Neuroprotective Lignans from the Stems of Schisandra glaucescens

• Material and Methods
• Supporting information
• Acknowledgements
• References

Abstract

Two new tetrahydrofuran lignans, schiglaucin A and B (1–2), together with eight known analogues (3–10), were isolated from the stems of Schisandra glaucescens Diels. Their structures were elucidated on the basis of spectroscopic techniques (HRESIMS, UV, IR, NMR, and CD experiments). All of the compounds were tested for their neuroprotective activities against H₂O₂- and CoCl₂-induced cell injuries in SH-SY5Y cells, respectively. Compounds 1–10 showed significant neuroprotective effects against H₂O₂-induced SH-SY5Y cell death, while compounds 1–5 and 8–10 exhibited significant neuroprotective effects against CoCl₂-induced SH-SY5Y cell injury.

Plants from the genus Schisandra of the family Schisandraceae are economically valuable and widely used in traditional Chinese medicine. In recent years, numerous studies performed on this genus have led to the isolation of a large number of lignans and triterpenes, some of which possess anti-HIV, anti-HBV, antitumor, anticholesteremics, antihepatotoxic, antioxidant, and neuroprotective effects [1], [2], [3], [4], [5], [6], [7], [8], [9].

Schisandra glaucescens Diels. is a vine plant mainly distributed in the west of Hubei province and southeast of Sichuan province in China. Its stems were traditionally used for the treatment of contusions, rheumatism, and arthritis [10]. Two different populations were collected and studied previously; one is from the Shennongjia mountain area of Hubei province, and the other from Qinling Mountain of Shanxi province in China. From the first population, three new triterpenoids were isolated [11], [12], whereas from the second one, fifteen new triterpenoids were identified [13], [14]. In addition to the presence of triterpenes, Schisandra species were also found to be rich in lignans with numerous pharmaceutical effects [2], [6], [7], [8], [9]. But until now, lignans from S. glaucescens have never been reported. As a continuation of our work with the discovery of bioactive natural products, here we describe the isolation and structural elucidation of two new tetrahydrofuran lignans (1–2), along with eight known lignans (3–10) ([Fig. 1]). The neuroprotective effects of the crude extract and compounds 1–10 were also evaluated and showed varying degrees of activities.

Compound 1 was obtained as colorless oil. Its molecular formula was established as C₂₂H₂₆O₇ by HRESIMS with ten degrees of unsaturation. The UV bands at 237, 282 nm and IR bands at 1595, 1513 cm⁻¹ suggested the presence of an aromatic ring in 1, and the strong absorption at 3537 cm⁻¹ for OH.

The ¹H NMR spectrum of 1 exhibited the presence of two 1,3,4-trisubstituted benzene systems, one at δ _H 6.99 (1H, d, J = 1.8 Hz), 6.83 (1H, d, J = 8.2 Hz), 6.93 (1H, dd, J = 8.2 and 1.8 Hz) and the other at δ _H 7.03 (1H, brs), 6.80 (1H, d, J = 8.2 Hz), 7.05 (1H, brd, J = 8.2 Hz); one methylenedioxy at δ _H 5.93 (2H, s); three methoxyls at δ _H 3.89 (3H, s), 3.85 (3H, s), and 3.21 (3H, s), respectively, and two methyls at δ _H 1.28 (3H, s) and 0.93 (3H, d, J = 6.8 Hz).

The ¹³C NMR and DEPT spectra of 1 showed 22 carbon signals, including five methyls (three OCH₃), one methylene (-O-CH₂-O-), eight methines (six sp² CH), and eight quaternary carbons (six sp² C). From the ¹H-¹H COSY correlations between H-7/H-8 and H-8/H-9, a structural unit of -CH-CH-CH₃- was deduced ([Fig. 2]).

The 1D NMR spectra of 1 were very similar to those of 4 [15], except for the disappearing of the signals of H-7′ and H-8′ in the ¹H NMR spectrum of 1, as well as the downshift signals of C-7′ and C-8′ (from δ _C 84.8 and 47.5 in 4 to δ _C 111.6 and 82.3 in 1) in the ¹³C NMR spectrum, which indicated that H-7′ and H-8′ were replaced by oxygenated groups in 1. All the data above suggested 1 to be a 7′,8′-substituted tetrahydrofuran lignan [16].

The HMBC correlation between the upshifted methoxyl protons (δ _H 3.21, 3H, s) and C-7′ (δ_C 111.6) indicated that the quaternary carbon at δ_C 111.6 should be substituted by the methoxyl at δ _H 3.21 (3H, s) ([Fig. 2]). According to the molecular formula of 1, the quaternary carbon at δ_C 82.3 should be substituted by a hydroxyl group. Moreover, the attachments of two other methoxyls and one methylenedioxy were disclosed according to the HMBC correlation between MeO-3/C-3, MeO-4/C-4, and -OCH₂O-/C-3′,4′. The substitutions of C-7 and C-7′ on the benzene rings were confirmed by the correlations from H-7 (δ_H 4.83, 1H, d, J = 10.2 Hz) to C-1 (δ_C 133.8), C-2 (δ_C 110.3), and C-6 (δ_C 120.2), and from H-6′ (δ_H 7.05, 1H, d, J = 8.2 Hz) to C-7′ (δ_C 111.6) in the HMBC spectrum ([Fig. 2]). Based on the data above, the planar structure of 1 was determined as 8′-hydroxy-3′,4′-methylenedioxy-3,4,7′-trimethoxy-7,7′-epoxylignan.

The J value (10.2 Hz) between H-7 (δ _H 4.83, 1H, d, J = 10.2 Hz) and H-8 (δ _H 2.44, 1H, dq, J = 10.2, 6.8 Hz) indicates that they are in a trans configuration [16]. Additionally, the obvious cross-peaks at δ _H 0.93/4.83 (H₃-9/H-7), δ _H 1.28/7.05 (H₃-9′/H-6′), and δ _H 3.21/6.99 (H₃-7′OCH₃/H-2) in the NOESY spectrum confirmed the relative configuration of 1 ([Fig. 2]).

The absolute configuration of 1 was established on the basis of the circular dichroism (CD) curve from 200 to 400 nm [for 1, CD (MeOH), [θ] (nm): 12 847 (217.5, tr), 30 305 (235.5, pk), 9321 (254.5, tr), 18 392 (285.5, pk)], which was similar to those of (+)-chicanine [for (+)-chicanine, CD (MeOH) [θ] (nm): 9670 (221, tr), 24 665 (236, pk), − 467 (256, tr), 4858 (285, pk), 0 (300)] [17]. Since the chiralities at C-7 and C-7′ were expected to have a major influence on the electronic transition of the aromatic chromophore [18], the absolute configuration of 1 was determined as (7S,8R,7′R,8'R)-8′-hydroxy-3′,4′-methylenedioxy-3,4,7′-trimethoxy-7,7′-epoxylignan and named schiglaucin A.

Compound 2, colorless oil, has the same molecular formula, C₂₂H₂₆ O₇, as 1, which was determined by HRESIMS. The 1D NMR spectrum data of 1 ([Table 1]) was very similar to that of 2. Detailed analysis of the HSQC and HMBC spectra of 2 indicated that the positions of the two aromatic groups of 1 were interchanged in 2, which was confirmed by the HMBC correlations between H-7 (δ _H 4.84, d, J = 10.2) and C-1 (δ _C 135.3), C-2 (δ _C 107.6), and C-6 (δ _C 121.5) ([Fig. 3]). Thus, the planar structure of 2 was determined as 8′-hydroxy-3,4-methylenedioxy-3′,4′,7′-trimethoxy-7,7′-epoxylignan.

In the NOESY spectrum of 2 ([Fig. 3]), the correlations between H-7/H-9, H-8/H-9′, 7′-OMe/H-2, and 7′-OMe/H-6 were observed. The CD spectrum of 2 was similar to that of 1 and (+)-chicanine, so the absolute configuration of 2 was determined as (7S,8R,7'R,8′R)-8′-hydroxy-3,4-methylenedioxy-3′,4′,7′-trimethoxy-7,7′-epoxylignan and named schiglaucin B.

The structures of compounds 3–10 were respectively confirmed as (+)-zuihonin A [15], (+)-zuihonin C [15], vladinol F [19], (+)-pinoresinol [20], (+)-syringaresinol [20], prinsepiol [21], tetrecentronside B [22], and (−)-secoisolariciresinol-9-O-β-D-xylopyranoside [23] by comparison with the corresponding literature data.

The neuroprotective effects of the crude extract and compounds 1–10 against H₂O₂- and CoCl₂-induced neuronal cell death in dopaminergic neuroblastoma SH-SY5Y cells were assessed. As shown in [Fig. 4], the crude extract exhibited significant neuroprotective effects in both assays. Compounds 1–10 showed significant neuroprotective effects against H₂O₂-induced SH-SY5Y cell death, and compounds 1–5 and 8–10 exhibited significant neuroprotective effects against CoCl₂-induced SH-SY5Y cell injury ([Table 2]). The crude extract and compounds 1–10 neither affected the cell viability nor showed any cytotoxicity with the absence of H₂O₂ or CoCl₂ (data not shown).

Several classes of lignans, such as dibenzylbutanes [24], dibenzocyclooctenes [9], tetrahydrofurans [25] and others, were reported to express neuroprotective actions. In the present study, we evaluated the neuroprotective potential of ten isolated lignans, including types of tetrahydrofurans (1–4), furofurans (6–8), dibenzylbutanes (9–10), and neolignans (5) ([Table 2]). All of the compounds were tested for their neuroprotective effects against H₂O₂- and CoCl₂-induced neuronal cell death in dopaminergic neuroblastoma SH-SY5Y for the first time.

Material and Methods

Specific optical rotations were measured on a Perkin-Elmer 341 polarimeter. IR spectra were recorded on a Perkin-Elmer spectrum one FT-IR spectrometer using KBr pellets. UV spectra were carried out on a Shanghai Spectrum 756PC spectrophotometer. HRESIMS was performed on a Thermo Scientific LTQ-Orbitrap XL mass spectrometer. CD spectra were recorded on a Jasco J-810 spectropolarimeter. 1D NMR and 2D NMR spectra were recorded on a Bruker-AM-400 spectrometer in CDCl₃. Chemical shifts (δ) are expressed in ppm and coupling constants are given in Hz.

TLC analysis was carried out on silica gel GF₂₅₄ plates (Yantai Institute of Chemical Technology). Visualization of the TLC plates was achieved under UV at 254 and 365 nm and by spraying with 50 % H₂SO₄ followed by heating on a hot plate. Column silica gel (200–300 or 300–400 mesh; Qingdao Marine Chemical, Inc.), Sephadex LH-20 gel (GE Healthcare), and MCI gel (CHP20P, 75–150 µm; Mitsubishi Chemical Industries Ltd.) were used for column chromatography. MPLC was performed using a Buchi pump module C-605 and a Buchi glass column (46 × 3.6 cm and 46 × 4.9 cm i. d.). HPLC was performed on an Agilent 1260 system. Hibar Merk C18 5 µm (250 × 4.6 mm i. d.) and YMC-Pack OSD-A C18 5 µm (250 × 10 mm i. d.) columns were used for analytical and semipreparative purposes. The purity of the isolated compounds was assessed by TLC and NMR at about 95 % for all compounds.

The stems of Schisandra glaucescens Diels. were collected in the Shennongjia mountain areas of Hubei province, P. R. China in November 2009 and identified by Mr. Shi-Gui Shi (Shennongjia Institute for Drug Control). A voucher specimen (ID 20091101) was deposited in the Herbarium of Materia Medica, Faculty of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, P. R. China.

The air-dried stems of Schisandra glaucescens (6.5 kg) were extracted with 70 % aq. acetone (25 L × 4) at room temperature. The acetone extracts were concentrated in vacuo to give a crude extract (750 g). Then the extract was sequentially partitioned with petroleum ether, EtOAc, and BuOH. The EtOAc fraction (126.7 g) was subjected to column chromatography (120 × 7 cm i. d., 200–300 mesh silica, 2000 g, eluted with a mixture of CHCl₃ and acetone from 1 : 0 to 0 : 1) to give fourteen major fractions. Fraction 3 (4.3 g, eluted with CHCl₃: acetone 10 : 1) was subjected to MPLC (46 × 3.6 cm i. d., 200–300 mesh silica, 200 g, eluted with a mixture of petroleum ether and acetone from 10 : 1 to 2 : 1) to afford three subfractions. From subfraction 3–1 (0.8 g, eluted with petroleum ether: acetone 10 : 1), compound 3 (17.0 mg) was obtained after being separated on a silca gel column (40 × 3.5 cm i. d., 200–300 mesh, 150 g, eluted with petroleum ether : acetone 12 : 1) and recrystallization. Subfraction 3–2 (1.0 g, eluted with petroleum ether : acetone 5 : 1) was separated on a silica column (40 × 3.5 cm i. d., 200–300 mesh, 150 g, eluted with petroleum ether : acetone 8 : 1) to afford compound 4 (7.0 mg). Subfraction 3–3 (0.7 g, eluted with petroleum ether : acetone 2 : 1) was further purified on a semipreparative reversed-phase HPLC column (250 × 10 mm i. d., eluted with H₂O : MeOH 20 : 80, flow rate: 3.0 mL/min) to afford compound 1 (106.5 mg; t _R 10.5 min) and compound 2 (81.8 mg; t _R 12.4 min).

Fraction 4 (10.3 g, eluted with CHCl₃ : acetone 9 : 1) was subjected to MPLC (46 × 4.9 cm i. d., 200–300 mesh silica, 380 g, eluted with a mixture of petroleum ether and acetone from 85 : 15 to 20 : 80) to afford nine subfractions. Subfraction 4–6 (1.0 g, eluted with petroleum ether : acetone 35 : 65) was separated on a silica column (40 × 3.5 cm i. d., 200–300 mesh, 150 g, eluted with a mixture of CH₂Cl₂ and MeOH from 100 : 1 to 50 : 1) to afford a mixture of compounds 6 and 7 (0.3 g). Finally, the mixture was separated on a semipreparative reversed-phase HPLC column (250 × 10 mm i. d., eluted with H₂O : MeOH 50 : 50, flow rate: 3.0 mL/min) to afford compound 6 (50.0 mg; t _R 21.0 min) and compound 7 (20.2 mg; t _R 26.2 min). Fraction 6 (8.5 g, eluted with CHCl₃ : acetone 7 : 3) was subjected to MPLC (46 × 4.9 cm i. d., 200–300 mesh silica, 380 g, eluted with a mixture of petroleum ether and acetone from 40 : 1 to 25 : 1) to afford seven subfractions. Subfraction 6–3 (0.5 g, eluted with petroleum ether : acetone 35 : 1) was subjected to MPLC (46 × 3.6 cm i. d., 200–300 mesh silica, 200 g, eluted with a mixture of CH₂Cl₂ and MeOH from 50 : 1 to 30 : 1) to afford compound 5 (185.5 mg). From subfraction 6–4 (0.2 g, eluted with petroleum ether : acetone 30 : 1), compound 8 (8.5 mg) was obtained after being separated on a silca column (40 × 3.0 cm i. d., 200–300 mesh, 100 g, eluted with CH₂Cl₂:MeOH 30 : 1) and recrystallization. Fraction 10 (19.7 g, eluted with a mixture of CHCl₃ and acetone from 3 : 7 to 2 : 8) was subjected to an MCI gel column (50 × 3.5 cm i. d., 70–150 µm, 300 mL, eluted with a mixture of H₂O and MeOH from 60 : 40 to 0 : 100) to afford six subfractions. Subfraction 10–4 (2.0 g, eluted with H₂O : MeOH 40 : 60) gave a light yellow precipitate. After filtering, compound 9 was obtained (1.12 g). Subfraction 10–5 (0.2 g, eluted with H₂O : MeOH 30 : 70) was further purified on a semipreparative reversed-phase HPLC column (250 × 10 mm i. d., eluted with H₂O : MeOH 40 : 60, flow rate: 2.0 mL/min) to afford compound 10 (25.5 mg; t _R 10.9 min).

Human dopaminergic neuroblastoma SH-SY5Y cells were obtained from the cell bank of the Basic Medical College of Huazhong University of Science and Technology (Wuhan, China). Cells were cultured in DMEM culture medium plus 10 % (v/v) calf serum with 100 U/mL penicillin and 75 U/mL streptomycin, and maintained at 37 °C in 5 % CO₂ and a 95 % humidified air incubator. Hydrogen peroxide solution (30 % H₂O₂), cobalt (II) chloride (CoCl₂, purity > 98 %), D-α-tocopherol succinate (vitamin E, purity > 96 %), and 3-[4,5-dimethyl-2-thiazolyl]-2,5- diphenyl-2-tetrazolium bromide (MTT) were purchased from Sigma.

In a preliminary study, a dose-dependent cytotoxic effect of H₂O₂ or CoCl₂ on SH-SY5Y cells was observed in the concentration range of 100–500 µM (data not shown). 300 µM H₂O₂ and 300 µM CoCl₂ (cell viability was nearly 70 % compared with the control group) were chosen to examine the protective effects of the crude extract and all the compounds. SH-SY5Y cells were trypsinized with 0.25 % trypsin, counted, and seeded in 96-well culture plates (1 × 10⁴ cells/well). After 24 h incubation, cells were pretreated with various concentrations of the crude extract (0.01, 0.10, 1.00 mg/mL) or compounds 1–10 (0.004, 0.02, 0.1 µM) for 2 h before incubation in medium containing H₂O₂ (300 µM) or CoCl₂ (300 µM). Then 15 µL MTT (5 mg/mL) was added at 24 hours after treatments. For the MTT assay, the supernatant was discarded and DMSO (100 µL/well) was added. Then the 96-well plate was vibrated on a micro-vibrator for 10 min, and the optical density at 570 nm was measured by an enzyme-immunoassay instrument (Thermo Labsystems MK-3). All samples were cultured in triplicate.

Statistical analysis was performed by one-way analysis of variance (ANOVA) followed by post hoc multiple comparisons using the Newman–Keuls multiple comparison method. The data are expressed as means ± SEM of three assays.

Schiglaucin A (1): colorless oil; R_f 0.67, silica gel GF₂₅₄ plate, petroleum ether and acetone 2 : 1; UV λ _max (CH₂Cl₂) nm (log ε): 237 (3.84), 282 (3.56); [α]_D ²⁰ + 53.56 (c 12.51, CHCl₃); IR (KBr) ν _max · cm⁻¹: 3537, 2962, 2935, 2834, 1595, 1513, 1487, 1462, 1440, 1252, 1165, 1139, 1093, 1033, 1010, 933, 880, 810, 755; HRESIMS m/z 425.1567 (calcd. for C₂₂H₂₆NaO₇, 425.1576); CD (c 1.77 × 10⁻⁴, MeOH) [θ] (nm): 12 847 (217.5, tr), 30 305 (235.5, pk), 9321 (254.5, tr), 18 392 (285.5, pk); ¹H NMR (400 MHz, CDCl₃) and ¹³C NMR (101 MHz, CDCl₃) data, see [Table 1].

Schiglaucin B (2): colorless oil; R_f 0.67, silica gel GF₂₅₄ plate, petroleum ether and acetone 2 : 1; UV λ _max (CH₂Cl₂) nm (log ε): 233 (3.90), 285 (3.60); [α]_D ²⁰ + 58.63 (c 9.95, CHCl₃); IR (KBr) ν _max · cm⁻¹: 3536, 2963, 2935, 2831, 1605, 1511, 1491, 1445, 1250, 1166, 1138, 1084, 1031, 934, 870, 810, 759; HRESIMS m/z 425.1569 (calcd. for C₂₂H₂₆NaO₇, 425.1576); CD (c 2.33 × 10⁻⁴, MeOH) [θ] (nm): 7183 (219.5, tr), 24 516 (235.5, pk), 4817 (254, tr), 12 129 (285, pk); ¹H NMR (400 MHz, CDCl₃) and ¹³C NMR (101 MHz, CDCl₃) data, see [Table 1].

Supporting information

The IR, UV, HRESIMS, NMR, and CD spectra of compounds 1–2 are available as Supporting Information.

Acknowledgements

Financial support from the Ministry of Science and Technology of the Peopleʼs Republic of China (International Cooperative Project, Grant No. 2010DFA32430) and the Natural Science Foundation of China (No. 30873361 and 31270394) is gratefully acknowledged.

Conflict of Interest

All the authors have no conflict of interest to declare.

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Correspondence

• References

• 1 Kuo YH, Li SY, Wu MD, Huang RL, Yang Kuo LM, Chen CF. A new anti-HBeAg lignan, kadsumarin A, from Kadsura matsudai and Schizandra arisanensis . Chem Pharm Bull 1999; 47: 1047-1048
  CrossrefPubMedSearch in Google Scholar
• 2 Chen M, Kilgore N, Lee KH, Chen DF. Rubrisandrins A and B, lignans and related anti-HIV compounds from Schisandra rubriflora . J Nat Prod 2006; 69: 1697-1701
  CrossrefPubMedSearch in Google Scholar
• 3 Li RT, Han QB, Zheng YT, Wang RR, Yang LM, Lu Y, Sang SQ, Zheng QT, Zhao QS, Sun HD. Structure and anti-HIV activity of micrandilactones B and C, new nortriterpenoids possessing a unique skeleton from Schisandra micrantha . Chem Commun 2005; 23: 2936-2938
  PubMedSearch in Google Scholar
• 4 Xiao WL, Li RT, Li SH, Li XL, Sun HD, Zheng YT, Wang RR, Lu Y, Wang C, Zheng QT. Lancifodilactone F: a novel nortriterpenoid possessing a unique skeleton from Schisandra lancifolia and its anti-HIV activity. Org Lett 2005; 7: 1263-1266
  CrossrefPubMedSearch in Google Scholar
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