Sinensiols H–J, three new lignan derivatives from Selaginella sinensis (Desv.) Spring

  1. Qinfeng Zhu1ORCID Logo,
  2. Beibei Gao2,
  3. Qian Chen1,
  4. Tiantian Luo1,
  5. Guobo Xu1 and
  6. Shanggao Liao1

1School of Pharmacy, Guizhou Medical University, No. 2 Dongqing Road, Guiyang, 550025, P. R. China
2State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, No.132 Lanhei Road, Kunming, 650203, P. R. China

  1. Corresponding author email

Associate Editor: S. Bräse
Beilstein J. Org. Chem. 2022, 18, 1410–1415. https://doi.org/10.3762/bjoc.18.146
Received 26 Jul 2022, Accepted 20 Sep 2022, Published 07 Oct 2022

Abstract

One new lignan sinensiol H (1) and two new bisnorlignans, sinensiols I and J (2 and 3), along with three known compounds were isolated from the whole plants of Selaginella sinensis. Their structures were elucidated on the basis of 1D and 2D NMR spectroscopy as well as high-resolution mass spectrometry. The absolute configuration of 1 was established by ECD calculation. Compounds 2 and 3 represent rare examples of naturally occurring 9,9'-bisnorlignans. All the isolated compounds were assayed for their inhibitory effects on LPS-induced nitric oxide production in RAW 264.7 macrophages.

Keywords: lignan derivatives; nitric oxide production inhibition; norlignans; Selaginella sinensis

Introduction

Selaginella is the only genus of Selaginellaceae. As a representative of the earliest and still-surviving vascular plant lineage that had arisen about 400 million years ago, it is important for studying the evolution of land plants [1,2]. This genus includes approximately 750 species worldwide, some of which are used in traditional medicines for the treatment of various diseases including diabetes, gastritis, hepatitis, skin diseases and urinary tract infections [3,4]. In fact, S. tamariscina and S. pulvinata are officially listed in the Chinese Pharmacopoeia for the treatment of amenorrhoea, dysmenorrhoea and traumatic injury [5].

Selaginella sinensis, an endemic species in China, is used as a folk medicine for the treatment of cholecystitis, hepatitis, nephritis, eczema and bleeding [6]. Previous phytochemical studies showed the presence of flavonoids, lignans, glucosides and pigments in the plant [7,8] while pharmacological evaluations showed that some of the compounds possessed anti-oxidant and antiviral activities [9-11]. However, chemical constituents responsible for its efficacy in treating various inflammatory diseases are still not clear. As part of our continuing research on the bioactive compounds from this genus [12,13], the chemical constituents of the whole plant of S. sinensis were investigated. As a result, three new lignan derivatives 13 together with three known lignan glycosides 46 (Figure 1) were isolated. Their isolation, structural elucidation and inhibitory effects on LPS-induced nitric oxide production are reported.

[1860-5397-18-146-1]

Figure 1: Structures of compounds 16.

Results and Discussion

Sinensiol H (1) was isolated as a pale yellow amorphous powder. The negative HRESIMS [M − H] at m/z 371.1133 (calcd for 371.1136) suggested its molecular formula to be C20H20O7, corresponding to 11 degrees of unsaturation. The IR spectrum showed absorption bands characteristic of hydroxy group (3450 cm−1), carbonyl (1765 cm−1), and aromatic system (1608, 1516, 1490 cm−1). Analysis of its 1H NMR (DMSO-d6) data (Table 1) revealed the presence of two ABX benzene rings [δH 6.92 (d, J = 1.2 Hz, 1H, H-2), 6.83 (d, J = 7.9 Hz, 1H, H-5) and 6.79 (dd, J = 7.9, 1.2 Hz, 1H, H-6); 6.59 (d, J = 1.5 Hz, 1H, H-2′), 6.62 (d, J = 8.0 Hz, 1H, H-5′), and 6.47 (dd, J = 8.0, 1.5 Hz, 1H, H-6′)]. The 13C NMR (Table 1) and HSQC data showed signals due to twelve aromatic carbons, three methylenes (one oxygenated), one oxygenated tertiary carbon, one ester group, one methylenedioxy group (δC 100.7), one methoxy group (δC 55.4), and one methine. The chemical shift values of the 1D NMR of 1 were similar to those of the known compound 8′β-hydroxyhinokinin [14], the major difference being the absence of signals for a methylenedioxy (δH 5.93, δC 101.2) and the presence of signals for a methoxy group (δH 3.67, δC 55.4) in 1. The HMBC correlations (Figure 2) from 3′-OCH3H 3.67, s, 3H) to C-3′ indicated the methoxy group was located at C-3′. In the ROESY spectrum, the correlations of 8′-OH/H2-7 and H-8/H2-7′ (Figure 3a) suggested a trans orientation of H-8 and 8′-OH. The experimental ECD spectrum of 1 (Figure S16 in Supporting Information File 1) showed two positive Cotton effects (CEs) at 204 and 231 nm, which matched well with those in the calculated ECD curve for the (8S,8′R)-stereoisomer (Figure 3b). Consequently, the structure of 1 was determined as shown in Figure 1, and named sinensiol H.

Table 1: 1H NMR and 13C NMR data of compounds 13 (δ in ppm and J in Hz).

No. 1a 1b 2c 3c
δH δC δH δC δH δC δH δC
1   132.9   133.8   138.2   140.6
2 6.85 (d, 1.5, 1H) 109.8 6.92 (d, 1.2, 1H) 109.6 6.34 (d, 1.8, 1H) 105.2 6.84 (s, 1H) 107.4
3   148.0   147.1   154.4   149.1
4   146.4   145.5   135.9   148.1
5 6.76 (d, 7.9, 1H) 108.5 6.83 (d, 7.9, 1H) 108.0   151.4 6.81–6.77 (m, 1H) 108.7
6 6.80 (dd, 7.9, 1.5, 1H) 122.4 6.79 (dd, 7.9, 1.2, 1H) 122.1 6.35 (d, 1.8, 1H) 110.2 6.78–6.74 (m, 1H) 120.5
7 3.13 (dd, 14.5, 5.0, 1H)
2.95 (dd, 14.5, 8.8, 1H)
30.1 2.76–2.71 (m, 2H) 29.1 3.23–3.25 (m, 2H) 39.8 4.54 (t, 6.4, 1H) 74.9
8 2.70 (dd, 8.8, 5.0, 1H) 50.3 2.83–2.78 (m, 1H) 49.9 5.67–5.57 (m, 1H) 131.6 7.82–1.71 (m, 1H)
1.70–1.60 (1H, overlapped)
39.6
9   177.4   178.0        
1′   126.5   127.1   138.2   139.8
2′ 6.48 (d, 1.9, 1H) 112.2 6.59 (d, 1.5, 1H) 114.0 6.34 (d, 1.8, 1H) 105.2 6.31 (s, 1H) 105.1
3′   146.9   147.1   154.4   154.3
4′   145.3   145.1   135.9   135.8
5′ 6.84 (d, 8.1, 1H) 115.0 6.62 (d, 8.0, 1H) 115.1   151.4   151.2
6′ 6.53 (dd, 8.1, 1.9, 1H) 122.7 6.47 (dd, 8.0, 1.5, 1H) 122.4 6.35 (d, 1.8, 1H) 110.2 6.30 (s, 1H) 110.1
7′ 2.62 (br s, 2H) 43.1 2.64–2.59 (m, 2H) 41.7 3.23–3.25 (m, 2H) 39.8 2.50 (t, 7.1, 2H) 36.7
8′   78.4   78.0 5.67–5.57 (m, 1H) 131.6 1.70–1.60 (1H, overlapped)
1.60–1.44 (m, 1H)
28.7
9′ 4.18 (d, 10.0, 1H)
3.91 (d, 10.0, 1H)
77.0 4.14 (d, 9.4, 1H)
3.81 (d, 9.4, 1H)
75.5        
3-OCH3         3.78 (s, 3H) 56.4    
3′-OCH3 3.84 (s, 3H) 56.1 3.67 (s, 3H) 55.4 3.78 (s, 3H) 56.4 3.81 (s, 3H) 61.0
4-OCH3         3.76 (s, 3H) 61.0    
4′-OCH3         3.76 (s, 3H) 61.0 3.76 (s, 3H) 56.3
–OCH2O– 5.94 (s, 2H) 101.1 5.96 (s, 2H) 100.7     5.93 (s, 2H) 102.2
4′-OH     8.78 (s, 1H)          
8′-OH     5.38 (s, 1H)          

aRecorded at 600/150 MHz for 1H/13C in CDCl3; brecorded at 600/150 MHz for 1H/13C in DMSO-d6; crecorded at 600/150 MHz for 1H/13C in MeOH-d4.

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Figure 2: Key HMBC and 1H-1H COSY correlations of 13.

[1860-5397-18-146-3]

Figure 3: (a) Key ROESY correlations of compound 1. (b) Experimental and calculated ECD spectra of 1.

Compound 2 was obtained as a white amorphous powder. Its molecular formula was determined to be C20H24O6 by the HRESIMS peak at m/z 359.1497 [M − H] (calcd for 359.1500). The IR spectrum of 2 showed the presence of hydroxy (3417 cm−1) and aromatic (1593, 1509 cm−1) groups. The 1H NMR spectrum recorded in MeOH-d4 (Table 1) of compound 2 displayed signals for two aromatic protons at δH 6.35 (d, J = 1.8 Hz, H-6) and δH 6.34 (d, J = 1.8 Hz, H-2), one methine at δH 5.67–5.57 (m, H-8), one methylene at δH 3.23–3.25 (2H, m, H2-7) and two methyl groups at δH 3.78 (3H, s, 3-OCH3 and δH 3.76 (3H, s, 4-OCH3). The 13C NMR spectrum of 2 (Table 1) revealed 10 carbon signals for a benzene, one olefinic carbon, one methylene and two methoxy groups. The above mentioned 1D NMR data of 2 in combination with its molecular formula indicated that the compound must be a symmetrical dimeric benzene derivative. Further analysis of NMR data suggested that the structure of 2 was quite similar to that of (E)-5,5′-(but-2-ene-1,4-diyl)bis(3-methoxybenzene-1,2-diol) [15]. The main difference was that the hydroxy group at C-4 and C-4′ in (E)-5,5′-(but-2-ene-1,4-diyl)bis(3-methoxybenzene-1,2-diol) was substituted by a methoxy group in 2, which was confirmed by the HMBC correlation (Figure 2) from δH 3.76 (4-OCH3, 4′-OCH3) to δC 135.9 (C-4, C-4′). The absorption band near 999 cm−1 in the IR spectrum (Figure S26 in Supporting Information File 1) indicated that the double bond has an E configuration [16-19]. Therefore, the structure of compound 2 was established as shown in Figure 1, and named as sinensiol I.

Sinensiol J (3) was isolated as a white amorphous powder. Its HRESIMS showed [M + HCOO] at m/z 391.1394 (calcd for 391.1398), consistent with the molecular formula of C19H22O6. The 1H and 13C NMR data (Table 1) of 3 were extremely similar to those of the rac-1-(benzo[d][1,3]dioxol-5-yl)-4-(3,4,5-trimethoxyphenyl)butan-1-ol [20], the significant difference being the absence of signals for a methoxy group in the 1H and 13C NMR spectra. The flat ECD curve (Figure S38 in Supporting Information File 1) and nearly zero optical rotation of 3 ([Graphic 1] −1.34, c 0.28, MeOH) suggested that 3 was possibly a racemic mixture. Enantioseparation of 3 by HPLC using a chiral-pak IA column provided the enantiomers with a ratio about 3:2 (Figure S28, Supporting Information File 1) suggested its mixture feature. Unfortunately, the limited amount available of this compound did not allow the elucidation of its absolute configuration.

The remaining known compounds were identified as (+)-pinoresinol di-O-β-ᴅ-glucopyranoside (4) [21], dehydrodiconiferyl alcohol-4-O-β-ᴅ-glucopyranoside (5) [22], and lariciresinol-4-O-β-ᴅ-glucopyranoside (6) [23] (Figure 1) by comparing their physiochemical properties and spectral data with those reported in the literature.

Biological activity

The isolated compounds were screened for their inhibitory effects on the LPS-induced NO production in RAW 264.7 macrophages. NG-Monomethyl-ʟ-arginine monoacetate salt (ʟ-NMMA, Sigma) was used as the positive control. As a result, compounds 1, 2, 4, and 5 showed mild inhibitory activities with inhibition rates in the range of 9.47–18.75%, compound 3 showed moderate activity with an inhibition rate of 42.06 ± 2.02% at a concentration of 50 μM (ʟ-NMMA, 59.31 ± 2.19%, Table 2).

Table 2: Inhibitory effects of compounds 16 on LPS-stimulated NO production.

sample concentration (μM) inhibition (%)
1 50 18.75 ± 2.13
2 50 69.16 ± 0.81 (cytotoxicity)
  12.5 15.93 ± 1.37
3 50 42.06 ± 2.02
4 50 9.47 ± 2.38
5 50 11.40 ± 0.81
6 50 3.36 ± 2.38
ʟ-NMMAa 50 59.31 ± 2.19

aPositive control.

Conclusion

In summary, three new lignan derivatives, sinensiols H–J (13) and three known compounds (46), were obtained from the whole plants of Selaginella sinensis. The absolute configuration of compound 1 was established by comparison of calculated and experimental ECD spectra. Compounds 2 and 3, which possess a 1,4-diphenylbutane skeleton, are rare examples of naturally occurring 9,9′-bisnorlignans. In in vitro bioassays, compound 3 was found to show a moderate inhibitory effect on NO production in LPS-induced RAW 264.7 cells with an inhibitory rate of 42.06 ± 2.02% at 50 μM.

Experimental

General experimental procedures

Optical rotations were carried out on an Autopol VI automatoc polarimeter. UV spectra were recorded on a Shimadzu UV-2401 PC spectrophotometer. IR spectra (KBr) were determined on a Bruker Vertex 70 infrared spectrometer. ESI and HRESIMS were performed on an UPLCIT-TOF spectrometer. ECD spectra were obtained on a Chirascan-plus CD spectrometer (Applied Photophysics Ltd., UK). NMR spectral data were measured on a Bruker DRX-600 spectrometer. Silica gel (200–300 mesh, Qingdao Haiyang Chemical Co. Ltd., China) was used for column chromatography. Semi-preparative HPLC was performed on an Agilent 1260 liquid chromatograph with a Zorbax SB-C18 (9.4 mm × 150 mm) column.

Plant material

Selaginella sinensis was collected from Luoyang, Henan, China, in April 2021 and identified by Prof. Liang Zhang (Kunming Institute of Botany, CAS). A voucher specimen (No. 20210412) has been deposited in the school of pharmacy, Guizhou Medical University.

Extraction and isolation

The air-dried powder of the whole plants of S. sinensis (5.2 kg) was extracted three times with 95% ethanol at room temperature. The combined extracts were concentrated and yielded 423 g of a crude extract which was subjected to reversed-phase MPLC (MCI; MeOH/H2O, 5–95%, v/v) to give fractions 1–5. Fr. 2 (58 g) was subjected to silica gel column chromatography (CC) eluting with CH2Cl2/MeOH 9:1 to yield six major fractions (1–6). Fr. 2.2 (0.5 g) then was further purified by preparative HPLC (MeOH/H2O 28:72) to afford compound 5 (20.5 mg) and compound 6 (13.7 mg). Fr. 2.5 (7.50 g) was further purified by silica gel CC with (CH2Cl2/MeOH 9:1) to give compound 4 (120.5 mg). Fr. 3 (37 g) was further purified by reversed-phase chromatography (RP-18 column) using MeOH/H2O 4:6 to afford compound 1 (4.8 mg). Fr. 4 (21 g) was chromatographed on a silicagel column eluting with a CH2Cl2/MeOH gradient system (v/v = 30:1–9:1) to give 8 fractions (Fr. 4.1–Fr. 4.8). Fr. 4.3 was separated by silica gel column chromatography and purified by semipreparative HPLC (3 mL/min) using MeOH/H2O 45:55 to give compounds 2 (5.3 mg) and 3 (2.6 mg).

Identification of new compounds

Compound 1: pale yellow amorphous powder, [Graphic 2] 27.81 (c 0.32, MeOH); IR (KBr) νmax: 3540, 1764, 1515, 1445, 1247, 1035 cm−1; ECD (c 2.2 × 10−4 M, MeOH) λmax (Δε) 204 (+4.36), 231 (+1.79) nm; 1H and 13C NMR data, see Table 1; HRESIMS (m/z): [M − H] calcd for C20H19O7, 371.1136; found, 371.1133.

Compound 2: white amorphous powder, [Graphic 3] −1.35 (c 0.24, MeOH); IR (KBr) νmax: 3417, 1593, 1510, 1350, 1104 cm−1; 1H and 13C NMR data, see Table 1; HRESIMS (m/z): [M − H] calcd for C20H23O6, 359.1500; found, 359.1497.

Compound 3: white amorphous powder, [Graphic 4] −1.34 (c 0.28, MeOH); IR (KBr) νmax: 3433, 2937.2, 1593.0, 1241.6, 814.9 cm−1; 1H and 13C NMR data, see Table 1; HRESIMS (m/z): [M + COOH] calcd for C20H23O8, 391.1398; found, 391.1394.

Nitric oxide production inhibitory assay

The inhibitory activity against the production of NO was evaluated using LPS induced RAW 264.7 cells as previously reported [24]. The cells were seeded in 96-well plates and co-incubated with the test compounds and positive control drug at a concentration of 50 μM or 12.5 μM, followed by stimulation with 1 μg/mL LPS for 18 h. The viability of RAW 264.7 cells was determined by an MTS assay to exclude the interference of the cytotoxicity of the test compounds before the nitric oxide (NO) production assay. NO production in each well was assessed by measuring the accumulation of nitrite in the culture supernatants using Griess reagent. After 5 min of incubation, the absorbance was measured using a microplate reader (Thermo, Bio-rad, USA) at 570 nm. ʟ-NMMA was used as the positive control. Experiments were operated in triplicate. All values are described as mean ± SD of three independent experiments.

Supporting Information

Supporting Information File 1: ECD calculation method of compound 1 and HPLC analysis of 3 and NMR, MS, and IR spectra of compounds 13.
Format: PDF Size: 1.8 MB Download

Funding

This work was supported by the Project for Youth Science and Technology Talent of Guizhou Provincial Education Department (No. [2021]156), the Natural Science Foundation of Yunnan province (No. 202001AT070052), Doctoral Fund of Guizhou Medical University (No. [2020]005) and the New-shoot Talents Project of Guizhou Medical University (No. 19NSP077).

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