A new ent-kaurane diterpene derivative from the stems of Eurya chinensis R.Br

Article abstract of DOI:10.1080/14786419.2017.1343327

One new ent-kaurane diterpene derivative (1), along with four known diterpenes, was isolated from the stems of Eurya chinensis R.Br. The structure of the new compound was established by extensive analysis of mass spectrometric and 1D and 2D NMR spectroscopic data. Compound 1 showed moderate anti-inflammatory activities with IC₅₀ value of 8.12?μM. This is the first example of diterpenoids with 4-hydroxy-4-(2-hydroxyethyl)-1-hydroxyl-cyclohexanoyl substituent.

Full text of DOI:10.1080/14786419.2017.1343327

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
A new ent-kaurane diterpene derivative from the
stems of Eurya chinensis R.Br
Jia-Ling Song, Yao Yuan, Ling-Hui Nie, Bai-Lin Li, Xu-Bing Qin, Yan Li, Jie-Wei
Wu & Sheng-Xiang Qiu
To cite this article: Jia-Ling Song, Yao Yuan, Ling-Hui Nie, Bai-Lin Li, Xu-Bing Qin, Yan Li, Jie-Wei
Wu & Sheng-Xiang Qiu (2017): A new ent-kaurane diterpene derivative from the stems of Eurya
chinensis R.Br, Natural Product Research, DOI: 10.1080/14786419.2017.1343327
To link to this article: http://dx.doi.org/10.1080/14786419.2017.1343327
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Date: 24 June 2017, At: 02:48

Natural Product research, 2017
https://doi.org/10.1080/14786419.2017.1343327
A new ent-kaurane diterpene derivative from the stems of
Eurya chinensis R.Br
Jia-Ling Songa, Yao Yuana, Ling-Hui Nieb, Bai-Lin Lia, Xu-Bing Qina, Yan Lia,
Jie-Wei Wua and Sheng-Xiang Qiua
aProgram for Natural Product chemical Biology, Key laboratory of Plant resources conservation and
sustainable utilization, Guangdong Provincial Key laboratory of applied Botany, south china Botanical
Garden, chinese academy of sciences, Guangzhou, People’s republic of china; bcollege of traditional chinese
Medicine, southern Medical university, Guangzhou, People’s republic of china
ABSTRACT
ARTICLE HISTORY
received 23 March 2017
accepted 27 May 2017
One new ent-kaurane diterpene derivative (1), along with four known
diterpenes, was isolated from the stems of Eurya chinensis R.Br. The
structure of the new compound was established by extensive analysis
of mass spectrometric and 1D and 2D NMR spectroscopic data.
Compound 1 showed moderate anti-inflammatory activities with
IC50 value of 8.12 μM. This is the first example of diterpenoids with
4-hydroxy-4-(2-hydroxyethyl)-1-hydroxyl-cyclohexanoyl substituent.
KEYWORDS
Eurya chinensis; diterpene;
derivative; anti-inflammatory
1. Introduction
The genus Eurya (approximately 130 species) belongs to the family Theaceae, which is dis-
tributed throughout the tropical areas of Asia and the south-west Pacific Islands (Chung &
Epperson 2000). Previous chemical studies on the genus Eurya led to the isolation of triter-
penes, phenylpropanoids, flavonoids and lignans (Morita et al. 1974; Khan et al. 1992; Oh
et al. 2011;Yang Kuo et al. 2013), in addition, many of these compounds possessed different
biological properties, including anti-inflammatory, cytostatic and antioxidant activities (Park,
Lee et al. 2005; Park, Yang et al. 2005; Yang Kuo et al. 2013).
Eurya chinensis R.Br. grows throughout the south of China, its fresh stems and leaves have
been used as remedy for a variety of ailments, such as fever, jaundice and trauma (Song
et al. 2017). In our previous studies, ( )-euryacoumarin A and 6-demethylobtusinin, two
CONTACT Jie-Wei Wu
wujieweiky@163.com; sheng-Xiang Qiu
sxqiu@scbg.ac.cn
supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2017.1343327.
© 2017 Informa uK limited, trading as taylor & Francis Group

2
J.-L. SONG ET AL.
new coumarins, were isolated from the stems of E. chinensis (Song et al. 2017). As a continuing
search for structurally unique and biologically active compounds, the stems of E. chinensis
were thoroughly isolated. As a result, one new ent-kaurane diterpene derivative, 16α,17-[4-
hydroxy-4-(2-hydroxyethyl)-cyclohexylidenedioxy]-ent-kauran-19-oic acid (1), along with
four known ent-kaurane diterpenoids (2–5) (Figure 1) have been identified: 17-hydroxy-16α-
ent-kauran-19-oic acid (2) (Wu et al. 1996), 7β,17-dihydroxy-16α-ent-kauran-19-oic acid (3)
(Furtado et al. 2013), 16α,17-dihydroxy-ent-kauran-19-oic acid (4) (Wu et al. 1996) and 16β,17-
dihydroxy-ent-kauran-19-oic acid (5) (Wu et al. 1996). Herein, we describes the isolation and
structural elucidation of these compounds, as well as the biological evaluation of antitumour
and anti-inflammatory activities.
2. Results and discussion
Compound 1 was obtained as an amorphous powder, and its molecular formula C28H44O6
was established by the 13C NMR data and an HRESIMS ion at m/z 475.3027 [M − H]− (calcd
475.3060), requiring seven degrees of unsaturation.
The 13C NMR data and the HSQC spectrum of 1 exhibited 28 carbons, attributing to two
tertiary methyls, 16 methylenes, three methines and seven quaternary carbons. Two down-
field signals at δC 90.1 and 70.6 suggesting the existence of an oxygenated quaternary carbon
and an oxygenated methylene, together with the diagnostic signals of three methines [δC
58.2 (C-5), 56.8 (C-9) and 47.3 (C-13)] and three quaternary carbons [δC 45.7 (C-4), 44.7 (C-8)
and 40.8 (C-10)], indicated an ent-kaurane diterpene skeleton (Chen et al. 2016; Galala et al.
2016; Xu et al. 2016; Liu et al. 2017), which could be supported by its 1H–1H COSY and HMBC
1
experiments. The H–1H COSY spectrum of 1 indicated the correlations from δH 1.88/0.84
(H2-1) to δH 1.93/1.40 (H2-2), then to δH 2.15/1.03 (H2-3), and from δH 1.08 (H-5) to δH 1.85
(H2-6), then to δH 1.56/1.47 (H2-7), and from δH 1.01 (H-9) to δH 1.65/1.40 (H2-11), then to δH
1.56 (H2-12) and δH 2.07 (H-13). Similarly, its HMBC data exhibited that the proton at δH 1.08
(H-5) correlated with the carbons at δC 29.5 (C-18), 181.7 (C-19) and 16.4 (C-20), δH 1.01 (H-9)
correlated with δC 42.0 (C-1), 28.0 (C-12), 39.1 (C-14) and 57.7 (C-15), while 2.07 (H-13) cor-
related with δC 44.7 (C-8), 20.3 (C-11), 57.7 (C-15) and 70.6 (C-17). Therefore, all the above
characteristic data were indicative of the same diterpene skeleton with that of 16,17-dihy-
droxy-ent-kauran-19-oic acid (Wu et al. 1996).
Figure 1. Ent-kaurane diterpenes 1–5 isolated from E. Chinensis r.Br.

NATURAL PRODUCT RESEARCH
3
Apart from the signals of the diterpene, one oxygenated methylene (δH 3.76, 2H, t,
J = 7.0 Hz), one non-cyclic aliphatic methylene (δH 1.58, 2H, overlapped) and four cyclic meth-
ylenes [(δH 1.68, 4H, overlapped), (δH 1.82, 2H, overlapped), (δH 1.55, 2H, overlapped)] were
exhibited in the 1H NMR spectrum. Besides, one ketal (δC 109.8) was readily identified in the
13C NMR spectrum. Moreover, the presence of three proton sequences of CH2 (2′)–CH2 (3′),
1
CH2 (5′)–CH2 (6′), and CH2 (1″)–CH2 (2″) was disclosed in H–1H COSY spectrum. Therefore,
the left eight carbons indicated the presence of a 4-hydroxy-4-(2-hydroxyethyl)-cyclohexy-
lidene substituent (Guiso et al. 1997; Kim et al. 2007). This residue was assigned to be located
at C-16 and C-17 from the HMBC correlation between H-17a (δH 4.10) and C-1′ (δC 109.8).
In the NOESY spectrum, the cross-peaks of H3-18/H-5, H-5/H-9 and H-9/H-15b suggested
H3-18, H-5, H-9 and H2-15 were all co-facial. Therefore, they were arbitrarily assigned as β-ori-
entation based on the comparisons with the spectral data of similar ent-kauran-19-oic acids
and biogenetic considerations (Wu et al. 1996; Chen et al. 2016; Galala et al. 2016; Xu et al.
2016; Liu et al. 2017). However, due to the missing of key correlations in the NOESY spectrum,
the configuration of C-16 in 1 was deduced by hydrolysis of 1 and subsequent LC-MS analysis.
Mild acidic hydrolysis of 1 afforded an 16α,17-dihydroxy-ent-kauran-19-oic acid (4) which
was confirmed by LC-MS analysis (Figure S9). Therefore, the chiral carbons including C-16 in
1 share the same configurations as those in 4, and thus, 1 is established to be to 16α,17-[4-hy-
droxy-4-(2-hydroxyethyl)-cyclohexylidenedioxy]-ent-kauran-19-oic acid.
In the previous studies, Eurya plants were found to be important sources of newly potential
anticancer and anti-inflammatory agents (Park, Lee et al. 2005; Park,Yang et al. 2005). Therefore,
all the isolated compounds were evaluated for their cytotoxic activities against three human
tumour cell lines NCI-H46, SW480 and HepG2 using MTT assay (Mosmann 1983). However,
none showed significant activity (cellular proliferation inhibition rate <50% at 20 μM). Besides,
all the isolated compounds were evaluated for their activities against the production of NO in
RAW264.7 macrophages stimulated by lipopolysaccharide. Compound 1 showed moderate
inhibitory effect on NO production in LPS-stimulated RAW264.7 cells with IC50 value of 8.12 μM,
but the remaining compounds were inactive (IC50 > 50 μM). It is interesting that only compound
1 with 4-hydroxy-4-(2-hydroxyethyl)-cyclohexylidene substituent acts as the active compound.
On one hand, it seems that the 4-hydroxy-4-(2-hydroxyethyl)-cyclohexylidene substituent is
essential for the inhibitory effect on NO production in LPS stimulated RAW264.7 cells. On the
other hand, the naked hydroxyl groups of diterpene skeleton in compounds 2–5 might be
adverse to the activity and should be protected by some functional groups such as the acetal
in compound 1.
3. Experimental
3.1. General experimental procedures
Optical rotations were measured on a Perkin-Elmer 341 polarimeter. UV spectra were
recorded in MeOH on a Perkin-Elmer Lambda 35 UV–Vis spectrophotometer. IR spectra were
acquired using a Bruker Vertex 33 infrared spectrophotometer (Bruker, Karlsruhe, Germany)
with KBr disc. Analytical HPLC was performed on a Waters 2690 instrument with a 996 PAD
(photodiode array detector) and coupled with an Alltech ELSD 2000 detector. HR-ESI-MS
spectra were recorded on a Bruker Bio TOF IIIQ mass spectrometer. NMR spectra were
recorded on a Bruker Advance-500 spectrometer using (tetramethylsilane)TMS as an internal
standard. All organic solvents used for extraction were of analytical grade (Shanghai Chemical

4
J.-L. SONG ET AL.
Plant, Shanghai, People’s Republic of China). Methanol used for HPLC was of HPLC-grade
(J&K, Beijing, People’s Republic of China). Silica gel (200–300 mesh) (Qingdao Haiyang
Chemical Plant, Qingdao, People’s Republic of China), C18 reversed-phase silica gel (150–200
mesh, Merck), MCI gel (CHP20P, 75–150 μM, Mitsubishi Chemical Industries Ltd.) and
Sephadex LH-20 gel (Amersham Biosciences) were used for column chromatography. TLC
spots were visualised under UV light and by dipping into 5% H2SO4 in alcohol followed by
heating. Purification by means of HPLC was conducted using Alltima C18 column
(250 mm × 10 mm, 5 μM, Tong Heng Innovation Technology Co., Ltd., Beijing, People’s
Republic of China).
3.2. Plant material
The stems of E. chinensis were collected in Nankang County, Jiangxi Province, China, in June
2013 and identified by prof. Fu-Wu Xing, South China Botanical Garden. A voucher specimen
(No. 201309) has been deposited at the Laboratory of Natural Product Chemistry Biology
(SCBG), South China Botanical Garden.
3.3. Extraction and isolation
Dried-powdered stems of E. chinensis (50.0 kg) were extracted by 95% ethanol at room tem-
perate and filtered, then the filtrate was concentrated under vacuum to give a crude residue
(2.1 kg). The residue (2.1 kg) was suspended in H2O and extracted with n-hexane and EtOAc.
The EtOAc-soluble fraction (1.2 kg) was subjected to column chromatography (CC) over silica
gel eluting with n-hexane/acetone in a stepwise manner to give six fractions (E1–E6). Fraction
E4 (237 g) was then subjected to CC over silica gel eluting with CH2Cl2/EtOAc in a stepwise
manner, affording four fractions (E4A–E4F). Fraction E4C was subjected to CC over MCI gel
(MeOH/H2O, 30–70%) to give five subfractions (E4C1–E4C5). Subfraction E4C2 was further
subjected to CC over silica gel eluting with CH2Cl2/EtOAc in a stepwise manner to yield 2
(70 mg). Fraction E5 (98.3 g) was subjected to CC over MCI gel (MeOH/H2O, 30–70%) to give
10 fractions (E5A–E5 J). E5H (2.6 g) was subjected to CC over Sephadex LH-20 (MeOH) to
afford five subfractions (E5H1–E5H5). E5H3 (78 mg) was subjected to CC over silica gel eluting
with CH2Cl2/EtOAc in a stepwise manner to yield 1 (12 mg). E5H4 (213 mg) was subjected
to CC over silica gel eluting with CH2Cl2/EtOAc in a stepwise manner to yield 4 (60 mg) and
yield 5 (93 mg). E5I (3.8 g) was subjected to CC over Sephadex LH-20 (MeOH) to afford six
subfractions (E5I1–E5I6). E5I3 (240 mg) was subjected to CC over silica gel eluting with
CH2Cl2/EtOAc in a stepwise manner to yield 3 (6 mg).
Ent-16α,17-[4-hydroxy-4-(2-hydroxyethyl)-cyclohexylidenedioxy]-(–)-19-oic acid (1): Amorphous
powder; [ꢀ]2D5−28.8 (c 1.70; CH OH); CD Δε (c 1.03, CH OH) −0.18 (224.3 nm); IR (KBr) ν
3
3
max
3409, 2929, 2853, 1699, 1449, 1371, 1263, 1106, 1030, 957 cm−1; HR-ESI-MS [M − H]− at m/z
475.3027 (Calcd for C28H44O6–H, 475. 3060); 1H NMR (500 MHz, CD3OD): δH 1.88 (1H, m, H-1a),
0.84 (1H, m, H-1b), 1.93 (1H, m, H-2a), 1.40 (1H, m, H-2b), 2.15 (1H, m, H-3a), 1.03 (1H, m,
H-3b), 1.08 (1H, m, H-5), 1.85 (2H, m, H-6), 1.56 (1H, overlapped, H-7a), 1.47 (1H, m, H-7b),
1.01 (1H, brs, H-9), 1.65 (1H, overlapped, H-11a), 1.40 (1H, overlapped, H-11b), 1.56
(2H, overlapped, H-12), 2.07 (1H, m, H-13), 2.01 (1H, overlapped, H-14a), 1.52 (1H, m, H-14b),
1.74 (1H, d, J = 4.2 Hz, H-15a), 1.79 (1H, d, J = 4.2 Hz, H-15b), 4.10 (1H, d, J = 8.6 Hz, H-17a),
3.96 (1H, d, J = 8.6 Hz, H-17b), 1.20 (3H, s, H-18), 0.99 (3H, s, H-20), 1.68 (2H, overlapped, H-2′),

NATURAL PRODUCT RESEARCH
5
1.82 (1H, overlapped, H-3′a), 1.55 (1H, overlapped, H-3′b), 1.82 (1H, overlapped, H-5′a), 1.55
(1H, overlapped, H-5′b), 1.68 (2H, overlapped, H-6′), 1.58 (2H, overlapped, H-1″), 3.76 (2H, t,
J = 7.0 Hz, H-2″). 13C NMR (125 MHz, CD3OD): δC 42.0 (C-1), 20.0 (C-2), 39.2 (C-3), 45.7 (C-4),
58.2 (C-5), 23.3 (C-6), 42.9 (C-7), 44.7 (C-8), 56.8 (C-9), 40.8 (C-10), 20.3 (C-11), 28.0 (C-12), 47.3
(C-13), 39.1 (C-14), 57.7 (C-15), 90.1 (C-16), 70.6 (C-17), 29.5 (C-18), 181.7 (C-19), 16.4 (C-20),
109.8 (C-1′), 35.8 (C-2′), 32.8 (C-3′), 71.2 (C-4′), 32.9 (C-5′), 35.8 (C-6′), 43.0 (C-1″), 59.2 (C-2″).
3.4. Acid hydrolysis of 1
Compound 1 (2 mg) was hydrolysed with 5% HCl (3 mL) at 50 °C for 2 h. The mixture was
neutralised with 10% NaHCO3 and extracted with CH2Cl2 (3 × 5 mL). Mild acidic hydrolysis
of 1 afforded an 16α,17-dihydroxy-ent-kauran-19-oic acid (4) which was confirmed by LC-MS
analysis (Figure S9).
3.5. Cytotoxic activity against NCI-H46, SW480 and HepG2
Compounds 1–5 were evaluated for inhibitory activity against human lung cancer cell (NCI-
H46), human colorectal cancer cells (SW480) and human liver cancer cells (HepG2) using the
MTT method reported previously (Mosmann 1983). Doxorubicin was used as positive control.
Cells were plated in 96-well tissue plates at a density of 1 × 104 cells/well. Adherent cell lines
were previously incubated for 24 h to ensure adhesion to the wells in an atmosphere of 5%
CO2. Compounds 1–5 were applied at various concentrations (0.01, 0.1, 1, 10, 100 μM) and
control cells were treated with DMSO at the highest concentration used in test wells (0.5%).
1 h prior to the end of the incubation period, 20 mL of MTT (5 mg/mL in PBS, 5% MTT) were
added to each well and further incubated at 37 °C for another 4 h. Supernatants were
removed and 150 μL DMSO were afterwards added to each well in order to dissolve the
formazan crystals. The mixture was oscillatored for 10 min at room temperature and its
absorbance was measured at 490 nm (Genios, Tecan, Austria). The concentration resulting
in 50% of cell-growth inhibition (IC50) was calculated using the Probit program in SPSS 19
for windows XP (SPSS Inc.Chicago)
3.6. Measurement of nitric oxide (NO) production in RAW264.7 macrophages
Compounds 1–5 were examined for inhibition on NO production in LPS-stimulated RAW264.7
cells according to previously described method (Park et al. 2013; Zhong et al. 2015). Murine
monocytic RAW264.7 macrophagesispensed into 96-well plates (5 × 105 cells/well) contain-
ing DMEM medium (Gibco) with 10% FBS under a humidified atmosphere of 5% CO2 at 37 °C.
After 24 h preincubation, cells were treated with serial dilutions of the compounds, with the
maximum concentration of 200 μM, in the presence of 1 μM LPS for 18 h. Each compound
was dissolved in DMSO and further diluted in medium to produce different concentrations.
NO production in each well was assessed by adding 100 μL of Griess reagent (Reagent A &
Reagent B, respectively, Biotine) to 100 μL of each supernatant from LPS (Sigma)-treated or
LPS- and compound-treated cells in triplicate. After 5-min incubation, the absorbance was
measured at 420 nm with a Multiscan Spectrum (TECAN Genios). L-NMMA (NG-Monomethyl-
l-arginine, Monoacetate Salt, beyotime biotechnology) was used as a positive control.

6
J.-L. SONG ET AL.
4. Conclusions
One new ent-kaurane diterpene derivative (1), along with four known diterpenes, were iso-
lated from the stems of E. chinensis. To the best of our knowledge, compound 1 was the first
example of diterpenoids with 4-hydroxy-4-(2-hydroxyethyl)-1-hydroxyl-cyclohexanoyl sub-
stituent. The cytotoxic and anti-inflammatory effect of these isolates were evaluated, com-
pound 1 showed moderate anti-inflammatory activities with IC50 value of 8.12 μM.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was financially supported by the Stratesgic Resources Service Network Program on Plant
Genetic Resources Innovation of the Chinese Academy of Sciences [grant number ZSZC-005];
Guangdong Province Science &Technology Project [grant number 2016A010105015]; National Natural
Science Foundation of China [grant number NSFC 813732930]; ‘Twelfth Five-Year’ National Science
and Technology Support Project of China [grant number 2015BAD15B03]; the DongGuan Innovative
Research Team Program [grant number 2014607101005]; and China Postdoctoral Science Foundation
[grant number 2015M582436].
ORCID
Jie-Wei Wu
http://orcid.org/0000-0003-0555-6086
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