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Abstract

This paper concerns the study of the roots and rhizomes of Glycyrrhiza uralensis where one new alkaloid glycoside, 3,4-dihydroxyquinoline 4-O-β-d-glucopyranoside, along with 13 known compounds (12 phenolic glycosides and one triterpene glycoside) were isolated and identified. The structure of the new compound and the known ones were identified on the basis of nuclear magnetic resonance (NMR) and mass spectrometric (MS) analysis. All the glycosides were tested for their anti-neuroinflammatory activities by inhibiting nitric oxide (NO) release in lipopolysaccharide (LPS)-induced murine microglial BV-2 cells. Several compounds were tested for their antioxidant activities in rat adrenal pheochromocytoma PC12 cells. A structure–activity relationship (SAR) analysis was carried out and revealed that the position and amount of sugar moieties have significant impact on antioxidant activities.

Keywords

glycosides anti-neuroinflammatory activity antioxidant activity

Licorice, one of the most popular Chinese herbal medicines, is, according to the Pharmacopeia of the People’s Republic of China, derived from the dried roots and rhizomes of Glycyrrhiza uralensis, G. inflata, and G. glabra (family Leguminosae). To date, different kinds of products have been isolated from licorice, including flavonoids, triterpenoid saponins, coumarins, polysaccharides and alkaloids.^1

-4 Pharmacological studies have revealed that licorice extracts and isolated constituents show significant anti-inflammatory,⁵ antioxidant⁶ and neuroprotective activities.⁷

The incidence of neurological disorders, such as Alzheimer’s and Parkinson’s diseases, is increasing worldwide due to the increase in the number of the aged population; mortality from these diseases accounts for 17% of global deaths.^8,9 Considerable evidence has demonstrated that overproduction of reactive oxygen species (ROS) and neuroinflammation are closely related to the pathogenesis of several neurological diseases.^10
-12 Previous studies have evidenced the efficacy of licorice extract and its purified ingredients as antioxidation and anti-inflammation agents.^13
-15

Therefore, based on phenolic compounds which have been isolated from licorice in our previous studies,¹⁶ our present study focused on investigations targeting neuroprotective effects of isolated compounds against inflammatory and oxidant damage in vitro. As a result, one new alkaloid glycoside (1), along with thirteen known compounds (2, 14, Figure 1) were isolated from the n-butyl alcohol (n-BuOH) soluble portion. The structures were determined by analysis of their spectroscopic data and comparison with references. All of the compounds were tested for their anti-neuroinflammatory activities, among which three compounds (4, 5, and 12) were further tested for their antioxidant activities since their structures are similar to those of liquiritin (2) and isoliquiritin (3). Herein, the isolation and structural elucidation of the new compound, and the bioactivity evaluation of compounds 1-14 are described.

Figure 1

Structures of compounds 1-14 from G. uralensis.

Results and Discussion

Structure Determination of Isolated Compounds

Compound 1 was obtained as a yellow amorphous powder. The molecular formula, C₁₅H₁₇NO₇, was determined from the HR-ESI-MS ion at m/z 322.0942 [M–H]^– (calcd for C₁₅H₁₆NO₇, 322.0927). (Supplemental Figure S1). The UV spectrum of 1 (Supplemental Figure S2) had maximum absorption wavelengths at 213, 250, and 289 nm, which indicated that 1 had a quinoline skeleton.¹⁷ The ¹H-NMR spectrum (Supplemental Figure S3) showed an o-substituted benzene ring, consisting of four aromatic protons [δ _H 8.02 (1H, dd, J = 4.4, 1.2 Hz); 7.50 (1H, dd, J = 4.4, 1.2 Hz); 7.22 (1H, ddd, J = 0.8, 4.0, 4.8 Hz); 7.20 (1H, ddd, J = 0.8, 4.0, 4.8 Hz)], a bond group δ _H 8.14 (1H, s), and a hydroxyl group at δ _H 12.04 (1H, s). In accordance with this molecular formula, 15 carbon signals were observed in the ¹³C-NMR spectrum (Supplemental Figure S4), with the assistance of DEPT and HSQC experiments, including one methylene, 10 methines, and four quaternary carbons. From the ¹³C- and ¹H- NMR spectra, a β-glucopyranosyl moiety [δ _H 5.59 (1H, d, J = 7.2 Hz, H-1'), 3.69 (1H, dd, J = 12.0, 3.6 Hz, H-6'), 3.48 (1H, dd, J = 12.0, 3.6 Hz, H-6'), 3.25‐3.40 (m); δ _C 94.2 (C-1'), 78.2 (C-3'), 77.1 (C-5'), 73.1 (C-2'), 70.1 (C-4'), 61.1 (C-6')] was clearly inferred. Apart from these signals for the substituent group, the remaining proton and carbon signals suggested compound 1 to be a hydroxyquinoline, which was supported by the following HMBC and ¹H-¹H COSY experiments.

The structure of 1 was further analyzed from its 2D NMR spectroscopic data, including ¹H-¹H COSY, HSQC, HMBC and NOESY spectra (Supplemental Figures S6-S9). In the ¹H-¹H COSY spectrum, combined with the HSQC spectrum, the aromatic proton at δ 7.22 (δ _C 123.0, C-7) correlated with two protons at δ 7.20 (δ _C 121.9, C-6) and 8.02 (δ _C 121.0, C-8). Additionally, the proton at δ 7.20 correlated with protons at δ 7.22 and 7.50 (δ _C 112.9, C-5). The proton and carbon signals attribution at different positions of the o-substituted benzene ring were identified. In the HMBC spectrum, the glycosidic site was established unambiguously by a long-range correlation between H-1' (δ _H 5.59) and C-4 (δ _C 163.4). In addition, the hydroxyl proton at δ 12.04 correlated with carbons at C-3 (δ 106.3) and C-10 (δ 126.2), while the proton at position 2 of the quinolone ring at δ 8.14 correlated with carbons at C-3 (δ 106.3), C-9 (δ 136.9), and C-10 (δ 126.2) (Figure 2). On the basis of detailed analysis, all the signals in the 1D- and 2D- NMR spectra were assigned. Following acid hydrolysis of 1 with 2N TFA, the sugar moiety was determined to be D-glucose based on HPLC analysis (t _R = 18.92 minutes) after chiral derivatization.¹⁸ Thus, the structure of 1 was identified as 3,4-dihydroxyquinoline 4-O-β-d-glucopyranoside.

Figure 2

Key ¹H-¹H COSY, HMBC correlations of compound 1.

The known compounds (2-14) were identified as liquiritin (2),¹⁹ isoliquiritin (3),²⁰ neoisoliquiritin (4),²¹ liquiritin apioside (5),²² neoliquiritin (6),²³ isoliquiritin apioside (7),²⁴ ononin (8),²⁵ licuraside (9),²⁶ (2S)-liquiritigenin-7-O-β-d-glucopyranosyl-(2→1)-O-β-d-apiofuranoside (10),²⁷ (2R)-liquiritigenin-7-O-β-d-glucopyranosyl-(2→1)-O-β-d-apiofuranoside (11),²⁷ liquiritigenin-7,4'-di-O-β-d-glucopyranoside (12),²⁸ isoliquiritigenin-4,4'-di-O-β-d-glucopyranoside (13),²⁹ and 18β-glycyrrhetinic acid-3-O-d-glucuronide (14),³⁰ based on the analysis and comparison of their NMR spectroscopic data with those reported in the literature.

Anti-neuroinflammatory Activities In Vitro

It has been reported that neuroinflammation might drive the pathogenic process in several degenerative neurological disorders.³¹ To obtain either new anti-neuroinflammatory agents or lead compounds for degenerative neurological diseases, all isolated compounds (1-14) were evaluated for their inhibitory activities on LPS-induced NO production in murine microglial BV-2 cells by the Griess reaction. Curcumin was used as a positive control (IC₅₀ value of 1.9 µg/mL). The NO inhibitory effects shown by all of these compounds are described using IC₅₀ values, which are summarized in Table 1. Based on comparison and analysis of their IC₅₀ values (Table 1), compounds 1, 3, 4, and 6 exerted the more inhibitory activity against LPS-stimulated NO production in BV-2 cells with IC₅₀ values less than 50 µg/mL. MTT assay indicated that none of the assayed compounds exhibited significant cytotoxicity to the BV-2 cells at their effective concentration for the inhibition of NO production (Figure 3).

Table 1

IC₅₀ Values of Compounds 1-14 Inhibiting NO Production in BV-2 Cells.

Compound	IC₅₀ (μg/mL)	Compound	IC₅₀ (μg/mL)
1	48.6 ± 1.7	8	>50
2	>50	9	>50
3	39.8 ± 1.6	10	>50
4	47.1 ± 1.7	11	>50
5	>50	12	>50
6	30.8 ± 1.5	13	>50
7	>50	14	>50
Curcumin^a	1.9 ± 0.3

^aCurcumin was used as a positive control. Data are presented based on three experiments.

Figure 3

The cellular viabilities of BV-2 cells treated with compounds 1-14. Representative graphs are from three independent experiments, with error bars representing SD values.

Antioxidant Activities In Vitro

6-Hydroxydopamine (6-OHDA) is a dopaminergic neurotoxin, the toxic effects of which have been linked to overproduction of ROS, such as hydrogen peroxide (H₂O₂), superoxide anion and hydroxyl radical. Under physiological conditions 6-OHDA is rapidly and nonenzymatically oxidized by molecular oxygen to form H₂O₂ and the corresponding p-quinone.³² High and sustained concentrations of ROS can cause damage to many cellular and extracellular constituents, including DNA, proteins, and lipids. Oxidation of proteins may lead to the formation of insoluble protein aggregates, which are the molecular basis of a number of diseases, particularly neurodegenerative pathologies.³³ Therefore, H₂O₂ and 6-OHDA are widely used to investigate the pathogenesis of some neurological disorders in vivo and in vitro.

The protective effect of liquiritin and isoliquiritin on corticosterone-induced neurotoxicity in rat adrenal pheochromocytoma PC12 cells has been proved.^34,35 For the exploration of neuroprotective activities in isolated compounds with similar structures as liquiritin (2) and isoliquiritin (3), compounds 4, 5, and 12 were tested for their protective activities against the H₂O₂- and 6-OHDA-induced injury model in PC12 cells by MTT assay. None of the assayed compounds exhibited significant cytotoxicity to the PC12 cells at either 20 or 50 μmol/L (Figure 4). The antioxidant effects were also evaluated for their protective activities against H₂O₂- or 6-OHDA-induced apoptosis, with the higher concentration (Figure 5). The final results showed that compounds 2 and 3 were capable of relieving the cell injury, notably in the 6-OHDA-treated group (P < .05). However, compounds 4, 5, and 12 lacked conspicuous antioxidant activity, and even led to further cellular damage at 50 μmol/L. The protective effect of 2 and 3 was better than that of 4, 5, and 12, both in the H₂O₂- and 6-OHDA-treated groups. According to the activity comparison of compounds with the same basic parent structure, the preliminary SAR analysis showed that different positions of the sugar moieties might have a significant impact on their antioxidant activities. Additionally, the more the number of sugar moieties, the less was the antioxidant activity of the compound.

Figure 4

The cellular viabilities of PC12 cells treated with compounds 2, 3, 4, 5, and 12. Representative graphs are from three independent experiments, with error bars representing SD values.

Figure 5

PC12 cells treated with indicated concentrations of 2, 3, 4, 5, and 12 for 24 hours and then exposed to either H₂O₂ (500 μmol/L) or 6-OHDA (200 μmol/L) for 12 hours. The cell viability was evaluated by the MTT assay. Representative graphs are from three independent experiments, with error bars representing SD values.**, P < .01 vs the control group; ^, P < .05, and ^^, P < .01 vs the H₂O₂- or 6-OHDA-treated group.

Experimental

General Experiments

The UV spectra were recorded on a Lambda 25 UV-Visible spectrophotometer (Perkin-Elmer, USA), 1D and 2D NMR spectra on a Bruker AVANCE AV III-400 instrument (Bruker, Switzerland, 100 MHz for ¹³C and 400 MHz for ¹H) with tetramethylsilane (TMS) as an internal reference at room temperature, and HR-ESI-MS on an Agilent LC-QTOF-MS (1290, 6560) spectrometer (Palo Alto, CA, USA). Medium pressure liquid chromatography (MPLC) was run using a NP7000 pump with a NU3000 UV detector (Hanbon Sci. & Tech, Jiangsu, People’s Republic of China) and a column (26 × 460 mm) filled with octadecylsilyl (75 C₁₈-OPN, Nacalai Tesque, Kyoto, Japan). HPLC separations were carried out on an EasyChrom system, equipped with the same detector as the MPLC system and a 5C₁₈-PAQ (10 × 250 mm, 10 µm) column (Waters, Milford, USA). Column chromatography was performed with silica gel (100, 200 mesh, Qingdao Haiyang Chemical Co., Ltd., People’s Republic of China) and two kinds of macroporous resin (D101; AB-8, 16‐60 mesh, Solarbio, Beijing, People’s Republic of China).

Plant Material

The roots and rhizomes of Glycyrrhiza uralensis Fisch. were collected from Minqin, Gansu Province, People’s Republic of China, in October 2016. The plant was identified by one of the authors, Dr. Zhigang Yang. A voucher specimen (No. MQG201610) has been deposited at the School of Pharmacy, Lanzhou University.

Extraction and Isolation

The dried roots and rhizomes (10 kg) of G. uralensis were powdered and extracted with 80% ethanol (EtOH) at room temperature, three times. After evaporation of the solvent under reduced pressure, the residues (810 g) were dispersed in water and successively extracted with chloroform (CHCl₃), ethyl acetate (EtOAc), and n-BuOH, respectively. The n-BuOH-soluble portion (240 g) was subjected to silica gel column chromatography (100, 200 mesh, 10 × 70 cm, 1.04 kg), using a gradient solvent system of DCM/MeOH (v/v = 100:0 to 0:100, each 7.5 L) to give fractions A-C.

Fraction B was chromatographed on an open macroporous resin column (D101, 16‐60 mesh, 10 × 70 cm, MeOH/H₂O, 0:100 to 100:0, v/v) to obtain six fractions (Fr. B1-Fr. B6). Numerous crystals formed during the separation were purified through recrystallization to obtain compound 2 (574.3 mg).

Fr. B3 was fractionated by MPLC with an ODS column with 25% to 65% MeOH in H₂O as eluent to afford 5 sub-fractions (Fr. B3A-Fr. B3E). Using semipreparative HPLC (5C₁₈-PAQ column, 10 × 250 mm) for the purification of these sub-fractions, compound 1 (22.8 mg, t _R = 19.7 minutes) was obtained from Fr. B3C (24% MeOH in H₂O).

Fr. B4 was separated by silica gel column chromatography with DCM/MeOH/H₂O (90:10:1 to 50:50:5, v/v) to give six fractions (Fr. B4A-Fr. B4F). Fr. B4B was subjected to MPLC over ODS eluting with a step gradient of 25% to 65% methanol (MeOH) in H₂O to afford 5 sub-fractions (Fr. B4B1-Fr. B4B5). Fr. B4B5 was further purified by semipreparative HPLC (47% MeOH in H₂O) to afford compounds 6 (32.0 mg, t _R = 6.7 minutes), 8 (6.0 mg, t _R = 13.8 minutes), 3 (38.7 mg, t _R = 18.7 minutes), and 4 (28.6 mg, t _R = 20.3 minutes). With the above MPLC system, Fr. B4D (25% to 45% MeOH in H₂O) provided 5 sub-fractions Fr. B4D1-Fr. B4D5. Compound 5 (131.5 mg, t _R = 39.4 minutes) was obtained from Fr. B4D2 (30% MeOH in H₂O) with the mentioned HPLC system. The subsequent purification of Fr. B4D4 (42% MeOH in H₂O) by the same HPLC procedure produced compounds 10 (17.0 mg, t _R = 9.5 minutes), 11 (4.0 mg, t _R = 12.1 minutes), 7 (95.0 mg, t _R = 38.6 minutes), and 9 (24.5 mg, t _R = 41.4 minutes). Fr. B4D5 was subjected to silica gel column chromatography to afford Fr. B4D5A-Fr. B4D5E using CHCl₃/MeOH/H₂O (90:10:1 to 50:50:5, v/v) gradient elution. Compounds 12 (64.0 mg, t _R = 9.7 minutes) and 13 (16.0 mg, t _R = 47.4 minutes) were isolated from Fr. B4D5E (30% MeOH in H₂O) by the above HPLC procedure.

Fraction C was chromatographed on an open macroporous resin column (AB-8, 16‐60 mesh, 10 cm×70 cm, MeOH/H₂O, 0:100 to 100:0, v/v) to obtain six fractions (Fr. C1-Fr. C6). Fr. C4 was purified by crystallization to yield compound 14 (98.2 mg). The extraction and isolation procedure of Glycyrrhiza uralensis is shown in Supplemental Scheme S1.

3,4-Dihydroxyquinoline 4-O-β-d-glucopyranoside (1). Yellow oil. UV (MeOH): λ _max (log ε) 213 (4.35), 250 (3.99), 289 (3.91) nm. ¹H and ¹³C-NMR data see Table 2. HREIMS: m/z 322.0942 [M–H]^– (calcd for C₁₅H₁₆NO₇, 322.0927) Supplemental Figure S1.

Table 2

¹H (400 MHz) and ¹³C (100 MHz) NMR Spectroscopic Data for Compound 1 in DMSO-D ₆.

No.	1
No.	δ _C	δ _H (mult. J in Hz)
2	133.9	8.14, s
3	106.3
4	163.4
5	112.9	7.50, dd (4.4, 1.2)
6	121.9	7.20, ddd (0.8, 4.0, 4.8)
7	123.0	7.22, ddd (0.8, 4.0, 4.8)
8	121.0	8.02, dd (4.4, 1.2)
9	136.9
10	126.2
1'	94.2	5.59, d (7.2)
2'	73.1	3.32, m
3'	78.2	3.28, m
4'	70.1	3.26, m
5'	77.1	3.30, m
6'	61.1	3.69,dd (12.0,3.6)3.48,dd (12.0,3.6)
3-OH		12.04, brs
2'-OH		5.30, br d (3.2)
3'-OH		5.12, br d (2.0)
4'-OH		5.02, br d (3.6)
6'-OH		4.58, br t (5.6)

Acid Hydrolysis of 1 and Determination of Sugar

Compound 1 (1.0 mg) was heated at 60 °C for 2 hours in 2 ml of 2 N trifluoroacetic acid, and the resulting product was extracted with EtOAc (5 ml ×3). The water-soluble layer was concentrated to dryness in vacuo. The residue was dissolved in pyridine (0.1 ml) and to it was added L-cysteine methyl ester hydrochloride (2.0 mg) at 60 °C for 1 hour. o-Tolylisothiocyanate (10 µL) was added to the mixture, which was heated at 60 °C for 1 hour. The reaction mixture was analyzed by HPLC using a C₁₈ column (5 µm, 4.6 ×250 mm, Waters), UV detection at 250 nm, and isocratic conditions of 23% aq. ACN in 0.1% formic acid (1 mL/min, 25 minutes).³⁶ Under the same conditions, the retention times of authentic samples were 18.95 minutes (D-glucose) and 20.93 minutes (L-glucose). The peak of 1 coincided with that of the derivative of authentic D-glucose (18.92 minutes).

Bioassay for Anti-neuroinflammatory Effects In Vitro

The anti-neuroinflammatory effects in vitro were examined by inhibiting NO release in LPS-induced murine microglial BV-2 cells. The cells were cultured at 37 °C in Dulbecco’s modified Eagle’s medium (DMEM), supplemented with 10% (v/v) inactivated fetal bovine serum (FBS) and 1% (v/v) penicillin/streptomycin under a water-saturated atmosphere of 95% air and in a humidified incubator containing 5% CO₂. BV-2 cells were seeded in 96-well culture plates (2 × 10⁴ cells/well) and preincubated for 24 hours. The cells were incubated for 24 hours either with or without 1 µg/mL of LPS (Beijing Solarbio Science & Technology Co., Ltd., People’s Republic of China) in either the absence or presence of the isolated compounds. Curcumin was used as a positive control. After treatment with various concentrations (10, 25, 50 µg/mL) of compounds and curcumin, the culture supernatant of cells (100 µL) was mixed with an equal volume of Griess reagent (1:1 mixture of 0.1% N-(1-naphtyl)ethylenediamine in H₂O and 1% sulfanilamide in 5% H₃PO₄) at room temperature for 20 minutes. NO concentration was quantified by the absorbance of the mixture read on a Tecan Spark 20M microplate reader (Tecan Inc., Swiss) at 550 nm, using a standard curve of known nitrite concentration versus absorbance at the same wavelength. The IC₅₀ values were determined with SPSS22.0 software from the corresponding experiments performed in triplicate.

Bioassay for Antioxidant Effects In Vitro

The antioxidant effects in vitro were tested for the protection against the H₂O₂ or 6-OHDA-induced injury model in rat adrenal pheochromocytoma PC12 cells. The cells were cultured in DMEM supplemented with 10% FBS, 2 mM glutamine, and 100 units/mL penicillin/streptomycin, maintained in a humidified atmosphere of 5% CO₂ at 37 °C. PC12 cells (1 × 10⁴ cells/well) were seeded in 96-well plates for 24 hours followed by the addition of indicated concentrations (20, 50 μmol/L) of compounds and incubated for another 24 hours. Afterwards, the cytotoxicity of compounds was determined by the MTT assay. Briefly, cells treated with DMSO alone were used as controls. At the end of the treatment, 10 µL MTT (5 mg/mL) was added to each well and incubated for an additional 4 hours at 37 °C. An extraction buffer (100 µL, 10% SDS, 5% isobutanol, 0.1% HCl) was added, and the cells incubated overnight at 37 °C. The absorbance was measured at 570 nm using a microplate reader (Thermo Scientific Multiskan GO, Finland). For the H₂O₂ or 6-OHDA injury model, PC12 cells (1 × 10⁴ cells/well) were plated in 96-well plates and allowed to adhere for 24 hours and then treated with different concentrations (10, 20, 50 μmol/L) of compounds without distinct cytotoxicity for 24 hours. After replacing with fresh medium containing 500 μmol/L H₂O₂ or 200 μmol/L 6-OHDA for 12 hours, the cell viability was determined by the MTT assay.

Supplemental Material

Supplementary Material 1 - Supplemental material for Glycoside Compounds From Glycyrrhiza uralensis and Their Neuroprotective Activities

Supplemental material, Supplementary Material 1, for Glycoside Compounds From Glycyrrhiza uralensis and Their Neuroprotective Activities by Guanhua Wei, Honghong Da, Kaixue Zhang, Junmin Zhang, Jianguo Fang and Zhigang Yang in Natural Product Communications

Footnotes

Acknowledgments

Authors are thankful to the Scientific Research and Experiment Center of the School of Pharmacy, Lanzhou University, and Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences for the measurement of NMR spectra.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a grant from the Major International S & T Cooperation Project, Ministry of Science and Technology of the People’s Republic of China (2016YFE0129000); Research project of Gansu Provincial Administration of Traditional Chinese Medicine (GZK-2015-21); The Natural Science Foundation of Gansu Province (20JR5RA311) and the Fundamental Research Funds for the Central Universities (lzujbky-2017-k26).

ORCID iD

Guanhua Wei

Supplemental Material

Supplemental material for this article is available online.

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