Anti-inflammatory Dendranacetylene A, a new polyacetylene glucoside from the flower of Chrysanthemum morifolium Ramat

Article abstract of DOI:10.1080/14786419.2020.1825425

A new polyacetylene glucoside, Dendranacetylene A (1), and a known compound 8E-decaene-4,6-diyn-1-O-β-d-glucopyranosyl-(1?→2?)-β-d-glucopyranoside (2) were isolated from the flowers of Dendranthema morifolium (Ramat.) kitam. The chemical structures of these compounds were elucidated by NMR and HR-ESI-MS analysis, and comparing these results with data reported in literatures. Additionally, the anti-inflammatory effects of compounds 1 and 2 were evaluated on RAW264.7 murine macrophage cells induced by lipopolysaccharide (LPS). The two compounds significantly inhibited the NO production in LPS-induced RAW 264.7 murine macrophage cells and exhibited anti-inflammatory effects.

Full text of DOI:10.1080/14786419.2020.1825425

Natural Product Research
Formerly Natural Product Letters
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Anti-inflammatory Dendranacetylene A, a new
polyacetylene glucoside from the flower of
Chrysanthemum morifolium Ramat
Meng Li , Mengnan Zeng , Jingke Zhang , Jingya Shi , Jinjin Lv , Yingying Tang ,
Xiao-ke Zheng & Wei-sheng Feng
To cite this article: Meng Li , Mengnan Zeng , Jingke Zhang , Jingya Shi , Jinjin Lv , Yingying
Tang , Xiao-ke Zheng & Wei-sheng Feng (2020): Anti-inflammatory Dendranacetylene A, a new
polyacetylene glucoside from the flower of Chrysanthemumꢀmorifolium Ramat, Natural Product
Research, DOI: 10.1080/14786419.2020.1825425
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2020.1825425
Anti-inflammatory Dendranacetylene A, a new
polyacetylene glucoside from the flower of
Chrysanthemum morifolium Ramat
Meng Lia,b, Mengnan Zenga,b, Jingke Zhanga,b, Jingya Shia,b, Jinjin Lva,b
Yingying Tanga,b, Xiao-ke Zhenga,b and Wei-sheng Fenga,b
,
b
aHenan University of Chinese Medicine, Zhengzhou, China; The Engineering and Technology
Center for Chinese Medicine Development of Henan Province, Zhengzhou, China
ABSTRACT
ARTICLE HISTORY
Received 7 June 2020
Accepted 4 September 2020
A new polyacetylene glucoside, Dendranacetylene A (1), and a
known compound 8E-decaene-4,6-diyn-1-O-b-D-glucopyranosyl-(1ʺ
!2ʺ )-b-D-glucopyranoside (2) were isolated from the flowers of
Dendranthema morifolium (Ramat.) kitam. The chemical structures
of these compounds were elucidated by NMR and HR-ESI-MS ana-
lysis, and comparing these results with data reported in litera-
tures. Additionally, the anti-inflammatory effects of compounds 1
and 2 were evaluated on RAW264.7 murine macrophage cells
induced by lipopolysaccharide (LPS). The two compounds signifi-
cantly inhibited the NO production in LPS-induced RAW 264.7
murine macrophage cells and exhibited anti-inflammatory effects.
KEYWORDS
Chrysanthemum morifolium
Ramat; polyacetylene
glucoside; structural
elucidation; RAW264.7
murine macrophage cells;
anti-inflammatory activity
1. Introduction
Polyacetylene glycosides are derivatives of polyacetylenes, and their carbon skeletons
are usually assembled from multiple units of acetylene with different chain lengths
and unsaturation degrees, as well as substitutions of the functional groups (Ki et al.
CONTACT Wei-sheng Feng
fwsh@hactcm.edu.cn; Xiao-ke Zheng
zhengxk.2006@163.com
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2020.1825425.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
M. LI ET AL.
2020). Natural polyacetylene compounds have been found in a broad extent of spe-
cies ranging from plants, fungus, marine organisms and insects. Polyacetylene glyco-
sides are widely distributed in a number of vegetables and medicinal plants. They are
especially found in the families Asteraceae, Apiaceae, Araliaceae and Campanulaceae
(Pollo et al. 2018). These compounds remain underexplored and understudied, despite
their inherent chemical and biological reactivity like other unsaturated organic sub-
stances, due to the presence of conjugated triple bonds. Previous studies reported
that polyacetylene glycosides have a diverse range of biological effects, such as cyto-
toxicity, anti-inflammation, antimicrobial and antiallergic activities (Guo et al. 2017).
Inflammation is an evolutionarily conserved complex biological process that occurs in
response to interruption of the tissue homeostasis caused by the presence of a biological,
physical, or chemical stimulus (Sanjeewa et al. 2020). Inflammatory cascade is recognized
as activation of various pro-inflammatory cytokines as well as signalling pathways which
are interlinked with various diseases such as heart attack, stroke and various autoimmune
disorders like arthritis (Bhardwaj et al. 2020). During the last decade, the importance of
Toll-like receptors (TLRs) during the inflammatory responses were well documented.
Specifically, several studies have identified overexpression of TLRs responsible for patho-
genesis of chronic inflammatory diseases. TLR4 is an important member receptor of TLRs
for identify LPS and is responsible to initiate LPS-mediated inflammatory responses
(Joosten et al. 2016). Drugs targeting inhibition of TLR4 pathway are widely used for man-
aging inflammation compared with other anti-inflammatory agents.
Chrysanthemum morifolium Ramat (Flos chrysanthemum), recorded in the Chinese
medical classics ‘Shennong’s Herba’, was considered to be able to ‘remove liver fire’
for improving eyesight, and has been widely used as a healthy beverage and medicine
in China for thousands of years (Kuang et al. 2018). Accumulating reports showed that
Flos chrysanthemum possessed a wide range of biological features including anti-
inflammatory, antioxidation, anticytotoxicity, antiarrhythmic effect and cardiovascular
protection. The main active components of Flos chrysanthemum were reported to be
flavonoids, phenolic acids, sesquiterpenoids, and volatile oils and so on (Wang et al.
2012; Tao et al. 2017).
Huai Flos Chrysanthemi, one of four major Huai medicines, also one of Flos chrysan-
themum, is mainly produced in jiaozuo of henan province. In our previous study, four
new sesquiterpenoids chrysanthguaianolactones C-F (compounds 1–4) and four known
sesquiterpenoids were isolated from an acetone extract of Huai Flos chrysanthemum
and investigated the anti-inflammatory activity through protecting H9c2 cardiomyo-
cyte from LPS induced injury (Chen et al. 2018; Zhang et al. 2019). As a part of our
continuing study of Huai Flos chrysanthemum, further phytochemical study was
undertaken, which led to the isolation of
a new polyacetylene glucoside
Dendranacetylene A (1), together with a known compound 8E-decaene-4,6-diyn-1-O-
b-D-glucopyranosyl-(1ʺ!2ʺ)-b-D-glucopyranoside (2). The structures of them were con-
firmed on the basis of extensive spectroscopic analysis, including 1D, 2D NMR,
HRESIMS, UV and IR. Additionally, the anti-inflammatory effects of compounds 1 and 2
were evaluated on RAW264.7 cells induced by LPS. Compound 1 and 2 significantly
inhibited the NO production in LPS-induced RAW 264.7 murine macrophage cells and
exhibited anti-inflammatory effects (Figure 1).

NATURAL PRODUCT RESEARCH
3
Figure 1. Structures of compounds 1 and 2.
2. Results and discussion
Compound 1 was obtained as a white powder. The molecular formula was determined
to be C22H32O11Na based on an observed peak at m/z 495.1834 [M þ Na]þ from HRESI-
MS analysis (calcd. for C22H32O11Na 495.1842). The specific absorption in the UV [UV
(MeOH) kmax: 207 (2.83), 212 (2.98), 239 (0.78), 252 (1.13), 266 (1.53), 281 (1.20) nm]
spectrum indicated the presence of one C ¼ C bond and two CꢀC bonds in conjuga-
tion (Jin et al. 2019). Its IR spectrum showed absorption bands for hydroxyl
(3340 cmꢁ1), methyl (2924 cmꢁ1), conjugated double bond (1674 cmꢁ1) and ether
1
bond (1072 and 1031 cmꢁ1) functionalities. The H NMR spectrum suggested the exist-
ence of a pairs of olefinic protons at dH 5.49 (1H, d, J ¼ 11.0 Hz, H-8) and 6.13 (1H, m,
H-9), two anomeric proton at dH 4.40 (1H, d, J ¼ 7.5 Hz, H-10) and 4.59 (1H, d,
J ¼ 7.5 Hz, H-1ʺ) (He et al. 2011). The 13C NMR spectrum (Table S1) showed 22 carbon
signals, combined with the DEPT 135 and HSQC spectra, which revealed the presence
of one methyl group at dC 16.9 (C-10), three methylenes group at dC 69.4 (C-1), 29.8
(C-3), 16.3 (C-2), two olefinic carbons at dC 142.9 (C-9) and 110.0 (C-8), four CꢀC
bonded quaternary carbons at dC 85.3 (C-4), 79.6 (C-7), 72.5 (C-6) and 66.1 (C-5) (Sun
et al. 2016), 12 carbon signals remained were assigned to the two glucopyranose moi-
eties [dC 103.0 (C-10), 83.1 (C-20), 78.3 (C-30), 71.5 (C-40), 77.9 (C-50), 62.8 (C-60)] and [dC
105.2 (C-1ʺ), 76.1 (C-2ʺ), 77.8 (C-3ʺ), 71.4 (C-4ʺ), 77.8 (C-5ʺ), 62.6 (C-6ʺ)] (Gao et al.
2019). The hexose was determined as D-glucose by HPLC analysis of the acid hydroly-
sis solution of 1 (Li et al. 2018). And the configurations of all glucose moieties were
3
3
0
0
identified as b-glucopyranosyl groups on the basis of their JH-1 , H-2 , JH-1ʺ, H-2ʺ, cou-
pling constants of 7.5 Hz and 7.5 Hz, respectively. After a glycosidation shift was
accounted for, the second glucose unit was assumed to be connected to C-20 of the
first. Together, these data suggested that compound 1 was a typical structure
of polyacetylene glycoside. The NMR data of 1 were similar to those of the known
compound 2 (Wang and Yu 1998), except that the constant coupling between
3
H-8 and H-9. The J value of JH-8, H-9 in compound 1 was 11.0 Hz which was different

4
M. LI ET AL.
from that of compound 2 (3JH-8,
¼ 15.9 Hz). Therefore, the configuration of the
1
H-9
double band in 1 was cis. A full analysis of the H-1H COSY, HMBC, NOESY spectra of
1
compound 1 allowed H and 13C NMR to be fully assigned (Figure S1). On the basis of
above data, the structure of compound 1 was determined as (8Z)-decaene-4,6-diyn-1-
O-b-D-glucopyranosyl-(1ʺ!2ʺ)-b-D-glucopyranoside and named Dendranacetylene A.
LPS-stimulated RAW264.7 macrophage cells were used as the TLR4-activated cell
model to investigate the inhibitory effect of compounds 1 and 2 on inflammatory
mediators. Stimulation with LPS resulted in significant increase in the production of
NO, compounds 1 and 2 decreased the production of NO (Figure S2(A)). The effects of
compounds 1 and 2 on pro-inflammatory medicators were investigated, including
iNOS and COX-2. Compounds 1 and 2 decreased the protein levels of iNOS and COX-2
in LPS-stimulated RAW264.7 cells (Figure S2(B–D)).
3. Experimental
3.1. General experimental procedures
UV spectra were measured on a UV-2401PC apparatus (Shimadzu, Japan). IR spectrom-
etry was recorded on a Nicolet iS10 Microscope Spectrometer (Thermo Fisher
1
Scientific, USA). NMR spectra were obtained at 500 MHz for H-NMR and 125 MHz for
13C-NMR, on Avance III 500 MHz spectrometer in MeOH-d4 (Bruker, Germany). HRESIMS
spectra were measured using a Bruker maXis HD mass spectrometer (Bruker, USA).
Preparative HPLC was conducted using a LC-50 instrument with a UV200 detector
(Saipuruisi, China) and YMC-Pack ODS-A column (250 ꢂ 20 mm, 5 lm and 250 ꢂ 10 mm,
5 lm). Column chromatography was performed using a Diaion HP-20 (Mitsubishi
Chemical Corporation), Toyopearl HW-40, MCI gel CHP-20 (TOSOH Corporation),
Sephadex LH-20 (Amersham Pharmacia Biotech AB), LiChroprep RP-18 gel (Merck,
Darmstadt) and silica gel (Marine Chemical Industry). TLC was performed using self-
made silica gel G plates (Qingdao Marine Chemical Industry). All chemical reagents
were supplied by Beijing Chemical Plant and Tianjin NO. 3 Reagent Plant.
3.2. Plant materials and reagent
Huai Flos Chrysanthemi was collected from Jiaozuo, Henan Province in China in 2015.
The plants were identified by Prof. Suiqing Chen of Henan University of Chinese
Medicine. A voucher specimen (No. 20150715A) was deposited in the Research
Department of Natural Medicinal Chemistry, School of Pharmacy, Henan University of
Chinese Medicine. The RAW267.4 murine macrophage cell line (ATCC TIB-71) was
obtained from the American Type Culture Collection (Manassas, VA, USA). LPS were
obtained from Sigma Chemicals Ltd. (St. Louis, MO, USA). Penicillin, streptomycin,
DMEM and FBS were purchased from Hyclone (Logan, UT, USA). Cyclooxygenase-2
(COX-2) and Inducible nitric oxide synthase (iNOS) were obtained from Cell Signaling
Technology (Boston, MA, USA).

NATURAL PRODUCT RESEARCH
5
3.3. Extraction and isolation
Huai Flos Chrysanthemi (11.2 kg) were fractured in 50% acetone (25 L ꢂ 3) thrice in a
flash extractor at room temperature (25 ꢃC). The filtrated solution was condensed
under reduced pressure to give an extract (2.5 kg). The extract was concentrated under
reduced pressure to give a brown syrup, which was partitioned into H2O (9 L) and
extracted successively with petroleum ether (5 ꢂ 3 L), EtOAc (5 ꢂ 104 L), and n-BuOH
(5 ꢂ 4 L); the extracts were kept separately. The EtOAc -soluble fraction (352.0 g) was
passed through a silica gel (1.0 kg) open column (30 cm ꢂ 16 cm i.d.) eluted with
CH2Cl2/MeOH (v/v, 50:1, 30 L ! 30:1, 30 L ! 20:1, 30 L ! 5:1, 30 L) to provide fractions
A–D (64.2 g, 58.6 g, 31.0 g and 72.2 g, respectively) on the basis of TLC analysis.
Fraction C (31.0 g) was separated on silica gel CC again, eluting with CH2Cl2-MeOH
(80:1, 60:1, 40:1, 20:1, 10:1, and 5:1), to obtain fractions C1–C6. Fraction C1 was sepa-
rated by MCI using gradient elution (100% H2O to 40% MeOH) to give seven fractions
(Fr.C4a–Fr.C4g) based on TLC analysis. Fr.C4a was further purified by RP C18 HPLC
[YMC-Pack ODS-AA, CH3CN ꢁ H2O (23:77, v/v) containing 0.2% TFA] to afford 1 (tR
26.0 min, 4.2 mg) and 2 (tR 35.1 min, 6.5 mg).
3.3.1. Dendranlignan A (1)
White powder; UV (CH3OH) kmax (loge): 207 (2.83), 212 (2.98), 239 (0.78), 252 (1.13),
266 (1.53), 281 (1.20) nm; IR ꢀmaxcmꢁ1(iTR) cmꢁ1: 334,029,241,674,143,000,000,
000,000,000,000,000 cmꢁ1. HR-ESI-MS m/z: 495.1842 [M þ Na]þ (calcd. For C22H32O11Na
1
495.1842). H NMR (500 MHz, CD3OD): d 3.97 (1H, m, H-1a), 3.67 (1H, m, H-1b), 2.52
(2H, t, 7.0, H-2), 1.86 (3H, d, 6.5, H-3), 5.49 (1H, d, J ¼ 11.0 Hz, H-8), 6.13 (1H, m, H-9),
1.86 (3H, d, 6.5, H-10), 4.40 (1H, d, J ¼ 7.5 Hz, H-10), 3.42 (1H, t, 8.0, H-20), 3.55 (1H, t,
8.0, H-30), 3.86 (1H, m, H-60a, 6ʺa), 3.67 (1H, m, H-60b, 6ʺb), 4.59 (1H, d, J ¼ 7.5 Hz, H-1ʺ);
13C NMR (125 MHz, CD3OD): d69.4 (C-1), 16.3 (C-2), 29.8 (C-3), 85.3 (C-4), 66.1 (C-5),
72.5 (C-6), 79.6 (C-7), 110.0 (C-8), 142.9 (C-9), 16.9 (C-10), 103.0 (C-10), 83.1 (C-20), 78.3
(C-30), 71.5 (C-40), 77.9 (C-50), 62.8 (C-60), 105.2 (C-1ʺ), 76.1 (C-2ʺ), 77.8 (C-3ʺ), 71.4 (C-4ʺ),
77.8 (C-5ʺ), 62.6 (C-6ʺ).
3.4. Acid hydrolysis
Compound 1 (1 mg) was treated with 2 mol/L aqueous HCl (2 mL) (sealed flask, heating
in Water bath, 80 ꢃC, 3 h). Then the acidic aqueous mixture was dried, H2O (2 mL) was
added, and the mixture was extracted with EtOAc (3 ꢂ 2 mL). The aqueous layer was
subjected to the chiral-phase HPLC analysis under the following condition, respect-
ively. The carbohydrate products of the hydrolysis of 1 was separated and detected
using a CHIRALPAK AD-H column (250 ꢂ 4.6 mm) using n-hexane: EtOH: TFA
(750:250:0.25) as the mobile phase (0.5 mL minꢁ1) and an evaporative light scattering
detector (ELSD). D-Glucose was detected in the acid hydrolysates of compound 1 by
comparing the retention times of their derivatives with those of known D-glucose
derivatives (tR, 18.3 min) prepared in the same manner. Comparison glucose samples
were supplied by Shanghai Yuanye Biotechnology Co., Ltd.

6
M. LI ET AL.
3.5. No production measurement
RAW264.7 cells were seeded on 96-well plates (1.0 ꢂ 105 cells/well) and allowed to
adhere overnight. The cells were treated with indicated concentrations (50mM) of C1
and C2 for 1 h, and then in the presence or absence of LPS (M, 1mg/mL) for another
24h. The supernatant of cultured RAW 264.7 cells was used to measure NO production
by determining the accumulated nitrite formed using the Griess reagent (Sigma). Briefly,
100mL of culture supernatant was mixed with an equal volume of 1% sulfanilamide-0.1%
naphthylethylenediamine dihydrochloride-2.5% H3PO4. Absorbance was measured at
540 nm, and values were quantified against a standard curve of sodium nitrite.
3.6. Western blotting
RAW 264.7 cells were seeded in 60-mm-diameter culture dishes (3 ꢂ 105 cells/mL) and
allowed to adhere overnight. The cells were treated with C1 and C2 at indicated concentra-
tions for 1 h, and then at the presence or absence of LPS (M, 1 mg/mL, 60 min). Soluble
lysates was centrifuged at 4 ꢃC, 15,000ꢂg for 15 min to obtain supernatant total protein
lysates which was adopted to detect the levels of target protein levels with b-actin as an
inner control. Protein concentrations were determined according to the Bio-Rad protein
assay reagent. Equal amounts of proteins were separated by 10% SDS-PAGE and then elec-
tro-transferred onto nitrocellulose membrane which was blocked with 5% skim milk.
Subsequently, the membrane was incubated at 4 ꢃC overnight with respective primary anti-
bodies followed incubation with anti-mouse or anti-rabbit IgG horseradish peroxidase
(HRP)-conjugated secondary antibodies at room temperature for 1 h. After washing in TBST,
immunereactive bands were visualized by the chemiluminescence substrate (Thermo
Scientific, Rockford, IL, USA), and the band intensity was analyzed using Image J software.
4. Conclusions
In conclusion, a new Dendranacetylene A (1) and a known compound 8E-decaene-4,6-
diyn-1-O-b-D-glucopyranosyl-(1ʺ !2ʺ )-b-D-glucopyranoside (2) were isolated from the
flowers of Huai Flos chrysanthemum, and compound 1 and 2 significantly inhibited
the NO production in LPS-induced RAW 264.7 murine macrophage cells and exhibited
anti-inflammatory effects. These findings provide further pharmacological basis for the
traditional clinical use of the formula in controlling inflammatory disorders.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
Our work was supported by the Central Government Guide Local Science and Technology
Development Funds (14104349), the Key Scientific Research Project of Institutions of Higher
Learning in Henan (21B360003), the Special Project of Scientific Research on Traditional Chinese
Medicine in Henan (20-21ZY2151) and the Doctoral Research Fund of Henan University of
Chinese Medicine (BSJJ2018-08).

NATURAL PRODUCT RESEARCH
7
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