Crystallographic and SAR analyses reveal the high requirements needed to selectively and potently inhibit SIRT2 deacetylase and decanoylase

Article abstract of DOI:10.1039/C8MD00462E

A high-quality X-ray crystal structure reveals the mechanism of compound 1a inhibiting SIRT2 deacetylase and decanoylase. Structure-activity relationship (SAR) analysis of the synthesized derivatives of 1a reveals the high requirements needed for selectiv

Full text of DOI:10.1039/C8MD00462E

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RESEARCH ARTICLE
Crystallographic and SAR analyses reveal the high
requirements needed to selectively and potently
inhibit SIRT2 deacetylase and decanoylase†
Cite this: DOI: 10.1039/
c8md00462e
Ling-Ling Yang,a Wei Xu,a Jie Yan,a Hui-Lin Su,a Chen Yuan,a Chao Li,a Xing Zhang,a
Zhu-Jun Yu,b Yu-Hang Yan,b Yamei Yu,b Qiang Chen,b Zhouyu Wang,a Lin Li,a
a
b
*
*
Shan Qian and Guo-Bo Li
Received 13th September 2018,
Accepted 6th December 2018
A high-quality X-ray crystal structure reveals the mechanism of compound 1a inhibiting SIRT2 deacetylase
and decanoylase. Structure–activity relationship (SAR) analysis of the synthesized derivatives of 1a reveals
the high requirements needed for selective inhibitors to bind with the induced hydrophobic pocket and
potently inhibit sirtuin 2 deacetylase.
DOI: 10.1039/c8md00462e
rsc.li/medchemcomm
Human sirtuins are nicotinamide adenine dinucleotide
(NAD+)-dependent deacylases, which are key regulators of
metabolism, stress, and immune and inflammatory
their binding to the specific hydrophobic pocket.19,21–23,25
Through structure-guided molecular designs, we recently
identified N-(3-(phenoxymethyl)phenyl)acetamide derivatives
as highly selective SIRT2 inhibitors, which show inhibitory
activities against SIRT2 highly-expressed human breast can-
cer cells and non-small cell lung cancer cells;26,27 similar to
other reported selective inhibitors, they bind with the in-
duced hydrophobic pocket as observed by crystallographic
analyses.27
responses, influencing
a range of diseases, including
cancer.1–3 There are seven isotypes of sirtuins (SIRT1–7),
which differ in their deacylase activity and subcellular
localization. Sirtuins can remove various acyl groups (e.g.,
acetyl, palmitoyl, myristoyl, crotonyl, succinyl, glutaryl, and
decanoyl) from histones and other protein substrates,1,4–6 but
each isoform has specific preference for acyl-lysine substrates.
SIRT2, mainly located in the cytoplasm, shows deacetylase
and defatty-acylase activities to various protein substrates, in-
cluding metabolic enzymes (e.g., S6K1, PEPCK1, G6PD, LDH,
and PGAM), differentiation proteins (e.g., tubulin, PAR3, kera-
tin 8, and PRLR), and transcription factors (e.g., p300, p53,
Foxo1, HIF1α, and NFκB).1,7,8 The abnormal activity of SIRT2,
found in disease models,3,9,10 promotes the development of
selective small-molecule inhibitors to investigate associated
molecular mechanisms and to exploit treatments for relevant
diseases.
Previous structure–activity relationship (SAR) analyses of
the derivatives with different moieties at the 3- or 4-position
of the phenyl of the N-(3-(phenoxymethyl)phenyl)acetamide
scaffold revealed that the 3-substituted derivatives are likely
more potent than the 4-substituted derivatives.26 Nevertheless,
we lately found that compound 1a (IC50 = 1.32 μM), which
bears a benzenethiol motif at the 4 position, shows more po-
tent inhibition to SIRT2 deacetylase than 3-substituted com-
pound 1b (IC50 = 6.65 μM, Fig. 1a and S1†). Since SIRT2 has
defatty-acylase activity in addition to its deacetylase activity,
and particularly, one compound (NPD11033) was reported re-
cently by Kudo et al. to have the ability to inhibit deacetylase
but not the defatty-acylase reaction catalysed by SIRT2,28 we
hence tested whether 1a and 1b inhibit SIRT2 decanoylase (as
a representative of defatty-acylases). We observed that 1a
could inhibit SIRT2 decanoylase with an IC50 value of 11.6
μM, more potently than 1b (IC50 = 62.1 μM, Fig. 1a and S2†).
These results reveal that 1a has different inhibitory potency
against SIRT2 deacetylase and decanoylase, which is, consis-
tently, more potent than 1b, reflecting that 1a binds with
SIRT2 via a manner which blocks the binding of acetylated
and canoylated substrates. We report the single-crystal X-ray
diffraction structure of the SIRT2:1a complex, and the SAR
analyses of new derivatives of 1a with SIRT2 deacetylase and
decanoylase in the following sections.
There are several reports of structurally diverse small-
molecule SIRT2 inhibitors,11–20 some of which exhibit high
selectivity for SIRT2 over other sirtuin isoforms, such as
aminothiazoles,21–23
2-anilinobenzamide,24
thienopyrimidinones,25 and 1,2,4-oxadiazoles.19 The common
inhibition mechanism of these selective inhibitors involves
a College of Food and Bioengineering, Xihua University, Sichuan 610039, China.
E-mail: qians33@163.com
b Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of
Education, Department of Medicinal Chemistry, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China. E-mail: liguobo@scu.edu.cn
† Electronic supplementary information (ESI) available: Experimental details,
crystallographic data collection and refinement statistics, details of chemical
synthesis, and additional figures and tables. See DOI: 10.1039/c8md00462e
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Leu138 (α5), Tyr139 (α5), Phe96 (loop N), Pro140 (loop L1),
Phe143 (loop L1), Ile169 (loop L2), and Phe190 (loop L3)
(Fig. 1b). The 4,6-dimethylpyrimidine motif of 1a forms π–π
stacking interactions with Phe190 (loop L3) and Phe96 (loop
N) (Fig. 1b). Notably, two water molecules are observed in the
hydrophobic pocket, which are likely important for the bind-
ing of 1a (Fig. 1b); equivalent water molecules are also ob-
served in the complex structures of SIRT2:A1 (PDB ID
5YQL),27 SIRT2:SirReal2 (PDB ID 4RMG),22 and SIRT2:SirReal
probes (PDB ID 5DY5).23
Superimposition of SIRT2:1a (PDB ID 5YQM) with SIRT2:
HKKIJAc)LRF (PDB ID 3JR3)29 reveals that the binding of 1a in-
duces substantial rearrangements of loop S and α4, e.g., the
positional change of Phe235 that is important for HKK(Ac)LRF
binding (Fig. 1b and S5†), which hence block the binding of
the acetylated substrates. We also observe that 1a occupies the
myristoyl binding pocket (Fig. S6†), which hence can disturb
the myristoylated or other fatty-acylated substrates for binding.
These results clearly reveal the mechanism of 1a inhibiting
both the SIRT2 deacetylase and decanoylase.
A comparison of the structures of SIRT2:1a (PDB ID 5YQM),
SIRT2:A1 (PDB ID 5YQL),27 SIRT2:SirReal2 (PDB ID 4RMG),22
SIRT2:thienopyrimidinone (PDB ID 5MAT),25 and SIRT2:2-
anilinobenzamide (PDB ID 5Y5N)24 reveals the common
pharmacophore features of these selective inhibitors and evi-
dence of the flexibility in the conformation of loop N,
suggesting that this loop (particularly Phe96 and Arg97) may
be important in inhibitor capture (Fig. S7†). Notably, 1a and
SirReal2 are positioned to perfectly bind with the hydrophobic
pocket around residues Phe119, Phe234, Phe131, Leu134, and
Ile232 (Fig. 1b and c and S8†); compared with 1a, the
diphenylsulfane moiety of 1b may not fit perfectly with this hy-
drophobic pocket as indicated by molecular docking analyses
(Fig. S9†). These results reflect the high requirements needed
for selective inhibitors to bind with the induced hydrophobic
pocket and potently inhibit SIRT2 catalytic activities.
Fig. 1 Crystallographic analysis reveals the binding mode of 1a with
SIRT2. (a) Chemical structures of 1a/1b and their inhibitory activities to
SIRT2 deacetylase and decanoylase. (b) View from the SIRT2:1a
complex structure (PDB ID 5YQM) showing that 1a is positioned to
form hydrophobic interactions with residues Phe234, Ile232, Phe119,
Phe131, Leu134, Leu138, Tyr139, Phe96, Pro140, Phe143, Ile169 and
Phe190, and π–π stacking interactions with Phe190 and Phe96. (c) View
from the molecular surface representation of the hydrophobic pocket
with 1a.
We next synthesized a series of new derivatives of 1a
(8a–8b and 12a–12l, Table 1) via the synthetic routes outlined
in Schemes 1 and 2 (for details, see the ESI†). Briefly,
4-iodoaniline (2a) or 3-iodoaniline (2b) reacts with ethane-1,2-
dithiol in the presence of copper sulfate pentahydrate and po-
tassium hydroxide under an argon atmosphere at 110 °C for
8 h, followed by adding iodobenzene (3) to react for another
18 h at 120 °C, resulting in the thioether intermediates (4a
and 4b) in 74–78% yields (Scheme 1). Next, the key interme-
diates 4a–4b were directly reacted with 2-bromoacetyl bro-
mide to give the condensation products 5a–5b in 90–92%
yields. On the other hand, intermediate 4a was oxidized to
sulfoxide derivative 6a (56% yield) or sulfone derivative 6b
(85% yield) using 3-chlorobenzoperoxoic acid, and then
reacted with 2-bromoacetyl bromide to produce intermediates
7a and 7b, respectively (Scheme 1). Finally, reactions of inter-
mediates 5a–5b or 7a–7b with 4,6-dimethylpyrimidine-2-thiol,
respectively, in the presence of potassium tert-butoxide as the
acid-binding agent afford the target compounds 1a–1b (89–
93% yields) or 8a–8b (91–92% yields) (Scheme 1).26
Co-crystallization experiments yielded a high-quality struc-
ture of SIRT2 in complex with 1a, which was solved to 1.75 Å
(PDB ID 5YQM). The crystallization conditions, data collec-
tion and refinement statistics are given in Tables S1 and S2.†
SIRT2 crystallized in the previously described space group
P1211 with one molecule per asymmetric unit (Table S2†),
and one molecule of 1a identified in the hydrophobic pocket
at the interface of the Rossmann fold domain and the zinc-
binding domain; 1a could be confidently modelled into the
clear Fo–Fc density map (B-factors 1.2 times greater than the
main chain) (Fig. S3†).
The crystal structure reveals the binding mode of 1a with
SIRT2, which is similar to that of 2-((4,6-dimethylpyrimidin-2-
yl)thio)-N-(3-(phenoxymethyl)phenyl)acetamide (A1) with SIRT2
(PDB ID 5YQL)27 (r.m.s.d. of 0.15 Å over 236 Cα atoms, Fig.
S4†). 1a is positioned to form hydrophobic interactions with
the residues in the hydrophobic site, including Phe234 (loop
S), Ile232 (loop S), Phe119 (α4), Phe131 (α5), Leu134 (α5),
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Table 1 Structure–activity relationships of the new derivatives of 1a with SIRT2 deacetylase and decanoylase
Cpd ID
R
Position
4
SIRT2 deacetylase Inh% @100 μM/@10 μM
SIRT2 decanoylase Inh% @100 μM/@10 μM
1a
80 5/70
73 5/65
40 5/5
5
53 6/38
30 10/5
23 5/4
9
1b
8a
3
4
5
2
3
4
3
3
8b
4
50 8/8
18 6/5
12a
12b
12c
4
4
4
67 6/42
62 5/50
53 4/42
7
8
5
60 6/23
58 7/18
58 3/42
5
5
5
12d
12e
4
4
70 5/51
76 3/70
5
3
38 6/23
65 8/54
5
5
12f
4
4
82 5/72
85 3/80
5
2
77 8/72
80 5/70
3
6
12g
12h
12i
4
4
63 6/30 10
70 5/10
42 5/18
5
5
51 7/28
65 8/55
8
6
12j
12k
12l
4
4
4
58 5/20
63 6/23
9
5
60 8/40
9
5
3/6
3
35 5/8
3
76 5/53
6
72 8/32
5
A1
Synthetic access to the target compounds 12a–12l was
achieved using similar methods, as described in Scheme 1.
We then performed structure–activity relationship studies
using the synthesized compounds 8a–8b and 12a–12l (Table 1);
the deacetylase and decanoylase activities of SIRT2 were tested
using RLIKIJAc)AMC and ETDKIJCa)AMC (Fig. S10†), respec-
tively. Compared with 1a, the oxidized derivatives 8a and 8b
show lower potency to inhibit SIRT2-catalysed deacetylation on
RLIKIJAc)AMC and decanoylation on ETDKIJCa)AMC. Replace-
ment of the benzenethiol moiety of 1a with pyridine-3-thiol
(12a), thiophene-3-thiol (12b), naphthalene-1-thiol (12c), and
naphthalene-2-thiol (12d) also led to decreased inhibitory po-
tency to SIRT2 catalytic activity on both RLIKIJAc)AMC and
The
commercially
available
3-iodopyridine
(9a),
3-iodothiophene (9b), 1-iodonaphthalene (9c), 2-iodo-
naphthalene (9d), and various substituted iodobenzenes
9e–9l were reacted with 4-iodoaniline (2a), respectively, to
give the intermediates 10a–10l (55–83%), followed by a con-
densation reaction of acyl halide with amine (82–93%) and
a t-BuOH-promoted nucleophilic substitution (79–96%) to af-
ford the desired target compounds 12a–12l in high yields
(Scheme 2).
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0.70 μM, respectively (Fig. S11†); 12f and 12g also exhibit
IC50 values of 17.6 μM and 8.33 μM to SIRT2 decanoylase, re-
spectively (Fig. S12†). Using our previously reported method,
we tested 12f and 12g against other sirtuin isotypes, includ-
ing SIRT1, SIRT3, SIRT5, and SIRT6, to examine the selectiv-
ity. Both compounds have no or low inhibitory activities at
100 μM to all of the tested sirtuin isotypes. These results in-
dicate that 12f and 12g could potently and selectively inhibit
SIRT2 deacetylase and decanoylase.
Conclusions
Scheme
1 The synthesis of 1a–1b and 8a–8b. Reagents and
conditions: (a) (i) ethane-1,2-dithiol, copper sulfate pentahydrate,
In summary, a high-quality X-ray crystal structure of SIRT2:1a
was reported, which clearly reveals the mechanism of 1a
inhibiting the SIRT2 deacetylase and decanoylase, i.e. via
binding to the induced hydrophobic pocket and disturbing
the binding of acetylated and fatty-acylated substrates. The
SAR analyses of the synthesized derivatives of 1a reveal a
clear correlation between their inhibition to SIRT2
deacetylase and decanoylase, and reveal the high require-
ments needed for compounds to bind with the hydrophobic
pocket. New selective, potent inhibitors (e.g., 12f and 12g) for
SIRT2 deacetylase and decanoylase were identified, which
might be useful chemical tools to probe SIRT2-related molec-
ular mechanisms. This study will aid future investigations in
developing new selective inhibitors against SIRT2 deacylase
to provide potential treatments for relevant diseases.
potassium hydroxide, DMSO/H2O, 110 °C, 8 h; (ii) DMF, 120 °C, 18 h.
(b) 2-Bromoacetyl bromide, TEA, DCM,
0 °C, 0.5–1 h. (c) 4,6-
Dimethylpyrimidine-2-thiol, t-BuOK, DMF, r.t., 0.5 h and 12 h. (d)
m-CPBA, DCM, r.t.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Scheme 2 The synthesis of 12a–12l. Reagents and conditions: (a) (i)
ethane-1,2-dithiol, copper sulfate pentahydrate, potassium hydroxide,
DMSO/H2O, 110 °C, 8 h; (ii) DMF, 120 °C, 18 h. (b) 2-Bromoacetyl
bromide, TEA, DCM, 0 °C, 0.5–1 h. (c) 4,6-Dimethylpyrimidine-2-thiol,
t-BuOK, DMF, r.t., 0.5 h and 12 h.
The authors thank the staff of the BL19U1 beamline of the
National Center for Protein Science Shanghai at Shanghai
Synchrotron Radiation Facility for assistance during data col-
lection. This work was supported by the funds from the Na-
tional Natural Science Foundation of China (Grant No.:
81703355 and 81502989), the Chun-Hui Project from the Min-
istry of Education of China (Grant No.: 172507), and the
Opening Project of Food Biotechnology (Grant No.: szjj2017-
079).
ETDKIJCa)AMC (Table 1). Compounds 12e–12g with
3-substituted benzenethiols inhibit SIRT2 deacetylase and
decanoylase more potently than 1a and A1, whereas com-
pounds 12h–12l, bearing various 4-substituted benzenethiols,
show decreased inhibitory activity (Table 1). Notably, there is a
clear correlation between the SIRT2 deacetylase and
decanoylase inhibition of these compounds (Table 1), implying
that their inhibition mode is similar to that of 1a. From the
SAR results, we observe that replacement or modification of
the benzenethiol motif of 1a appears prone to decreased inhi-
bition, which may reflect the high requirements needed for
specific compounds to bind with the hydrophobic pocket
(Fig. 1b and c) and potently inhibit the SIRT2 catalytic activity.
For potent compounds 12f and 12g, we measured their
IC50 values for inhibiting SIRT2 deacetylase and decanoylase.
Compared with 1a and A1, 12f and 12g show better inhibitory
activity to SIRT2 deacetylase, with IC50 values of 0.85 μM and
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