Synthesis and decreasing Aβ content evaluation of arctigenin-4-yl carbamate derivatives

Article abstract of DOI:10.1016/j.bmcl.2016.05.028

A series of arctigenin-4-yl carbamate derivatives were synthesized and evaluated for potency in reducing β-amyloid (Aβ) content in HEK293-APPswe cells. Most of the arctigenin-4-yl aralkyl or aryl carbamate derivatives showed improved potency in reducing Aβ content. Among the synthesized compounds, arctigenin-4-yl (3-chlorophenyl)carbamate (20) exhibited the strongest potency with 78.7% Aβ content reduction at 20 μM. Furthermore, the effect of arctigenin-4-yl (4-chlorophenyl)carbamate (19) and arctigenin-4-yl (3-chlorophenyl)carbamate (20) on lowing Aβ content was better than arctigenin under the concentrations of 1, 10 and 20 μM.

Full text of DOI:10.1016/j.bmcl.2016.05.028

Accepted Manuscript
Synthesis and decreasing Aβ content evaluation of arctigenin-4-yl carbamate
derivatives
Xingyu Xu, Cong Li, Min Lei, Zhiyuan Zhu, Jianming Yan, Xu Shen, Lihong
Hu
PII:
S0960-894X(16)30513-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.05.028
BMCL 23887
Reference:
Bioorganic & Medicinal Chemistry Letters
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4 May 2016
10 May 2016
Please cite this article as: Xu, X., Li, C., Lei, M., Zhu, Z., Yan, J., Shen, X., Hu, L., Synthesis and decreasing Aβ
content evaluation of arctigenin-4-yl carbamate derivatives, Bioorganic & Medicinal Chemistry Letters (2016), doi:
http://dx.doi.org/10.1016/j.bmcl.2016.05.028
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Synthesis and decreasing Aβcontent
evaluation of arctigenin-4-yl carbamate
derivatives
Xingyu Xu, Cong Li, Min Lei, Zhiyuan Zhu, Jianming Yan, Xu Shen, Lihong Hu
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Synthesis and decreasing Aβcontent evaluation of arctigenin-4-yl carbamate
derivatives
Xingyu Xua,†, Cong Lib,†, Min Leia, ∗, Zhiyuan Zhua, Jianming Yana, Xu Shena, b, ∗and Lihong Hua, ∗
a State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 201203, P. R. of China
b School of Life Science, Shanghai University, 99 Shangda Road, Shanghai 200444, P. R. of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A series of arctigenin-4-yl carbamate derivatives were synthesized and evaluated for potency in
reducing β-Amyloid (Aβ) content in HEK293-APPswe cells. Most of the arctigenin-4-yl aralkyl
or aryl carbamate derivatives showed improved potency in reducing Aβ content. Among the
synthesized compounds, arctigenin-4-yl (3-chlorophenyl)carbamate (20) exhibited the strongest
potency with 78.7% Aβ content reduction at 20 μM. Furthermore, the effect of arctigenin-4-yl
(4-chlorophenyl)carbamate (19) and arctigenin-4-yl (3-chlorophenyl)carbamate (20) on lowing
Aβ content was better than arctigenin under the concentrations of 1, 10 and 20 μM.
Keywords:
Arctigenin (ATG)
Natural product
2009 Elsevier Ltd. All rights reserved.
Arctigenin-4-yl 3-carbamate
Structure-activity relationships (SARs)
Alzheimer’s disease (AD)
Alzheimer’s disease (AD), the most common type of dementia,
is a progressively neurodegenerative disease characterized by
emotional disturbance, cognitive decline and memory loss. AD is
a serious global threat to public health, imposing enormous social
and economic burdens on patients and their families. To date,
there is no effective therapy for AD, and marketed drugs are
limited in efficacy. In 2002, Hardy J. and Selkoe D. J.
hypothesized that overproduction and aggregation of β-amyloid
peptides (Aβ) was one of important causes leading to AD.1 From
then on, inhibiting production, promoting elimination, and
decreasing aggregation of Aβ have been becoming an important
strategy for anti-AD drugs development.2
neuroprotective activity.9 In 2013, Zhang N. and his co-workers
reported that arctigenin could prevent cell viability loss and
reduce intracellular Aβ production in the SH-SY5Y cells.10 Our
group has long been engaged in the research of modification and
bioactivity of arctigenin.6b,11 We have previously reported11a that
arctigenin could inhibited Aβproduction by suppressing BACE1
expression and promote Aβ clearance by enhancing autophagy
through AKT/mTOR signaling inhibition and AMPK/Raptor
pathway activation. Furthermore, arctigenin also could
ameliorate AD mouse memory impairment. All these results
clearly indicated that arctigenin was a potential lead compound
for anti-AD drug discovery.
In recent years, a number of natural products targeting Aβ
were found and developed into clinical studies, such as scyllo-
inositol,3 curcumin,4 and homotaurine.5 Therefore, seeking and
finding lead compounds of anti-AD from natural products has
received considerable attention and emphasis in the world.
Arctigenin (1, Figure 1), a naturally occurring lignanolide of the
dibenzylbutyrolactone type isolated from the seeds of Arctium
lappa L., has been reported to possess diverse pharmacological
activities such as antitumor,6 anti-inflammatory,7 and antioxidant
activities.8 Furthermore, it was reported that arctigenin had
Figure 1. The structure of arctigenin (ATG).
———
† These authors contributed equally to this work.
∗Corresponding author. Tel.: +86-21-2023-0223; fax: +86-21-2023-0233; e-mail: mlei@simm.ac.cn
∗Corresponding author. Tel.: +86-21-5080-6031; fax: +86-21-5080-6031; e-mail: xshen@simm.ac.cn
∗Corresponding author. Tel.: +86-21-2023-1965; fax: +86-21-2023-1965; e-mail: lhhu@simm.ac.cn

Although several literature reported the anti-AD activity of
arctigenin in vitro and vivo, the structure-activity relationships
(SARs) of arctigenin derivatives was still not clear. Therefore, it
is necessary to synthesis arctigenin analogues for further research
of lowering Aβ content. As part of our current studies on the
extraction, separation and modification of active natural products,
we herein report a series of arctigenin derivatives for their
lowering Aβ content activity.
In a previous study, we found that the etherification and
esterification of hydroxyl on C-4 of arctigenin would lead to the
activity of lowering Aβ content disappeared. Conversely,
arctigenin-4-yl carbamate derivatives could maintain and
improve the activities than that of arctigenin. In order to find new
compounds with better bioactivity, a series of arctigenin-4-yl
carbamate derivatives were synthesized, and evaluated for their
lowering Aβ content activities.
Scheme 1. The synthesis of arctigenin-4-yl carbamate derivatives.
As shown in Scheme 1, in order to synthesize of arctigenin-4-
yl carbamate derivatives, we developed two methods which
including: (a) arctigenin reacted with 4-nitrophenyl
chloroformate in the presence of pyridine as base in DCM at rt to
obtain the intermediate. Then, the intermediate reacted with
alkylamine in DCM in rt or aromatic amine in THF under reflux
to obtain compounds 2−9, 11−15, and 22−31; (b) arctigenin
reacted with isocyanate in THF under reflux to obtain
compounds 10, and 16−21.
6
0.25
30
35.4
7
8
0.25
0.25
79
75
28.5
11.9
Table 1
Lowering Aβ content activity of arctigenin-4-yl carbamate
derivatives 1−11 in 20 µM
9
0.25
12
67
42
70
26.2
43.5
41.3
Time
(h)
Yield
(%)a
Lowering Aβ
content (%)
Compd
10
or
−
1
2
−
−
44.6
29.8
0.25
69
11
0.25
3
4
0.25
0.25
67
77
36.3
20.3
a Isolated yields.
Series of arctigenin-4-yl carbamate derivatives (2−11) were
synthesized and the Aβ lowering potencies of these compounds
were investigated at the concentration of 20 μM on HEK293-
APPswe cell (Table 1). As shown in Table 1, arctigenin was
potent with 44.6% Aβ reduction at 20 μM. Arctigenin-4-yl alkyl
carbamate derivatives 2−9 showed potency of lowing Aβ content
ranged from 11.9−36.3%, which was lower than arctigenin. In
addition, arctigenin-4-yl phenyl and benzyl carbamates 10 and 11
(43.5% and 41.3% of lowing Aβ content, respectively) displayed
5
0.25
49
21.4

similar activities with arctigenin. These results revealed that
introduction alkyl(s) on nitrogen of arctigenin-4-yl carbamate
derivatives would cause an adverse impact on bioactivities.
Therefore, in order to find arctigenin-4-yl carbamate derivatives
with more potent on lowing Aβ content activities, we further
synthesized more arctigenin-4-yl aryl and aralkyl carbamate
derivatives 11−21 (Table 2).
20
12
48
42
30
78.7
58.3
21
Among the synthesized compounds 11−14, arctigenin-4-yl N-
S-(α)-phenylcarbamate 13 showed the best potency with 70.8%
Aβ reduction at 20 μM (Table 2). Furthermore, methoxyl or
chloro substitute phenyl analogues 16−21 were synthesized and
evaluated for decreasing Aβ content activities. Compounds
16−21 displayed higher activities than arctigenin with potency
52.8−78.7%, and arctigenin-4-yl (3-chlorophenyl)carbamate 20
showed the best potency with 78.7%.
a Isolated yields.
Based on the structure of 20, arctigenin-4-yl (3-substitued
phenyl)carbamate derivatives 22−26 were synthesized and
evaluated (Table 3). However, these compounds 22−26 no matter
with electro-donating group (-CH3) or electro-withdraw group (-F,
-NO2 and -CN) showed decreased potencies (41.0−63.0%) than
20 (78.7%), which indicated that 3-chlorophenyl might be better
than others for potencies of lowering Aβ content.
Table 2
Lowering content activity of arctigenin-4-yl carbamate
derivatives 1, 10−21 in 20 µM
Table 3
Lowering Aβ content activity of arctigenin-4-yl carbamate
derivatives 1, 20, 22−26 in 20 µM
Lowering
Time
(h)
Yield
(%)a
Lowering Aβ
content (%)
Compd
Time
(h)
Yield
(%)a
or
−
Compd
Aβ content
1
−
−
44.6
43.5
(%)
or
−
1
−
−
44.6
78.7
10
11
12
12
42
20
22
23
24
25
12
42
0.25
0.25
70
59
41.3
49.0
12
24
48
48
26
23
32
32
55.0
61.0
63.0
56.0
13
14
15
0.25
0.25
48
51
37
47
70.8
45.0
30.0
26
48
37
41.0
16
17
12
12
39
32
52.9
52.8
a Isolated yields.
In addition, substituent was introduced on 3-chlorophenyl
moiety and the results were listed in Table 4. It was disappointed
that all of the compounds 27−31 showed lower potencies
(42.4−62.8%) than 20 (78.7%).
Table 4
Lowering Aβ content activity of arctigenin-4-yl carbamate
derivatives 1, 20, 27−31 in 20 µM
18
19
48
12
27
39
61.7
66.9
Time
(h)
Yield
(%)a
Lowering Aβ
content (%)
Compd
or
−
1
−
−
44.6

Acknowledgments
20
27
12
24
42
23
78.7
42.4
This work was supported by the National Natural Science
Foundation of China (grants 81473110), Shanghai Science &
Technology Support Program (13431900401), the Chinese
National Science & Technology Major Project “Key New Drug
Creation and Manufacturing Program” (grant 2013ZX09508104).
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48
24
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56.0
60.5
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30
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62.8
53.7
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a Isolated yields.
Because compound 19 and 20 exhibited good activities of
lowering Aβ content as well as they were easy to synthesize,
therefore 19 and 20 were chosen to evaluate the activities of
lowering Aβ content at different concentrations of 0.1, 1, 10 and
20 μM (Figure 2). As shown in Figure 2, the results exhibited
that 1, 19 and 20 were not significantly different at the
concentrations of 0.1 μM from the control. 19 and 20 displayed
the activities of lowering Aβ at 1 μM, however 1 still was
inactive under this concentration. The results in Figure 2 clearly
indicated that the bioactivities of 19 and 20 were superior to 1
under different concentrations.
120
100
80
60
Supplementary Material
40
Supplementary data (synthesis of 2–31 and biological assay
methods) associated with this article can be found, in the online
version, at
20
0
0 20 10 1 0.1 20 10 1 0.1 20 10 1 0.1
1 (µM)
19 (µM)
20 (µM)
Figure 2. The structure of arctigenin (ATG).
In summary, 30 arctigenin-4-yl carbamate derivatives were
synthesized and evaluated for potencies of lowering Aβ content.
In all of the synthesized compounds, arctigenin-4-yl alkyl
carbamate derivatives showed lower activities, while arctigenin-
4-yl aryl or aralkyl carbamate derivatives showed higher
activities
than
arctigenin.
Arctigenin-4-yl
(3-
chlorophenyl)carbamate (20) exhibited the strongest potency of
lowering Aβ content. Furthermore, both arctigenin-4-yl (4-
chlorophenyl)carbamate
(19)
and
arctigenin-4-yl
(3-
chlorophenyl)carbamate (20) were superior to arctigenin under
the concentrations of 1, 10 and 20 μM.