Design, synthesis and biological evaluation of curcumin analogues as novel LSD1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2019.126683

Histone lysine-specific demethylase 1 (LSD1) was the first discovered histone demethylase. Inactivating LSD1 or downregulating its expression inhibits cancer-cell development, and thus, it is an attractive molecular target for the development of novel cancer therapeutics. In this study, we worked on the structural optimization of natural products and identified 30 novel LSD1 inhibitors. Utilizing a structure-based drug design strategy, we designed and synthesized a series of curcumin analogues that were shown to be potent LSD1 inhibitors in the enzyme assay. Compound WB07 displayed the most potent LSD1 inhibitory activity, with an IC₅₀ value of 0.8 μM. Moreover, WA20 showed an anticlonogenic effect on A549 cells with an IC₅₀ value of 4.4 μM. Molecular docking simulations were also carried out, and the results indicated that the inhibitors bound to the protein active site located around the key residues of Asp555 and Asp556. These findings suggested that compounds WA20 and WB07 are the first curcumin analogue-based LSD1 inhibitors with remarkable A549 suppressive activity, providing a novel scaffold for the development of LSD1 inhibitors.

Full text of DOI:10.1016/j.bmcl.2019.126683

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Design, synthesis and biological evaluation of curcumin
analogues as novel LSD1 inhibitors
Jiming Wang, Xiangyu Zhang, Jiangkun Yan, Wei Li, Qinwen
Jiang, Xinran Wang, Dongmei Zhao, Maosheng Cheng
PII:
S0960-894X(19)30633-X
https://doi.org/10.1016/j.bmcl.2019.126683
BMCL 126683
DOI:
Reference:
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Received date:
Revised date:
Accepted date:
9 May 2019
10 September 2019
12 September 2019
Please cite this article as: J. Wang, X. Zhang, J. Yan, et al., Design, synthesis and biological
evaluation of curcumin analogues as novel LSD1 inhibitors, (2019), https://doi.org/
1
0.1016/j.bmcl.2019.126683
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Design, synthesis and biological evaluation of curcumin analogues as
novel LSD1 inhibitors
a
a
a
a
a
a
Jiming Wang , Xiangyu Zhang , Jiangkun Yan , Wei Li , Qinwen Jiang , Xinran Wang ,
Dongmei Zhao *, Maosheng Chenga
a,
aKey Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education,
Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, P. R. China.
*
Corresponding author. Prof. Zhao: E-mail address: medchemzhao@163.com;

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Abstract:
Histone lysine-specific demethylase 1 (LSD1) was the first discovered histone
demethylase. Inactivating LSD1 or downregulating its expression inhibits cancer-cell
development, and thus, it is an attractive molecular target for the development of novel
cancer therapeutics. In this study, we worked on the structural optimization of natural
products and identified 30 novel LSD1 inhibitors. Utilizing a structure-based drug design
strategy, we designed and synthesized a series of curcumin analogues that were shown to
be potent LSD1 inhibitors in the enzyme assay. Compound WB07 displayed the most
potent LSD1 inhibitory activity, with an IC50 value of 0.8 μM. Moreover, WA20 showed
an anticlonogenic effect on A549 cells with an IC50 value of 4.4 μM. Molecular docking
simulations were also carried out, and the results indicated that the inhibitors bound to the
protein active site located around the key residues of Asp555 and Asp556. These findings
suggested that compounds WA20 and WB07 are the first curcumin analogue-based LSD1
inhibitors with remarkable A549 suppressive activity, providing a novel scaffold for the
development of LSD1 inhibitors.
Keywords: Natural Product; LSD1 inhibitors; Curcumin Analogues; Molecular Docking;
Cellular Activity

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Several studies have shown that epigenetic modifications play important roles in
[1]
regulating carcinogenesis . Epigenetic regulation includes DNA methylation
modification and histone acetylation, phosphorylation, methylation and other
modifications. So far, acetylation and phosphorylation of histones have been studied
for a long time. However, histone methylation has only been extensively studied in
the past 10 years. Before 2004, histone methylation was considered to be an
irreversible reaction until the discovery of histone lysine-specific demethylase 1
(
LSD1), which officially marked the confirmation of a histone methylation
[2]
reversibility process . The revolutionary discovery provided new research ideas for
the development of histone modifications in epigenetics. In the past 10 years, it has
become a research hotspot.
LSD1 belongs to the family of monoamine oxidases and uses FAD (flavin
adenine dinucleotide) as a cofactor to specifically remove mono- or dimethylated
[3]
histones H3 lysine 4 (H3K4) and H3 lysine 9 (H3K9) . LSD1 has been reported to be
[4]
overexpressed in numerous types of cancer, including lung and bladder cancers ,
[5]
[6]
and breast cancer[7-8]. LSD1 is involved in
neuroblastoma , retinoblastoma
promoting cell proliferation, migration, invasion, and metastasis by epithelial
mesenchymal transition (EMT) induction.
Numerous LSD1 inhibitors have been synthesized and evaluated in preclinical
and clinical studies. Currently in the clinical stage are three representative irreversible
tranylcypromine derivatives, ORY-1001 , GSK-2879552[10-11], and IMG-7289[12-13]
[9]
.
These three inhibitors can be used alone or in combination with other therapeutic

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agents. With the deepening of research into LSD1 inhibitors, a large number of LSD1
inhibitors have been reported[14-15]. However, in the continuous development of
histone demethylase inhibitor research, promising drug candidates are rare, and novel
potent LSD1 inhibitors still need further exploration.
Natural products have made significant contributions to cancer chemotherapy
over the past decades[16]. Even with the advances of alternative drug discovery
technologies, such as rational drug design, high throughput screening, and
combinatorial chemistry, natural products remain an essential element in drug
discovery. As an indispensable source for lead generation and drug discovery, natural
products have provided molecular diversity and structural novelty inaccessible by
other means.
Curcumin is the main active ingredient of turmeric (Curcuma longa) and is one
of the most popular natural multitarget molecule[17]. Curcumin has a simple molecular
[
18]
structure, low toxicity, and various pharmacological activities. It has antibacterial ,
anti-inflammatory[19-20], anti-oxidant[21], and anti-cancer effects[22]. Recent studies
have found that curcumin has a certain inhibitory effect on LSD1[23]. This report
aroused our interest in structural optimization of natural products to obtain new LSD1
inhibitor skeleton structures. Combined with the docking results of computer
molecules, we synthesized a series of curcumin derivatives to increase their LSD1
inhibitory potency. The new compounds clearly demonstrated the relevant
substituents for inhibitory activity and their interaction with the key residues of the
active site.

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Abdulla A et al. reported that curcumin is a potent inhibitor of LSD1, but further
studies have not been disclosed. We consider that curcumin may provide a new
skeleton for developing LSD1 inhibitors, so we tested its inhibitory activity against to
LSD1 and found IC50 = 9.6 μM. The activity results confirmed our confidence in the
optimization of curcumin as the lead. To understand the inhibitory activities of
curcumin against LSD1, we subjected them to molecular docking analysis using
maestro 9.6 and predicted their binding affinity with LSD1 (PDB code: 5lhi). As
shown in Figure 1, co-crystallization of 5lhi (white) approaches the FAD co-factor
(
yellow) and is located around Asp555 and Asp556, which are located below the
thienopyrrole plane. The modeling of curcumin 1 (Figure 1) is similar to moiety 1 in a
binding pocket, and the phenolic hydroxyl group H-bonds to Trp552 in a narrow
catalytic binding groove. Meanwhile, the dicarbonyl structure of curcumin is apt to be
tautomerized and transformed into an enol structure, which is the main reason for the
instability of the curcumin structure and its low bioavailability[24-26]. Therefore, we
transformed the structure of the dicarbonyl into a monocarbonyl, thus destroying its
conjugate system, increasing its stability and fundamentally changing its
pharmacokinetic characteristics, and we introduced a positively charged piperidine
tail to form H-bonds with the key residues of Asp555 and Asp556 (Scheme 1). We
therefore have reasonably designed a set of curcumin analogues to produce a series of
new LSD1 inhibitors.

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Figure 1. The predicted binding modes between curcumin (magenta) and LSD1 (PDB code:
5LHI). The ligand of LSD1 was highlighted in grey, and key residues of LSD1 was showed in
light blue. The FAD of LSD1 was represented as yellow sticks.
Scheme 1. Structures of curcumin and target compounds WA01-20
We changed the substituent on the part A to study the effect of the electrical,
spatial position and volume of the substituent on its pharmacological activity. As
shown in Scheme 2, a different substituted nitrobenzene was esterified via methanol
to give the intermediate IM1, and its nitro groups were transformed into anilines IM2
and through an amide condensation reaction with 3-(4-acetoxy-3-methoxyphenyl)
acrylic acid generated IM3 that was further hydrolyzed to IM4. The final compounds
WA10-15 were obtained by treatment with hydrazine hydrate or hydroxylamine
hydrochloride.

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Scheme 2. Synthesis of compounds WA10-15. Reagents and conditions: (a) SOCl2, MeOH,
r.t., 92.8%-93.5%; (b)
-(4-acetoxy-3-methoxyphenyl)acrylic acid, HATU, DIEA, DMF, r.t., 72.6%-74.5%; (d) NaOH
aq), MeOH, r.t., 92.6%-93.9%; (e) ⅰ) EDCI, HOBT, DMF, 0 ℃; ⅱ) Hydrazinium hydroxide or
H
2
,
Pd/C (10% w/w), MeOH, r.t., 94.7%-96.2%; (c)
3
(
Hydroxylamine hydrochloride, DIEA, DMF, 0 ℃, 69.2%-81.2%.
All of the compounds synthesized in this study were investigated for their
inhibitory activities against LSD1 in vitro, and TCP was chosen as the positive control.
As shown in Table 1, the β-diketone group is not essential for the biological activity
of curcumin. It is possible to screen for more potential compounds by structural
modification of monocarbonyl curcumin derivatives. Compared with compound
WA01, the addition of substituents to the part A is beneficial to maintaining or
enhancing the inhibitory activity of the compound against LSD1. Among them, WA
0
2–06 showed that the electrical property and spatial position of the substituents had
no significant effect on the pharmacological activity, with IC50 values ranging from
.9 μM to 6.2 μM. WA07-15 showed that when groups such as amides, oximes and
4
hydrazines were introduced, the inhibitory activity of the compound was significantly
increased after the carbon chain length was extended by one. However, among all the
groups, the activity of the piperidine side chain was optimal, with an IC50 value of 1.4
μM for WA18, and its inhibitory activity was not significantly changed when the

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carbon chain length of the piperidine side chain was increased, showing IC50 values
ranging from 1.8 μM to 2.8 μM.
Table 1. In Vitro LSD1-Inhibitory activities of compounds WA01-20
compound
WA01
R
IC50 (μM)a compound
R
IC50 (μM)a
30±1.02
4.9±0.21
WA10
WA11
10.3±0.09
WA02
WA03
WA04
WA05
WA06
WA07
WA08
WA09
WA16
1.4±0.33
5.8±0.22
11.5±0.65
7.8±1.03
6.2±0.38
5.9±0.27
1.8±0.12
1.4±0.96
＞50
4.5±0.36
6.0±0.22
5.6±0.96
6.2±0.23
12.1±0.76
2.6±0.33
4.0±0.46
WA12
WA13
WA14
WA15
WA17
WA18
WA19
WA20
2.8±0.15

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curcumin
9.6±0.68
a
Data are presented as the means ± SDs of three independent experiments. p < 0.05.
After optimizing the structure of the part A, we began to focus on the structural
modification of the benzene ring on the part B. Scheme 3 summarizes the initial
approach to compounds WB01-10. A Mitsunobu reaction between o-nitropheno and
N-Boc-4-piperidinemethanol produced IM5, which was reduced to give the anilino
derivative IM6, a substituted benzaldehyde reacts with acetic anhydride to form
intermediate IM7, and then condensates with IM6 to form IM8, and IM8 deprotected
gives the final products WB01-10.
Scheme 3. Synthesis of compounds WB01-10. Reagents and conditions: (a) N-Boc-4-
3
piperidinemethanol, DEAD, PPh , THF, -20℃, 55.5%; (b) Fe, NH
4
Cl, H O, MeOH, r.t., 90.3%; (c)
2
Pyridine, DMF, 90℃, 69.3%-81.5%; (d) HATU, DIEA, DMF, r.t., 75.6%-89.5%; (e) HCl-EtOH,
r.t., 79.8%-88.3%
Comparing the results of enzyme inhibition activity of compounds WB01-10
(
Table 2), it was found that the hydroxyl group is the key to the antitumor activity of
the curcumin derivative at the 4 position of the phenyl ring, with an IC50 value of 0.8
μM for WB07, and the activity disappeared when other groups were introduced.
Replacing the 3-methoxy group with a hydroxyl group is beneficial to activity, with

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an IC50 value of 8.6 μM for WB08. In addition, we designed compounds WB09 and
WB10, which considered with no LSD1 inhibition activity. This results indicating that
changing the position of the hydroxyl group or blocking the hydroxyl group with a
large steric block fragment will cause the activity to disappear, and the phenolic
hydroxyl group in the structure of the compounds would not cause false positive
problems.
Table 2. In Vitro LSD1-Inhibitory activities of compounds WB01-10
compound
WB01
R
IC50 (μM)a compound
R
IC50 (μM)a
＞50b
＞50b
＞50b
3,4-di-OCH
3
WB06
WB07
WB08
WB09
WB10
4-CN
4-OH
WB02
3,4,5-tri-OCH
3-Br
3
0.8±0.11
8.6±0.36
WB03
33.9±0.85
＞50b
3-OH
3
-methylphenyl
b
WB04
4-F
＞50
-
4-OH
＞50b
WB05
3-CF
3
2-OH
49.6
a
Data are presented as the means ± SDs of three independent experiments. p < 0.05.
b
Considered with no LSD1 inhibition activity.
The docking results were evaluated by comparing the binding energy and
docking poses via Glide SP mode. The docking results differing by <2.0 Å on the
basis of a positional root mean square deviation (RMSD), were clustered together and
were ranked on the basis of their free binding energy. Analysis of the results of the
native docking simulations showed most binding energy scores could accurately
forecast the ligand activitie s（ all results were shown in table S1）. (The binding modes
and 2D interaction maps of other inhibitors were shown in figure S1). Among the

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series of WA, the inhibitory activity of the compounds increased due to alkaline
group introduced, like amides, oximes, hydrazines and piperazine groups. Because
they could form H-bond interactions with Asp 555 or Glu559. To our surprised, the
tails of WA17 formed hydrogen bond with Lys661, which also reported essential
residue for LSD1 inhibitors. Meanwhile, phenyl ring is well important, compare the
dock poses of WB, we can know that the compounds which have 4 position of the
phenyl ring can well form aromatic−aromatic interaction between FAD and occupy
the activity pocket of LSD1. When the phenolic hydroxyl group was substituted for
big group like methoxy group and trifluoromethyl, the molecular could not generate
comfortable docking poses to occupy the active site and less interactions at the active
pocket. If replacing it with a halogen group, it is unfavorable to activity like WB03
which got a lower docking score (Docking energy = -3.879 kcal/mol).
Preferred binding patterns of WB07 within the binding site of LSD1 were shown
in the Figure 2, which the binding energy of compound WB07 (IC50 = 0.8 μM) was
−7.33 kcal/mol. The tail of compound WB07 extended towards an interesting cluster
of negatively charged residues at Asp556 and Glu559 while there was an
aromatic−aromatic interaction between FAD and the ring of benzamide. Meanwhile,
the ring of the benzamide formed hydrophobic interactions with Ala539 and Tyr761.
The head of WB07 was located among residues Leu677, Leu679, and Tyr356. Due to
the much interactions at the active pocket, WB07 showed the highest activity in a
series of curcumin analogues.

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Figure 2. Binding models of WB07 (cyan) in active site. Key residues of LSD1 was showed in
light blue, and the FAD of LSD1 was represented as yellow sticks.
To further confirm the cellular activity of the curcumin analogues, different
concentrations of the target compounds (LSD1 IC50<4.5 μM) were applied to the lung
cancer cell line A549, which overexpresses LSD1, and the human glioblastoma cell
line U87. As indicated in Table 3, in general, the tested compounds exhibited
moderate activity in inhibition of the proliferation of these two cancer cells. Among
them, compounds WA03 and WA09 had no activity on the A549 and U87 cell lines
for unknown reasons, while compound WA20, which only showed a moderate
inhibitory effect against LSD1 in the enzyme assay with an IC50 value of 2.80 μM,
exhibited the best activity in inhibition of the growth of A549 cells, with an IC50 value
of 4.14 μM. Also noteworthy is that compound WA19 showed superior activity
against the U87 human glioblastoma cell (Figure 3). Compounds WA08, 11, 18, and
1
9 also showed moderate inhibitory effects against LSD1 in the A549 cell line,
ranging from 32.473±1.41 μM to 24.526±2.52 μM. Additionally, the ClogP of
compounds were also calculated with Sybyl 6.91, showing that compounds WA18-20,
WB07 exhibited acceptable values (Table 3). The selectivity of the compounds WA20

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and WB07 were tested and the results showed that the two compounds exhibited
excellent selectivity (Table 4).
Table 3. Cellular activity and calculated ClogP-values of Partial compounds
–
1 a
IC50 (μmol·L )
LSD1
R1
R2
ClogPb
1.6192
compound
WA03
IC50(μM)
A549
>50
U87
>50
OMe
4.5±0.36
WA08
WA09
WA11
OMe
OMe
OMe
2.6±0.33 32.473 ± 1.41
>50
>50
1.2536
1.2192
0.8482
4.0±0.46
>50
1.4±0.33 30.347 ± 3.03 49.255 ± 1.66
1.8±0.12 24.526 ± 2.52 30.989 ± 6.19
WA18
OMe
OMe
3.1526
4.2342
WA19
WA20
1.4±0.96 28.537 ± 0.59
>50
OMe
H
2.8±0.15
0.8±0.11
4.419 ± 0.38 14.241 ± 1.07
3.5842
3.3034
WB07
9.333 ± 1.09
>50
a
Data are presented as the means ± SDs of three independent experiments. p < 0.05.
b
ClogP values were calculated using Sybyl 6.91.

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Table 4. MAO-A/B inhibitory activity of selected compounds.
MAO-A
IC50(μM)a
MAO-B
IC50(μM)a
Entry
Compound
TCPb
1
2
3
2.04 ± 0.100
0.72 ± 0.126
> 50
WA20
> 50
> 50
WB07
> 50
a
Data are presented as the means ± SDs of three independent experiments. *p < 0.05.
Used as a positive control.
b
In conclusion, on the basis of previously reported LSD1 inhibitors, a series of
curcumin analogues containing a piperidine group were designed and synthesized.
Based on biochemical assays, most of them exhibited in vitro inhibitory activities
against LSD1. In particular, the inhibitory activity of compound WB07 against LSD1
was nearly tenfold higher than that of curcumin, with an IC50 value reaching 0.8 μM.
Furthermore, WA20 showed potent inhibition against LSD1 in the A549 cells with
IC50 values of 4.4 μM, while it showed no outstanding inhibitory activity against the
U87 cells, which have low levels of LSD1 expression. This result indicates to some
extent that the compound WA20 specifically targeted LSD1. These curcumin
analogues represent a novel class of LSD1 inhibitors, and our laboratory is carrying
out further chemical modifications and anticancer activity evaluation of these
compounds.

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Acknowledgments
We gratefully acknowledge the Program for Innovative Research Team of the
Ministry of Education, and the Program for Liaoning Innovative Research Team in
University.
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WB 07
IC50 = 0.8μM (LSD1)
=
9.3μM (A549)
>
50μM (MAO-A)
50μM (MAO-B)
>
ClogP = 3.3
curcumin IC50 = 9.6 μM
Utilizing a structure-based drug design strategy, we designed and synthesized a
series of curcumin analogues that were shown to be potent LSD1 inhibitors in the
enzyme assay. Compound WB07 displayed the most potent LSD1 inhibitory activity,
with an IC50 value of 0.8 μM.

Figure 1

Figure 2

Figure 3