Design and synthesis of novel arctigenin analogues for the amelioration of metabolic disorders

Article abstract of DOI:10.1021/acsmedchemlett.5b00007

Analogues of the natural product (-)-arctigenin, an activator of adenosine monophosphate activated protein kinase, were prepared in order to evaluate their effects on 2-deoxyglucose uptake in L6 myotubes and possible use in ameliorating metabolic disorders. Racemic arctigenin 2a was found to display a similar uptake enhancement as does (-)-arctigenin. As a result, the SAR study was conducted utilizing racemic compounds. The structure-activity relationship study led to the discovery of key substitution patterns on the lactone motif that govern 2-deoxyglucose uptake activities. The results show that replacement of the para-hydroxyl group of the C-2 benzyl moiety of arctigenin by Cl has a pronounced effect on uptake activity. Specifically, analogue 2p, which contains the p-Cl substituent, stimulates glucose uptake and fatty acid oxidation in L6 myotubes.

Full text of DOI:10.1021/acsmedchemlett.5b00007

Letter
pubs.acs.org/acsmedchemlett
Design and Synthesis of Novel Arctigenin Analogues for the
Amelioration of Metabolic Disorders
Shudong Duan,†,§ Suling Huang,†,§ Jian Gong,† Yu Shen,† Limin Zeng,† Ying Feng,† Wenming Ren,†
Ying Leng,*,† and Youhong Hu*,†,‡
†State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi
Road, Shanghai 201203, China
‡ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of
Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
S
* Supporting Information
ABSTRACT: Analogues of the natural product (−)-arctige-
nin, an activator of adenosine monophosphate activated
protein kinase, were prepared in order to evaluate their effects
on 2-deoxyglucose uptake in L6 myotubes and possible use in
ameliorating metabolic disorders. Racemic arctigenin 2a was
found to display a similar uptake enhancement as does
(−)-arctigenin. As a result, the SAR study was conducted
utilizing racemic compounds. The structure−activity relationship study led to the discovery of key substitution patterns on the
lactone motif that govern 2-deoxyglucose uptake activities. The results show that replacement of the para-hydroxyl group of the
C-2 benzyl moiety of arctigenin by Cl has a pronounced effect on uptake activity. Specifically, analogue 2p, which contains the p-
Cl substituent, stimulates glucose uptake and fatty acid oxidation in L6 myotubes.
KEYWORDS: Natural product, arctigenin analogues, 2-deoxyglucose uptake in L6 myotubes, amelioration of metabolic disorders
through inhibition of mitochondria complex I.8,9 AMPK is a
ype 2 diabetes is a metabolic disorder characterized by
Thigh blood glucose levels in the context of insulin
major regulator of energy homeostasis, and pharmacological
activation of AMPK improves glucose and lipid metabolism in
resistance and impaired insulin secretion.1,2 Because it is the
insulin-resistant state. Taking together the pleiotropic beneficial
functions of AMPK, targeting AMPK appears as a promising
tool for treating metabolic disorder and diabetes.10 Other
investigations have shown that arctigenin and its derivatives
have antitumor,11 anti-HIV,12,13 anti-inflammation14 activities,
and AMPK activating effects.15,16 However, only limited
systematic SAR studies of the lactone scaffold of this natural
product have been carried out thus far.11−13,15 Below, we
describe the design and synthesis of a series of novel arctigenin
analogues and the results of a structure−activity relationship
(SAR) investigation, which has led to the identification of a
substance possessing the lactone motif that is a potent
promoter of 2-deoxyglucose uptake in L6 myotubes.
The general procedure employed for the synthesis of the
arctigenin analogues is shown in Scheme 1.17,18 The routes
begin with condensation of a substituted benzaldehyde 3 with
dimethyl succinate to afford 4, which undergoes hydrogenation
to give 5. The acid 5 is then transformed to its potassium salt 6,
which is selectively reduced using NaBH4 giving γ-hydoxyacid
that cyclizes to generate the lactone intermediate 7. Treatment
of 7 with LDA at −78 °C followed by reaction of the resulting
main target tissue of insulin action, skeletal muscle plays an
important role in the regulation of glucose metabolism,
accounting for 80% of whole-body glucose disposal under
insulin stimulation.3 Observations made in a number of studies
indicate that reducing glucose uptake in skeletal muscle results
in type 2 diabetes and a related metabolic syndrome.4−6 Thus,
therapies that regulate glucose uptake are promising strategies
for the treatment of metabolic disorders.
Natural products are important sources for lead substances in
drug discovery.7 In a recent effort, we screened an in house
library of natural products and natural product-like substances
for their ability to increase 2-deoxyglucose uptake in L6
myotubes. This study led to the identification of the dibenzyl-γ-
lactone, (−)-arctigenin (1, Figure 1), as a potent indirect
activator of adenosine monophosphate-activated protein kinase
(AMPK) in the regulation of glucose and lipid homeostasis,
Received: October 27, 2014
Accepted: March 1, 2015
Published: March 5, 2015
Figure 1. Structure of (−)-arctigenin.
© 2015 American Chemical Society
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Letter
a
a
Scheme 1. Synthesis of Arctigenin Analogues 2a−2u
Scheme 2. Synthesis of Arctigenin Analogues 10 and 13
a
Reagents and conditions: (a) dimethyl succinate, t-BuOK, t-BuOH,
25 °C. (b) H2, palladium 10% on carbon, MeOH, 25 °C. (c) t-BuOK,
EtOH, 25 °C. (d) (1) NaBH4, CaCl2, EtOH, −10 °C to −78 °C; (2)
conc. HCl, 80 °C. (e) LDA, THF, −78 to 25 °C. (f) H2, palladium
10% on carbon, MeOH, 25 °C. (g) Fe, CH3COOH, EtOH, 80 °C.
a
Reagents and conditions: (a) LiAlH4, THF, 70 °C. (b) PTSA, DCM,
40 °C. (c) (1) n-BuLi, cyclopent-2-enone, THF, −78 °C; (2) HMPA.
enolate with a commercially available or prepared benzyl
bromide 812,19 then forms the desired analogues 2g−2h, 2j−2k,
2m, 2o-2r, and 2u. Catalytic hydrogenolysis of the lactones
generated from the corresponding oxygen-protected benzyl
bromides produces the phenol analogues 2a−2f, 2i, 2l, 2s, and
2t and reduction of the corresponding nitro-benzyl products
forms the desired aniline derivatives 2n. By using this approach,
racemic arctigenin 2a was also produced. It should be noted
that, as expected, the benzyl groups in the synthetic analogues
are trans-disposed.
The results of a preliminary study of the dose-dependent
increase in glucose uptake in L6 myotubes show that natural
(−)-arctigenin and its racemic analogue 2a display similar
enhancement properties (Figure 2). Glucose uptake was
(d) Raney nickel, EtOH, 80 °C.
hydrogenolysis and desulfurization with the Raney nickel gives
13.
The results of biological studies show that 10 has only a
maximum 1.31-fold stimulating effect on 2-deoxyglucose uptake
in L6 myotubes at a dose of 6 μmol/L. This value is much
lower than that of 1 (Figure S1A, see Supporting Information).
In contrast, compound 13 exhibits a moderate 2.08-fold
enhancement of uptake activity at 3 μmol/L (2 h), which is
close to the 2.76-fold increase promoted by 1 under identical
conditions (Figure S1B, see Supporting Information). These
data indicate the potency of lactone motif in keeping
compound activity.
To probe the influence of substituents on the arene ring of
the C-3 benzyl moiety in the arctigenin analogues, 2b−2e were
synthesized using an approach that is identical to the one
shown in Scheme 1. Investigations of the effects of these
substances on glucose uptake at different concentrations (see
Supporting Information) demonstrate that the glucose uptake
activities of 2b with a meta-methoxy-phenyl and 2d with a
3,4,5-trimethoxy-phenyl group have no significant effect (Table
1). Furthermore, 2e, in which the 3,4-dimethoxyl group on the
C-3 benzyl moiety in 2a is changed to 3,4-dioxole, also has a
dramatically lower uptake activity. Only 2c, possessing a para-
methoxy group, has a ca. 2.4-fold effect at 24 μmol/L that is
close to that of 1 at 3 μmol/L.
On the basis of the above results, our attention turned to
SAR studies of analogues that contain various substituents on
the phenyl group in the C-2 benzyl moiety (i.e., 2f−2u).
Analysis of the results arising from studies of 2f−2u (Table 1)
show that introduction of an ortho or meta electron donating
and withdrawing group on this ring (2f−2k) results in no effect
on glucose uptake activity. Only 2i, with a meta-OH group,
displays a moderate activity. Significantly, substitution at the
para position of the phenyl group of the C-2 benzyl moiety
brings about a remarkable change in the glucose uptake activity
in L6 myotubes. For example, 2l with a p-hydroxyl group has
the close activity at 12 μmol/L as does (−)-arctigenin at 3
μmol/L. However, 2m, in which the p-hydroxyl is changed to
methoxyl, has a greatly diminished glucose uptake activity.
Furthermore, electron donating (−NH2) and withdrawing
group (−CN) substitution at this position results in a decrease
in activity. Interestingly, in contrast to other related halogen
substituted substances (2q and 2r), the para-chloro substituted
analogue 2p displays the highest activity of the substances
Figure 2. Structure of 2a and dose-dependent increase in glucose
uptake by L6 myotubes exposed to 1 and 2a at the indicated
concentrations for 2 h. Results are expressed as mean SEM, n = 3
independent experiments. **p < 0.01 vs control.
measured as described in Supporting Information. Glucose
uptake increases by 1.62-fold compared to that of a control
when 3 μmol/L of 2a is present, whereas the same dose of
(−)-arctigenin causes a 1.75-fold uptake enhancement.
Furthermore, 2a displays the same dose dependence as does
(−)-arctigenin. These results indicate that a SAR study with
racemic arctigenin analogues would generate informative
results.
To investigate the impact of the lactone moiety in arctigenin
on glucose uptake, the tetrahydrofuran 10 and cyclopentanone
13 analogues were synthesized using the methods outlined in
Scheme 2A,B, respectively. Preparation of 10 utilized a route
that begins with the reduction of 2a to give diol 9, which is
cyclized to form 10 (Scheme 2A).12 The scheme for synthesis
of 13, described earlier by Ziegler,20 begins by treatment of
dithiane 11 with n-butyllithium followed by conjugate addition
of the resulting anion to cyclopent-2-enone. The formed
cyclopentanone is then α-alkylated with substituted benzyl
bromide 8a to give the intermediate 12, which upon catalytic
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Table 1. Enhancement of Glucose Uptake in L6 Myotubes Induced by Compounds 2b−2u
concentration
effect on glucose uptake in L6
effect on glucose uptake [3 μM] of 1 in
a
b
c
compd.
2b
R1
3″-OMe
4″-OMe
R2
(μM)
myotubes (%)
L6 myotubes (%)
ratio
3′-OMe-4′-OH
3′-OMe-4′-OH
3′-OMe-4′-OH
3′-OMe-4′-OH
2′-OH
2′-OMe
2′-Cl
3′-OH
3′-OMe
3′-Cl
4′-OH
4′-OMe
4′-NH2
1.5
24
6
121.2 3.0
235.1 11.7
128.8 3.3
131.7 4.5
137.6 1.5
97.4 6.3
241.0 13.6
262.4 3.6
233.9 16.0
265.3 10.8
237.6 8.8
190.1 9.7
206.4 6.5
217.8 13.5
211.3 9.1
212.4 6.6
200.6 10.9
182.1 1.1
205.4 2.6
258.7 9.4
185.5 4.8
239.6 19.6
269.2 11.7
188.9 10.7
238.9 21.2
237.6 8.8
185.5 4.8
208.9 10.7
0.503
0.896
0.551
0.496
0.579
0.512
0.545
0.828
0.564
0.540
0.895
0.595
0.616
0.528
0.936
0.486
0.654
0.531
1.018
0.577
1.030
0.494
2c
2d
3″,4″,5″-OMe
3″,4″-OCH2O−
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
3″,4″-OMe
2e
1.5
1.5
3
2f
2g
2h
3
112.4 4.0
180.3 23.3
119.2 1.3
114.8 0.7
179.5 21.1
108.4 6.5
126.6 11.0
136.7 4.3
173.7 7.7
116.4 5.7
176.0 6.7
100.4 5.9
243.2 29.9
137.1 14.0
191.1 6.2
103.1 3.8
2i
24
12
3
2j
2k
2l
12
1.5
3
2m
2n
2o
4′-CN
4′-Cl
4′-F
4′-Br
3
2p
6
2q
1.5
6
2r
2s
3′-OH-4′-OMe
3′,4′-OH
3′,4′-OMe
4′-Cl
1.5
3
2t
2u
3
(2R,3R)-2p
(2S, 3S)-2p
6
4′-Cl
1.5
a
The effect on glucose uptake by L6 myotubes exposed to 2b−2u at a series of concentrations for 2 h, including 1.5, 3, 6, 12, and 24 μM (see
b
c
Supporting Information), and the maximum enhancement was displayed. Compound 1 was employed as a positive control at 3 μM. The ratio of
the activity between the test compound with 1 was calculated.
explored in this effort. More importantly, 2s, in which the
positions of the 3′-hydroxyl and 4′-methoxyl in 1 are exchanged
does not exhibit any uptake activation effects.
The combined observations clearly suggest that para-
hydroxyl or -chloro groups on the phenyl ring of the C-2-
benzyl moiety play critical roles in the enhancement of glucose
uptake in L6 myotubes. In accord with this finding is the
observation that 2t, bearing 3′,4′-dihydroxy groups, has an
excellent activity in comparison to that of 2u.
Considering the potential metabolic problem for phenol
group, 2p was chosen for the separation to obtain the two
isomers in ∼1:1 ratio. These exhibited quite different effects on
glucose uptake in L6 myotubes. (2R,3R)-2p, with the
configuration matching (see Supporting Information) (−)-arc-
tigenin, maintained the stimulation and reached maximal effect
at 6 μmol/L equal to (−)-arctigenin at 3 μmol/L, while isomer
(2S,3S)-2p did not possess any activity on glucose uptake
(Table 1). However, the racemic 2p and (2R,3R)-2p show the
identical dose−effect tendency (Figure S4, see Supporting
Information).
Because it has a remarkably high glucose uptake stimulating
effect in skeletal muscle cells, the chloro-substituted analogue
2p along with racemic arctigenin (2a) were selected for further
investigation. We have previously demonstrated that (−)-arcti-
genin mildly depolarizes the mitochondrial membrane potential
(Δψm) and increases AMPK phosphorylation. In the current
effort, we observed that both 2a and 2p depolarize Δψm in a
moderate dose-dependent manner (Figure 3A). Because
mitochondrial function is linked with AMPK activation, the
effect of these analogues on AMPK phosphorylation in L6
myotubes was determined (Figure 3B). As expected, AMPK
phosphorylation is significantly enhanced by 2a and 2p in
association with increased phosphorylation of acetyl-CoA
carboxylase (ACC), a downstream target of AMPK. In
accordance with the effects on glucose uptake, (2S,3S)-2p
did not stimulate AMPK and ACC phosphorylation. To
determine whether 2a and 2p stimulation of glucose uptake
involves activation of AMPK, the effects of the AMPK inhibitor,
compound C,21 on the abilities of 2a and 2p to stimulate
glucose uptake in L6 myotubes were probed. As the results
displayed in Figure 3C show, increases in glucose uptake caused
by 2p and 2a are completely blocked by compound C. Thus,
the increased glucose uptake in skeletal muscle stimulated by 2a
or 2p is mediated by activation of AMPK in a similar manner as
has been observed for 1.
It has been reported that acute activation of AMPK in
skeletal muscle cells increases fatty acid oxidation by decreasing
malonyl-CoA concentrations through the inhibition ACC and
activation of malonyl-CoA decarboxylase (MCD).22,23 Our
studies (Figure 4A) demonstrate that 2a significantly induces
fatty acid oxidation at a dose of 6 μmol/L. Treatment with 3 or
6 μmol/L of 2p also enhances fatty acid oxidation in L6
myotubes, whereas pretreatment with compound C fully blocks
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plot shown in Figure 5. Because 2p increases fatty acid
oxidation, its effect on whole-body fat oxidation was explored
Figure 5. Acute effect of 2p on RER in ob/ob mice. Results are
expressed as mean SEM, n = 6. *p < 0.05 compared with vehicle.
using undirected calorimetry. The ob/ob mice were intra-
peritoneal injected with a single dose of 50 mg/kg of 2p or a
vehicle. The animals were then monitored for oxygen
consumption and CO2 production for 23 h. The observations
show that treatment with 2p results in a rapid decrease in RER
that is sustained for 8 h (Figure 5). The finding is consistent
with the effect of 2p on fatty acid oxidation in L6 myotubes,
suggesting that this substance induces a switch to fatty acid
utilization and an improvement of whole body lipid
metabolism.
To assess the in vivo antidiabetic potential of 2p, ob/ob mice
were intraperitoneal injected with 50 mg/kg of this substance
or a vehicle twice per day for 23 d. Mice treated with 2p display
a significant decline in body weight gain after 3d treatment
(Figure 6A) although they have an unaltered feeding behavior
Figure 3. Compound 2p, like 2a, stimulates glucose uptake through
AMPK. (A) Dose-dependent depolarization of Δψm in L6 myotubes
by 10 min treatments of 2a and 2p with the indicated concentrations.
(B) Compounds 2a, 2p, and (2R,3R)-2p but not (2S,3S)-2p increase
AMPK and ACC phosphorylation (p-AMPK, p-ACC) in L6 myotubes
following 2 h treatment at the indicated concentrations. (C)
Compounds stimulated glucose uptake in an AMPK-dependent
manner. Results are expressed as mean SEM, n = 3 independent
experiments. **p < 0.01 vs control.
Figure 4. Compound 2a and 2p stimulate fatty acid oxidation through
AMPK. (A) Compound 2a and 2p increase fatty acid oxidation. (B)
Compounds stimulated fatty acid oxidation in an AMPK-dependent
manner. Results are expressed as mean SEM, n = 3 independent
experiments. *p < 0.05, **p < 0.01 vs control.
this effect (Figure 4B). The results demonstrate that 2a and 2p
improve fatty acid oxidation by activating AMPK.
To assess the pharmacokinetic properties of 2a and 2p, the
compounds were dosed to ob/ob mice as shown in Figure S5
(see Supporting Information). After administration by intra-
peritoneal injection, 2a and 2p were observed with very fast
absorption (tmax = 30 min). Comparison of Cmax and AUC0‑t
indicate that 2p displays higher plasma exposure compared to
2a, showing a Cmax of 508 ng/mL and AUC0‑t of 1876 h·ng/mL.
It is clear that replacement of the para-hydroxyl group of the C-
2 benzyl moiety of arctigenin by Cl as 2p could avoid one of
the possible metabolic sites. The compound 2p was chosen for
further investigation in vivo.
Figure 6. Effect on body weight and blood glucose of ob/ob mice. (A)
Compound 2p slightly decreases body weights of ob/ob mice after
treatment for 20 d. Body weight (A) and food intake (B) were
recorded regularly during the treatment period. Levels of fed blood
glucose (C) and fasting blood glucose (D) were determined
throughout the treatment. Serum triacylglycerol (E), cholesterols
(F), and NEFA (G) concentrations were evaluated at the end of the
treatment period. Data are mean SEM for n = 6−8 mice. *p < 0.05
vs vehicle mice.
Compound 2p having acute effects on the respiratory
exchange ratio (RER) in ob/ob mice is demonstrated by the
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2 benzyl moiety of the arctigenin framework by Cl leads a
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ASSOCIATED CONTENT
* Supporting Information
■
S
Synthetic details and characterization data for all new
compounds reported in this letter. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*(Y.H.) E-mail: yhhu@mail.shcnc.ac.cn.
*(Y.L.) E-mail: yleng@simm.ac.cn.
■
Author Contributions
§S.-D.D. and S.-L.H. contributed equally to this work.
Funding
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This work was supported by grants from Major Projects in
National Science and Technology, “Creation of major new
drugs” (No. 2102ZX09103101-062), and the National Nature
Science Foundation of China (No. 81202570 and 81225022).
Notes
The authors declare no competing financial interest.
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ABBREVIATIONS
■
SAR, structure−activity relationship; LDA, lithium diisopropy-
lamide; PTSA, p-toluenesulfonic acid; THF, tetrahydrofuran;
DCM, dichloromethane; HMPA, hexamethylphosphoramide
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