A new nitrogen-containing iridoid glycoside from lonicera macranthoides

Article abstract of DOI:10.1080/14786419.2019.1705819

A new nitrogen-containing iridoid glycoside, named (7 R,3′R)-lonijapospiroside A (1), together with thirteen known iridoid glycosides, were isolated from the flower buds of Lonicera macranthoides. The structures of these compounds were established on the basis of spectroscopic analyses. Among them, compounds 1-4 are four diastereoisomers, and their absolute configurations were accurately established by the NOE spectra as well as comparison of their experimental and calculated ECD spectra. The anti-inflammatory activities of all isolates were evaluated by measuring their inhibitory effects on NO, IL-6, and TNF-α production in LPS stimulated RAW 264.7 macrophages. Compound 14 exhibited anti-inflammatory activities by inhibiting IL-6 with an IC₅₀ value of 54.70 μM, comparable to that of the positive control (hydrocortisone, IC₅₀: 62.6 ± 1.7 μM).

Full text of DOI:10.1080/14786419.2019.1705819

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
A new nitrogen-containing iridoid glycoside from
lonicera macranthoides
Yu-Dan Mei, Hai-Bo Li, Ling-Xian Liu, Dan-feng Shi, Da-bo Pan, Xin-Sheng Yao
& Yang Yu
To cite this article: Yu-Dan Mei, Hai-Bo Li, Ling-Xian Liu, Dan-feng Shi, Da-bo Pan, Xin-Sheng
Yao & Yang Yu (2020): A new nitrogen-containing iridoid glycoside from loniceraꢀmacranthoides,
Natural Product Research, DOI: 10.1080/14786419.2019.1705819
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2019.1705819
A new nitrogen-containing iridoid glycoside from lonicera
macranthoides
a
b
a
a
a
ꢀ
ꢀ
Yu-Dan Mei , Hai-Bo Li , Ling-Xian Liu , Dan-feng Shi , Da-bo Pan , Xin-Sheng
Yaoa and Yang Yua
aInstitute of Traditional Chinese Medicine & Natural Products, College of Pharmacy and Guangdong
Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan
b
University, Guangzhou, People’s Republic of China; Jiangsu Kanion Pharmaceutical Co. Ltd. and
State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Jiangsu,
Lianyungang, People’s Republic of China
ABSTRACT
ARTICLE HISTORY
A new nitrogen-containing iridoid glycoside, named (7 R,30R)-loni-
japospiroside A (1), together with thirteen known iridoid glyco-
sides, were isolated from the flower buds of Lonicera
macranthoides. The structures of these compounds were estab-
lished on the basis of spectroscopic analyses. Among them, com-
pounds 1-4 are four diastereoisomers, and their absolute
configurations were accurately established by the NOE spectra as
well as comparison of their experimental and calculated ECD
spectra. The anti-inflammatory activities of all isolates were eval-
uated by measuring their inhibitory effects on NO, IL-6, and TNF-a
production in LPS stimulated RAW 264.7 macrophages.
Compound 14 exhibited anti-inflammatory activities by inhibiting
IL-6 with an IC50 value of 54.70 lM, comparable to that of the
positive control (hydrocortisone, IC50: 62.6 1.7 lM).
Received 11 October 2019
Accepted 2 December 2019
KEYWORDS
Lonicera macranthoides;
iridoid glycoside; anti-
inflammatory; NO; IL-6;
TNF-a
CONTACT Yang Yu
The first two authors contributed equally to this work.
1018yuyang@jnu.edu.cn; Xin-Sheng Yao
tyaoxs@jnu.edu.cn
ꢀ
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1705819.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
Y.-D. MEI ET AL.
1. Introduction
Lonicerae Flos (LF, Shan-yin-hua in Chinese) and Lonicerae japonicae Flos (LJF, Jin-yin-
hua in Chinese) were two independent items from different plants sources of Lonicera
genus. They have the same descriptions of flavor, meridian tropism (MT), functions,
and indications in Chinese Pharmacopoeia Commission (2015 edition), and commonly
used for the treatment of upper respiratory tract infections, fever, sores, headache,
and epidemic disease. Chemical studies have disclosed their bioactive components as
iridoids (Liu et al. 2012, Ge et al. 2019,), flavonoids (Xu et al. 2006), polyphenols (Liu
et al. 2014; Mei et al. 2019) and saponins (Chen et al. 2012; 2014, Mei et al. 2019).
Also, a systematic pharmacology review was reported to compare their broad bioactiv-
ities (Li et al. 2015). However, the research was mostly focused on LJF, and studies
concerning LF was comparatively limited. Thus, to further assess the functions of LF
on its chemicals and bioactivities, our previous studies on the 70% EtOH extract of the
flower buds of L. macranthoides, an important plant source of LF, resulted in the isola-
tion of eleven chlorogenic acids (Mei et al. 2019), twelve triterpenoids (Mei et al.
2019), and three novel iridoid glucosides (Mei et al. 2019). Herein, as a part of our con-
tinuous study for bioactive iridoids, a new nitrogen-containing iridoid glycoside,
named (7 R,30R)-lonijapospiroside A (1), together with thirteen known iridoids, were
obtained from L. macranthoides. Their structures were accurately confirmed by spectro-
scopic or literature reported data. Furthermore, the anti-inflammatory activities of the
isolated compounds were evaluated in vitro, but only compound 14 exhibited moder-
ate inhibitory effect on IL-6 with an IC50 value of 54.70 lM.
2. Results and discussion
2.1. Structure determination
Compound 1 was isolated as light yellow solid ([a]29 D-32.7, c ¼ 0.53, in CH3OH). Its
molecular formula was determined as C27H31NO12 on the basis of the HR-ESI-MS data
(m/z 584.1725 [M þ Na]þ, calcd for C27H31NO12Na: 584.1744). The UV spectrum showed
the absorption maximum at 210 and 236 nm, respectively. The IR spectrum exhibited
the absorption bands of hydroxyl (3412 cmꢁ1), carbonyl (1708 cmꢁ1), and aromatic
1
group (1627 and 1439 cmꢁ1) groups. The H-NMR spectrum of 1 exhibited characteris-
tic signals of a secoiridoid-type glycoside, including an acetal proton [dH 5.41 (1H, d,
J ¼ 4.0 Hz, H-1)], a tri-substituted olefinic proton [dH 7.37 (1H, d, J ¼ 1.8 Hz, H-3)], a
mono-substituted vinyl group [dH 5.42 (1H, ddd, J ¼ 17.2, 10.4, 9.6 Hz, H-8), 5.18 (1H,
dd, J ¼ 17.2, 1.7 Hz, H-10a), 5.16 (1H, dd, J ¼ 10.4, 1.7 Hz, H-10b)], and a sugar [dH 4.62
(1H, d, J ¼ 7.9 Hz, H-100), dH 3.21-3.89 (H-100ꢂ H-600)]. Additionally, an ortho-substituted
phenyl moiety [dH 7.30 (1H, ddd, J ¼ 7.9, 7.7, 1.0 Hz, H-60), 7.19 (1H, dd, J ¼ 7.9, 1.0 Hz,
H-40), 7.09 (1H, ddd, J ¼ 7.9, 7.7, 1.0 Hz, H-50), 6.96 (1H, dd, J ¼ 7.9, 1.0 Hz, H-70)] and an
isolated methylene [dH 3.27 (1H, d, J ¼ 17.2 Hz, H-80a), 2.67 (1H, d, J ¼ 17.2 Hz, H-80b)]
were obviously observed.
The sugar moiety of 1 was determined to be D-glucose by HPLC analysis after acid
hydrolysis and glucosyl derivatization (Tanaka et al. 2007) (Figure S5). Combined with
the J value (J ¼ 7.9 Hz) of the proton at the anomeric center mentioned above, a b-D-

NATURAL PRODUCT RESEARCH
3
Figure 1. Structures of compounds 1-14.
glucosyl residue was deduced (Mei et al. 2019). Furthermore, a secologanin unit can
1
be assigned by the H-1H COSY correlations of H-1/H-9(H-8/H2-10)/H-5/H2-6/H-7 and
the HMBC correlations of H-1/C-3, 5, 8, 9, 100, H-3/C-1, 4, 5, 11 and H-5/C-1, 4, 6, 7, 8, 9
(Figure S1). Besides the secologanin moiety, the rest carbon signals were revealed as
two carbonyls [dC 178.3 (C-20) and 176.0 (C-90)], a phenyl group [dC 142.6 (C-70a), 130.5
(C-40a), 130.1 (C-60), 125.1 (C-40), 123.8 (C-50), and 111.8 (C-70)], a quaternary carbon [(dC
56.8 (C-30)] and a methylene [dC 40.9 (C-80)], requiring 8 degrees of unsaturation.
Therefore, a 3-acetyl-2-indolone unit could be established and assigned by the key
HMBC correlation at H-40/C-4a0, 3, and H-80/C-20, 30, 40a, 90 (Figure S1), as well as the
typical chemical shifts of C-70a, 20. And then, the HMBC correlations of H-7/C-20, 30, 40a,
80, 90, indicated that the two partial structures were connected between C-30-C-7, and
C-90-O-C-7 bonds to form a five-membered lactone ring, satisfying the remaining one
degree of unsaturation. Thus, the planar structure of compound 1 was established.
Compounds 1-4 were suggested to possess the same planar structures by analyzing
their NMR data. As for the chiral centers, C-1, C-5, and C-9 were identical with secolo-
ganin and determiened as 1S, 5S and 9 R, for the obvious NOE correlations of H-1/H2-6
and H-1/H-8 (Figure S2). Additionally, modeling analysis of the 3-acetyl-2-indolone
structure afforded four possible candidate stereoisomers 7 R/30R, 7S/30S, 7S/30R, and
7 R/30S. In 1 and 2, the benzene ring and H-7 were of the opposite side, which can be
supported by the NOE correlations of H-7/H-80exo and H-80endo/H-40 (Figure S2). So, 1
and 2 were assigned as 7 R/30R or 7S/30S. Conversely, 3 and 4 were assigned as 7S/30R
or 7 R/30S for the NOE correlations of H-7/H-80exo/H-40 (Figure S2), which showed that
the benzene ring and H-7 were on the same side. Accordingly, relative configurations
of 1-4 were determined, and their absolute configurations were further distinguished
by comparison of the experimental and calculated ECD spectra (Figure S3). As a result,

4
Y.-D. MEI ET AL.
the absolute configurations of C-7 and C-30 in 1-4 were assigned as 7 R/30R, 7S/30S, 7S/
1
30R, and 7 R/30S, respectively. The H- and 13C-NMR signals of 1-4 were provided in
supporting information (Table S1).
Thus, 1 was a new compound named (7 R,30R)-lonijapospiroside A (1), while 2 was
reported and named lonijapospiroside A (Zheng et al. 2012). 3 and 4 were revised as
(7S,30R)-lonijapospiroside A (3) and (7 R,30S)-lonijapospiroside A (4) for some mistake in
the configurations reported by the original literature (Liu et al. 2016).
The known compounds 5-14 (Figure 1) were identified as stryspinoside (5) (Itoh
et al. 2005), kingiside (6) (Garcia et al. 1990), geniposide (7) (Guvenalp et al. 2006),
secoxyloganin (8) (Li et al. 2013), dimethyl acetal secologanin (9) (Ma et al. 2011), L-
phenylalaninosecologanin C (10) (Zheng et al. 2012), L-phenylalaninosecologanin B
(11) (Zheng et al. 2012), sweroside (12) (Li et al. 2013), xylostosidine (13) (Chaudhuri
et al. 1980) and lonicerjaponin A (14) (Kashiwada et al. 2013), respectively.
2.2. Anti-inflammatory activities
The inhibitory effects on NO (nitric oxide), IL-6 (interleukin 6) and TNF-a (tumor necro-
sis factor) of compounds 1-14 were evaluated with LPS-stimulated RAW 264.7 cells.
The procedure of anti-inflammatory activities assay was conducted following a
reported procedure (Hou et al. 2017). As a result, compound 14 exhibited inhibitory
effect on IL-6 with an IC50 value of 54.70 lM (Figure S4), comparable to that of the
positive control (hydrocortisone, IC50: 62.6 1.7 lM). Unfortunately, none of them dis-
played TNF-a and NO inhibitory activities at 100 lM.
3. Experimental
3.1. Plant material
Dried flower buds of L. macranthoides, a synonym of Lonicera macrantha (D.Don)
Spreng1, were collected in Shandong Province and purchased from Kunyuan pharma-
ceutical Co., Ltd. in Nov, 2014, and identified by Prof. GuangXiong Zhou (expert in
plant identification) of Jinan University. A sample (No. LM201411) is deposited in insti-
tute of Traditional Chinese Medicine & Natural Products, college of pharmacy, Jinan
University, Guangzhou, China.
3.2. Extraction and isolation
Dried flower buds of L. macranthoides (35 kg) were extracted twice with 70% ethanol
(280 L, for 2 h each time) under reflux. The ethanol was evaporated under vacuum,
affording a crude extract (8.5 kg), which was suspended in water and then subjected
to an HP-20 macroporous resin CC (25 kg, / 20 ꢃ 85 cm) eluted with EtOH-H2O (0:100,
30:70, 50:50, 95:5, v/v) to offer four fractions (LM-1ꢂLM-4). LM-3 (700 g) was chromato-
graphed over a silica gel CC (1.75 kg, / 110 ꢃ 420 cm) by using a CHCl3-CH3OH-H2O
gradient (95:5:0 to 60:40:8, v/v/v), yielding sixteen fractions (3 A-3P). Fraction 3E
(17.7 g) was separated by ODS (200 g, / 3.3 ꢃ 33 cm) eluted with CH3OH-H2O (30:70 to
100:0, v/v) to offer eleven subfractions (E1-E11). E1 was subjected to an ODS CC

NATURAL PRODUCT RESEARCH
5
(100 g, 3.3 ꢃ 18 cm CH3OH-H2O, 30:70, v/v) to yield fractions E1A-F. Then fractions E1A
and E1F were purified by semi-preparative HPLC (CH3CN-H2O, 15:85, v/v), giving 6 (tR:
7.45 min, 33.3 mg) and 12 (tR: 6.6 min, 22.2 mg), respectively, while E1B was separated
by a SiO2 CC (CHCl3-CH3OH-H2O, 80:20:2, v/v/v) and a semi-preparative HPLC (CH3CN-
H2O-HCOOH, 15:85:0.1, v/v/v), to furnish 7 (tR: 9.0 min, 59.7 mg) and 8 (tR: 10.0 min,
69.6 mg). Successive SiO2 CC (CHCl3-CH3OH-H2O 80:20:2, v/v/v) and semi-preparative
HPLC chromatography of fractions E2, E3, E4, E5, E8, and E9, offered 9 (CH3CN-H2O,
15:85, v/v, tR: 11.3 min, 20.3 mg), 5 (CH3CN-H2O, 18:82, v/v, tR: 10.1 min, 4.0 mg), 3
(CH3CN-H2O, 18:82, v/v, tR: 19.9 min, 31.7 mg), 13 (CH3CN-H2O-HCOOH, 23:77:0.1, v/v/v,
tR: 27.3 min, 6.7 mg), 2 (CH3CN-H2O-HCOOH, 25:75:0.1, v/v/v, tR: 16.0 min, 6.1 mg), and
11 (CH3CN-H2O-HCOOH, 25:75:0.1, v/v/v, tR: 27.3 min, 6.7 mg), respectively. Fraction E6
was subjected to SiO2 CC (CHCl3-CH3OH-H2O 80:20:2, v/v/v), offering fraction E6C, from
which 1 (tR: 5.0 min, 20.0 mg) and 4 (6.5 min, 33.0 mg) were obtained by a chiral col-
umn (Daicel CHIRALCEL OX-3R, 5 lm, / 4.6 ꢃ 250 mm) using preparative HPLC (CH3CN-
H2O-HCOOH, 23:77:0.1, v/v/v,). Fraction 3 F (58.5 g) was separated into three subfrac-
tions (F1-3) by a SiO2 CC (1 kg, / 7 ꢃ 74 cm CHCl3-CH3OH-H2O, 80:20:2, v/v/v), and
then fraction F1 (25 g) was separated by an ODS CC (200 g, / 3.3 ꢃ 33 cm, CH3OH-H2O,
30:70 to 100:0, v/v), giving fractions F1A-G. 14 (tR: 25.0 min, 10.0 mg) and 10 (tR:
35.5 min, 30.5 mg) were obtained from fraction F1G by further purified using semi-pre-
parative HPLC (CH3CN-H2O-HCOOH, 75:25:0.1, v/v/v).
3.2.1 (7R, 30R)-lonijapospiroside A (1)
Light yellow solid, [a]29 D-32.7 (c ¼ 0.53, in CH3OH); HR-ESI-MS: m/z 584.1725
[M þ Na]þ (calcd for C35H46O17 Na, 584.1744); UV (CH3OH) kmax (loge): 210 (4.45), 236
(4.16); ECD (MeOH) kmax (De) 208 nm (þ6.7), 224 nm (ꢁ10.9), 253 nm (þ7.6). IR (KBr)
1
ꢀmax: 3412, 2927, 1778, 1708, 1627, 1439, 1287, 1187, 1078, 757 cmꢁ1; H and 13C NMR
data see Table S1.
3.3. Acid hydrolysis of compound 1 and HPLC analysis of sugar
The absolute configuration of the sugar moieties was determined according to the
reported method. Compounds 1 (1.5 mg) was hydrolyzed with HCl (2 mL, 2 M) for 2 h
at 90 ꢄC. After extracting with EtOAc, the H2O layer was evaporated in vacuum to
furnish a monosaccharide residue. The residue was dissolved in pyridine (1.0 mL) con-
taining L-cysteine methyl ester hydrochloride (2.5 mg) and heated at 60 ꢄC. One hour
later, o-tolyl isothiocyanate (10 lL) was added and further reacted at 60 ꢄC for 1 h.
Then, the reaction mixture was directly analyzed by the HPLC system and detected
with a UV detector at the wavelength of 250 nm on a C18 column at 35 ꢄC. The
mobile phase was CH3CN-H2O-HCOOH (25:75:0.1, v/v/v) at a flow rate of 0.8 mL/min.
The standard monosaccharides, namely D-glucose, and L-glucose, were subjected to
the same method. As a result, the sugar moiety of 1 was determined to be D-glu-
cose by comparing retention time with glucosyl derivatization in HPLC chromato-
graph (Figure S5).

6
Y.-D. MEI ET AL.
4. Conclusions
In this study, a new nitrogen-containing iridoid glycoside, named (7 R,30R)-lonijapo-
spiroside A, together with thirteen known iridoid glycosides were isolated from
70% ethanol extract of the flower buds of L. macranthoides (Figure 1). Among
them, compounds 1-4 are four diastereoisomers, and their absolute configurations
were determined by NOESY spectra combined with comparison of their experi-
mental and calculated ECD spectra. Anti-inflammatory (NO, IL-6, TNF-a) activities of
the isolated compounds were evaluated in vitro, but only compound 14 displayed
anti-inflammatory activities with an IC50 value of 54.70 lM by inhibiting the pro-
duction of IL-6, comparable to that of the positive control (hydrocortisone,
IC50: 62.6 1.7 lM).
Acknowledgements
The authors are grateful to State Key Laboratory of New-Tech for Chinese Medicine
Pharmaceutical Process, Jiangsu Kanion Pharmaceutical Co. Ltd. for their assistance of
activity test.
Note
1. The record derives from WCSP which reports it as a synonym with original publication
details: Symb. Sin. 7: 1050 1936.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by grants from the National Natural Science Foundation of China (pro-
gram No. 81630097, 81602984 and 81803347), National Major Scientific and Technological
Special Project for “Significant New Drugs Development” during the Thirteen Five-year Plan
Period (2018ZX09711001-008-005).
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