Synthesis and biological evaluation of arctigenin ester and ether derivatives as activators of AMPK

Article abstract of DOI:10.1016/j.bmc.2013.04.010

A series of new arctigenin and 9-deoxy-arctigenin derivatives bearing different ester and ether side chains at the phenolic hydroxyl positions are designed, synthesized, and evaluated for activating AMPK potency in L6 myoblasts. Initial biological evaluation indicates that some alkyl ester and phenethyl ether arctigenin derivatives display potential activities in AMPK phosphorylation improvement. Further structure-activity relationship analysis shows that arctigenin ester derivatives 3a, 3h and 9-deoxy-arctigenin phenethyl ether derivatives 6a, 6c, 6d activate AMPK more potently than arctigenin. Moreover, the 2-(3,4-dimethoxyphenyl)ethyl ether moiety of 6c has been demonstrated as a potential functional group to improve the effect of AMPK phosphorylation. The structural optimization of arctigenin leads to the identification of 6c as a promising lead compound that exhibits excellent activity in AMPK activation.

Full text of DOI:10.1016/j.bmc.2013.04.010

Bioorganic & Medicinal Chemistry 21 (2013) 3882–3893
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and biological evaluation of arctigenin ester and ether
derivatives as activators of AMPK q
a,b,
Sida Shen a, , Jingjing Zhuang a, , Yijia Chen b, Min Lei b, Jing Chen b,c, Xu Shen a,b, , Lihong Hu
⇑
⇑
a School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
b Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
c State Key Laboratory of Natural and Biomimetic Drugs, Peking University, 38 Xueyuan Road, Beijing 100191, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new arctigenin and 9-deoxy-arctigenin derivatives bearing different ester and ether side
chains at the phenolic hydroxyl positions are designed, synthesized, and evaluated for activating AMPK
potency in L6 myoblasts. Initial biological evaluation indicates that some alkyl ester and phenethyl ether
arctigenin derivatives display potential activities in AMPK phosphorylation improvement. Further struc-
ture–activity relationship analysis shows that arctigenin ester derivatives 3a, 3h and 9-deoxy-arctigenin
phenethyl ether derivatives 6a, 6c, 6d activate AMPK more potently than arctigenin. Moreover, the
2-(3,4-dimethoxyphenyl)ethyl ether moiety of 6c has been demonstrated as a potential functional group
to improve the effect of AMPK phosphorylation. The structural optimization of arctigenin leads to the
identification of 6c as a promising lead compound that exhibits excellent activity in AMPK activation.
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Received 1 March 2013
Revised 1 April 2013
Accepted 4 April 2013
Available online 18 April 2013
Keywords:
Arctigenin
9-Deoxy-arctigenin
AMPK
2-(3,4-Dimethoxyphenyl)ethyl
1. Introduction
anti-hyperglycemic, anti-lipidemic, endurance enhancement and
anti-cancer properties of arctigenin in vivo.5
AMP-activated protein kinase (AMPK), a heterotrimeric serine/
threonine protein kinase, plays a vital role in regulation of whole-
body energy homeostasis.1 As a cellular energy-sensor, AMPK acti-
vation stimulates glucose uptake and fat oxidation, suppresses lipo-
genesis and gluconeogenesis.2 Therefore, AMPK is considered as a
potential therapeutic target for treatment of obesity and type 2 dia-
betes.3 Until recently, there exists a very limited number of known
pharmacological AMPK activators. The biguanides and thiazolidin-
ediones have been shown to indirectly activate AMPK.4 Demonstra-
tion that AMPK activation may contribute the efficacies of these
established antidiabetic drugs, along with the understanding of
the pivotal roles that AMPK plays in metabolism, has engendered
intense interests in discovering and developing novel activators.
As part of our ongoing screening program to search for new
AMPK activators from plants, we have identified arctigenin, iso-
lated from the seeds of Arctium lappa L. as an indirect AMPK activa-
tor.5a Then, the inhibitory effect of arctigenin on complex I in the
mitochondrial respiration chain was reported, which might be
the reason for the activation of AMPK by arctigenin.5b Moverover,
AMPK activation is proved to contribute at least partially to the
Although arctigenin derivatives were synthesized and evalu-
ated for anti-HIV,6 anti-cancer7 and b-amyloid inhibition activities8
in order to find more potent derivatives, efforts aiming to improve
its activity in AMPK activation are relatively few. Herein, we de-
scribe the synthesis of arctigenin derivatives and assessment of
their effects on AMPK activation.
2. Design and syntheses
In the initial research, some arctigenin derivaitives bearing dif-
ferent ester and ether side chains at the phenolic hydroxyl posi-
tions were prepared and evaluated for activating AMPK potency
in L6 myoblasts. The arctigenin derivatives’ effects on promoting
AMPK phosphorylation were translated into the relative ratios of
arctigenin derivatives-induced and arctigenin-induced AMPK
phosphorylation levels by using Quantity One software. The preli-
minary structure–activity relationship in Table 1 indicated that
introducing alkyl ester groups or phenethyl ether groups into the
phenolic hydroxyl position of arctigenin might has some advanta-
ges in obtaining better activities in AMPK activation.
In our effort to investigate further SAR, arctigenin (1) and
9-deoxy-arctigenin (2) (Fig. 1) were used as basic scaffolds to pre-
pare new derivatives with different ester and ether substituents.
All semi-synthetic compounds were subjected to in vitro AMPK
phosphorylation screening to identify new lead activators of AMPK.
Arctigenin (1) was extracted and purified from the traditional
medicine the seeds of Arctium lappa L. 9-Deoxy-arctigenin (2)
was semi-synthesized via a two-step process from arctigenin (1)
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-No Derivative Works License, which per-
mits non-commercial use, distribution, and reproduction in any medium, provided
the original author and source are credited.
⇑
Corresponding authors. Tel.: +86 21 50806600x2118; fax: +86 21 50806031
(X.S.); tel./fax: +86 21 20231965 (L.H.).
E-mail addresses: xshen@mail.shcnc.ac.cn (X. Shen), lhhu@simm.ac.cn (L. Hu).
These authors contributed equally to this work.
0968-0896/$ - see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.04.010

S. Shen et al. / Bioorg. Med. Chem. 21 (2013) 3882–3893
3883
Table 1
Preliminary SAR analysis of arctigenin derivativesa
O
O
O
O
a
R
O
O
O
O
O
O
HO
3a-e
O
O
O
O
O
R'
b or c
O
1:Arctigenin
O
O
4a-f
Compd
R
Ratio
Compd
R0
Ratio
Arctigenin
—
1
4a
0.14
0.20
3a
3b
1.11
4b
4c
O
O
O
0.64
0.30
0.17
0.36
O
3c
3d
3e
4d
4e
4f
O
O
O
O
0.69
0.87
0.93
0.71
O
O
O
O
N
a
Synthesis of arctigenin derivative: reagents and conditions: (a) RCOCl, TEA, CH2Cl2, 0 °C for 3a–e; (b) R0X, K2CO3, acetone, rt for 4a–4d; (c) R0OTs, K2CO3, DMF, 60 °C for 4e–
f.
O
2
7
O
3. Evaluation of AMPK phosphorylation
9
O
3
4
8
O
O
1
6
O
On the basis of our previous study,5a arctigenin has effect on the
promotion of AMPK phosphorylation in skeletal muscle, leading to
AMPK activation-induced enhancement of mice treadmill endur-
ance and amelioration of metabolic disorders. Therefore, skeletal
muscle cells were used to determine the effects of arctigenin
derivatives on AMPK activation in our research. L6 myoblasts
were treated with indicated concentrations of arctigenin and
HO
8'
1'
HO
9'
7'
5
2'
6'
5'
3' O
4'
O
O
1: Arctigenin
2: 9-Deoxy-arctigenin
9-deoxy-arctigenin derivatives (40 lM) for 30 min, then AMPK
phosphorylaton and total AMPK levels were examined by
Western-blotting assay. In this assay, arctigenin acted as a positive
control and exhibited the significant effect on AMPK phosphoryla-
tion improvement. The results shown were representative of three
independent experiments. The bands were quantified using Quan-
tity One software. The results were shown in Figure 2.
Figure 1. The structures of arctigenin and 9-deoxy-arctigenin.
by NaBH4/BF3ꢀEt2O catalyzed reduction and p-toluenesulfonic acid
(TSA) catalyzed cyclization. Esterification reactions of arctigenin
(1) and 9-deoxy-arctigenin (2) were performed by treatment with
the related acyl chlorides to give the corresponding ester deriva-
tives 3a–r and 5a–k. Etherification reactions of arctigenin (1) and
9-deoxy-arctigenin (2) were performed by treatment with the re-
lated toluenesulfonyic acid ester compounds and K2CO3 in DMF
to afford the corresponding ether products 4e–s and 6a–k as well
as by treatment with the related alkyl halides and K2CO3 in acetone
to give 4a–d and 6l.
4. Results and discussion
4.1. Preliminary SAR of arctigenin derivatives
In the initial research, several arctigenin ester and ether
derivatives were synthesized and assessed for activities in AMPK

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S. Shen et al. / Bioorg. Med. Chem. 21 (2013) 3882–3893
acitivation. The in vitro AMPK phosphorylation studies were sum-
marized in Table 1. The results indicated that acetate derivative
(3a) maintained the activity in promoting AMPK phosphorylation
efficiently, but 3-methoxybenzoyloxy (3b), 3,4-dimethoxybenzoyl-
oxy (3c), 2-(3,4-dimethoxyphenyl)acetoxy) (3d) and nicotinoyloxy
(3e) derivatives reduced the effects. In addition, arctigenin ether
derivatives including ethoxy (4a), isopropoxy (4b), 2-methoxyeth-
oxy (4c), and (3,4-dimethoxybenzyl)oxy (4d) derivatives exhibited
esters (3f–h) maintained activities in AMPK activation as well as
3a. Among them, acetate (3a) and valerate (3h) displayed better ef-
fects on the promotion of AMPK phosphorylation than arctigenin.
Nevertheless, the introduction of unsaturated bond (3i), steric hin-
drance alkyl chains (3j–l), and cyclic aliphatic chain (3m) into ali-
phatic ester groups decreased activities. Benzoate derivative (3n)
showed moderate promoting effect on AMPK phosphorylation
compared to arctigenin. However, the substituent introduction of
aryl ester on the benzene ring such like methoxyl (3b–c and 3o),
methyl (3p), and halogen (3q) groups resulted in a significant loss
of potency in AMPK activation. In addition, the heterocyclic ring es-
ters (3e and 3r) showed moderate activities in promoting AMPK
phosphorylation. The SAR results of arctigenin ester derivatives
indicated that the aliphatic linear chain ester substituents could
maintain the arctigenin-induced activating AMPK potency. Com-
pounds 3a and 3h exhibited slightly better activities in enhancing
AMPK phosphorylation compared to arctigenin.
a
significant loss of potency. However, 2-(3,4-dimethoxy-
phenyl)ethyl ether substituent at the phenol hydroxyl position of
arctigenin (4e) showed similar effect on AMPK activation compared
with arctigenin. When the aryl aliphatic carbon chain was extended
(4f), the AMPK phosphorylation level was reduced.
4.2. SAR of arctigenin ester derivatives
Following the preliminary SAR results of arctigenin ester deriv-
atives, several alkyl and aryl ester compounds were prepared and
evaluated for activating AMPK potency. The effects of arctigenin
ester derivatives on AMPK phosphorylation improvement were
shown in Table 2. The results indicated that aliphatic linear chains
4.3. SAR of arctigenin ether derivatives
The initial SAR studies of arctigenin ether derivatives
suggested that 2-(3,4-dimethoxyphenyl)ethyl substituent at the
Figure 2. The effects of control (D), arctigenin (A), and related derivatives on AMPK phosphorylation in L6 cells. Differentiated L6 cells were treated with arctigenin and
related derivatives (40 M) for 30 min, AMPK phosphorylation level and total AMPK level were determined by Western-blotting. The bands were quantified with Quantity
One software. Protein levels were normalized by total AMPK.
l

S. Shen et al. / Bioorg. Med. Chem. 21 (2013) 3882–3893
3885
Table 2
Table 3
SAR analysis of arctigenin ester derivativesa
SAR analysis of arctigenin ether derivativesa
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
R2
HO
R1
R2(CH2)2OTs
K2CO3, DMF
HO
R1COCl
TEA, CH2Cl2
O
O
O
O
O
O
O
1
1
3f-r
4g-s
Compd
R1
—
Ratio
1
Compd
R1
Ratio
0.32
Compd
R2
—
Ratio
1
Compd
R2
Ratio
0.09
1
3l
1
4m
3f
0.92
0.94
3m
3n
0.62
0.81
4g
4h
0.2
4n
4o
0.35
0.26
3g
F
O
0.69
3h
3i
1.16
0.86
0.82
0.48
3o
3p
3q
3r
0.46
0.46
0.63
0.69
Cl
O
F
4i
4j
0.32
0.32
4p
4q
0.34
0.24
O
O
Cl
3j
F
O
3k
O
4k
4l
0.73
0.57
4r
4s
0.34
0.28
O
Synthesis of arctigenin derivative: reagents and conditions: R1COCl, TEA,
CH2Cl2, 0 °C for 3f–r.
a
O
O
O
O
O
O
O
phenol hydroxyl position of arctigenin (4e) showed similar effect
on AMPK activation compared with arctigenin. To further
investigate SAR of arctigenin ether derivatives, several phenethyl
ether compounds were prepared and evaluated for activating
AMPK potency. The effects of arctigenin phenethyl ether deriva-
tives on AMPK phosphorylation improvement were presented in
Table 3. These results indicated that phenylethyl ether derivative
(4g) without substitutent on the benzene ring could not maintain
the activity in AMPK activation. The 3-methoxy (4h) substituted
benzene ring was significant for the effect on the promotion of
AMPK phosphorylation compared to 4-methoxy (4i) and 2-meth-
oxy (4j), and the substituents on the benzene rings including
3-methoxy such as 3,4-dimethoxy (4e), 3-methoxy (4h),
3,5-dimethoxy (4k), and 3,4,5-trimethoxy (4l) were more benefi-
cial for activities in AMPK activation compared to tert-butyl (4m)
and halogen (4n–q) substituents. However, among of arctigenin
phenethyl ether derivatives, only 2-(3,4-dimethoxyphenyl)ethyl
ether derivative (4e) exhibited similar effect on AMPK activation
compared with arctigenin. Looking back to the initial SAR of
arctigenin ether derivatives, no matter the aryl aliphatic carbon
chain was reduced (4d) or extended (4f), activities were reduced
compared with 4e. Moreover, 3,4-diethoxy (4r) and 3,4-methyl-
enedioxy (4s) substituents displayed poor effects on AMPK
activation. Therefore, the 2-(3,4-dimethoxyphenyl)ethyl ether
substituent at the phenolic hydroxyl position of arctigenin could
be considered as a potential functional group to maintain the
effect of arctigenin-induced AMPK activation.
a
Synthesis of arctigenin phenethyl ether derivatives: reagents and conditions:
R2(CH2)2OTs, K2CO3, DMF, 60 °C for 4g–s.
4.4. SAR of 9-deoxy-arctigenin ester derivatives
Based on the SAR results of arctigenin ester compounds, several
9-deoxy-arctigenin alkyl and aryl ester derivatives were synthe-
sized. The results of AMPK phosphorylation assessment in Table 4
showed that 9-deoxy-arctigenin (2) only displayed half AMPK
phosphorylation level compared with arctigenin. All the alkyl esters
(5a–d) of 9-deoxy-arctigenin displayed much lower activities than
arctigenin and 9-deoxy-arctigenin, which was different from the
SAR results of arctigenin aliphatic ester derivatives. The aryl ester
derivatives including 4-methoxyl (5e) and 4-fluoro (5f) substitu-
ents on the benzene rings obviously decreased effects on the
promotion of AMPK phosphorylation as well as the heterocyclic ring
esters including nicotinate (5g) and furan-2-carboxylate (5h) sub-
stituents. Notely, 3-methoxyl benzoate (5i) of 9-deoxy-arctigenin
showed moderate activity in AMPK activation compared with arc-
tigenin. Moreover, 3,4-dimethoxyl benzoate (5j) and 2-(3,4-dime-
thoxyphenyl)acetate (5k) displayed similar activities with 5i. The
SAR of 9-deoxy-arctigenin ester derivatives showed different re-
sults with arctigenin ester derivatives, but these compounds’ weak
activities in AMPK activation hindered their further development.

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S. Shen et al. / Bioorg. Med. Chem. 21 (2013) 3882–3893
Table 4
SAR analysis of arctigenin ester derivativesa
O
O
O
O
O
O
a.(i) NaBH4, BF3E2O
(ii)TSA, CH2Cl2
HO
HO
O
O
O
1
2:9-Deoxy-arctigenin
O
O
O
O
R3
O
b. R3COCl
TEA, CH2Cl2
O
5a-k
Compd
R3
Ratio
Compd
R3
Ratio
0.37
1
1
5f
—
F
2
0.49
5g
0.71
—
N
5a
5b
0.26
0.25
5h
5i
0.41
0.82
O
O
O
5c
5d
5e
0.25
0.23
0.25
5j
0.82
0.83
O
O
5k
O
O
a
Synthesis of 9-deoxy-arctigenin ester derivatives: reagents and conditions: (a) (i) NaBH4, BF3ꢀEt2O, THF, rt; (ii) TSA, CH2Cl2, 100 °C
for 2; (b) R3COCl, TEA, CH2Cl2, 0 °C for 5a–k.
4.5. SAR of 9-deoxy-arctigenin ether derivatives
the AMPK activity. In addition, the halogen (6f–h) and heterocycle
(6i–j) substituted compounds exhibited moderate to good activi-
ties. It was noted that the 2-(3,4-dimethoxyphenyl)ethyl substi-
tuted 9-deoxy-arctigenin ether (6c) displayed the best effect on
promoting AMPK phosphorylation in 9-deoxy-arctigenin and
arctigenin derivatives. The evaluation results also showed that
compound 6k which has an extended carbon chain compared with
6c reduced effect on AMPK phosphorylation, and compound 6l
including a carbonyl group in the carbon chain reduced the logP
of compounds as well as activities in AMPK activation compared
to 6c. Therefore, the 2-(3,4-dimethoxyphenyl)ethyl ether substitu-
ent at the phenolic hydroxyl position of 9-deoxy-arctigenin was
further demonstrated as a potential functional group to promote
9-Deoxy-arctigenin phenethyl ether derivatives were prepared
based on the SAR results of arctigenin ether compounds about
the effects on AMPK phosphorylation. The in vitro AMPK phosphor-
ylation studies of 9-deoxy-arctigenin phenethyl ether derivatives
were summarized in Table 5. The results indicated that the 3-
methoxy substituent (6a) was still significant for the effect on
AMPK phosphorylation compared to 4-methoxy substituent (6b),
and the 3-methoxy (6a), 3,4-dimethoxy (6c), and 3,4,5-trimethoxy
(6d) substituted phenethyl ether 9-deoxy-arctigenin derivatives
did exhibit excellent effects on enhancing AMPK phosphorylation.
Nevertheless, 3,5-dimethoxy substitutent (6e) could not maintain

S. Shen et al. / Bioorg. Med. Chem. 21 (2013) 3882–3893
3887
Table 5
SAR analysis of 9-deoxy-arctigenin ether derivativesa
O
O
O
O
O
O
a. R4(CH2)2OTs,
K2CO3, DMF
R4
HO
Y
or b. R4COCH2X,
K2CO3, acetone
O
O
O
6a-k Y= CH2
6l
2
Y= C=O
Compd
R4
—
Ratio
Compd
R4
Ratio
0.91
F
F
1
1
6g
6h
6i
O
6a
6b
6c
1.33
0.90
1.45
0.79
0.81
0.64
Cl
O
O
N
6j
O
O
N
O
6d
1.25
6k
6l
0.97
0.66
O
O
O
O
O
O
O
6e
6f
0.68
0.97
F
a
Synthesis of 9-deoxy-arctigenin phenethyl ether derivative: reagents and conditions: (a) R4(CH2)2OTs, K2CO3, DMF, 60 °C for 6a–k; (b)
R4COCH2X, K2CO3, acetone, rt for 6l.
the effect on AMPK phosphorylation. Based on the SAR results,
compound 6c could be studied as an effective lead compound of
AMPK activator.
ether derivatives show that compound 6a, 6c and 6d activate
AMPK more potently than arctigenin. Moreover, the 2-(3,4-dime-
thoxyphenyl)ethyl ether moiety of 6c is further demonstrated as
a potential functional group to improve the effect of AMPK phos-
phorylation; (v) The structural optimization of arctigenin leads to
the identification of 6c as a promising lead compound that exhibits
excellent activity in AMPK activation.
5. Conclusions
In conclusion, the new ester and ether derivatives of arctigenin
and 9-deoxy-arctigenin were synthesized and evaluated for acti-
vating AMPK potency in L6 myoblasts. The semi-synthetic com-
pounds exhibited a range of activities. Thereby, a partial SAR is
established and summarized as follows: (i) the arctigenin aliphatic
linear chain ester derivatives can maintain the arctigenin-induced
activating AMPK potency, compounds 3a and 3h display better
activities in AMPK activation compared to arctigenin; (ii) the 9-
deoxy-arctigenin ester derivatives show different SAR results from
the arctigenin ester derivatives, but weak activities in AMPK acti-
vation; (iii) among of the arctigenin ether derivatives, 2-(3,4-dime-
thoxyphenyl)ethyl ether substituted compound 4e exhibit similar
activating AMPK potency with arctigenin, and is considered as a
potential functional group to maintain the effect of arctigenin-in-
duced AMPK activation; (iv) the SAR studies of 9-deoxy-arctigenin
6. Experimental
6.1. Chemistry
Reagents and all solvents were analytically pure grade and were
used without further purification. Column chromatography (CC)
was performed silica gel (200–300 mesh). TLC was performed on
GF254 silica gel plates (Yantai Huiyou Inc., China). 1H (300 and
400 MHz) spectra and 13C (100 MHz) spectra were recorded on
Bruker MX 300 spectrometer and Bruker MX 400 spectrometer in
the solvent indicated. HRESIMS were determined on a Micromass
Q-Tif Global mass spectrometer and ESIMS were obtained on a Bru-
ker Esquire 3000 Plus spectrometer.

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S. Shen et al. / Bioorg. Med. Chem. 21 (2013) 3882–3893
6.1.1. The procedure for the synthesis of 9-deoxy-arctigenin (2)
To a stirred solution of arctigenin (2.217 g, 6 mmol) and NaBH4
(660 mg, 18 mmol) in 50 mL dry THF was added BF3ꢀE2O (2.5 mL,
21.6 mmol) at 0 °C slowly. Then the mixture was stirred at room
temperature for 3 h. After completion of the reaction, 20 mL satu-
rated NaHCO3 were added, and the solution was extracted with
EtOAc (3 ꢁ 30 mL). The combined organic extracts were washed
with brine, dried, filtered, and concentrated under reduced pres-
sure. The crude product was dissolved in 5 mL DCM, and p-TsOH
(20 mg) was added to the solution. The mixture was stirred under
reflux for 1 h. After completion of the reaction, water (20 mL) was
added, and the solution was extracted with EtOAc (3 ꢁ 20 mL). The
combined organic extracts were washed with brine, dried, filtered,
and concentrated under reduced pressure. The crude product was
purified by chromatography on silica gel from (EtOAc/PE = 1/3) to
afford the pure product 2.
(s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.56 (d,
J = 7.9 Hz, 1H), 6.52 (s, 1H), 4.18 (t, J = 8.1 Hz, 1H), 3.97 (s, 3H),
3.95 (s, 2H), 3.91 (t, J = 8.1 Hz, 1H), 3.85 (s, 2H), 3.84 (s, 3H), 3.76
(s, 3H), 3.06–2.97 (m, 2H), 2.70–2.51 (m, 4H); MS (ESI) m/z:
559.6 (M+Na)+; HRMS (ESI): calcd for C30H32NaO9 (M+Na)+
559.1939, found: 559.1952.
4-(2-(3,4-Dimethoxyphenyl)acetoxy))-arctigenin (3d): Yield 78%;
colorless gum; 1H NMR (400 MHz, CDCl3): d 6.93–6.89 (m, 3H),
6.85 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 9.3 Hz, 1H), 6.73 (s, 1H), 6.64
(d, J = 8.4 Hz, 1H), 6.52 (d, J = 7.8 Hz, 1H), 6.48 (s, 1H), 4.15 (t,
J = 8.2 Hz, 1H), 3.96 (s, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.86 (s, 1H),
3.83 (s, 3H), 3.81 (s, 2H), 3.80 (s, 3H), 3.72 (d, J = 11.2 Hz, 3H),
2.96 (d, J = 5.7 Hz, 2H), 2.67–2.46 (m, 4H); MS (ESI) m/z: 573.6
(M+Na)+; HRMS (ESI): calcd for C31H34NaO9 (M+Na)+ 573.2095,
found: 573.2102.
4-Nicotinoyloxy-arctigenin (3e): Yield 75%; colorless gum; 1H
NMR (400 MHz, CDCl3): d 9.39 (d, J = 1.5 Hz, 1H), 8.85 (dd, J = 4.9,
1.6 Hz, 1H), 8.44 (dt, J = 8.0, 1.9 Hz, 1H), 7.47 (dd, J = 7.9, 4.9 Hz,
1H), 7.07 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 1.8 Hz, 1H), 6.78 (d,
J = 8.1 Hz, 1H), 6.73 (dd, J = 8.0, 1.9 Hz, 1H), 6.57 (dd, J = 8.2,
2.0 Hz, 1H), 6.53 (d, J = 2.0 Hz, 1H), 4.20 (dd, J = 9.1, 7.3 Hz, 1H),
3.92 (dd, J = 9.1, 7.7 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.76 (s,
3H), 3.01 (d, J = 5.9 Hz, 2H), 2.73–2.50 (m, 4H); MS (ESI) m/z:
478.2 (M+H)+; HRMS (ESI): calcd for C27H28NO7 (M+Na)+
478.1860, found: 478.1885.
Arctigenin (1): 1H NMR (300 MHz, CDCl3): d 6.81 (d, J = 7.9 Hz,
1H), 6.74 (d, J = 8.1 Hz, 1H), 6.65–6.57 (m, 2H), 6.54 (dd, J = 8.1,
1.9 Hz, 1H), 6.45 (d, J = 1.9 Hz, 1H), 4.13 (dd, J = 9.1, 7.0 Hz, 1H),
3.88 (m, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 2.91 (m, 2H),
2.69–2.38 (m, 4H); 13C NMR (100 MHz, CDCl3): d 178.7, 148.9,
147.7, 146.6, 144.4, 130.3, 129.4, 122.0, 120.5, 114.0, 111.6,
111.4, 111.1, 71.3, 55.8, 55.7, 55.7, 46.5, 40.8, 38.1, 34.4; MS (ESI)
m/z: 395.4 (M+Na)+; HRMS (ESI): calcd for C21H24NaO6 (M+Na)+
395.1465, found: 395.1478.
9-Deoxy-arctigenin (2): Yield 81% (two steps); colorless gum; 1H
NMR (300 MHz, CDCl3): d 6.80 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.1 Hz,
1H), 6.62 (dd, J = 8.4, 1.5 Hz, 1H), 6.59 (dd, J = 8.4, 1.5 Hz, 1H), 6.56
(d, J = 1.5 Hz, 1H), 6.56 (d, J = 1.5 Hz, 1H), 5.53 (br s, 1H), 3.91 (dd,
J = 8.7, 6.6 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.52 (d,
J = 8.6, 5.8 Hz, 2H), 2.61–2.48 (m, 4H), 2.18 (m, 2H); 13C NMR
(100 MHz, CDCl3): d 148.7, 147.2, 146.3, 143.8, 132.9, 132.2,
121.2, 120.4, 114.1, 111.7, 111.0, 110.9, 73.2(2C), 55.8, 55.7(2C),
46.50, 46.3, 39.1, 39.0; MS (ESI) m/z: 381.4 (M+Na)+; HRMS (ESI):
calcd for C21H26NaO5 (M+Na)+ 381.1672, found: 381.1680.
4-(Propionyloxy)-arctigenin (3f): Yield 96%; colorless gum; 1H
NMR (300 MHz, CDCl3):
d 6.93 (d, J = 8.1 Hz, 1H), 9.76 (d,
J = 8.1 Hz, 1H), 6.75 (s, 1H), 6.65 (dd, J = 8.0, 2.0 Hz, 1H), 6.53 (dd,
J = 8.0, 2.0 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 4.16 (dd, J = 9.1, 7.2 Hz,
1H), 3.90 (dd, J = 9.1, 7.2 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.76
(s, 3H), 3.01–2.91 (m, 2H), 2.65–2.52 (m, 6H), 1.26 (t, J = 7.5 Hz);
MS (ESI) m/z: 451.6 (M+Na)+; HRMS (ESI): calcd for C24H28NaO7
(M+Na)+ 451.1727, found: 451.1735.
4-(Butyryloxy)-arctigenin (3g): Yield 93%; colorless gum; 1H
NMR (400 MHz, CDCl3):
d 6.92 (d, J = 7.9 Hz, 1H), 6.76 (d,
J = 8.1 Hz, 1H), 6.74 (s, 1H), 6.66 (d, J = 7.9 Hz, 1H), 6.53 (d,
J = 8.2 Hz, 1H), 6.49 (s, 1H), 4.16 (t, J = 8.1 Hz, 1H), 3.89 (t,
J = 8.2 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.75 (s, 3H), 3.01–2.93
(m, 2H), 2.66–2.48 (m, 6H), 1.81–1.73 (m, 2H), 1.04 (t, J = 7.4 Hz,
3H); MS (ESI) m/z: 465.6 (M+Na)+; HRMS (ESI): calcd for
6.1.2. General procedure for synthesis of compounds 3a–r
To a stirred solution of arctigenin 1 (180 mg, 0.4 mmol) and TEA
(0.11 mL, 0.8 mmol) in 3 mL CH2Cl2 was added R1COCl (0.6 mmol)
at 0 °C slowly. Then the mixture was stirred at 0 °C for 1 h. After
completion of the reaction, water (20 mL) was added, and the solu-
tion was extracted with CH2Cl2 (3 ꢁ 20 mL). The combined organic
extracts were washed with brine, dried, filtered, and concentrated
under reduced pressure. The crude product was purified by chro-
matography on silica gel from (EtOAc/PE = 1/2) to afford the pure
product 3a–r.
C
25H30NaO7 (M+Na)+ 465.1884, found: 465.1898.
4-(Valeryloxy)-arctigenin (3h): Yield 95%; colorless gum; 1H
NMR (300 MHz, CDCl3):
d 6.92 (d, J = 8.1 Hz, 1H), 9.75 (d,
J = 8.1 Hz, 1H), 6.75 (s, 1H), 6.66 (dd, J = 8.0, 2.0 Hz, 1H), 6.53 (dd,
J = 8.0, 2.0 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 4.16 (dd, J = 9.1, 7.2 Hz,
1H), 3.90 (dd, J = 9.1, 7.2 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.75
(s, 3H), 3.03–2.91 (m, 2H), 2.64–2.52 (m, 6H), 1.78–1.68 (m, 2H),
1.48–1.39 (m, 2H), 0.96 (t, J = 7.5 Hz); MS (ESI) m/z: 479.6
(M+Na)+; HRMS (ESI): calcd for C26H32NaO7 (M+Na)+ 479.2040,
found: 479.2055.
4-Acetoxy-arctigenin (3a): Yield 92%; colorless gum; 1H NMR
(300 MHz, CDCl3): d 6.93 (d, J = 7.9 Hz, 1H), 9.76 (d, J = 8.0 Hz,
1H), 6.75 (s, 1H), 6.65 (dd, J = 7.9, 1.9 Hz, 1H), 6.53 (dd, J = 7.9,
1.9 Hz, 1H), 6.49 (d, J = 1.9 Hz, 1H), 4.18 (dd, J = 9.1, 7.2 Hz, 1H),
3.90 (dd, J = 9.1, 7.2 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.80 (s,
3H), 2.97 (d, J = 6.0 Hz, 2H), 2.65–2.52 (m, 4H), 2.20 (s, 3H); MS
(ESI) m/z: 437.6 (M+Na)+; HRMS (ESI): calcd for C23H26NaO7
(M+Na)+ 437.1571, found: 437.1593.
4-(3-Methoxybenzoyloxy)-arctigenin (3b): Yield 88%; colorless
gum; 1H NMR (400 MHz, CDCl3): d 7.80 (d, J = 7.3 Hz, 1H), 7.69 (s,
1H), 7.41 (t, J = 8.0 Hz, 1H), 7.17 (dd, J = 7.9, 1.9 Hz, 1H), 7.06 (d,
J = 7.9 Hz, 1H), 6.80 (s, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.72 (d,
J = 8.1 Hz, 1H), 6.56 (d, J = 8.2 Hz, 1H), 6.52 (s, 1H), 4.19 (t,
J = 8.1 Hz, 1H), 3.91 (t, J = 8.1 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H),
3.84 (s, 3H), 3.76 (s, 3H), 3.06–2.96 (m, 2H), 2.69–2.52 (m, 4H);
MS (ESI) m/z: 529.6 (M+Na)+; HRMS (ESI): calcd for C29H30NaO8
(M+Na)+ 529.1833, found: 529.1850.
4-((E)-But-2-enoyloxy))-arctigenin (3i): Yield 83%; colorless
gum; 1H NMR (400 MHz, CDCl3): d 7.17 (dd, J = 15.4, 7.0 Hz, 1H),
6.96 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.75 (s, 1H), 6.67
(d, J = 8.1 Hz, 1H), 6.54 (d, J = 8.5 Hz, 1H), 6.50 (s, 1H), 6.06 (d,
J = 15.5 Hz, 1H), 4.17 (t, J = 8.2 Hz, 1H), 3.90 (t, J = 8.2 Hz, 1H),
3.85 (s, 3H), 3.82 (s, 3H), 3.76 (s, 3H), 3.03–2.93 (m, 2H), 2.69–
2.48 (m, 4H), 1.96 (d, J = 6.9 Hz, 3H); MS (ESI) m/z: 463.6
(M+Na)+; HRMS (ESI): calcd for C25H28NaO7 (M+Na)+ 463.1727,
found: 463.1740.
4-Isobutyryloxy-arctigenin (3j): Yield 75%; colorless gum; 1H
NMR (300 MHz, CDCl3):
d 6.92 (d, J = 8.0 Hz, 1H), 6.76 (d,
J = 8.0 Hz, 1H), 6.73 (s, 1H), 6.66 (dd, J = 8.0, 2.0 Hz, 1H), 6.53 (dd,
J = 8.0, 2.0 Hz, 1H), 6.49 (s, 1H), 4.16 (dd, J = 9.1, 7.2 Hz, 1H), 3.90
(dd, J = 9.1, 7.2 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.75 (s, 3H),
3.01–2.96 (m, 2H), 2.91–2.87 (m, 1H), 2.84–2.45 (m, 4H), 1.32 (s,
4-(3,4-Dimethoxybenzoyloxy)-arctigenin (3c): Yield 87%; color-
less gum; 1H NMR (400 MHz, CDCl3): d 7.86 (d, J = 8.6 Hz, 1H),
7.67 (s, 1H), 7.06 (d, J = 7.9 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.81

S. Shen et al. / Bioorg. Med. Chem. 21 (2013) 3882–3893
3889
3H), 1.30 (s, 3H); MS (ESI) m/z: 465.6 (M+Na)+; HRMS (ESI): calcd
for C25H30NaO7 (M+Na)+ 465.1884, found: 465.1904.
6.70 (d, J = 8.0 Hz, 1H), 6.59–6.51 (m, 3H), 4.19 (dd, J = 9.1, 7.2 Hz,
1H), 3.92 (dd, J = 9.1, 7.2 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.76
(s, 3H), 3.03–2.93 (m, 2H), 2.70–2.47 (m, 4H); MS (ESI) m/z:
489.6 (M+Na)+; HRMS (ESI): calcd for C26H26NaO8 (M+Na)+
489.1520, found: 529.1550.
4-(3-Methylbutanoyloxy)-arctigenin (3k): Yield 80%; colorless
gum; 1H NMR (300 MHz, CDCl3): d 6.92 (d, J = 8.0 Hz, 1H), 6.76
(d, J = 8.0 Hz, 1H), 6.73 (s, 1H), 6.66 (dd, J = 8.0, 2.0 Hz, 1H), 6.53
(dd, J = 8.0, 2.0 Hz, 1H), 6.49 (s, 1H), 4.16 (dd, J = 9.1, 7.2 Hz, 1H),
3.90 (dd, J = 9.1, 7.2 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.75 (s,
3H), 2.97 (d, J = 6.0 Hz, 2H), 2.69–2.52 (m, 4H), 2.46 (d, J = 7.0 Hz,
2H), 2.30–2.16 (m, 1H), 1.06 (s, 3H), 1.04 (s, 3H); MS (ESI) m/z:
479.6 (M+Na)+; HRMS (ESI): calcd for C26H32NaO7 (M+Na)+
479.2040, found: 479.2061.
4-(3,3-Dimethylbutanoyloxy)-arctigenin (3l): Yield 65%; colorless
gum; 1H NMR (300 MHz, CDCl3): d 6.92 (d, J = 8.0 Hz, 1H), 6.76 (d,
J = 8.0 Hz, 1H), 6.73 (s, 1H), 6.66 (dd, J = 8.0, 2.0 Hz, 1H), 6.53 (dd,
J = 8.0, 2.0 Hz, 1H), 6.49 (s, 1H), 4.16 (dd, J = 9.1, 7.2 Hz, 1H), 3.90
(dd, J = 9.1, 7.2 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.75 (s, 3H),
2.97 (d, J = 6.0 Hz, 2H), 2.63–2.50 (m, 4H), 2.44 (s, 2H), 1.13 (s,
9H); MS (ESI) m/z: 493.6 (M+Na)+; HRMS (ESI): calcd for
C27H34NaO7 (M+Na)+ 493.2197, found: 493.2210.
4-Cyclopropanecarbonyloxy-arctigenin (3m): Yield 86%; colorless
gum; 1H NMR (400 MHz, CDCl3): d 6.94 (d, J = 8.0 Hz, 1H), 6.76 (d,
J = 8.1 Hz, 1H), 6.73 (d, J = 1.9 Hz, 1H), 6.65 (dd, J = 8.0, 1.9 Hz, 1H),
6.53 (dd, J = 8.1, 2.0 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 4.16 (dd, J = 9.1,
7.2 Hz, 1H), 3.89 (dd, J = 9.1, 7.6 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H),
3.76 (s, 3H), 3.01–2.92 (m, 2H), 2.67–2.46 (m, 4H), 1.89–1.83 (m,
1H), 1.18–1.14 (m, 2H), 1.04–0.99 (m, 2H); MS (ESI) m/z: 463.6
(M+Na)+; HRMS (ESI): calcd for C25H28NaO7 (M+Na)+ 463.1727,
found: 463.1740.
6.1.3. General procedure for synthesis of compounds 4a–s
Method A: To a stirred solution of arctigenin 1 (180 mg,
0.4 mmol) in 3 mL acetone were added K2CO3 (110 mg, 0.8 mmol)
and R0X (0.6 mmol) at room temperature. Then the mixture was
stirred at room temperature for 3 h. After completion of the reac-
tion, water (20 mL) was added, and the solution was extracted
with EtOAc (3 ꢁ 20 mL). The combined organic extracts were
washed with brine, dried, filtered, and concentrated under reduced
pressure. The crude product was purified by chromatography on
silica gel from (EtOAc/PE = 1/6) to afford the pure product 4a–d.
Method B: To a stirred solution of arctigenin 1 (180 mg,
0.4 mmol) in 3 mL DMF were added K2CO3 (110 mg, 0.8 mmol)
and R2(CH2)2OTs (0.6 mmol) at room temperature. Then the mix-
ture was stirred at 60 °C for 12 h. After completion of the reaction,
water (20 mL) was added, and the solution was extracted with
EtOAc (3 ꢁ 20 mL). The combined organic extracts were washed
with brine, dried, filtered, and concentrated under reduced pres-
sure. The crude product was purified by chromatography on silica
gel from (EtOAc/PE = 1/3) to afford the pure product 4e–s.
4-Ethoxy-arctigenin (4a): Yield 93%; colorless gum; 1H NMR
(300 MHz, CDCl3): d 6.76 (t, J = 7.8 Hz, 2H), 6.68 (d, J = 2.0 Hz,
1H), 6.63 (dd, J = 8.1, 2.0 Hz, 1H), 6.54 (dd, J = 8.1, 2.0 Hz, 1H),
6.48 (d, J = 2.0 Hz, 1H), 4.14–4.01 (m, 3H), 3.87 (dd, J = 6.4, 2.9 Hz,
1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.82 (s, 3H), 3.00–2.87 (m, 2H),
2.67–2.43 (m, 4H), 1.44 (t, J = 7.0 Hz, 4H); MS (ESI) m/z: 401.5
(M+H)+; HRMS (ESI): calcd for C23H29O6 (M+H)+ 401.1959, found:
401.1967.
4-Benzoyloxy-arctigenin (3n): Yield 96%; colorless gum; 1H NMR
(400 MHz, CDCl3): d 8.21–8.19 (m, 2H), 7.63 (dd, J = 10.5, 4.3 Hz,
1H), 7.51 (t, J = 7.7 Hz, 2H), 7.06 (d, J = 8.0 Hz, 1H), 6.80 (d,
J = 1.9 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.72 (dd, J = 8.0, 1.9 Hz,
1H), 6.56 (dd, J = 8.1, 1.9 Hz, 1H), 6.52 (d, J = 1.9 Hz, 1H), 4.19 (dd,
J = 9.1, 7.1 Hz, 1H), 3.92 (dd, J = 9.1, 7.5 Hz, 1H), 3.85 (s, 3H), 3.84
(s, 3H), 3.75 (s, 3H), 3.06–2.96 (m, 2H), 2.71–2.50 (m, 4H); MS
(ESI) m/z: 499.6 (M+Na)+; HRMS (ESI): calcd for C28H28NaO7
(M+Na)+ 499.1727, found: 499.1740.
4-Isopropoxy-arctigenin (4b): Yield 88%; colorless gum; 1H NMR
(300 MHz, CDCl3): d 6.79 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H),
6.67 (s, 1H), 6.62 (dd, J = 8.1, 1.8 Hz, 1H), 6.52 (d, J = 8.1 Hz, 1H),
6.48 (d, J = 1.6 Hz, 1H), 4.54–4.40 (m, 1H), 4.12–4.07 (m, 1H),
3.87–3.84 (m, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 2.99–
2.85 (m, 2H), 2.68–2.41 (m, 4H), 1.33 (s, 3H), 1.31 (s, 3H); MS
(ESI) m/z: 437.5 (M+Na)+; HRMS (ESI): calcd for C24H30NaO6
(M+Na)+ 437.1935, found: 437.1943.
4-(2-Methoxyethoxy)-arctigenin (4c): Yield 67%; colorless gum;
1H NMR (400 MHz, CDCl3): d 6.81 (d, J = 8.1 Hz, 1H), 6.74 (d,
J = 8.1 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 6.63 (dd, J = 8.1, 2.0 Hz,
1H), 6.53 (dd, J = 8.1, 2.0 Hz, 1H), 6.48 (d, J = 1.9 Hz, 1H), 4.13 (dd,
J = 5.6, 4.2 Hz, 2H), 4.14–4.12 (m, 1H), 3.87 (m, 1H), 3.85 (s, 3H),
3.82 (s, 3H), 3.80 (s, 3H), 3.76 (dd, J = 5.5, 4.3 Hz, 2H), 3.43 (s,
3H), 2.99–2.88 (m, 2H), 2.67–2.43 (m, 4H); MS (ESI) m/z: 431.6
(M+H)+; HRMS (ESI): calcd for C24H31O7 (M+H)+ 431.2064, found:
431.2070.
4-((3,4-Dimethoxybenzyl)oxy)-arctigenin (4d): Yield 73%; color-
less gum; 1H NMR (300 MHz, CDCl3): d 6.98 (s, 1H), 6.94 (d,
J = 8.1 Hz, 1H), 6.81 (dd, J = 8.2, 3.6 Hz, 2H), 6.74 (d, J = 8.2 Hz,
1H), 6.70 (s, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H),
6.48 (s, 1H), 5.04 (s, 2H), 4.10 (t, J = 8.1 Hz, 1H), 3.88 (m, 1H),
3.86 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H),
2.93 (m, 2H), 2.54 (m, 4H); MS (ESI) m/z: 545.6 (M+Na)+; HRMS
(ESI): calcd for C30H34NaO8 (M+Na)+ 545.2151, found: 545.2159.
4-(3,4-Dimethoxyphenethoxy)-arctigenin (4e): Yield 90%; color-
less gum; 1H NMR (400 MHz, CDCl3): d 6.86 (s, 1H), 6.82 (s, 2H),
6.75 (t, J = 7.8 Hz, 2H), 6.70 (d, J = 1.9 Hz, 1H), 6.63 (dd, J = 8.1,
1.9 Hz, 1H), 6.55 (dd, J = 8.1, 1.9 Hz, 1H), 6.49 (d, J = 1.9 Hz, 1H),
4.15 (t, J = 7.3 Hz, 2H), 4.11 (dd, J = 9.2, 7.0 Hz, 1H), 3.89–3.87 (m,
1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 3.81 (s,
3H), 3.09 (t, J = 7.4 Hz, 2H), 2.99–2.88 (m, 2H), 2.67–2.44 (m, 4H);
4-(4-Methoxybenzoyloxy)-arctigenin (3o): Yield 85%; colorless
gum; 1H NMR (300 MHz, CDCl3): d 8.15 (d, J = 9.0 Hz, 2H), 7.04
(d, J = 8.0 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 6.79 (s, 1H), 6.75 (d,
J = 8.0 Hz, 1H), 6.72 (d, J = 8.0, 1H), 6.55 (d, J = 8.0, 1H), 6.52 (s,
1H), 4.21–4.10 (m, 1H), 3.93–3.91 (m, 1H), 3.89 (s, 3H), 3.85 (s,
3H), 3.83 (s, 3H), 3.75 (s, 3H), 3.01–2.99 (m, 2H), 2.69–2.54 (m,
4H); MS (ESI) m/z: 529.6 (M+Na)+; HRMS (ESI): calcd for
C
29H30NaO8 (M+Na)+ 529.1833, found: 529.1850.
4-(4-Methylbenzoyloxy)-arctigenin (3p): Yield 77%; colorless
gum; 1H NMR (400 MHz, CDCl3): d 8.08 (d, J = 8.2 Hz, 2H), 7.30
(d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H), 6.77 (s,
1H), 6.72 (dd, J = 8.0, 1.9 Hz, 1H), 6.55 (dd, J = 8.1, 2.0 Hz, 1H),
6.52 (d, J = 2.0 Hz, 1H), 4.19 (dd, J = 9.1, 7.1 Hz, 1H), 3.91 (dd,
J = 9.1, 7.5 Hz, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.75 (s, 3H), 3.05–
2.96 (m, 2H), 2.70–2.50 (m, 4H), 2.45 (s, 3H); MS (ESI) m/z: 513.6
(M+Na)+; HRMS (ESI): calcd for C29H30NaO7 (M+Na)+ 513.1884,
found: 513.1904.
4-(4-Fluorobenzoyloxy)-arctigenin (3q): Yield 84%; colorless
gum; 1H NMR (400 MHz, CDCl3): d 8.23–8.19 (m, 2H), 7.20–7.18
(m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 1.9 Hz, 1H), 6.78 (d,
J = 8.1 Hz, 1H), 6.72 (dd, J = 8.0, 1.9 Hz, 1H), 6.56 (dd, J = 8.1,
1.9 Hz, 1H), 6.52 (d, J = 1.9 Hz, 1H), 4.19 (dd, J = 9.1, 7.2 Hz, 1H),
3.91 (dd, J = 9.1, 7.6 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.75 (s,
3H), 3.01 (d, J = 6.0 Hz, 2H), 2.71–2.50 (m, 4H); MS (ESI) m/z:
517.6 (M+Na)+; HRMS (ESI): calcd for C28H27FNaO7 (M+Na)+
517.1633, found: 517.1650.
4-(Furan-2-carbonyloxy)-arctigenin (3r): Yield 69%; colorless
gum; 1H NMR (300 MHz, CDCl3): d 7.66 (s, 1H), 7.37 (d, J = 3.0 Hz,
1H), 7.05 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H), 6.77 (d, J = 8.0 Hz, 1H),

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S. Shen et al. / Bioorg. Med. Chem. 21 (2013) 3882–3893
MS (ESI) m/z: 559.6 (M+Na)+; HRMS (ESI): calcd for C31H36NaO8
(M+Na)+ 559.2302, found: 559.2308.
7.21 (d, J = 8.4 Hz, 2H), 6.75 (dd, J = 9.3, 8.2 Hz, 2H), 6.69 (d,
J = 1.9 Hz, 1H), 6.63 (dd, J = 8.2, 1.9 Hz, 1H), 6.53 (dd, J = 8.1,
2.1 Hz, 1H), 6.48 (d, J = 1.9 Hz, 1H), 4.16 (t, J = 7.5 Hz, 2H), 4.11
(dd, J = 9.1, 7.1 Hz, 1H), 3.86 (m, 1H), 3.84 (s, 3H), 3.81 (s, 3H),
3.80 (s, 3H), 3.12 (t, J = 7.6 Hz, 2H), 2.98–2.88 (m, 2H), 2.65–2.47
(m, 4H), 1.31 (s, 9H); MS (ESI) m/z: 555.6 (M+Na)+; HRMS (ESI):
calcd for C33H40NaO6 (M+Na)+ 555.2717, found: 555.2725.
4-(4-Fluorophenethoxy)-arctigenin (4n): Yield 85%; colorless
gum; 1H NMR (300 MHz, CDCl3): d 7.24 (dd, J = 7.5, 5.4 Hz, 2H),
6.98 (t, J = 8.4 Hz, 1H), 6.74 (dd, J = 8.1, 1.4 Hz, 1H), 6.69 (s, 1H),
6.62 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 6.48 (s, 1H), 4.17–
4.08 (m, 3H), 3.87 (d, J = 7.4 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 6H),
3.10 (t, J = 7.2 Hz, 2H), 2.99–2.87 (m, 2H), 2.68–2.42 (m, 4H); MS
(ESI) m/z: 495.6 (M+H)+; HRMS (ESI): calcd for C29H32FO6 (M+H)+
495.2177, found: 495.2185.
4-(4-Chlorophenethoxy)-arctigenin (4o): Yield 80%; colorless
gum; 1H NMR (300 MHz, CDCl3): d 7.33 (d, J = 6.9 Hz, 2H), 7.26–
7.16 (m, 2H), 6.80 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.69
(s, 1H), 6.63 (d, J = 7.9 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.48 (s,
1H), 4.20 (t, J = 7.5 Hz, 2H), 4.09 (t, J = 6.3 Hz, 1H), 3.88–3.86 (m,
1H), 3.84 (s, 3H), 3.81 (s, 6H), 3.27 (t, J = 7.4 Hz, 2H), 2.99–2.87
(m, 2H), 2.68–2.41 (m, 4H); MS (ESI) m/z: 511.5 (M+H)+; HRMS
(ESI): calcd for C29H32ClO6 (M+H)+ 511.1882, found: 511.1889.
4-(2-Fluorophenethoxy)-arctigenin (4p): Yield 85%; colorless
gum; 1H NMR (300 MHz, CDCl3): d 7.31 (t, J = 7.3 Hz, 1H), 7.21 (t,
J = 5.8 Hz, 1H), 7.06 (m, 2H), 6.78 (d, J = 7.9 Hz, 1H), 6.74 (d,
J = 8.0 Hz, 1H), 6.69 (s, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.53 (d,
J = 8.1 Hz, 1H), 6.47 (s, 1H), 4.19 (t, J = 7.8 Hz, 2H), 4.10 (t,
J = 7.5 Hz, 1H), 3.87 (d, J = 7.9 Hz, 1H), 3.83 (s, 3H), 3.80 (s, 6H),
3.17 (t, J = 7.3 Hz, 2H), 2.93–2.87 (m, 2H), 2.68–2.43 (m, 4H); MS
(ESI) m/z: 495.6 (M+H)+; HRMS (ESI): calcd for C29H32FO6
(M+H)+: 495.2177, found: 495.2187.
4-(2-Chlorophenethoxy)-arctigenin (4q): Yield 83%; colorless
gum; 1H NMR (300 MHz, CDCl3): d 7.34–7.17 (m, 4H), 6.74 (d,
J = 8.1 Hz, 2H), 6.69 (d, J = 1.7 Hz, 1H), 6.62 (dd, J = 8.1, 1.8 Hz,
1H), 6.53 (d, J = 8.2 Hz, 1H), 6.48 (d, J = 1.7 Hz, 1H), 4.14 (t,
J = 7.1 Hz, 2H), 4.09 (d, J = 7.2 Hz, 1H), 3.87 (d, J = 7.2 Hz, 1H),
3.83 (s, 3H), 3.80 (s, 6H), 3.09 (t, J = 7.1 Hz, 2H), 2.99–2.86 (m,
2H), 2.65–2.42 (m, 4H); MS (ESI) m/z: 511.5 (M+H)+; HRMS (ESI):
calcd for C29H32ClO6 (M+H)+ 511.1882, found: 511.1889.
4-(3,4-Diethoxyphenethoxy)-arctigenin (4r): Yield 81%; colorless
gum; 1H NMR (300 MHz, CDCl3): d 6.84 (d, J = 1.8 Hz, 1H), 6.80 (s,
1H), 6.78 (d, J = 1.8 Hz, 1H), 6.76 (d, J = 4.9 Hz, 1H), 6.73 (d,
J = 4.8 Hz, 1H), 6.69 (d, J = 1.9 Hz, 1H), 6.62 (dd, J = 8.1, 2.0 Hz,
1H), 6.54 (dd, J = 8.1, 2.0 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 4.18–
4.00 (m, 8H), 3.90–3.85 (m, 1H), 3.84 (s, 4H), 3.81 (s, 3H), 3.80 (s,
3H), 3.06 (t, J = 7.4 Hz, 2H), 2.93 (m, 2H), 2.67–2.42 (m, 4H), 1.43
(td, J = 5.4, 3.0 Hz, 6H); MS (ESI) m/z: 587.6 (M+Na)+; HRMS (ESI):
calcd for C33H40NaO8 (M+Na)+ 587.2621, found: 587.2632.
4-(2-(Benzo[d][1,3]dioxol-5-yl)ethoxy)-arctigenin (4s): Yield 86%;
colorless gum; 1H NMR (300 MHz, CDCl3): d 6.79–6.73 (m, 5H),
6.69 (d, J = 2.1 Hz, 1H), 6.62 (dd, J = 8.2, 1.9 Hz, 1H), 6.53 (dd,
J = 8.2, 1.9 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 5.93 (s, 2H), 4.11–4.08
(m, 3H), 3.87–3.84 (m, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H),
3.05 (t, J = 7.3 Hz, 2H), 2.95–2.92 (m, 2H), 2.62–2.47 (m, 4H); MS
(ESI) m/z: 543.6 (M+Na)+; HRMS (ESI): calcd for C30H32NaO8
(M+Na)+ 543.1989, found: 543.1997.
4-(3,4-Dimethoxyphenyl)propoxy)-arctigenin (4f): Yield 83%; col-
orless gum; 1H NMR (300 MHz, CDCl3) d 6.79–6.70 (m, 6H), 6.68 (d,
J = 1.9 Hz, 1H), 6.62 (dd, J = 8.1, 1.9 Hz, 1H), 6.53 (dd, J = 8.1, 1.9 Hz,
1H), 6.48 (d, J = 1.9 Hz, 1H), 4.08 (dd, J = 9.3, 6.9 Hz, 1H), 3.96 (t,
J = 6.5 Hz, 2H), 3.86 (dd, J = 9.3, 6.9 Hz, 1H), 3.83 (s, 3H), 3.82 (s,
3H), 3.82 (s, 3H), 3.80 (s, 6H), 2.98–2.86 (m, 2H), 2.75 (t,
J = 7.6 Hz, 2H), 2.63–2.46 (m, 4H), 2.15–2.09 (m, 2H); MS (ESI) m/
z: 551.6 (M+H)+; HRMS (ESI): calcd for C32H39O8 (M+H)+
551.2645; found: 551.2656.
4-Phenethoxy-arctigenin (4g): Yield 89%; colorless gum; 1H NMR
(300 MHz, CDCl3): d 7.31–7.26 (m, 5H), 6.75 (t, J = 8.1 Hz, 2H), 6.69
(d, J = 2.0 Hz, 1H), 6.63 (dd, J = 8.0, 1.9 Hz, 1H), 6.53 (dd, J = 8.2,
1.9 Hz, 1H), 6.47 (d, J = 1.9 Hz, 1H), 4.18 (t, J = 7.6 Hz, 2H), 4.10
(dd, J = 9.3, 6.9 Hz,1H), 3.89–3.85 (m, 1H), 3.84 (s, 3H), 3.81 (s,
3H), 3.80 (s, 3H), 3.14 (t, J = 7.6 Hz, 2H), 3.00–2.87 (m, 2H), 2.67–
2.44 (m, 4H); MS (ESI) m/z: 499.6 (M+Na)+; HRMS (ESI): calcd for
C29H32NaO6 (M+Na)+ 499.2091, found: 499.2099.
4-(3-Methoxyphenethoxy)-arctigenin (4h): Yield 86%; colorless
gum; 1H NMR (300 MHz, CDCl3): d 7.22 (t, J = 8.0 Hz, 1H), 6.87–
6.84 (m, 2H), 6.78 (dd, J = 5.4, 2.7 Hz, 1H), 6.76 (t, J = 7.2 Hz, 2H),
6.69 (d, J = 2.0 Hz, 1H), 6.63 (dd, J = 8.1, 1.9 Hz, 1H), 6.54 (dd,
J = 8.1, 2.0 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 4.17 (t, J = 7.5 Hz, 1H),
4.11 (dd, J = 9.1, 6.9 Hz, 1H), 3.88–3.84 (m, 1H), 3.84 (s, 1H), 3.83
(s, 3H), 3.80 (s, 3H), 3.12 (t, J = 7.5 Hz, 2H), 2.99–2.88 (m, 2H),
2.65–2.47 (m, 4H); MS (ESI) m/z: 529.6 (M+Na)+; HRMS (ESI): calcd
for C30H34NaO7 (M+Na)+ 529.2197, found: 529.2204.
4-(4-Methoxyphenethoxy)-arctigenin (4i): Yield 84%; colorless
gum; 1H NMR (300 MHz, CDCl3): d 7.19 (d, J = 8.6 Hz, 2H), 6.85
(d, J = 8.7 Hz, 2H), 6.75 (dd, J = 8.0, 6.6 Hz, 2H), 6.69 (d, J = 1.9 Hz,
1H), 6.62 (dd, J = 8.1, 1.9 Hz, 1H), 6.53 (dd, J = 8.1, 1.9 Hz, 1H),
6.48 (d, J = 1.9 Hz, 1H), 4.14 (t, J = 7.7 Hz, 1H), 4.09 (d, J = 6.8 Hz,
1H), 3.86 (dd, J = 7.5, 4.2 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.80
(s, 3H), 3.78 (s, 3H), 3.08 (t, J = 7.5 Hz, 2H), 2.93–2.86 (m, 2H),
2.65–2.39 (m, 4H); MS (ESI) m/z: 507.6 (M+H)+; HRMS (ESI): calcd
for C30H35O7 (M+H)+ 507.2377, found: 507.2385.
4-(2-Methoxyphenethoxy)-arctigenin (4j): Yield 88%; colorless
gum; 1H NMR (300 MHz, CDCl3): d 7.22 (d, J = 7.2 Hz, 2H), 6.92–
6.82 (m, 3H), 6.74 (d, J = 8.1 Hz, 1H), 6.69 (d, J = 1.9 Hz, 1H), 6.64
(dd, J = 8.1, 1.9 Hz, 1H), 6.54 (dd, J = 8.1, 1.9 Hz, 1H), 6.48 (d,
J = 1.8 Hz, 1H), 4.17 (t, J = 7.8 Hz, 2H), 4.11 (dd, J = 9.1, 6.8 Hz,
1H), 3.88–3.86 (m, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H),
3.81 (s, 3H), 3.16 (t, J = 8.1 Hz, 2H), 3.00–2.88 (m, 2H), 2.65–2.48
(m, 4H); MS (ESI) m/z: 529.6 (M+Na)+; HRMS (ESI): calcd for
C
30H34NaO7 (M+Na)+ 529.2197, found: 529.2204.
3-(4-(3,5-Dimethoxyphenethoxy)-arctigenin (4k): Yield 91%; col-
orless gum; 1H NMR (400 MHz, CDCl3): d 6.76 (t, J = 8.4 Hz, 2H),
6.70 (d, J = 2.0 Hz, 1H), 6.63 (dd, J = 8.1, 2.0 Hz, 1H), 6.54 (dd,
J = 8.1, 2.0 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 6.45 (d, J = 2.3 Hz, 2H),
6.34 (t, J = 2.3 Hz, 1H), 4.17 (t, J = 7.5 Hz, 2H), 4.11 (dd, J = 9.0,
7.0 Hz, 1H), 3.87 (dd, J = 9.0, 7.0 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H),
3.81 (s, 3H), 3.78 (s, 6H), 3.08 (t, J = 7.4 Hz, 2H), 2.98–2.89 (m,
2H), 2.68–2.43 (m, 4H); MS (ESI) m/z: 537.6 (M+H)+; HRMS (ESI):
calcd for C31H37O8 (M+H)+ 537.2483, found: 537.2490.
4-(3,4,5-Trimethoxyphenethoxy)-arctigenin (4l): Yield 87%; color-
less gum; 1H NMR (300 MHz, CDCl3): d 6.75 (dd, J = 8.0, 6.0 Hz, 2H),
6.69 (d, J = 1.7 Hz, 1H), 6.63 (dd, J = 8.4, 1.5 Hz, 1H), 6.55 (dd, J = 8.4,
1.2 Hz, 1H), 6.52 (s, 2H), 6.48 (d, J = 1.7 Hz, 1H), 4.16 (t, J = 7.1 Hz,
2H), 4.09 (ddd, J = 9, 7.2, 1.8 Hz, 1H), 3.86–3.84 (m, 1H), 3.84 (s,
6H), 3.83 (s, 3H), 3.81 (s, 3H), 3.80 (s, 6H), 3.06 (t, J = 7.1 Hz, 2H),
2.98–2.86 (m, 2H), 2.68–2.42 (m, 4H); MS (ESI): m/z 567.6
(M+H)+; HRMS (ESI): calcd for C32H39O9 (M+H)+ 567.2589, found:
567.2595.
6.1.4. General procedure for synthesis of compounds 5a–k
To
a stirred solution of 9-deoxy-arctigenin 2 (140 mg,
0.4 mmol) and TEA (0.11 mL, 0.8 mmol) in 3 mL CH2Cl2 was added
R3COCl (0.6 mmol) at 0 °C slowly. Then the mixture was stirred at
0 °C for 1 h. After completion of the reaction, water (20 mL) was
added, and the solution was extracted with CH2Cl2 (3 ꢁ 20 mL).
The combined organic extracts were washed with brine, dried, fil-
tered, and concentrated under reduced pressure. The crude
4-(4-(Tert-butyl)phenethoxy)-arctigenin (4m): Yield 83%; color-
less gum; 1H NMR (300 MHz, CDCl3): d 7.34 (d, J = 8.5 Hz, 2H),

S. Shen et al. / Bioorg. Med. Chem. 21 (2013) 3882–3893
3891
product was purified by chromatography on silica gel from (EtOAc/
PE = 1/2) to afford the pure product 5a–k.
2.26–2.19 (m, 2H); MS (ESI) m/z: 475.6 (M+Na)+; HRMS (ESI): calcd
for C26H28NaO7 (M+Na)+ 475.1727, found: 475.1739.
4-Acetoxy-9-deoxy-arctigenin (5a): Yield 86%; colorless gum; 1H
NMR (400 MHz, CDCl3): d 6.91 (d, J = 7.9 Hz, 1H), 6.77 (d, J = 8.1 Hz,
1H), 6.67–6.60 (m, 4H), 3.92 (ddd, J = 8.6, 6.6, 0.9 Hz, 2H), 3.85 (s,
3H), 3.85 (s, 3H), 3.78 (s, 3H), 3.54 (dd, J = 8.7, 5.9 Hz, 2H), 2.67–
2.53 (m, 4H), 2.30 (s, 3H), 2.24–2.17 (m, 2H); MS (ESI) m/z: 423.6
(M+Na)+; HRMS (ESI): calcd for C23H28NaO6 (M+Na)+ 423.1778,
found: 423.1795.
4-Butyryloxy-9-deoxy-arctigenin (5b): Yield 86%; colorless gum;
1H NMR (400 MHz, CDCl3): d 6.93 (d, J = 7.8 Hz, 1H), 6.79 (d,
J = 8.0 Hz, 1H), 6.69–6.62 (m, 4H), 3.94 (ddd, J = 8.7, 6.5, 0.6 Hz,
2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.79 (s, 3H), 3.56 (dd, J = 8.7,
5.8 Hz, 2H), 2.69–2.55 (m, 6H), 2.26–2.20 (m, 2H), 1.81 (dd,
J = 14.8, 7.4 Hz, 2H), 1.07 (t, J = 7.4 Hz, 3H); MS (ESI) m/z: 451.6
(M+Na)+; HRMS (ESI): calcd for C25H32NaO6 (M+Na)+ 451.2091,
found: 451.2106.
4-(3-Methylbutanoyloxy)-9-deoxy-arctigenin (5c): Yield 76%; col-
orless gum; 1H NMR (400 MHz, CDCl3): d 6.90 (d, J = 7.9 Hz, 1H),
6.77 (d, J = 8.0 Hz, 1H), 6.63 (m, 4H), 3.92 (dd, J = 8.4, 6.8 Hz, 2H),
3.85 (s, 3H), 3.84 (s, 3H), 3.76 (s, 3H), 3.54 (dd, J = 8.7, 5.7 Hz,
2H), 2.82 (dt, J = 13.9, 6.9 Hz, 1H), 2.60 (m, 4H), 2.20 (m, 2H),
1.61 (s, 2H), 1.31 (d, J = 7.0 Hz, 6H); MS (ESI) m/z: 465.6 (M+Na)+;
HRMS (ESI): calcd for C26H34NaO6 (M+Na)+ 465.2248, found:
465.2260.
4-Cyclohexanecarbonyloxy-9-deoxy-arctigenin (5d): Yield 83%;
colorless gum; 1H NMR (400 MHz, CDCl3): d 6.89 (d, J = 7.9 Hz,
1H), 6.77 (d, J = 8.0 Hz, 1H), 6.66–6.60 (m, 4H), 3.92 (t, J = 7.6 Hz,
2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.75 (s, 3H), 3.53 (dd, J = 8.7,
5.6 Hz, 2H), 2.67–2.53 (m, 5H), 2.23–2.17 (m, 2H), 2.08–2.04 (m,
2H), 1.83–1.79 (m, 2H), 1.69–1.61 (m, 3H), 1.40–1.26 (m, 3H);
MS (ESI) m/z: 491.6 (M+Na)+; HRMS (ESI): calcd for C28H36NaO6
(M+Na)+ 491.2404, found: 491.2420.
4-(4-Methoxybenzoyloxy)-9-deoxy-arctigenin (5e): Yield 85%;
colorless gum; 1H NMR (400 MHz, CDCl3): d 8.15 (d, J = 9.0 Hz,
2H), 7.02 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.78 (d,
J = 8.1 Hz, 1H), 6.73–6.67 (m, 2H), 6.66–6.60 (m, 2H), 3.97–3.90
(m, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.86 (s, 3H), 3.60–3.52 (m, 2H),
2.72–2.54 (m, 4H), 2.27–2.18 (m, 2H); MS (ESI) m/z: 515.6
(M+Na)+; HRMS (ESI): calcd for C29H32NaO7 (M+Na)+ 515.2204,
found: 515.2220.
4-(4-Fluorobenzoyloxy-9-deoxy-arctigenin (5f): Yield 77%; color-
less gum; 1H NMR (400 MHz, CDCl3): d 8.24–8.19 (m, 2H), 7.26–
7.15 (m, 2H), 7.03 (d, J = 7.9 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H),
6.72–6.69 (m, 2H), 6.66–6.62 (m, 2H), 3.94 (ddd, J = 8.2, 6.6,
1.2 Hz, 2H), 3.86 (s, 3H), 3.86 (s, 3H), 3.77 (s, 3H), 3.58–3.53 (m,
2H), 2.72–2.55 (m, 4H), 2.26–2.07 (m, 2H); MS (ESI) m/z: 503.6
(M+Na)+; HRMS (ESI): calcd for C28H29FNaO6 (M+Na)+ 503.1840,
found: 503.1853.
4-Nicotinoyloxy-9-deoxy-arctigenin (5g): Yield 59%; colorless
gum; 1H NMR (400 MHz, CDCl3): d 9.40 (dd, J = 2.2, 0.8 Hz, 1H),
8.85 (dd, J = 4.9, 1.7 Hz, 1H), 8.47–8.44 (m, 1H), 7.47 (ddd, J = 8.0,
4.9, 0.9 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H),
6.73 (dd, J = 8.0, 1.9 Hz, 1H), 6.70 (d, J = 1.8 Hz, 1H), 6.65 (dd,
J = 8.0, 2.0 Hz, 1H), 6.63 (d, J = 1.9 Hz, 1H), 3.95 (dd, J = 8.7,
6.6 Hz, 2H), 3.86 (s, 3H), 3.86 (s, 3H), 3.78 (s, 3H), 3.59–3.54 (m,
2H), 2.73–2.56 (m, 4H), 2.27–2.20 (m, 2H); MS (ESI) m/z: 464.6
(M+H)+; HRMS (ESI): calcd for C27H30NO6 (M+H)+ 464.2068, found:
464.2080.
4-(Furan-2-carbonyloxy)-9-deoxy-arctigenin (5h): Yield 73%; col-
orless gum; 1H NMR (400 MHz, CDCl3): d 7.67 (dd, J = 1.7, 0.8 Hz,
1H), 7.38 (dd, J = 3.5, 0.7 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 6.78 (d,
J = 8.0 Hz, 1H), 6.71–6.68 (m, 2H), 6.64–6.61 (m, 2H), 6.59 (dd,
J = 3.5, 1.7 Hz, 1H), 3.94 (ddd, J = 8.6, 6.6, 2.0 Hz, 2H), 3.85 (s, 6H),
3.77 (s, 3H), 3.55 (ddd, J = 8.7, 5.8, 2.7 Hz, 2H), 2.71–2.54 (m, 4H),
4-(3-Methoxybenzoyloxy)-9-deoxy-arctignin (5i): Yield 93%; col-
orless gum; 1H NMR (400 MHz, CDCl3): d 7.81 (dt, J = 8.0, 1.2 Hz,
1H), 7.70 (dd, J = 2.6, 1.5 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.17
(ddd, J = 8.3, 2.7, 0.9 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 6.78 (d,
J = 8.1 Hz, 1H), 6.73–6.69 (m, 2H), 6.65–6.61 (m, 2H), 3.96–3.92
(m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.86 (s, 3H), 3.77 (s, 3H), 3.58–
3.53 (m, 2H), 2.73–2.55 (m, 4H), 2.28–2.18 (m, 2H); MS (ESI) m/
z: 515.6 (M+Na)+; HRMS (ESI): calcd for C29H32NaO7 (M+Na)+
515.2204, found: 515.2220.
4-(3,4-Dimethoxybenzoyloxy)-9-deoxy-arctignin (5j): Yield 89%;
colorless gum; 1H NMR (400 MHz, CDCl3): d 7.87 (dd, J = 8.4,
2.0 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 6.95
(d, J = 8.5 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.73–6.70 (m, 2H),
6.66–6.62 (m, 2H), 3.97 (s, 3H), 3.96 (s, 3H), 3.95–3.92 (m, 2H),
3.86 (s, 3H), 3.86 (s, 3H), 3.77 (s, 3H), 3.56 (ddd, J = 8.9, 5.8,
4.3 Hz, 2H), 2.73–2.54 (m, 4H), 2.27–2.18 (m, 2H); MS (ESI) m/z:
545.6 (M+Na)+; HRMS (ESI): calcd for C30H34NaO8 (M+Na)+
545.2146, found: 545.2146.
4-(2-(3,4-Dimethoxyphenyl)acetyloxy))-9-deoxy-arctignin (5k):
Yield 77%; colorless gum; 1H NMR (400 MHz, CDCl3): d 6.95–6.83
(m, 4H), 6.76 (d, J = 7.9 Hz, 1H), 6.65–6.59 (m, 4H), 3.97–3.90 (m,
2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.82 (s,
2H), 3.72 (s, 3H), 3.53 (ddd, J = 9.7, 5.8, 3.9 Hz, 2H), 2.71–2.49 (m,
4H), 2.25–2.14 (m, 2H); MS (ESI) m/z: 559.6 (M+Na)+; HRMS
(ESI): calcd for C31H36NaO8 (M+Na)+ 559.2302, found: 559.2315.
6.1.5. General procedure for synthesis of compounds 6a–l
Method A: To a stirred solution of 9-deoxy-arctigenin 2 (140 mg,
0.4 mmol) in 3 mL DMF were added K2CO3 (0.8 mmol) and
R4(CH2)2OTs (0.6 mmol) at room temperature. Then the mixture
was stirred at 60 °C for 12 h. After completion of the reaction,
water (20 mL) was added, and the solution was extracted with
EtOAc (3 ꢁ 20 mL). The combined organic extracts were washed
with brine, dried, filtered, and concentrated under reduced pres-
sure. The crude product was purified by chromatography on silica
gel from (EtOAc/PE = 1/2) to afford the pure product 6a–k.
Method B: To a stirred solution of 9-deoxy-arctigenin 2 (140 mg,
0.4 mmol) in 3 mL acetone were added K2CO3 (110 mg, 0.8 mmol)
and R4COCH2X (0.6 mmol) at room temperature. Then the mixture
was stirred at room temperature for 3 h. After completion of the
reaction, water (20 mL) was added, and the solution was extracted
with EtOAc (3 ꢁ 20 mL). The combined organic extracts were
washed with brine, dried, filtered, and concentrated under reduced
pressure. The crude product was purified by chromatography on
silica gel from (EtOAc/PE = 1/6) to afford the pure product 6l.
4-(3-Methoxyphenethoxy)-9-deoxy-arctigenin (6a): Yield 90%;
colorless gum; 1H NMR (300 MHz, CDCl3): d 7.21 (t, J = 7.4 Hz,
1H), 6.86 (d, J = 7.3 Hz, 2H), 6.79–6.74 (m, 3H), 6.64–6.60 (m,
4H), 4.18 (t, J = 7.5 Hz, 2H), 3.90 (dd, J = 8.7, 6.6 Hz, 2H), 3.84 (s,
3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.52 (dd, J = 8.6,
6.0 Hz, 3H), 3.11 (t, J = 7.5 Hz, 2H), 2.63 (dd, J = 13.7, 5.9 Hz, 2H),
2.52 (dd, J = 13.6, 8.1 Hz, 2H), 2.26–2.09 (m, 2H); MS (ESI) m/z:
515.6 (M+Na)+; HRMS (ESI): calcd for C30H36NaO6 (M+Na)+
515.2404, found: 515.2410.
4-(4-Methoxyphenethoxy)-9-deoxy-arctigenin (6b): Yield 88%;
colorless gum; 1H NMR (400 MHz, CDCl3): d 7.20 (d, J = 8.7 Hz,
2H), 6.85 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.3 Hz, 2H), 6.65–6.57 (m,
4H), 4.14 (t, J = 7.6 Hz, 2H), 3.90 (dd, J = 8.6, 6.6 Hz, 2H), 3.85 (s,
3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.79 (s, 3H), 3.57–3.48 (m, 2H),
3.08 (t, J = 7.6 Hz, 2H), 2.63 (dd, J = 13.6, 5.7 Hz, 2H), 2.52 (dd,
J = 13.8, 8.2 Hz, 2H), 2.22–2.17 (m, 2H); MS (ESI) m/z: 515.6
(M+Na)+; HRMS (ESI): calcd for C30H36NaO6 (M+Na)+ 515.2404,
found: 515.2410.

3892
S. Shen et al. / Bioorg. Med. Chem. 21 (2013) 3882–3893
4-(3,4-Dimethoxyphenethoxy)-9-deoxy-arctigenin (6c): Yield
(s, 3H), 3.52 (ddd, J = 8.4, 6.0, 2.1 Hz, 2H), 3.28 (t, J = 7.2 Hz, 2H),
2.65–2.59 (m, 4H), 2.57–2.47 (m, 2H), 2.23–2.12 (m, 2H), 1.24 (t,
J = 7.6 Hz, 3H); MS (ESI) m/z: 491.6 (M+Na)+; HRMS (ESI): calcd
for C30H37NNaO5 (M+Na)+ 491.2564, found: 491.2577.
92%; colorless gum; 1H NMR (300 MHz, CDCl3): d 6.85 (s, 1H),
6.82 (s, 1H), 6.81 (s, 1H), 6.77 (s, 1H), 6.74 (s, 1H), 6.64 (d,
J = 2.0 Hz, 1H), 6.61–6.58 (m, 3H), 4.15 (t, J = 7.3 Hz, 2H), 3.90
(dd, J = 8.7, 6.0 Hz, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H),
3.83 (s, 3H), 3.82 (s, 3H), 3.51 (dd, J = 8.4, 5.4 Hz, 2H), 3.08 (t,
J = 7.3 Hz, 2H), 2.63 (dd, J = 13.6, 5.9 Hz, 2H), 2.52 (dd, J = 13.0,
7.7 Hz, 2H), 2.24–2.11 (m, 2H); MS (ESI) m/z: 545.6 (M+Na)+; HRMS
(ESI): calcd for C31H38NaO7 (M+Na)+ 545.2510, found: 545.2519.
4-(3,4,5-Trimethoxyphenethoxy)-9-deoxy-arctigenin (6d): Yield
4-(3-(3,4-Dimethoxyphenyl)propoxy)-9-deoxy-arctigenin
(6k):
Yield 82%; colorless gum; 1H NMR (400 MHz, CDCl3): d 6.80–6.72
(m, 5H), 6.68–6.56 (m, 4H), 3.98 (t, J = 6.5 Hz, 2H), 3.92–3.88 (m,
2H), 3.85 (s, 6H), 3.84 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 3.52 (dd,
J = 8.6, 5.9 Hz, 2H), 2.83–2.72 (m, 2H), 2.71–2.60 (m, 2H), 2.59–
2.46 (m, 2H), 2.26–2.07 (m, 4H); MS (ESI) m/z: 559.9 (M+Na)+;
HRMS (ESI): calcd for C32H40NaO7 (M+Na)+ 559.2666, found:
515.2671.
84%; colorless gum; 1H NMR (400 MHz, CDCl3):
d 6.76 (d,
J = 8.4 Hz, 2H), 6.66–6.59 (m, 4H), 6.67–6.55 (m, 5H), 6.53 (s, 2H),
4.17 (t, J = 7.2 Hz, 2H), 3.90 (ddd, J = 9.1, 6.6, 2.8 Hz, 2H), 3.85 (s,
6H), 3.84 (s, 3H), 3.83 (s, 3H), 3.82 (s, 6H), 3.52 (dd, J = 8.7, 5.0 Hz,
2H), 3.08 (t, J = 7.2 Hz, 2H), 2.64 (dd, J = 13.7, 4.7 Hz, 2H), 2.56–
2.46 (m, 2H), 2.22–2.16 (m, 2H); MS (ESI) m/z: 575.6 (M+Na)+; HRMS
(ESI): calcd for C32H40NaO8 (M+Na)+ 575.2615, found: 515.2623.
4-(3,5-Dimethoxyphenethoxy)-9-deoxy-arctigenin (6e): Yield
4-(1-(3,4-Dimethoxyphenyl)ethoxy-1-one)-9-deoxy-arctigenin
(6l): Yield 78%; colorless gum; 1H NMR (400 MHz, CDCl3): d 7.67 (dd,
J = 8.3, 1.9 Hz, 1H), 7.59 (d, J = 1.8 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H),
6.76 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 6.63–6.55 (m, 4H),
5.27 (s, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.90–3.88 (m, 2H), 3.85 (s,
3H), 3.84 (s, 3H), 3.84 (s, 3H), 3.52 (ddd, J = 8.7, 5.3, 3.3 Hz, 2H),
2.62 (ddd, J = 13.6, 5.8, 3.1 Hz, 2H), 2.57–2.45 (m, 2H), 2.18 (td,
J = 11.4, 6.6 Hz, 2H); MS (ESI) m/z: 559.6 (M+Na)+; HRMS (ESI): calcd
for C31H36NaO8 (M+Na)+ 559.2302, found: 559.2309.
87%; colorless gum; 1H NMR (400 MHz, CDCl3):
d 6.76 (d,
J = 8.0 Hz, 2H), 6.64–6.59 (m, 4H), 6.45 (d, J = 2.3 Hz, 2H), 6.34 (t,
J = 2.3 Hz, 1H), 4.17 (t, J = 7.5 Hz, 2H), 3.90 (dd, J = 8.7, 6.6 Hz,
2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 3.78 (s, 6H), 3.52 (ddd,
J = 8.5, 6.1, 1.4 Hz, 2H), 3.08 (t, J = 7.5 Hz, 2H), 2.63 (dd, J = 13.6,
5.3 Hz, 2H), 2.52 (dd, J = 12.8, 7.7 Hz, 2H), 2.22–2.14 (m, 2H); MS
(ESI) m/z: 545.6 (M+Na)+; HRMS (ESI): calcd for C31H38NaO7
(M+Na)+ 545.2510, found: 545.2517.
4-(4-Fluorophenethoxy)-9-deoxy-arctigenin (6f): Yield 85%; col-
orless gum; 1H NMR (400 MHz, CDCl3): d 7.24–7.20 (m, 2H),
7.04–6.95 (m, 2H), 6.76 (d, J = 4.6 Hz, 1H), 6.74 (d, J = 5.1 Hz, 1H),
6.66–6.56 (m, 4H), 4.15 (t, J = 7.3 Hz, 2H), 3.93–3.87 (m, 2H), 3.85
(s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.52 (ddd, J = 8.4, 6.1, 1.9 Hz,
2H), 3.10 (t, J = 7.3 Hz, 2H), 2.63 (dd, J = 13.6, 5.5 Hz, 2H), 2.52
(ddd, J = 13.8, 8.4, 2.7 Hz, 2H), 2.25–2.12 (m, 2H); MS (ESI) m/z:
503.7 (M+Na)+; HRMS (ESI): calcd for C29H33FNaO5 (M+Na)+
503.2204, found: 503.2212.
4-(3,4-Difluorophenethoxy)-9-deoxy-arctigenin (6g): Yield 67%;
colorless gum; 1H NMR (400 MHz, CDCl3): d 7.20–6.97 (m, 3H),
6.77 (t, J = 8.5 Hz, 2H), 6.65 (dd, J = 8.1, 1.9 Hz, 4H), 6.63–6.61 (m,
3H), 4.18 (t, J = 7.0 Hz, 2H), 3.92 (ddd, J = 9.1, 6.6, 2.6 Hz, 2H),
3.87 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.54 (ddd, J = 8.7, 6.1,
2.2 Hz, 2H), 3.10 (t, J = 6.9 Hz, 2H), 2.66 (dd, J = 13.3, 5.4 Hz, 2H),
2.55 (ddd, J = 13.5, 8.4, 4.7 Hz, 2H), 2.26–2.16 (m, 2H); MS (ESI)
m/z: 521.6 (M+Na)+; HRMS (ESI): calcd for C29H32F2NaO8 (M+Na)+
521.2110, found: 521.2118.
4-(4-Chlorophenethoxy)-9-deoxy-arctigenin (6h): Yield 88%; col-
orless gum; 1H NMR (400 MHz, CDCl3): d 7.27 (d, J = 8.8 Hz, 2H),
7.22 (d, J = 8.3 Hz, 2H), 6.79–6.70 (m, 2H), 6.64 –6.59 (m, 4H),
4.15 (t, J = 7.2 Hz, 2H), 3.90 (t, J = 7.0 Hz, 2H), 3.85 (s, 3H), 3.83 (s,
3H), 3.81 (s, 3H), 3.55–3.48 (m, 2H), 3.10 (t, J = 7.2 Hz, 2H), 2.63
(dd, J = 13.5, 5.7 Hz, 2H), 2.57–2.47 (m, 2H), 2.23–2.14 (m, 2H);
MS (ESI) m/z: 519.7 (M+Na)+; HRMS (ESI): calcd for C29H33ClNaO5
(M+Na)+ 519.1909, found: 519.1915.
6.2. Biological evolution materials and methods
6.2.1. Materials
Cell culture plastic ware was purchased from Corning Inc.
DMEM, fetal bovine, and horse serum was purchased from Invitro-
gen. Anti-phospho-AMPK and anti-AMPK antibodies were pur-
chased from Cell Signaling Technology. L6 cells were obtained
from ATCC.
6.2.2. Cell culture
L6 cell line was maintained in DMEM supplemented with 10%
fetal bovine serum and the cells were grown at 37 °C in an environ-
ment of 5% CO2. L6 cell line was differentiated in DMEM with 2%
horse serum after 90% confluent to form contractile myotubes
and express characteristic muscle proteins.
6.2.3. Western blot analysis
Cells were plated in 12-well plates and lysed with lysis buffer
containing 25 mmol/L Tris–HCl (PH = 7.5), 150 mmol/L NaCl,
1 mmol/L Na3VO4, 1% Triton X-100 and a protease inhibitor cock-
tail. Equal amounts of cell lysates were fractionated by SDS–PAGE
and transferred to Hybond-c nitrocellulose membrane (Amersham
Bioscience). The proteins were detected with corresponding anti-
bodies and visualized by incubation with SuperSignal West Dura
chemiluminescence kit (Pierce Biotechnology).
The bands were quantified as ‘intensity ꢁ area’ using Quantity
One software (Bio-Rad) and statistically analyzed. SD was calcu-
lated from three repeats of the experiments.
Acknowledgments
4-(2-(Pyridin-3-yl)-ethoxy)-9-deoxy-arctigenin (6i): Yield 63%;
yellow gum; 1H NMR (400 MHz, CDCl3): d 8.54 (d, J = 4.9 Hz, 1H),
7.61 (t, J = 7.8 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.14 (t, J = 6.0 Hz,
1H), 6.82 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.65–6.55 (m,
4H), 4.38 (t, J = 7.1 Hz, 2H), 3.90 (t, J = 7.8 Hz, 2H), 3.84 (s, 3H),
3.83 (s, 3H), 3.79 (s, 3H), 3.52 (t, J = 6.8 Hz, 2H), 3.31 (t, J = 7.0 Hz,
2H), 2.63 (dd, J = 13.6, 5.1 Hz, 2H), 2.52 (dd, J = 13.2, 8.3 Hz, 2H),
2.24–2.11 (m, 2H); MS (ESI) m/z: 486.6 (M+Na)+; HRMS (ESI): calcd
for C28H33NNaO5 (M+Na)+ 486.2251, found: 486.2258.
This work was supported by the National Natural Science Foun-
dation of China (Grants 30925040, 81102329, 81273430), the Chi-
nese National Science & Technology Major Project ‘Key New Drug
Creation and Manufacturing Program’ (Grants 2013ZX09508104,
2012ZX09301001-001, 2011ZX09307-002-03), the Science Foun-
dation of Shanghai (Grant 12XD14057), and the State Key Labora-
tory of Natural and Biomimetic Drugs (Grant K20120220).
4-(2-(5-Ethylpyridin-3-yl)ethoxy)-9-deoxy-arctigenin (6j): Yield
55%; yellow gum; 1H NMR (400 MHz, CDCl3): d 8.39 (s, 1H), 7.44
(dd, J = 7.9, 2.4 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.82 (d, J = 8.0 Hz,
1H), 6.75 (d, J = 8.1 Hz, 1H), 6.64–6.56 (m, 4H), 4.36 (t, J = 7.1 Hz,
2H), 3.90 (dd, J = 8.7, 6.6 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.80
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2013.04.010.

S. Shen et al. / Bioorg. Med. Chem. 21 (2013) 3882–3893
3893
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