Two new ent-kaurane glucosides from the fruits of Xanthium strumarium subsp. sibiricum

Article abstract of DOI:10.1080/14786419.2020.1819268

The chemical investigation of the fruits of Xanthium strumarium (Asteraceae) led to the isolation of two new ent-kauranoid glucosides named 2-O-(6-O-isocaleryl-β-D-glucopyranosyl) atractyligenin (1) and 2-O-(2-O-isovaleryl-β-D-glucopyranosyl) atractyligen

Full text of DOI:10.1080/14786419.2020.1819268

Natural Product Research
Formerly Natural Product Letters
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Two new ent-kaurane glucosides from the fruits of
Xanthium strumarium subsp. sibiricum
Tie Yao , Jiaxin Wang , Shijie Cao , Da Liu , Jingshi Duan , Yaqin Yu , Ning Kang
&
Feng Qiu
To cite this article: Tie Yao , Jiaxin Wang , Shijie Cao , Da Liu , Jingshi Duan , Yaqin Yu , Ning
Kang & Feng Qiu (2020): Two new ent-kaurane glucosides from the fruits of Xanthiumꢀstrumarium
subsp. sibiricum , Natural Product Research, DOI: 10.1080/14786419.2020.1819268
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2020.1819268
Two new ent-kaurane glucosides from the fruits of
Xanthium strumarium subsp. sibiricum
a,b
ꢀ
b
ꢀ
c
d
d
d
Tie Yao , Jiaxin Wang , Shijie Cao , Da Liu , Jingshi Duan , Yaqin Yu , Ning
d
a,b
Kang and Feng Qiu
a
School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P.R.
b
China; School of Chinese Materia Medica and Tianjin State Key Laboratory of Modern Chinese
Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China; Tianjin State Key
c
Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin,
d
P.R. China; Department of Biochemistry, School of Integrative Medicine, Tianjin University of
Traditional Chinese Medicine, Tianjin, P.R. China
ABSTRACT
ARTICLE HISTORY
The chemical investigation of the fruits of Xanthium strumarium
Received 9 April 2020
Accepted 24 August 2020
(
Asteraceae) led to the isolation of two new ent-kauranoid glucosides
named 2-O-(6-O-isocaleryl-b-D-glucopyranosyl) atractyligenin (1) and
-O-(2-O-isovaleryl-b-D-glucopyranosyl) atractyligenin (2), together
KEYWORDS
2
Xanthium strumarium; ent-
kaurane glucosides;
structural elucidation
with one known compound. Their structures were established by
comprehensive spectroscopic analysis coupled with single-crystal X-
ray diffraction and electronic circular dichroism data. All compounds
and their aglycone were evaluated for their anti-proliferative activities
in vitro against three human cancer cell lines.
1. Introduction
The genus Xanthium belongs to Asteraceae family, with four species and two varieties
growing in mainland China. The dry fruits of Xanthium strumarium subsp. sibiricum,
known as Xanthii fructus in TCM, are widely used to treat headache, fever, sinusitis,
chronic rhinitis and herpes (Shi et al. 2015). Previous research indicated that Xanthium
strumarium had multiple chemical composition, mainly including sesquiterpene
CONTACT Ning Kang
Tie Yao and Jiaxin Wang contributed equally to this work.
kangndd@163.com; Feng Qiu
fengqiu20070118@163.com
ꢀ
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2020.1819268.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
T. YAO ET AL.
Figure 1. Chemical structures of isolated compounds 1–3.
lactone, phenolic acid, thiazinedione and ent-kauranoid glucosides (Sonia et al. 1996;
Zhang et al. 2006; Kan et al. 2011; Cheng et al. 2013; Chen et al. 2015; Yin et al. 2016;
Xu et al. 2017), and these constituents showed anti-inflammatory, antibacterial, anti-
viral, and antitumor activities (Lin et al. 2014; Romero et al. 2015; Yeom et al. 2015;
Jiang et al. 2016; 2019). As a part of our continuing studies on the bioactive constitu-
ents from Xanthium strumarium, 75% EtOH extract of the fruits of this species was
investigated, thereby two new ent-kauranoid glucosides (1 and 2) and one known
compound (3) were isolated and characterized, as shown in Figure 1. And their bioac-
tivities against the human liver cancer cells, larynx cancer cells, and colon cancer cells
were evaluated. Herein, the isolation and structure elucidation of two new com-
pounds, as well as the bioactivities of all the isolated compounds are reported.
2. Results and discussion
The molecular formula of compound 1 was deduced to be C H O (eight indices of
3
0 46 10
-
hydrogen deficiency) based on the pseudomolecular ion at m/z 565.3008 [M-H] (calcd
for 565.3013) from the HRESIMS analysis. The H NMR data of 1 indicated the presence
1
0
0
00
of three methyls [d 0.95 (3H ꢁ 2, d, J ¼ 6.6 Hz, 4 , 5 -CH ) and 1.00 (3H, s, 20-CH )],
H
3
3
one olefinic methylene [d 5.18 (1H, br s, H-17a) and 5.08 (1H, br s, H-17b)]. Moreover,
H
1
a set of signals between d 3.10–4.50 in H NMR spectrum in combination with the
H
signal for an anomeric methine (d 4.42, d 103.4), indicated the presence of a sugar
H
C
0
moiety. The coupling constant of anomeric proton signal (d 4.42, d, J ¼ 8.0 Hz, H-1 )
H
indicated that the sugar was attached to aglycone via a b-linkage. The acid hydrolysis
13
of 1 afforded D-glucose, which was identified by HPLC analysis. The C NMR and
HSQC data for 1 revealed 30 carbon resonances including two nonprotonated olefinic
carbons (dC 160.4 and 109.2), two carbonyl carbons (dC 179.0 and 174.7), three
methyls (d 22.9, 22.9, and 17.4). Apart from aforementioned 7 carbons, the remaining
C
2
3 carbon signals were assigned to nine methylenes (one oxygenated), twelve tertiary
1
13
carbons (seven oxygenated), and two quaternary carbons. The H and C NMR data
for 1 were similar to those for previously known compound, 2-O-(2-O-Isocaleryl-b-D-
glucopyranosyl)-4-epi atractyligenin (Liu et al. 2012), suggesting compound 1 might
have a skeleton of ent-kaurane glucoside, which was further confirmed by H- H COSY
and HMBC experiments (Figure S1). After careful 2 D NMR data analysis, the main dif-
ference between these two compounds were the substitution position of the isobu-
1
1
0
00
tyryl group. The key HMBC correlation from H-6 to C-1 (dC 174.7) revealed the
isobutyryl group was attached to C-6 in 1. Therefore, the planar structure of 1 was
0
elucidated. On biogenetic grounds, compound 1 was confirmed as an ent-kaurane

NATURAL PRODUCT RESEARCH
3
glycoside with the configuration of Me-20 being a-oriented. The relative configur-
ation of 1 was deduced from coupling constants, the NOESY experiment, and X-ray
diffraction, as shown in Figure S1. The NOE correlation of H-2 with Me-20 indicated
that they were on the same side of ring A and H-2 was assigned to be a-oriented.
The NOE correlations of H-9 with H-5 and H-15 indicated that these protons were
3
are oriented on the same side of ring B. And the observed JH-2, H-1b value of
1
1.9 Hz (Brucoli et al. 2012) and the NOE correlation of H-1b with H-9 indicated
that H-5, H-9 and H-15 were b-oriented. The assignment of the relative configur-
ation of 1 was further confirmed by X-ray diffraction (Figure S2). However, due to
the tiny crystal form, the flack parameter of 1 was too large, which would lead to
an uncertain absolute configuration. Therefore, the olefin octant rule (Scott and
Wrixon 1971) was applied to establish the absolute configuration of 1, the absolute
configuration of C-15 was assigned as S by the observation of a negative Cotton
effect (De ꢂ 3.0) at 205 nm in the electronic circular dichroism (ECD) spectrum
(
2
Figure S23) for aglycone. Finally, the absolute configuration of 1 was assigned as
R, 4 R, 5 R, 8 R, 9S, 10 R, 13 R, 15S, and named 2-O-(6-O-isocaleryl-b-D-glucopyrano-
syl) atractyligenin.
The molecular formula of compound 2 was established as C H O (eight indices
3
1 48 10
-
of hydrogen deficiency) on the basis of HRESIMS at m/z 579.3161 [M-H] (calcd for
1
3
13
5
79.3169) and C NMR data. The C NMR and HSQC spectra indicated the presence
of 31 carbons, including two nonprotonated olefinic carbons (d 160.4 and 109.1),
C
two carbonyl carbons (d 178.9 and 174.1), three methyls (d 19.3, 17.3 and 11.8),
C
C
and the remaining 24 carbon signals were assigned to ten methylenes (one oxygen-
ated), twelve tertiary carbons (seven oxygenated), and two quaternary carbons.
These data of 2 were reminiscent of those 1, especially the typical signals related to
the skeleton of ent-kaurane diterpenoid [dC/H 17.3/0.99 (C-20), 74.1/4.23 (C-2), 83.6/
3
3
.76 (C-15), 109.1/5.18, 5.07 (C-17), 178.9 (C-18)] and a set of sugar signals (dH
.10–4.70), suggesting the same skeleton of the two compounds with ent-kaurane
1
13
glycoside. Careful analyses of the H and C NMR data resulted that these signals of
compound 2 were very similar to those of fructusnoid D (Cheng et al. 2019) except
0
0
for the chemical shifts of C-3 , suggested that 2 might be a 3 -desulfated analogue
1
1
of fructusnoid D, which was further confirmed by H- H COSY and HMBC experi-
ments (Figure S1). According to the aforementioned data, the planar structure of 2
was elucidated. In the NOESY spectrum of 2 showed the same NOE correlations as 1,
suggesting the relative configuration of 2 was consistent with that of 1. Therefore,
the absolute configuration of 2 was assigned as 2 R, 4 R, 5 R, 8 R, 9S, 10 R, 13 R, 15S
by displaying a negative Cotton effect (De ꢂ 3.9) at 205 nm in the electronic circular
dichroism (ECD) spectrum (Figure S23) for aglycone, and named as 2-O-(2-O-isova-
leryl-b-D-glucopyranosyl) atractyligenin.
0
0
Apart from compounds 1 and 2, one known compound was identified as 3 , 4 -
1
13
desulfated atractyloside (3) by comparing H and C NMR data with the literatures
(Cheng et al. 2019).
The cytotoxic effect of compounds 1–3 and their aglycone on HepG2 cells, HCT
116 cells and Hep-2 cells were investigated. However, none of the isolates obtained
showed cytotoxic activities against the studied cell lines (Figure S25).

4
T. YAO ET AL.
3. Experimental
3.1. General experimental procedures
Silica gel (100–200 mesh and 200–300 mesh, Qingdao Haiyang Chemical Co., LTD),
Sephadex LH-20 (Pharmacia, Sweden) and ODS-A-HG (50 lm) (YMC Group, Japan)
were used for column chromatography. IR spectroscopic data were measured on a
Bruker IFS 55 spectrometer with KBr pellets. UV spectra were recorded on a Shimadzu
ꢃ
UV 2201 spectrophotometer. Optical rotation was obtained in CH OH at 20 C, using a
3
AUTOPOLV polarimeter (Rudolph, USA). The CD was recorded on a JASCO J-1500 spec-
1
13
tropolarimeter. H and C NMR spectra were obtained on Bruker Avance III 600 MHz
1
13
(
600 MHz for H and 150 MHz for C) spectrometers. HRESIMS was performed on
an Waters Xevo G-2-S UPLC-Q/TOF MS (Waters, USA). Preparative HPLC (LC-6AD) was
performed on CAPCELL PAK C-18 column (5 lm, 10 ꢁ 250 mm) with SPD-20A. All
reagents were HPLC or analytical grade and were purchased from Tianjin Damao
Chemical Company.
3.2. Plant material
The fruits of Xanthium strumarium subsp. sibiricum were purchased from Tong Ren
Tang Co., Ltd. and then identified by Professor Lijuan Zhang, Tianjin University of
Traditional Chinese Medicine. A voucher specimen (herbarium No. 20151015) has been
deposited in the lab.
3.3. Extraction and isolation
The dry fruits of Xanthium strumarium subsp. sibiricum (29 kg) were extracted with
7
5% ethanol (3 ꢁ 300 L, each 2 h) and sequentially with petroleum ether and ethyl
acetate saturated with water, successively. The ethyl acetate layer (890 g) was sub-
jected to passage over a silica gel chromatography column, eluted with a gradient of
CH Cl /MeOH (from 100:1 to 0:1), to obtain eight fractions, Fr.1–Fr.8. Fr.4 (30 g) was
2
2
subjected to ODS column to afford five fractions, Fr.41–Fr.45. Fr.41 (3 g) was separated
on sephadex LH-20 column chromatography that eluting with MeOH to yield six frac-
tions, Fr.411–Fr.416. Fr.411 (600 mg) was subjected to silica gel chromatography col-
umn that using a gradient of CH Cl /MeOH/H O (from 100:3:1 to 10:3:1) to give three
2
2
2
fractions, Fr.4111–Fr.4113. Fr.4112 (100 mg) was purified by semi-preparative HPLC
(
(
ACN/H O 30%) to afford 1 (t ¼ 19.0 min; 10 mg) and 2 (t ¼ 25.6 min; 5 mg). Fr.4113
2
R
R
80 mg) was purified with HPLC (ACN/H O 30%) to yield 3 (t ¼ 24.8 min; 8 mg).
2
R
3.4. Physical and spectroscopic data of isolated compounds
2
-O-(6-O-isocaleryl-b-D-glucopyranosyl) atractyligenin (1): Initially obtained as white
amorphous powder, by recrystallization in CH Cl /MeOH (1:1), the colorless needles
2
2
ꢃ
25
were obtained; mp 172.7–173.2 C; ½aꢄ þ 30.3 (c 0.1, MeOH); IR (KBr) v
3628, 2923,
D
max
ꢂ1
-
1
717, 1650 cm ; UV (MeOH) k
log(e) 202 (2.73) nm; HRESIMS m/z 565.3008 [M-H]
max
1
(
calcd 565.3013); H NMR (600 MHz, CD OD): d 2.31 (1H, dd, J ¼ 12.0, 3.7 Hz, H-1a), 0.80
3

NATURAL PRODUCT RESEARCH
5
(
1H, dd, J ¼ 12.0, 11.9 Hz, H-1b), 4.23 (1H, m, H-2), 2.47 (1H, m, H-3), 1.34 (1H, m, H-3),
2
7
1
.67 (1H, m, H-4), 1.49 (1H, m, H-5), 1.93 (1H, m, H-6), 1.64 (1H, m, H-6), 1.69 (1H, m, H-
), 1.45 (1H, m, H-7), 1.06 (1H, br d, J ¼ 7.6 Hz, H-9), 1.62 (1H, m, H-11), 1.48 (1H, m, H-
1), 1.63 (1H, m, H-12), 1.47 (1H, m, H-12), 2.71 (1H, m, H-13), 1.87 (1H, br d, J ¼ 11.6,
H-14), 1.40 (1H, dd, J ¼ 11.6, 5.0 Hz, H-14), 3.76 (1H, s, H-15), 5.18 (1H, br s, H-17a), 5.08
0
(
8
1H, br s, H-17b), 1.00 (3H, s, H-20), 4.42 (1H, d, J ¼ 8.0 Hz, H-1 ), 3.12 (1H, dd, J ¼ 9.0,
0
0
0
.0 Hz, H-2 ), 3.35 (1H, dd, J ¼ 9.3, 9.0 Hz, H-3 ), 3.25 (1H, t, J ¼ 9.3 Hz, H-4 ), 3.47 (1H,
0
0
ddd, J ¼ 9.3, 6.5, 1.6 Hz, H-5 ), 4.46 (1H, dd, J ¼ 11.7, 1.6 Hz, H-6 ), 4.13 (1H, dd, J ¼ 11.7,
0
00
00
6
4
3
1
1
.5 Hz, H-6 ), 2.21 (2H, d, J ¼ 7.6 Hz, H-2 ), 2.07 (1H, m, H-3 ), 0.95 (3H, d, J ¼ 6.6 Hz, H-
0
0
00 13
), 0.95 (3H, d, J ¼ 6.6 Hz, H-5 ); C NMR (150 MHz, CD OD): d 49.0 (C-1), 74.3 (C-2),
3
5.7 (C-3), 44.8 (C-4), 50.5 (C-5), 26.7 (C-6), 36.3 (C-7), 48.9 (C-8), 54.5 (C-9), 41.9 (C-10),
9.4 (C-11), 33.8 (C-12), 43.8 (C-13), 37.3 (C-14), 83.6 (C-15), 160.4 (C-16), 109.2 (C-17),
0
0
0
0
0
79.0 (C-18), 17.4 (C-20), 103.4 (C-1 ), 75.2 (C-2 ), 78.0 (C-3 ), 71.9 (C-4 ), 75.3 (C-5 ), 64.7
0
00
00
00
00
00
(C-6 ), 174.7 (C-1 ), 44.3 (C-2 ), 27.0 (C-3 ), 22.9 (C-4 ), 22.9 (C-5 ).
2
-O-(2-O-isovaleryl-b-D-glucopyranosyl) atractyligenin (2): white amorphous powder;
2
5
ꢂ1
½
aꢄ þ 28.9 (c 0.1, MeOH); IR (KBr) vmax 3628, 2921, 1716, 1650 cm ; UV (MeOH) kmax
D
-
1
log(e) 201 (2.85) nm; HRESIMS m/z 579.3161 [M-H] (calcd 579.3169); H NMR (600 MHz,
CD OD): d 2.30 (1H, dd, J ¼ 12.0, 3.6 Hz, H-1a), 0.75 (1H, t, J ¼ 12.0 Hz, H-1b), 4.23 (1H,
3
m, H-2), 2.40 (1H, m, H-3), 1.20 (1H, m, H-3), 2.66 (1H, m, H-4), 1.45 (1H, m, H-5), 1.92
(1H, m, H-6), 1.64 (1H, m, H-6), 1.68 (1H, m, H-7), 1.44 (1H, m, H-7), 1.05 (1H, br d,
J ¼ 7.5 Hz, H-9), 1.62 (1H, m, H-11), 1.47 (1H, m, H-11), 1.63 (1H, m, H-12), 1.47 (1H, m,
H-12), 2.70 (1H, m, H-13), 1.87 (1H, m, H-14), 1.39 (1H, m, H-14), 3.76 (1H, s, H-15), 5.18
0
(
4
1H, br s, H-17a), 5.07 (1H, br s, H-17b), 0.99 (3H, s, H-20), 4.60 (1H, d, J ¼ 8.0 Hz, H-1 ),
0
0
.68 (1H, dd, J ¼ 9.0, 8.0 Hz, H-2 ), 3.50 (1H, dd, J ¼ 9.2, 9.0 Hz, H-3 ), 3.38 (1H, dd,
0
0
J ¼ 9.5, 9.2 Hz, H-4 ), 3.32 (1H, ddd, J ¼ 9.5, 5.3, 1.3 Hz, H-5 ), 3.85 (1H, dd, J ¼ 12.0,
0
0
00
1
2
.3 Hz, H-6 ), 3.69 (1H, dd, J ¼ 12.0, 5.3 Hz, H-6 ), 2.37 (1H, dd, J ¼ 14.8, 6.2 Hz, H-2 ),
0
0
00
00
.17 (1H, dd, J ¼ 14.8, 8.0 Hz, H-2 ), 1.88 (1H, m, H-3 ), 1.43 (1H, m, H-4 ), 1.24 (1H, m,
0
0
00
00 13
H-4 ), 0.97 (3H, d, J ¼ 6.7 Hz, H-5 ), 0.91 (3H, t, J ¼ 7.4 Hz, H-6 ); C NMR (150 MHz,
CD OD): d 48.8 (C-1), 74.1 (C-2), 35.8 (C-3), 44.7 (C-4), 50.6 (C-5), 26.7 (C-6), 36.3 (C-7),
3
4
9.0 (C-8), 54.5 (C-9), 41.9 (C-10), 19.8 (C-11), 33.7 (C-12), 43.8 (C-13), 37.3 (C-14), 83.6
0 0
(C-15), 160.4 (C-16), 109.1 (C-17), 178.9 (C-18), 17.3 (C-20), 101.1 (C-1 ), 75.2 (C-2 ), 76.4
0 0 0 0 00 00 00
(C-3 ), 71.8 (C-4 ), 78.0 (C-5 ), 62.7 (C-6 ), 174.1 (C-1 ), 42.6 (C-2 ), 33.3 (C-3 ), 30.5 (C-
0
0
00 00
), 19.3 (C-5 ), 11.8 (C-6 ).
4
3.5. Acid hydrolysis of 1 and 2
Each compounds (2.0 mg) was heated in 3 M CF COOH (3.0 mL) for 3 h in a
3
water bath. Each mixture was extracted three times with EtOAc. The aqueous layer
was evaporated to dryness with ethanol in vacuo until neutral. The residue was dis-
solved in pyridine (1.0 mL), and then added the L-cysteine methyl ester (1.0 mg) and
o-tolyisothiocyanate (1.0 mL) for derivatization. The reaction mixture was centrifuged
and precipitate was removed. Then the solution was analyzed by Water e2695 HPLC
system (CAPCELL PAK C-18 column), eluting with A (0.1% formic acid): B (acetonitrile)
ꢃ
¼
83: 17 (v/v) at 1.0 mL/min. The column temperature was set at 30 C and the

6
T. YAO ET AL.
effluent was monitored at 250 nm. The D-glucose (t ¼ 44.2 min) was determined by
R
comparing with the standard sugar (Figure S24).
3.6. Cell viability assay
HepG2 cells, Hep-2 cells, and HCT 116 cells were seeded onto a 96-well culture plates
3
at a density of 5 ꢁ 10 cells/well for 24 h respectively, and then treated with various
concentration of the tested compounds (3.125, 6.25, 12.5, 25, and 50 lM). After 48 h,
the cell viability was conducted by MTT assay as previously described (Kang et al.
2010; Fan et al. 2018).
3.7. X-ray crystallographic experiment
CCDC 1993831 contains the supplementary crystallographic data for this paper. The detailed
experimental procedures and crystal data were described in the Supplementary Material.
Disclosure statement
No potential conflict of interest was reported by the authors.
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