Two new nor-lignans from Selaginella pulvinata (Hook. & Grev.) Maxim and their antihyperglycemic activities

Article abstract of DOI:10.1080/14786419.2020.1779267

Two new nor-lignans, pulvin A (1) and moellenoside C (2), along with two known compounds (3–4) were isolated from the whole plant of Selaginella pulvinate (Hook. & Grev.) Maxim. The structures of the new compounds were established on the basis of spectroscopic data and acid hydrolysis. All the isolates were investigated for their antihyperglycemic activities in 3T3-L1 adipocytes. The results showed that compounds 1 and 2 promoted the glucose consumption prominently in 3T3-L1 adipocytes in a dose-response manner. Compound 1 and 2 induced 1.14–1.73 folds and 1.03–1.55 folds changes relative to the basal level, respectively, in the concentration range of 12.5 μM to 50 μM.

Full text of DOI:10.1080/14786419.2020.1779267

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Two new nor-lignans from Selaginella pulvinata
(Hook. & Grev.) Maxim and their antihyperglycemic
activities
Hua-Wei Lv, Yu-Xia Li, Meng Luo, Jia-Meng Qi, Ze-Fei Fu, Hong-Jian Zhang,
Yuan-Qiang Guo, Chu Chu, Han-Bing Li & Ji-Zhong Yan
To cite this article: Hua-Wei Lv, Yu-Xia Li, Meng Luo, Jia-Meng Qi, Ze-Fei Fu, Hong-Jian Zhang,
Yuan-Qiang Guo, Chu Chu, Han-Bing Li & Ji-Zhong Yan (2020): Two new nor-lignans from
Selaginellaꢀpulvinata (Hook. & Grev.) Maxim and their antihyperglycemic activities, Natural Product
Research, DOI: 10.1080/14786419.2020.1779267
To link to this article: https://doi.org/10.1080/14786419.2020.1779267
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2020.1779267
Two new nor-lignans from Selaginella pulvinata
(
Hook. & Grev.) Maxim and their antihyperglycemic
activities
a
a
a
a
b
c
Hua-Wei Lv , Yu-Xia Li , Meng Luo , Jia-Meng Qi , Ze-Fei Fu , Hong-Jian Zhang ,
d
a
a
a
Yuan-Qiang Guo , Chu Chu , Han-Bing Li and Ji-Zhong Yan
a
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, P.R. China;
Production center, Zhejiang Yuanlijian Pharmaceutical Co., Ltd, Jiande, P.R. China; Center for
b
c
Medicinal Resources Research, Key Laboratory of Research and Development of Chinese Medicine of
d
Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, P.R. China; State
Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of
Molecular Drug Research, Nankai University, Tianjin, P.R. China
ABSTRACT
ARTICLE HISTORY
Two new nor-lignans, pulvin A (1) and moellenoside C (2),
along with two known compounds (3–4) were isolated from the
whole plant of Selaginella pulvinate (Hook. & Grev.) Maxim. The
structures of the new compounds were established on the basis
of spectroscopic data and acid hydrolysis. All the isolates were
investigated for their antihyperglycemic activities in 3T3-L1
adipocytes. The results showed that compounds 1 and 2 promoted
the glucose consumption prominently in 3T3-L1 adipocytes in a
dose-response manner. Compound 1 and 2 induced 1.14–1.73 folds
and 1.03–1.55 folds changes relative to the basal level, respectively,
in the concentration range of 12.5 lM to 50lM.
Received 9 March 2020
Accepted 23 May 2020
KEYWORDS
Pulvin A; moellenoside C;
Selaginella pulvinate
(
Hook. & Grev.) Maxim;
Selaginellaceae;
antihyperglycemic activity;
3T3-L1 adipocyte
CONTACT Ji-Zhong Yan
yjz@zjut.edu.cn; Han-Bing Li
hanbing.li@163.com
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2020.1779267.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
H.-W. LV ET AL.
1. Introduction
The genus Selaginella P. Beauv., belonging to the Selaginellaceae family, consists of
approximately 700 species worldwide and 66 species in China (Little et al. 2007).
Selaginella pulvinata (Hook. & Grev.) Maxim is a traditional Chinese medicine for pro-
moting blood circulation, and is commonly used to treat amenorrhoea, dysmenor-
rhoea, traumatic injury (Cao et al. 2010; Liu et al. 2014). The whole plants of S.
pulvinata and Selaginella tamariscina (P. Beauv.) Spring have been recorded officially
as the original material of ‘juanbai’ in the Chinese Pharmacopoeia (National
Pharmacopoeia Committee 2015). S. pulvinata is lithophytic pteridophyte that can sur-
vive severe drought conditions, maintaining the plant’s structural stability, and resur-
rect during rains. Rhizophores of the whole plants are restricted to base of stem and
much forked at end, forming thick massive rootstock. Stems present typical rosette
and the main stems are pinnately branched near and above base. Primary leafy
branches are 4–7 pairs, 2 or 3 times pinnately branched. Axillary leaves on main stems
are larger than those on branches, and axillary leaves on branches are symmetrical.
Phytochemical studies of S. pulvinata have led to discovering the occurrence of several
polyphenol (Cao et al. 2010; Liu et al. 2014; Cao et al. 2015; Liu et al. 2018) and flavo-
noids (Tan et al. 2004). As part of an ongoing search for new antihyperglycemic agents
from genus Selaginella, the phytochemical investigation was performed. As a result,
two new compounds, pulvin A (1) and moellenoside C (2), along with two known
compounds syringaresinol (3) and (2R,3S)-dihydro-2-(3,5-dimethoxy-4-hydroxy-phenyl)-
7-methoxy-5-acetylbenzofuran (4), were isolated from the whole plants of S. pulvinata.
Herein, we describe the structural elucidation of the new compounds as well as their
in vitro antihyperglycemic activities in 3T3-L1 adipocytes.
2. Results and discussion
Compound 1 was obtained as a white, amorphous powder. The negative HRESIMS
-
data at m/z 375.1466 [M-H] (calcd. 375.1499) established its molecular formula as
C H O . The UV spectrum of 1 showed absorption peaks at 208 and 278 nm. In The
2
0 24 7
1
H NMR spectrum, four characteristic aromatic protons signals at dH 6.34 (2H, s), dH
7
.39 (1H, d, J ¼ 1.8 Hz) and d 7.41 (1H, d, J ¼ 1.8 Hz) indicated the presence of one
H
symmetrical 1,2,3,5-tetrasubstituded benzene ring and one asymmetrical 1,2,3,5-tetra-
substituded benzene ring, respectively. Signals at d 3.70 (6H, s) and d 3.89 (3H, s)
H
H
13
were attributed to three methoxy groups. The C NMR spectrum revealed the pres-
ence of 20 carbon resonances comprising of twelve aromatic carbons, one ketocar-
bonyl carbons, three methoxyl carbons and four aliphatic carbons. The 1D NMR data
of 1 were similar to those of moellenoside B (Feng et al. 2011) which contains an add-
itional C-9 glucosyl unit. Further analysis of the HSQC and HMBC spectra verified the
0
0
planar structure of 1. In the HMBC spectrum, correlations of H-2 (d 7.41)/C-7 (d
H
C
0
0
0
1
99.9), H-8 (d 2.49)/C-1 (d 129.5) indicated the ketocarbonyl was located at C-1 .
H
C
0
0
The HMBC correlations of H-7 to C-3 , C-2 and C-9, H-9 to C-3 , confirmed the linkage
between two benzene rings. The absolute configuration of 1 was established as (8R)
on the basis of the negative Cotton effect at 270 nm in its CD spectrum (Zhuo et al.

NATURAL PRODUCT RESEARCH
3
Figure 1. The structures of compounds 1–4.
016). Thus, the structure of 1 was determined as shown (Figure 1) and
2
named pulvin A.
Compound 2 was obtained as a white, amorphous powder. The molecular formula
of 2 was determined to be C H O based on the HRESIMS signal at m/z 539.2152
2
6 36 12
-
[
M-H] (calcd. for C H O , 539.2134). The UV spectrum of 2 showed absorption
26 35 12
1
peaks at 254 and 282 nm. The H NMR data of 2 suggested characteristic signals of
four aromatic protons at d 6.30 (2H, s), d 6.89 (1H, d, J ¼ 1.8 Hz) and d 6.88 (1H, d,
H
H
H
J ¼ 1.8 Hz), three methoxy groups at d 3.70 (6H, s) and d 3.82 (3H, s), one terminal
H
H
hydrogen at d 4.62 (1H, d, J ¼ 7.8 Hz) and one methyl signal at d 1.41 (3H, d,
H
1
H
3
J ¼ 6.6 Hz). The C NMR spectrum revealed the presence of 26 carbon signals consist-
ing of twelve aromatic carbons, six glycosyl carbons, three methoxyl carbons and five
1
13
aliphatic carbons. The H and C NMR data of 2 were similar to those of 1, with the
main differences being the presence of one glucosyl group in 2. Acid hydrolysis of 2
affords D-glucose based on HPLC analysis of their chiral derivatives. The D-glucose
3
units were determined to have b-configurations from the J
coupling constants
H1,H2
0
0
0
(
7.8 Hz). In the HMBC spectrum, correlations from H-1 (dH 4.62) to C-4 (d 144.6)
suggested that the glucosyl unit is linked at C-4 . Correlations of H-8 (d 1.41)/C-1 (d
44.5) and H-2 (d 6.88)/C-7 (d 70.9) revealed one 1-hydroxyethyl linked to C-1 .
Complete assignment of H and C NMR data was achieved by further analysis of the
HSQC and HMBC spectra. The absolute configuration of C-8 in 2 was established as R
by comparison of its CD spectrum (negative Cotton effect at 270 ꢀ 295 nm) with that
C
0
0
0
H
C
0
0
0
1
H
C
13
1

4
H.-W. LV ET AL.
0
of selaginellol 4 -O-b-D-glucopyranoside (Zhuo et al. 2016). Therefore, the structure of
2
was identified as shown and named moellenoside C.
The known compounds were identified as syringaresinol (3) (Ouyang et al. 2007)
and (2R,3S)-dihydro-2-(3,5-dimethoxy-4-hydroxy-phenyl)-7-methoxy-5-acetylbenzofuran
4) (Bi et al. 2004), by comparison of their spectroscopic data with previously
(
reported values.
The Selaginella species, belonging vascular plants, have the potential to synthesise
a repertoire of novel secondary metabolites for the existing of many independent
diversification of gene families (Banks et al. 2011). The nor-lignans mentioned above
contain the units of syringyl, indicating that the nor-lignans in the Selaginella species
may be synthesised via the shikimic acid pathway which is the biosynthetic pathway
of angiospermous lignans. Previous studies indicate the genus Selaginella is rich in
benzofuran lignans. However, nor-lignans without furan-rings, such as analogues of
compounds 1 and 2, are only found in Selaginella moellendorffii Hieron (Feng et al.
2
011; Zhuo et al. 2016) and S. tamariscina (Dat et al. 2017). To our knowledge, com-
pound 3 is discovered in several Selaginella species, such as S. tamariscina (Bi et al.
004), S. moellendorffii (Zhu et al. 2018). S. sinensis (Feng et al. 2008) and S. picta
Cheng et al. 2018), while compound 4 is only isolated from S. tamariscina (Bi et al.
004). Therefore, it was the first isolation of compounds 3 and 4 from S. pulvinata. As
2
(
2
a result, The isolation of compounds 1–4 provides a certain relationship between S.
pulvinata and S. tamariscina in terms of chemotaxonomy.
Antihyperglycemic activities of the isolates were evaluated in vitro in 3T3L-1 adipo-
cytes. Compounds 1 and 2 show activities on promoting glucose consumption in
3T3L-1 adipocytes in preliminary screening experiments (Data not shown). Then, differ-
ent concentration levels of compounds 1 and 2 were set to evaluate their activities.
As a result, compounds 1 and 2 induced the glucose consumption with 1.14–1.73
folds and 1.03–l.55 folds changes relative to the basal level (normalized to 1.0),
respectively, by a dose-response manner in the concentration range of 12.5 lM to
50 lM. Insulin (0.1 lM) was used as positive control and caused 1.47 folds to change
relative to the basal level (Figure 2).
3. Experimental
3.1. General
Optical rotations were measured using a JASCO P-1020 polarimeter (Jasco Tokyo
Japan); UV spectra were recorded in MeOH using a Shimadzu UV spectrometer-1800
(Shimadzu Corp., Kyoto, Japan); IR spectra (KBr) were recorded on a Nicolet 6700 FT-IR
spectrometer (Thermoelectric nicoli, United States); A JASCO J-810 spectrometer was
used to detect CD spectra; 1D and 2D NMR spectra were recorded on a Bruker
1
13
AVANCE III 600 MHZ spectrometer (600 MHz for H NMR and 150 MHz for C NMR)
equipped with a 5 mm TCI cryoprobe (Bruker company, Switzerland) at 298 K, and TMS
was used as internal standard; HRESIMS were measured with an Agilent 6210 TOF LC/
MS (Agilent Technologies, Santa Clara, CA); ESIMS were measured with a Thermo LCQ
Deca XP plus (Thermo Finnigan, San Jose, CA). The compounds were purified by
LUMTECH prepared HPLC (Lumiere Tech Ltd, China) equipped with a LUMTECH dual-

NATURAL PRODUCT RESEARCH
5
wavelength UV-detector and a Shim-pack GIST C18 column (20 ꢁ 250 mm, 5 lm,
Shimadzu Corp., Kyoto, Japan); HPLC was carried out using Agilent-1260 (Agilent, USA)
equipped with an Agilent single wavelength UV-detector and an Inertsustain C18 col-
umn (4.6 ꢁ 250 mm, 5 lm particle size, Shimadzu Corp., Kyoto, Japan); TLC was con-
ducted on silica gel G (Qingdao Haiyang Chemical Co., Ltd., China); HPLC solvents was
used from TEDIA in American (TEDIA company, American); All others reagents were of
the analytical grade.
3.2. Plant material
Whole Selaginella pulvinata plants were purchased from Guangzhou Qingping market,
Guangdong Province, China, in June 2017. The seller collected the plants from
ꢂ
0
ꢂ
0
Meizhou City at 116 07 E and 24 19 N, Guangdong Province. This sample was identi-
fied by Professor Chu Chu, College of Pharmaceutical Science, Zhejiang University of
Technology. A voucher specimen (201706ST) was deposited at the Herbarium of
Chinese medicine, Zhejiang University of Technology, China.
3.3. Extraction and isolation
Dry plants of S. pulvinata (15 kg) were ground into a coarse powder, and extracted
with 25 L of 95% ethanol at room temperature for 3 times (48 h for each time). The
extracted solvent was combined and concentrated under reduced pressure by a rotary
evaporator to yield 1.7 kg of crude extract. The crude extract was suspended with
water and extracted with CH Cl , EtOAc and n-BuOH to obtain three fractions, a
2
2
CH Cl fraction (540 g), an EtOAc fraction (122 g), and an n-BuOH fraction (212 g). The
2
2
CH Cl fraction was subjected to an MCI column, eluting with MeOH-H O (30:70–100:0,
2
2
2
v/v), to obtain four subfractions A–F. Subfraction B (12.6 g) was separated by a silica
gel column with CH Cl :MeOH (20:1 to 10:1, v/v, total volume: 2100 mL) to obtain
2
2
eighteen subfractions B1–B18. Subfraction B3 (180 mg) was separated by medium
pressure preparative liquid chromatography, eluting with MeOH:H O (20:80 to 100:0,
2
v/v), to obtain five fractions B3a to B3e. B3a (34 mg) was separated by a silica gel col-
umn to give two fractions B3a-1 and B3a-2. B3a-2 (13.2 mg) was subsequently purified
by prep-HPLC to obtain compound 2 (10.0 mg). Fractions B3b (16.4 mg) was separated
by prep-HPLC (MeCN:H O, 25:75, v/v) to yield compound 3 (8.9 mg). B3c (41 mg) was
2
subjected to a silica gel column to obtain two fractions B3c-1 and B3c-2. Fraction B3c-
2
4
(26.6 mg) was performed on prep-HPLC to afford compound 1 (4.0 mg) and
(18.6 mg).
Compound 1: white, amorphous powder; [a]25 D -23.6 (c 0.11, MeOH); CD (MeOH):
2
3
11 (neg), 270 (neg); UV (MeOH) kmax (log e) 278 (3.03), 258 (4.87) nm; IR ꢀ
(KBr)
max
H NMR
0
ꢃ1
1
393, 2934, 1612, 1518, 1459, 1428, 1326, 1218, 1154, 1114, 1073 cm
;
0
(600 MHz, MeOH-d ): d 7.41 (1H, d, J ¼ 1.8 Hz, H-2 ), 7.39 (1H, d, J ¼ 1.8 Hz, H-6 ), 6.34
4
0
(each 1H, s, H-2 and H-6), 3.89 (3H, s, 5 -OCH ), 3.81 (2H, m, H-9), 3.70 (each 3H, s, 3,5-
3
OCH ), 3.55 (1H, m, H-8), 3.03, (1H, dd, J ¼ 13.8, 6.0 Hz, H-7a), 2.91 (1H, dd, J ¼ 13.8,
3
0 0
.0 Hz, H-7b), 2.49 (3H, s, H-8 ); C NMR (150 MHz, MeOH-d ): d 199.9 (C-7 ), 151.6 (C-
4
), 148.9 (C-3, C-5), 148.8 (C-5 ), 134.6 (C-4), 132.4 (C-1), 129.5 (C-1 ), 129.4 (C-3 ), 125.0
13
9
4
0
0
0
0

6
H.-W. LV ET AL.
0
0
0
(
8
C-2 ), 109.6 (C-6 ), 107.5 (C-2, C-6), 65.4 (C-9), 56.7 (3,5-OCH ), 56.6 (5 -OCH ), 45.0 (C-
3
3
0
), 37.9 (C-7), 26.3 (C-8 ); HRESIMS m/z 375.1466 [M-H] (calcd. for C H O , 375.1449).
20 23 7
-
Compound 2: white, amorphous powder; [a]25 D -30.3 (c 0.12, MeOH); CD (MeOH):
2
17 (neg), 289 (neg); UV (c 0.02, MeOH) kmax (log e) 254 (3.74), 282 (4.05) nm; IR ꢀ
max
ꢃ1
1
(
(
(
KBr) 3405, 2939, 1662, 1591, 1518, 1427, 1305, 1359, 1215, 1116 cm
;
H NMR
0
0
600 MHz, MeOH-d ): d 6.89 (1H, d, J ¼ 1.8 Hz, H-6 ), 6.88 (1H, d, J ¼ 1.8 Hz, H-2 ), 6.30
4
0
00
each 1H, s, H-2 and H-6), 4.78 (1H, m, H-7 ), 4.62 (1H, d, J ¼ 7.8 Hz, H-1 ), 4.00 (1H, m,
0
00
H-8), 3.82 (3H, s, 5 -OCH ), 3.80 (1H, m, H-6 a), 3.77 (2H, m, H-9), 3.70 (each 3H, s, 3,5-
3
0
0
00
00
00
OCH ), 3.68 (1H, m, H-6 b), 3.45 (1H, m, H-2 ), 3.39 (1H, m, H-4 ), 3.37 (1H, m, H-3 ),
3
0
0
3
7
3
.11 (1H, m, H-5 ), 3.01 (1H, dd, J ¼ 13.8, 5.4 Hz, H-7a), 2.72 (1H, dd, J ¼ 13.8, 9.6 Hz, H-
13
0
0
b), 1.41 (3H, d, J ¼ 6.6 Hz, H-8 ); C NMR (150 MHz, MeOH-d ): d 153.3 (C-5 ), 148.7 (C-
4
0
0
0
0
, C-5), 144.6 (C-4 ), 144.5 (C-1 ), 134.3 (C-4), 138.7 (C-3 ), 132.5 (C-1), 117.2 (C-2 ), 108.8
0 00 00 00 00 00
(
7
2
C-6 ), 107.2 (C-2, C-6), 105.6 (C-1 ), 78.1 (C-5 ), 77.9 (C-3 ), 76.0 (C-2 ), 71.3 (C-4 ),
0 00 0
0.9 (C-7 ), 67.1 (C-9), 62.5 (C-6 ), 56.7 (3,5-OCH ), 56.4 (5 -OCH ), 42.8 (C-8), 39.6 (C-7),
3 3
0
ꢃ
5.9 (C-8 ); HRESIMS m/z 539.2152 [M-H] (calcd. for C H O , 539.2134).
2
6 35 12
3.4. Acid hydrolysis of 2
ꢂ
Compound 2 (1.0 mg) was dissolved in 2 M HCl (aq) (5.0 mL) at 100 C refluxed for 4 h.
After removal of the solvent, the compound was dissolved in water and filtered to
obtain a monosaccharide sample, the solvent was removed, and dried under vacuum
overnight. The sample was then dissolved in pyridine (1.0 mL) containing 1 mg/mL L-
ꢂ
cysteine methyl ester. The mixture was heated at 60 C for 1 h. o-Tolylisothiocyanate
(2.0 lL) was added, and heating was continued for an additional hour. The mixture
was concentrated under vacuum to afford a residue that was dissolved in MeOH and
ꢂ
analyzed by RP-HPLC at 30 C, with isocratic elution of CH CN-H O-HCOOH (25:75:0.1,
3
2
v/v) for 40 min and subsequent washing of the column with 90% CH CN at a flow rate
3
of 0.8 mL/min. D-glucose derivative was detected in the acid hydrolysate of 2 by com-
paring the retention time of its derivatives (t 21.51 min) with those of the authentic
R
D-glucose and L-Glucose derivatives (t 21.38 min and t 19.38 min) prepared in the
R
R
[
12]
same manner (Lv et al. 2014)
.
3.5. Glucose consumption in 3T3-L1 adipocytes
The differentiation of 3T3-L1 preadipocytes was performed as previously reported (Lv
et al. 2014). The adipocytes were incubated with or without the test compounds, as
well as with insulin (0.1 lM), for an additional 24 h. Their glucose concentrations were
determined using the glucose oxidase method with commercially available kits.
Insulin, 0.1 lM (Sigma-Aldrich, St. Louis, MO, USA), served as the positive control. The
amount of glucose consumption was calculated by subtracting the glucose concentra-
tions of the treated wells from those of the blank wells. Glucose consumption due to
cell proliferation could be determined by calculating the ratio of glucose consumption
to MTT (GC/MTT). The final results were expressed as the GC/MTT value in each
treated group compared with that of the vehicle control group.

NATURAL PRODUCT RESEARCH
7
All results are presented as the mean ± standard deviation (S.D.) of three replicate deter-
minations. Significant differences were determined by one-way analysis of variance
(
ANOVA), followed by Dunnett’s post hoc test using GraphPad Prism version 5.0 (GraphPad
ꢄ
ꢄꢄp< 0.01.
Software, San Diego, CA). Statistical significance was set at p< 0.05 and
4. Conclusions
Two new nor-lignans, pulvin A (1) and moellenoside C (2), along with two known
compounds, syringaresinol (3) and (2 R,3S)-dihydro-2-(3,5-dimethoxy-4-hydroxy-phenyl)-
-7-methoxy-5-acetylbenzofuran (4), were isolated from the whole plants of S. pulvinata.
Compounds 1 and 2 show potential antihyperglycemic activities in 3T3-L1 adipocytes.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by National Natural Science Foundation of China under
Grant NO.81603255.
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