAC3 HDAC9 HDAC1/HDAC9
largazole
0.146
17.6
2.35
7.42
0.1
1.72
32.1
3.88
30.8
0.224
25.1
0.604
14.0
8.33
63.2
32.0
>100
0.02
0.3
4
5
0.885
3.99
0.07
6
<0.04
0.003
7
0.031
34.6
18.4
16.2
15.6
8
NA
10.4
9
1.67
0.196
3.27
0.649
0.11
0.1
SAHA
0.537
0.01
a
SAHA was used as a positive control. Values are means of three
experiments, and standard error of the IC50 was generally less than
10%.
HDACs isoform selectivity. Largazole displayed good selectivity
for the classes I HDACs (HDAC1, IC50 = 0.146 μM; HDAC2,
IC50 = 1.72 μM; and HDAC3, IC50 = 0.604 μM) over the
classes II HDAC (HDAC9, IC50 = 8.33 μM). Our assay showed
that a decreased level of selectivity between HDAC1 and
HDAC9 was found for compound 4 (15-fold), in which the 4-
methylthiazoline moiety was replaced with a triazole ring. For
its thiol analogues 5, the selectivity between HDAC1 and
HDAC9 is 3.5-fold less to that of largazole. Molecular modeling
shows that the binding conformation of compound 5 with
HDAC1 has a big change in comparison with largazole in
Figure 3A. The triazole ring of compound 5 has van der Waals
interaction with Leu271 not Phe 150. This suggests that a 4-
methylthiazoline moiety is needed for more potent inhibition of
HDAC1 of largazole. On the basis of this result, we assumed
that the 4-methylthiazoline moiety of largazole may interact
with the hydrophobic pocket in the cap of HDAC1, which
could increase the selectivity between HDAC1 and HDAC9.
Therefore, introducing a more aromatic residue in the 4-
methylthiazoline moiety part of largazole would be able to
improve van der Waals interactions. We thus designed and
synthesized compound 6 with a tetrazole ring to increase the
van der Waals interactions. As shown in Table 1, the inhibition
of compound 6 to HDAC1 decreased slightly, but the
selectivity between HDAC1 and HDAC9 is similar to that of
largazole. To our delight, its free thiol 7 shows much better
ASSOCIATED CONTENT
■
S
* Supporting Information
Moleular modeling, experimental procedures, compound
characterization data, and selected NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
C
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ACS Medicinal Chemistry Letters
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(17) Paris, M.; Porcelloni, M.; Binaschi, M.; Fattori, D. Histone
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1505−1529.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: (86) 20-32015318. Fax: (86) 20-32015318. E-mail:
jiang_sheng@gibh.ac.cn.
(18) Arrowsmith, C. H.; Bountra, C.; Fish, P. V.; Lee, K.; Schapira,
M. Epigenetic protein families: S new frontier for drug discovery. Nat.
Rev. Drug Discovery 2012, 11, 384−400.
Funding
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This work was supported by the National Natural Science
Foundation (Grant Nos. 21172220 and 20972160) and the
National Basic Research Program of China (2009CB940900)
and CSA-Guangdong Joint Foundation (Grant No.
2011B090300069).
Notes
The authors declare no competing financial interest.
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