Four new phenolic constituents from the rhizomes of Gastrodia elata Blume

Article abstract of DOI:10.1080/14786419.2018.1460836

Four new gastrodin derivatives containing a trans-cinnamoyl unit (1–4) and nine known compounds (5–13) were isolated from the rhizomes of Gastrodia elata Blume. All these compounds were evaluated for their neuroprotective effects against 6-hydroxydopamine-induced cell death, and compounds 7 and 12 showed potent activities with EC₅₀ values of 10.5 and 10.2?μM, respectively.

Full text of DOI:10.1080/14786419.2018.1460836

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
Four new phenolic constituents from the rhizomes
of Gastrodia elata Blume
Zhi-Wei Wang, Yun Li, Da-Hui Liu, Yan Mu, Hong-Jing Dong, Hong-Lei Zhou,
Lan-Ping Guo & Xiao Wang
To cite this article: Zhi-Wei Wang, Yun Li, Da-Hui Liu, Yan Mu, Hong-Jing Dong, Hong-Lei Zhou,
Lan-Ping Guo & Xiao Wang (2018): Four new phenolic constituents from the rhizomes of Gastrodia
elata Blume, Natural Product Research, DOI: 10.1080/14786419.2018.1460836
To link to this article: https://doi.org/10.1080/14786419.2018.1460836
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Natural Product research, 2018
https://doi.org/10.1080/14786419.2018.1460836
Four new phenolic constituents from the rhizomes of
Gastrodia elata Blume
Zhi-Wei Wanga§, Yun Lia,b§, Da-Hui Liuc, Yan Mua, Hong-Jing Donga, Hong-Lei Zhoub,
Lan-Ping Guoa and Xiao Wanga
ashandong Key laboratory of tcM Quality control technology, shandong analysis and test center, Qilu
b
university of technology (shandong academy of sciences), Jinan, People’s republic of china; college of
Pharmacy, shandong university of traditional chinese Medicine, Jinan, People’s republic of china; cInstitute
of Medicinal Plants, Yunnan academy of agriculture science, Kunming, People’s republic of china
ABSTRACT
ARTICLE HISTORY
received 7 February 2018
accepted 1 april 2018
Four new gastrodin derivatives containing a trans-cinnamoyl unit (1–4)
and nine known compounds (5–13) were isolated from the rhizomes
of Gastrodia elata Blume. All these compounds were evaluated for
their neuroprotective effects against 6-hydroxydopamine-induced
cell death, and compounds 7 and 12 showed potent activities with
EC50 values of 10.5 and 10.2 μM, respectively.
KEYWORDS
Phenolics; Gastrodia elata
Blume; neuroprotective
effects; N6-(4-hydroxybenzyl)
adenosine; grossamide
1. Introduction
Gastrodia elata Blume (G. elata), commonly called‘Tian-ma’in Chinese, is an extensively used
traditional Chinese herbal medicine to treat neurological disorders, such as epilepsy, stroke
and convulsion (Liu and Mori 1992; Chen and Sheen 2011). The neuroprotective effect of
G. elata has been attracting more attentions. Indeed, pharmacological studies have demon-
strated that G. elata extract, gastrodin, p-hydroxybenzaldehyde and parishin possessed
neuroprotective effect through anti-inflammatory and anti-oxidative mechanism (Ng et al.
CONTACT Xiao Wang
wangx@sdas.org
§Z.-W. Wang and Y. li contributed equally to this work.
supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2018.1460836
© 2018 Informa uK limited, trading as taylor & Francis Group

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Z.-W. WANG ET AL.
2016; Zhan et al. 2016; Tang et al. 2017). So far, more than 80 compounds (Li et al. 2015;
Wu et al. 2017) have been isolated from G. elata, but only a few of them have been evaluated
for their neuroprotective activity (Huang et al. 2007; Chen et al. 2016; Li et al. 2016). These
results promoted us to continue to investigate the potential neuroprotective components
of G. elata.
G. elata f. glauca S. Chow, G. elata f. elata, G. elata f. viridis Makino, G. elata f. flavida
S. Chow, and G. elata f. alba S. Chow are the five varieties of G. elata cultivated in China, which
are considered as the original plants of the traditional Chinese medicine ‘Tian-ma’ (Chen
et al. 2015). Among these varieties, G. elata f. glauca S. Chow is the most widely cultivated.
Here, we reported the isolation and structural elucidation of four new phenolic constituents
from the ethanol extract of the rhizomes of G. elata (G. elata f. glauca S. Chow), together with
nine known compounds. Neuroprotective effects of all isolated compounds against 6-hydrox-
ydopamine-induced cell death were evaluated in vitro.
2. Results and discussion
Compound 1 was isolated as a light yellow powder. The molecular formula of 1 was determined
as C22H24O8 by HR-ESI-MS at m/z 439.1362 [M + Na]+ (calcd. 439.1363 [M + Na]+). The IR spec-
trum indicated the presence of ester (1711 cm−1) and aromatic ring (1614 and 1512 cm−1). The
existence of a p-hydroxybenzyl alcohol moiety in 1 was evidenced by NMR signals (Table S1)
at δH 7.20 (1H, d, J = 8.8 Hz, H-3ʹ, 5ʹ), 6.91 (1H, d, J = 8.4 Hz, H-2ʹ, 6ʹ), 5.07 (1H, t, J = 5.6 Hz, 7ʹ-OH)
and 4.39 (2H, d, J = 5.6 Hz, H-7ʹ), and at δC 156.3, 137.0, 128.2 (2C), 116.5 (2C), 62.9; the presence
of a trans-cinnamoyl group was supported by the observed proton signals at δH 7.72 (2H, m),
7.42 (3H, m), trans-olefinic proton signals at δH 7.70 and 6.66 (each 1 H, d, J = 16.0 Hz), and
carbon resonances at δC 165.8, 145.3, 134.4, 131.0, 129.4 (2C), 128.8 (2C), 118.5. The proton
resonance at δH 5.17 (1H, d, J = 8.0 Hz, H-1) and carbon signals at δC 99.0, 77.7, 74.5, 74.2, 70.4,
61.0 suggested the existence of a β-glucose. In the HMBC spectrum (Figure S0), the correlation
from the anomeric proton δH 5.17 (1H, d, J = 8.0 Hz) to δC 156.3 (C-1ʹ) confirmed the p-hydrox-
ybenzyl alcohol moiety was linked to C-1. The HMBC correlation between δH 4.93 (H-2) and
δC 165.8 (C-9ʺ) was located the trans-cinnamoyl group at C-2. The detailed assignment of all
NMR signals arising from 1 was performed by 1H-1H COSY, HSQC and HMBC spectroscopy. The
absolute configuration of the sugar was determined to be D-glucose on the basis of GC-MS
analysis of its chiral derivative. Thus, the structure of compound 1 (Figure 1) was determined
to be 1-O-(4-hydroxymethylphenoxy)-2-O-trans-cinnamoyl-β-D-glucoside.
Compound 2 was obtained as a light yellow powder. The molecular formula of 2 was deter-
mined as C22H24O8 by HR-ESI-MS at m/z 439.1366 [M + Na]+ (calcd. 439.1363 [M + Na]+). The
absorption bands in the IR spectrum suggested the existence of ester (1712 cm−1) and aromatic
ring (1613 and 1512 cm−1). Careful comparison of the NMR data (Table S1) of 2 and 1 demon-
strated they possessed the similar structural moieties. The major differences were upfield shift
at C-2 (ΔδC −2.5 ppm) and C-4 (δC −2.4 ppm), and downfield shift at C-3 (ΔδC +3.7 ppm). This
revealed that the locations of p-hydroxybenzyl alcohol moiety or trans-cinnamoyl group in
compound 2 may be changed. The HMBC correlations from δH 5.05 (1H, d, J = 7.2 Hz, H-1) to
δC 156.5 (C-1ʹ), and from δH 5.06 (1H, t, J = 9.6 Hz, H-3) to δC 166.2 (C-9ʺ) confirmed p-hydroxy-
benzyl alcohol moiety and trans-cinnamoyl group was respectively connected to C-1 and C-3.
The sugar moiety was identified as D-glucose in the same way to that of 1. Thus, the structure
of 2 was established as 1-O-(4-hydroxymethylphenoxy)-3-O-trans-cinnamoyl-β-D-glucoside.

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Figure 1. structures of compounds 1–4.
Compound 3 was isolated as a light yellow powder. It was found to have the same molec-
ular formula of C22H24O8 as compound 2 from HR-ESI-MS at m/z 439.1368 [M + Na]+ (calcd.
439.1363 [M + Na]+). The absorption bands in the IR spectrum suggested the existence of
ester (1695 cm−1). The data of 1H and 13C (Table S1) were similar to those of 2 except for the
upfield shift at C-3 (ΔδC −3.9 ppm) and C-5 (ΔδC −2.2 ppm), and downfield shift at C-2 (ΔδC
+2.1 ppm) and C-4 (ΔδC +3.6 ppm), which suggested the different connections of p-hydrox-
ybenzyl alcohol moiety or trans-cinnamoyl group in compound 3. In the HMBC spectrum,
the correlations of H-1 with C-1ʹ, and of H-4 with C-9ʺ located the p-hydroxybenzyl alcohol
moiety and trans-cinnamoyl group at C-1 and C-4, respectively. The sugar moiety was iden-
tified as D-glucose followed the same protocol for 1. Thus, compound 3 was deduced to be
1-O-(4-hydroxymethylphenoxy)-4-O-trans-cinnamoyl-β-D-glucoside.
Compound 4 was obtained as a light yellow powder. The molecular formula of 4 was
deduced as C22H24O8 based on a sodium adduct ion at m/z 439.1364 [M + Na]+ (calcd.
439.1363 [M + Na]+). The IR spectrum showed the characteristic absorptions for ester at
1696 cm−1 and aromatic ring at 1613 and 1512 cm−1. The 1D NMR data (Table S1) of 4 showed
similar to those of 3. The major differences between 4 and 3 were the downfield shift of
proton signals at δH 4.44 (ΔδH +0.98 ppm, H-6a) and δH 4.22 (ΔδH +0.85 ppm, H-6b), and of
carbon resonance at δC 64.1 (ΔδC +3.2 ppm, C-6), indicating that the position of C-6 may be
substituted. The HMBC correlation from H-6 to C-9ʺ revealed that the trans-cinnamoyl group
was linked to C-6. The position of p-hydroxybenzyl alcohol moiety at C-1 was further con-
firmed by the HMBC correlation of H-1 (δH 4.90) with C-1ʹ (δC 156.5). According to the same
way as in compound 1, the sugar was determined to be D-glucose. Thus, compound 4
(1-O-(4-hydroxymethylphenoxy)-6-O-trans-cinnamoyl-β-D-glucoside) was established as
shown in Figure 1.
Additionally, the other previously reported compounds 5–13 were identified as 4-
hydroxybenzyl ethyl ether (5) (Zhou et al. 1981), adenosine (6) (Huang et al. 2005),

4
Z.-W. WANG ET AL.
N6-(4-hydroxybenzyl) adenosine (7) (Huang et al. 2006), gastrodioside (8) (Taguchi et al.
1981), bis(4-hydroxybenzyl) ether (9) (Taguchi et al. 1981), 4,4ʹ-dihydroxybenzyl sulfoxide
(10) (Yun-Choi and Pyo 1997), bis(4-hydroxybenzyl) sulfide (11) (Huang et al. 2007), grossa-
mide (12) (Lajide et al. 1995), and S-(4-hydroxybenzyl) glutathione (13) (Andersson et al.
1995) by comparing NMR and MS data reported in the literature.
All isolated compounds were evaluated in vitro for their neuroprotective effects against
6-hydroxydopamine-induced cell death, with curcumin used as a positive control (EC50:
6.5 μM). Compounds N6-(4-hydroxybenzyl) adenosine (7) and grossamide (12) exhibited
potent activities with EC50 values of 10.5 and 10.2 μM, respectively, while the other com-
pounds were inactive with EC50 far beyond 50 μM.
3. Experimental
3.1. General methods
NMR spectra were recorded on Varian INOVA-600 (1H: 600 MHz, 13C: 150 MHz) and Bruker
Avance Ⅲ 400 (1H: 400 MHz, 13C: 100 MHz) instruments, with tetramethylsilane as internal
standard. Mass spectra were obtained on an Agilent Technology 6520 Accurate-Mass Q-TOF
spectrometer. UV spectra were recorded using a Shimadzu UV-2550 spectrophotometer. IR
(KBr disks) spectra were performed on Bruker Vertex 70 spectrometer. Optical rotations were
measured on an Anton Paar MCP 200 polarimeter. Macroreticular resins (D101, Cangzhou
Bon AdsorberTechnology Co., Ltd., Cangzhou, China) were used for column chromatography.
Medium pressure liquid (MPLC) was performed on an Agela CHEETAHTM MP instrument using
prepacked RP-C18 column (500 × 80 mm). Preparative HPLC was carried out using a RIGOL
L-3000 series instrument with a YMC-PEAK RP-C18 column (250 mm × 10.0 mm, 5 μm). Gas
chromatography analyses were performed using a Thermo Trace 1310 system equipped
with a FID detector.
3.2. Plant material
The rhizomes of G. elata (G. elata f. glauca) were collected at the plantation field of Xiaocao
Ba, Yunnan province, China, in December 2015, and were authenticated by Dr. Da-Hui Liu
(Institute of Medicinal Plants, Yunnan Provincial Academy of Agricultural Sciences, China).
A voucher sample (No. GE-201511) was deposited at Shandong Analysis and Test Center,
Shandong Academy of Sciences, China.
3.3. Extraction and isolation
The steamed and air-dried G. elata rhizomes (12 kg) were powdered, and extracted with 85%
EtOH under reflux. The EtOH extract was evaporated under reduced pressure to yield a
concentrated solution (2.6 L), which was subjected to macroporous resin column (D101,
12 cm × 70 cm), and eluted successively with 10% EtOH, 20% EtOH, 30% EtOH, 50% EtOH,
70% EtOH, 95% EtOH, to give six further fractions (Fr. MR-1‒MR-6). Fr. MR-1 (37.4 g) was
applied to a prepacked ODS MPLC column (500 × 80 mm) and eluted with MeOH-H2O (5:95,
10:90, 15:85, 30:70, 40:60, 100:0) to give five sub-fractions (MR-1A‒MR-1E). Sub-fraction
MR-1B was purified by repeated preparative RP-HPLC (10% methanol in water containing

NATURAL PRODUCT RESEARCH
5
0.1% formic acid) to afford compound 1 (25 mg, 11.5 min). Compound 2 (2.6 mg, 14.5 min)
was obtained from Fr. MR-1C by preparative HPLC (28% methanol in water containing 0.1%
formic acid). Sub-fraction MR-1D was recrystallized by methanol to yield compound 4
(890 mg). Sub-fraction MR-1E was purified by RP-HPLC using MeOH-H2O (28:72, containing
0.1% formic acid) as mobile phase to give compound 3 (11.9 mg, 11.9 min). Fr. MR-3 (35.8 g)
was chromatographed on MPLC (ODS) successively eluted with 10, 25, 30, 35, 40% methanol
in water to obtain seven sub-fractions (Fr. MR-3A‒Fr. MR-3G). Compound 5 (528 mg, 17.1 min)
was obtained from Fr. MR-3E by RP-HPLC (18% acetonitrile in water containing 0.1% formic
acid). Fr. MR-4 (11 g) was chromatographed on silica gel eluted with CH2Cl2-MeOH (100:0 to
0:100) to afford six fractions (Fr. MR-4A‒Fr. MR-4F). Compounds 10 (51 mg, 6.4 min) 11 (4 mg,
6.8 min) and 12 (10 mg, 14.5 min) was isolated from Fr. MR-4C by repeated preparative HPLC
(MeOH-H2O, 50:50, 0.1% formic acid). Fr. MR-4D was separated by preparative HPLC eluted
with 50% methanol in water containing 0.1% formic acid to yield compounds 8 (29 mg,
11.0 min) and 9 (15 mg, 9.0 min). Fr. MR-4E was purified by repeated preparative HPLC
(MeOH-H2O, 50:50, 0.1% formic acid) to obtain compounds 6 (71 mg, 9.7 min) and 7 (8 mg,
12.4 min). Fr. MR-5 (18 g) was subjected to silica gel eluted with CH2Cl2-MeOH (100:0 to 0:100)
to give six sub-fractions (Fr. MR-5A‒Fr. MR-5G). Fr. MR-5C was purified by preparative HPLC
with acetonitrile-H2O (47:53, containing 0.1% formic acid) to obtain compound 13 (20 mg,
6.1 min).
3.4. Compound 1
Light yellow powder; [ꢀ]2D0: –4.6 (c = 0.1, methanol); UV λ (acetonitrile) nm (log ε): 277
max
(4.30), 217 (4.39); IR (KBr) cm−1: 3395, 2922, 1711, 1637, 1614, 1512; 1H- and 13C-NMR spectral
data: see Table S1; ESI-MS m/z: 439.1 [M + Na]+; HR-ESI-MS m/z: 439.1362 [M + Na]+ (Calcd
for C22H24O8Na: 439.1363).
3.5. Compound 2
Light yellow powder; [ꢀ]2D0: +26.5 (c = 0.1, methanol); UV λ (acetonitrile) nm (log ε): 276
max
(4.33), 217 (4.40); IR (KBr) cm−1: 3416, 2920, 1712, 1636, 1613, 1512; 1H- and 13C-NMR spectral
data: see Table S1; ESI-MS m/z: 439.1 [M + Na]+; HR-ESI-MS m/z: 439.1366 [M + Na]+ (Calcd
for C22H24O8Na: 439.1363).
3.6. Compound 3
Light yellow powder; [ꢀ]2D0: –41.0 (c = 0.1, methanol); UV λ (acetonitrile) nm (log ε): 275
max
(4.20), 216 (4.32); IR (KBr) cm−1: 3430, 2924, 1695, 1637, 1512; 1H- and 13C-NMR spectral data:
see Table S1; ESI-MS m/z: 439.1 [M + Na]+; HR-ESI-MS m/z: 439.1368 [M + Na]+ (Calcd for
C22H24O8Na: 439.1363).
3.7. Compound 4
light yellow powder; [ꢀ]2D0: –50.2 (c = 0.1, methanol); UV λ (acetonitrile) nm (log ε): 275
max
(4.28), 217 (4.38); IR (KBr) cm−1: 3428, 2922, 1696, 1637, 1613, 1512; 1H- and 13C-NMR spectral

6
Z.-W. WANG ET AL.
data: see Table S1; ESI-MS m/z: 439.1 [M + Na]+; HR-ESI-MS m/z: 439.1364 [M + Na]+ (Calcd
for C22H24O8Na: 439.1363).
3.8. Sugar analysis
The absolute configuration of the sugar was determined according to the method previous
reported (Wang et al. 2012). Compounds 1–4 (each 3 mg) dissolved in acetonitrile (3 mL)
and 2 M HCl (3 mL) was respectively refluxed at 90 °C for 3 h. After this period, the reaction
solution was concentrated under reduced pressure, and then the residue was suspended
with H2O and extracted with EtOAc (3 mL × 3). The aqueous layer was evaporated to dryness
and then dissolved in 0.3 mL of anhydrous pyridine, to which 5 mg of L-cysteine methyl ester
hydrochloride was added. The mixture was reacted at 60 °C for 2 h, and then hexamethyld-
isilazan (0.3 mL) and trimethylsilyl chloride (0.3 mL) were added, continued to react at 60 °C
for 1 h. After partitioning between H2O and n-hexane (each 0.4 mL), the n-hexane extract
was analyzed with gas chromatography under the following conditions: column, HP-5MS
(30 m × 0.25 mm × 0.5 μm); column temperature, initial temperature of 150 °C for 10 min,
ramped up to 300 °C at a rate of 3 °C per minute followed by a hold at 300 °C for 5 min. In
the acid hydrolysates of 1–4, only D-glucose was detected by comparison of the retention
time with that of authentic samples prepared in the same way (the tR of D- and L-glucose
was 39.47 and 40.06 min, respectively).
3.9. Determination of HT22 cell viability against 6-OHDA
The potential neuroprotective effects of all isolated compounds were conducted as previous
reports (Kwon et al. 2016). HT22 cells (mouse hippocampal neuronal cells) were plated in a
density of 5 × 103 cells/100 μL/well in 96-wellplates. After 24 h, the cells were treated with
6-OHDA (100 μM) and a series of concentrations of samples (50, 20, 10, 5 and 1 μM) for an
additional 24 h. The cell viability was determined by SRB assay and curcumin was used as a
positive control.
Supplementary material
1D, 2D NMR and MS spectra of the compounds 1–4 are available as supplementary material, alongside
Table S1 and Figure S0.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This research work was financially supported by the Natural Science Foundation of Shandong [grant
number ZR2016YL006]; the Shandong ProvinceTaishan Scholar Program (Lanping Guo); and the Priority
Research Program of the Shandong Academy of Sciences (Lanping Guo).

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