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The constituents of Schizandra chinensis Baill. III. The structures of four new lignans, gomisin H and its derivatives, angeloyl-, tigloyl- and benzoyl-gomisin H
Abstract
Four new dibenzocyclooctadiene lignans, angeloyl-(1), tigloyl-(2) and benzoyl-gomisin H (3) and gomisin H (4), were isolated from the fruits of Schizandra chinensis BAILL. (Schizandraceae). Their structures were elucidated by chemical and spectral techniques.
... In our previous study, we reported four new dibenzocyclooctadiene lignans from the stems of Schisandra neglecta, which is indigenous to the Tibet Autonomous Region of China [14,15]. Our further investigation of the same plant has now led to the isolation and identification of two new dibenzocyclooctadiene lignans, named neglschisandrins E (1) and F (2) (Figure 1), together with thirteen known lignans, 6-O-benzoylgomisin O (3) [16], (+)-γ-rubschisandrin (4) [17], rubschisantherin (5) [17], benzoylisogomisin O (6) [18], schisandrin A (7) [19], schisanhenol (8) [20], angeloylgomisin H (9) [21], gomisin H (10) [21], tigloylgomisin H (11) [21], benzoylgomisin H (12) [21], schisandrin (13) [22], gomisin B (14) [23], and angeloyl-(+)-gomisin K 3 (15) [24]. This paper reports the isolation and structural elucidation of these compounds as well as their in vitro cytotoxicity against human lung carcinoma A549 and human colorectal carcinoma HCT-8 cell lines. ...
... In our previous study, we reported four new dibenzocyclooctadiene lignans from the stems of Schisandra neglecta, which is indigenous to the Tibet Autonomous Region of China [14,15]. Our further investigation of the same plant has now led to the isolation and identification of two new dibenzocyclooctadiene lignans, named neglschisandrins E (1) and F (2) (Figure 1), together with thirteen known lignans, 6-O-benzoylgomisin O (3) [16], (+)-γ-rubschisandrin (4) [17], rubschisantherin (5) [17], benzoylisogomisin O (6) [18], schisandrin A (7) [19], schisanhenol (8) [20], angeloylgomisin H (9) [21], gomisin H (10) [21], tigloylgomisin H (11) [21], benzoylgomisin H (12) [21], schisandrin (13) [22], gomisin B (14) [23], and angeloyl-(+)-gomisin K 3 (15) [24]. This paper reports the isolation and structural elucidation of these compounds as well as their in vitro cytotoxicity against human lung carcinoma A549 and human colorectal carcinoma HCT-8 cell lines. ...
... In our previous study, we reported four new dibenzocyclooctadiene lignans from the stems of Schisandra neglecta, which is indigenous to the Tibet Autonomous Region of China [14,15]. Our further investigation of the same plant has now led to the isolation and identification of two new dibenzocyclooctadiene lignans, named neglschisandrins E (1) and F (2) (Figure 1), together with thirteen known lignans, 6-O-benzoylgomisin O (3) [16], (+)-γ-rubschisandrin (4) [17], rubschisantherin (5) [17], benzoylisogomisin O (6) [18], schisandrin A (7) [19], schisanhenol (8) [20], angeloylgomisin H (9) [21], gomisin H (10) [21], tigloylgomisin H (11) [21], benzoylgomisin H (12) [21], schisandrin (13) [22], gomisin B (14) [23], and angeloyl-(+)-gomisin K 3 (15) [24]. This paper reports the isolation and structural elucidation of these compounds as well as their in vitro cytotoxicity against human lung carcinoma A549 and human colorectal carcinoma HCT-8 cell lines. ...
Phytochemical investigation of an ethanolic extract of stems of Schisandra neglecta led to the isolation and identification of two new dibenzocyclooctadiene lignans, designated neglschisandrins E (1) and F (2), and thirteen known lignans. All structures and stereochemistries were determined by spectroscopic methods, including 2D-NMR techniques. The isolates were evaluated for in vitro cytotoxic activity. Among them, compounds 2-6 exhibited moderate to weak cytotoxicity against the human colorectal carcinoma HCT-8 cell line with EC(50) values of 7.33~19.8 μg/mL. In addition, compounds 2-4 also exhibited marginal cytotoxicity against the human lung carcinoma A549 cell line with EC(50) values of 11.8~15.0 μg/mL.
... The dried fruits of S. chinensis were successively extracted with hexane, EtOAc, and then MeOH. The hexane extract led to the isolation of schisandrin A (1), 19 gomisin K3 (2), 20 schisandrin (3), 21 gomisin A (4), 22 tigloylgomisin H (6), 23 benzoylgomisin H (7), 22 schisandrin C (8), 23 gomisin N (9), 23 and gomisin J (10). 23 The EtOAc extract was chromatographed on a silica gel column to afford gomisin B (11), 21 tigloylgomisin H (6), and schisandrene (13). ...
... The dried fruits of S. chinensis were successively extracted with hexane, EtOAc, and then MeOH. The hexane extract led to the isolation of schisandrin A (1), 19 gomisin K3 (2), 20 schisandrin (3), 21 gomisin A (4), 22 tigloylgomisin H (6), 23 benzoylgomisin H (7), 22 schisandrin C (8), 23 gomisin N (9), 23 and gomisin J (10). 23 The EtOAc extract was chromatographed on a silica gel column to afford gomisin B (11), 21 tigloylgomisin H (6), and schisandrene (13). ...
... 23 The EtOAc extract was chromatographed on a silica gel column to afford gomisin B (11), 21 tigloylgomisin H (6), and schisandrene (13). The MeOH extract was chromatographed on a silica gel column to yield gomisin G (12), 21 angeloylgomisin H (5), 22 and schisandrin (3). The structures of these compounds are shown in Table 1. ...
Phytochemical investigation of the fruits of Schisandra chinensis led to the isolation of 13 lignans including schisandrene (13), a new lignan based on a dibenzocyclooctadiene backbone with an exocyclic double bond. Its structure and absolute configuration were established using NMR, MS, and CD data. Antioxidant activity of the lignans was evaluated using a DCFH-DA cellular-based assay. The structure-activity relationships of the dibenzocyclooctadiene lignans showed that the exocyclic methylene functionality was essential for antioxidant activity, with the benzoyloxy group probably enhancing such effects.
... In our screening program, a n-hexane-soluble extract of Fructus Schisandrae Chinensis showed a relative fluorescence intensity (FI) value of 99.0 at 100 μg/mL, which exhibited a potential effect on stimulating glucose uptake compared with the vehicle-treated control group (IF value 49.0). Further fractionation of the n-hexane-soluble extract led to the isolation of 13 dibenzocyclooctadiene lignans, which were identified as gomisin J (1), gomisin N (2), wuweizisu B (3), wuweizisu C (4), gomisin C (5), gomisin D (6), (+)-schisandrin A (7), schisandrin C (8), schisandrol A (9), gomisin H (10), angeloylgomisin H (11), gomisin A (12), and schizandrin (13) by analysis and comparison of the spectral data with those in the literature (Figure 1) [10][11][12][13][14][15][16]. ...
Glucose uptake assay-guided fractionations of the methanol extract of Schisandra chinensis led to the isolation of the dibenzocyclooctadiene lignans: gomisin J (1), gomisin N (2), wuweizisu B (3), wuweizisu C (4), gomisin C (5), gomisin D (6), (+)-schisandrin A (7), schisandrin C (8), schisandrol A (9), gomisin H (10), angeloylgomisin H (11), gomisin A (12), and schizandrin (13). Among these, 1, 2, 7, and 8 significantly improved basal glucose uptake in HepG2 cells. Their improving effects were concentration-dependent. Compound 2 exhibited a stronger effect than that of rosiglitazone, which has been used as an antidiabetic drug. The results suggest that these lignans may partially contribute to the antidiabetic activity of Fructus Schisandrae Chinensis in traditional use by stimulating the glucose uptake into peripheral tissue, which may be responsible for reducing the level of blood glucose in circulation. Thus, these findings show the potential of these lignans for development as hypoglycemic drugs.
... Dried S. chinensis fruits were extracted with aqueous EtOH, and the concentrated extract was partitioned into EtOAc, n-BuOH, and H 2 O. Repeated separations of the EtOAc fraction by SiO 2 , ODS, and Sephadex LH-20 c.c. led to the isolation of dibenzocyclooctadiene-type lignans 1-7, identified as schisandrin A (1), [16] (-)-gomisin K1 (2), [17] gomisin J (3), [6] gomisin A (4), [6,17] angeloyl gomisin H (5), [2,17,18] schisandrin (6), [6,19,20] and gomisin C (7) [17] through detailed analysis of the spectroscopic data from 1D and 2D NMR and IR spectroscopy, FAB/MS, and specific rotation data as well as comparison with the data in the literature (Fig. 2). Of the seven compounds, The NMR data reported in the literatures for angeloyl gomisin H (5) were identified to be a little bit incorrect [2,4,13,17,18]. ...
Repeated chromatographic separations of the EtOAc fraction of Schisandra chinensis fruits on silica gel, octadecyl silica gel, and Sephadex LH-20 led to the isolation and identification of seven dibenzocyclooctadiene lignans ( 1 – 7 ). The NMR data reported in the literature for angeloyl gomisin H ( 5 ) were shown to be incorrect. We unambiguously identified the compounds based on detailed analysis of the 1D and 2D NMR data, especially from HMBC and NOESY experiments. In addition, MTT assays and cell viability experiments verified the cytotoxicity of the isolated dibenzocyclooctadiene lignans against the human cancer cell lines AGS, HeLa, and HT-29.
... H NMR, δ 6.625 (s, 2H, H-4 and H-11), 5.728 (s, OH, OH-3′), 5.691 (s, OH, OH-12′), 3.930 (s, 3H, H-2′), 3.922 (s, 3H, H-13′), 3.518 (s, 6H, H-1′ and H-14′), 2.549 (dd, 1H, H6a), 2.452 (dd, 1H, H6b), 2.240 (dd, 1H, H9a), 2.017 (dd, 1H, H9b), 1.881 (dddq, 1H, H7), 1.787 (dddq, 1H, H-8), 0.967 (s, 3H, H17), 0.724 (d, 3H, H18); 13 C NMR. H NMR, δ 6.619 (s, 1H, H-4), 6.478 (s, 1H, H-11), 5.960, 5.956 (d, 2H, H-12′/13′), 3.903 (s, 6H, H-3′ and H-14′), 3.837 (s, 3H, H-2′), 3.517 (s, 3H, H-1′), 2.684 (d, 1H, H6a), 2.578 (dd, 1H, H9a), 2.349 (d, 1H, H6b), 2.327 (dd, 1H, H9b), 1.867 (dq, 1H, H8), 1.252 (s, 3H, H-18), 0.814 (d, 3H, H17); [MH] + , (calcd for C 23 H 29 O 7 , 416.2277). Angeloylgomisin H [6,8], NMR (400 MHz, CDCl 3 ): 1 H NMR, δ 6.691 (s, 1H, H-4), 6.557 (s, 1H, H-11), 5.885 (q, 1H, H-21), 3.908 (s, 3H, H-13′), 3.874 (s, 3H, H-12′), 3.837 (s, 6H, H-2′ and H-3′), 3.543 (s, 3H, H-1′), 2.741 (d, 1H, H6a), 2.702 (dd, 1H, H9a), 2.412 (dd, 1H, H9b), 2.333 (d, 1H, H6b), 1.882 (dq, 1H, H8), 1.760 (d, 3H, H-23), 1.753 (s, 3H, H-22), 1.248 (s, 3H, H18′), 0.846 (d, 3H, H18); 13 C NMR. (calcd for C 28 H 37 O 8 , 500.2488). ...
Natural Deep Eutectic Solvent (NADES) species can exhibit unexpected solubilizing power for lipophilic molecules despite their simple composition, hydrophilic organic molecules and water. In the present study, the unique properties of NADES species were applied in combination with a model polymer system: a hydrophilic chitosan/alginate hydrogel. Briefly, NADES species (e.g., mannose-dimethylurea-water, 2:5:5, mole/mole) formed matrices to 1) dissolve lipophilic molecules (e.g., curcumin), 2) load lipophilic molecule(s) into the hydrogel, and 3) spontaneously vacate from the system. NADES species ubiquitously occur in natural sources, and a crude extract is a mixture of the NADES species and bioactive metabolites. Based on these ideas, we hypothesized that the crude extract may also allow the loading of natural bioactive molecules from a natural NADES species into (bio)hydrogel systems. To evaluate this hypothesis in vitro, Schisandra chinensis fruit extract was chosen as a representative mixture of lipophilic botanical molecules and hydrophilic NADES species. The results showed that the NADES matrix of S. chinensis was capable of loading at least three bioactive lignans (i.e., gomisin A, gomisin J, and angeloylgomisin H) into the polymer system. The lipophilic metabolites can subsequently be released from the hydrogel. The outcomes suggest that a unique drug delivery mechanism may exist in nature, thereby potentially improving the bioavailability of lipophilic metabolites through physicochemical interactions with the NADESs.
... With an aims to discover more bioactive secondary metablites from the fruits of S. chinensis (Turcz.) Baill, a further investigation of the extract led to isolation of seven new C 18 -dibenzocyclooctadiene lignans (Fig. 1), termed schinlignans A-G (1-7), and a rare 6,7seco-homolignan, termed schischinone (8), together with seven known lignans, angeloylgomisin H (9) (Ikeya et al., 1979d), rubrisandrins A (10/11) , schisanchinin B (12) (Hu et al., 2014), methylgomisin O (13) (Ren et al., 2010), wuweilignan E (14) (Huang, 2007d), and neglschisandrin E (15) (Chen et al., 2013). Structures of the new compounds were determined by means of spectroscopic methods including HRESIMS, IR, UV, NMR, and ECD techniques. ...
Seven lignans with a dibenzocyclooctadiene skeleton, termed schinlignans A-G, and a 6,7-seco-homolignan, schischinone, together with seven known lignans, were isolated from the fruits of Schisandra chinensis (Turcz.) Baill. Their structures were elucidated by extensive spectroscopic methods, including HRESIMS, IR, UV, and 2D NMR (COSY, HMQC, COSY, and HMBC experiments). The stereochemistry at the chiral centers and the biphenyl moiety, were determined using ROESY, as well as via interpretation of their ECD spectra. Schinlignan G and methylgomisin O exhibited potent anti-hepatitis B virus activity against HBV DNA replication with IC50 values of 5.13 and 5.49 μgmL(-1), respectively.
... A proposed pathway describing the formation of pregomicin, gomicin J and schisphenone (2) via oxidative coupling of two C6–C3 units was illustrated inFig. 4. The structural elucidations from the spectral data of the 11 known 8–18 are in agreement with those found in the literatures and characterised as pre-gomisin (8) (Ikeya, Taguchi, Yosioka, & Kobayashi, 1979), meso-dihydroguaiaretic acid (9) (Nakatan, Ikeda, Kikuzaki, Kido, & Yamaguchi, 1988), veraguensin (10) (Sung, Huh, & Kim, 2001), (À)-8epi-aristoligone (11) (Silva & Lopes, 2004 ), benzoylgomisin P (12) (Ikeya, Miki, Okada, Mitsuhashi, & Chai, 1990), benzoylgomisin U (13) (Ikeya, Sugama, Okada, & Mitsuhashi, 1991), gomisin F (14) (Taguchi & Ikeya, 1977), (+)-gomisin K3 (15) (Ikeya et al., 1980), and schisantherin D (16) (Ikeya, Taguchi, & Yosioka, 1982), together with two triterpenenoids, kadsuric acid (17) (Yamada et al., 1976) and coccinic acid (18) (Lian Niang & Hong, 1986). Hepatic stellate cells (HSCs) are considered to play a key role in the pathogenesis of liver fibrosis. ...
Phytochemical investigation of the ethanol extract from the fruits of Schisandra sphenanthera has resulted in isolation of seven new oxygenated lignans (1–7), in addition to 11 known compounds (8–18). Their structures were determined on the basis of 2D-NMR (COSY, HMQC, HMBC and NOESY) analyses. The isolated components were evaluated with a reporter gene assay that measures their anti-liver fibrosis activity. Compounds 1, 2, 4, 11, 13, 14 and 18 exhibited significant anti-inflammatory activity on HSC-T6 test.
... The highest concentration, about 4% (dry weight), has been found in seeds, whilst up to 2% is present in fruits (Hikino et al., 1984). Up until now lignans were studied mainly in Japan, China and Russia (Kochetkov et al., 1961;Ikeya et al., 1979;Cui and Wang, 1993) where isolation methods based on Soxhlet extraction by petroleum ether, methanol or ethanol were worked out. The aim of the present work was to use SFE with pure carbon dioxide for the isolation of lignans from seeds and leaves of S chinensis and to compare the efficiency, selectivity and kinetics of SFE with those of Soxhlet extraction. ...
Supercritical carbon dioxide was used to extract lignans from seeds and leaves of Schizandra chinensis (Turcz.) Baill. Kinetics of the extraction was found to be controlled by intra-particle diffusion of lignans. The extraction yields were approximately 96% of lignans from seeds and about 26% from leaves, both yields being based on the total lignan content determined from two successive Soxhlet extractions with petroleum ether and methanol. © 1997 John Wiley & Sons, Ltd.
... Subsequently, four lignans that were extracted in large quantities compared to the other lignans were harvested. The structure of these lignans was determined by LC-MS and NMR analysis, and the lignans were identified as gomisin n (16), schisandrin (17), schisandrin c (16) and gomisin A (18,19) (Fig. 1). Chromatography verified that the four lignans were pure enough to be used in experiments to determine their anti-cancer effects (Fig. 2). ...
Lignans isolated from Schisandria chinensis have been prescribed as anti-cancer and anti-hepatitis treatments in Chinese medicine. To investigate the applications of lignans isolated from Schisandria chinensis in hepatic carcinoma therapy, their apoptotic ability was screened using a cell proliferation assay. Compared to the other lignans, gomisin N induced high apoptotic levels in hepatic carcinoma. Cell morphology and flow cytometric analysis demonstrated that this lignan induced cell death at high concentrations, but did not induce any changes at low concentrations. In addition, the expression levels of Bcl-2 and Bax proteins, which are involved in the apoptotic pathway, were markedly increased in only the 320 µM-treated group compared to the vehicle and other concentration groups, while the expression level of p53 protein remained unchanged in this group. These results suggest that gomisin N is an anti-cancer drug candidate capable of inhibiting the proliferation and inducing the apoptosis of human hepatic carcinomas.
... The structures of this compound type are very complex, because of multiple chiral features and stereoisomers. Some 2,3-dimethyl-1,4-diarylbutane lignans, including pregomisin [16], meso-dihydroguaiaretic acid [35], and nordihydroguaiaretic acid [36], were also isolated from S. chinensis fruits (Table 1). Structural elucidation is mainly by the use of spectroscopic techniques, including ultraviolet (UV), infrared (IR), mass (MS), nuclear magnetic resonance (NMR), and circular dichroism (CD) spectra, as well as advanced 2D NMR. ...
Wuweizi (Fructus Schisandrae) is classified in traditional Chinese medicine as a superior drug, and has been used for thousands of years. Modern pharmacological research has demonstrated that most of the biological actions and pharmacological effects of Wuweizi can be attributed to its lignan constituents, particularly the dibenzocyclooctadiene-type lignans, which can lower the serum glutamate-pyruvate transaminase (SGPT) level, inhibit platelet aggregation, and show antioxidative, calcium antagonism, antitumor-promoting, and anti-HIV (human immunodeficiency virus) effects. The dried ripe fruits of both Schisandra chinensis and Schisandra sphenanthera have long been used as Wuweizi, although their chemical constituents and contents of the bioactive components are quite different. Since 2000, they have been accepted as two different crude drugs, Bei-Wuweizi and Nan-Wuweizi, respectively, by the Chinese Pharmacopoeia. In order to provide a useful reference for good quality control of Wuweizi, many studies on the chemical constituents, pharmacological effects, identification and quality control methods of the two drugs have been reported in the literature and are summarized herein. Particular attention was given to the different methodologies developed for the qualitative and quantitative analysis of the major bioactive lignans. In our opinion, thin-layer chromatography (TLC) is the most simple and convenient method for identification of these two crude drugs, and high-performance liquid chromatography with UV detection (HPLC-UV) is the preferred method for quantitative analysis based on the bioactive lignans. Some newly developed methods, particularly hyphenated chromatographic-analytical techniques, are effective in determination of the lignans that occur in low content and those difficult to be fully separated with HPLC.
The fruit of Schisandra chinensis (Chinese magnolia vine) is one of the many raw materials derived from traditional Chinese medicine that is appreciated in modern phytotherapy, as well as in the cosmetics and food industries. Apart from this raw material, the lesser-known fruit of S. sphenanthera is also highly valued in Far Eastern medicine. This species is often confused with S. chinensis. In this chapter, comparative characteristics of both species are presented. Particular attention is paid to the differences in their occurrence, chemical compositions and possible applications. A broad review of the scientific literature has been made, and the most important information on the biological activity, industrial use and the progress in biotechnology research on the two species has been collected.
Schisandra chinensis (Turcz.) Baill is a climbing plant widely distributed in the northeastern part of China, Korea, and Japan, and used in traditional Chinese herb as a tonic, antitussive, and sedative agent. This review focuses on the phytochemicals, biological activities and analytical methods, in order to promote further studies on the plant. 202 chemical compounds have been isolated and identified from this plant, and the most important are dibenzocyclooctadiene lignans and triterpenoids. The isolated compounds of S. chinensis were shown to possess anti-cancer, anti-oxidant, neuroprotective, hepatoprotective, anti-inflammatory activities and so on. Further studies should be carried on this plant in order to disclose many more active principles and mechanisms of active components.
We initiated and optimized in vitro culture conditions of the endemic Chinese plant species—Schisandra henryi C. B. Clarke. Different types of in vitro solid cultures (microshoot and callus), cultivation periods (10, 20, and 30 days), and selected concentrations of BA, IBA, GA3 (0 to 3 mg/l) in the Murashige and Skoog (MS) medium were tested. The presence of dibenzocyclooctadiene lignans (schisandrin, gomisin G, schisantherin A and B, deoxyschisandrin and schisandrin C), dibenzylbutane lignans (hernicine B), aryltetralin lignans (wulignan A1 and A2, epiwulignan A1, enshicine, epienshicine and dimethylwulignan A1), and triterpenoids: kadsuric acid and schisanhenric acid was confirmed by UHPLC–MS/MS analysis. Using HPLC–DAD, the qualitative and quantitative profiles of dibenzocyclooctadiene lignans, phenolic acids and flavonoids in methanolic extracts from biomass were estimated. The maximum total amounts of these groups of metabolites were 873.71, 840.89 and 421.98 mg/100 g DW, respectively. The main compounds were: schisantherin B (max. 622.59 mg/100 g DW), schisantherin A (max. 143.74 mg/100 g DW), neochlorogenic acid (max. 472.82 mg/100 g DW), caftaric acid (max. 370.81 mg/100 g DW), trifolin (max. 138.56 mg/100 g DW) and quercitrin (max. 122.54 mg/100 g DW). The highest total amounts of secondary metabolites estimated in the extracts from in vitro cultures were, respectively, 13.0, 7.0, and 1.4 times higher than in the leaf extracts analyzed for comparison. This is the first report on the biosynthetic potential of cells from Schisandra henryi in vitro cultures.
Glycogen synthase kinase-3β (GSK-3β) is a key enzyme in hyper-phosphorylation of tau proteins and is a promising therapeutic target in Alzheimer’s disease (AD). Here, we reported, for the first time, that the stereoisomers of Schisandrin B (Sch B), (+)–1, (–)–1, (+)–2, and (–)–2, were potent GSK-3β inhibitors. They were demonstrated to selectively target GSK-3β in an orthosteric binding mode, with IC50 values of 340, 290, 80, and 70 nM, respectively. Further study showed that these stereoisomers can significantly increase the expression of p-GSK-3β (Ser9), and decrease the expressions of p-GSK-3β (Tyr216) and p-GSK-3β (Tyr279). Finally, these compounds can alleviate the cell injury induced by Aβ, and the cognitive disorders in AD mice, especially (+)-2 and (-)-2. Collectively, the stereoisomers of Sch B, especially (+)–2 and (–)–2, were found to be potential selective ATP-competitive GSK-3β inhibitors, which further affected their anti-AD effects. These promising findings explained the biological target of Sch B in AD, and bring a new understanding in the stereochemistry and bioactivities of Sch B.
Sixteen dibenzocyclooctadiene lignans, including eight new ones, kadheterins A–H (1–8), and a new natural product, 9-benzoyloxy-gomisin B (9), were isolated from the stems of K. heteroclita. The structures of 1–9 were elucidated by extensive spectroscopic methods, and their absolute configurations were determined by combining CD with ROESY experiments. Additionally, the absolute configuration of 1 was further confirmed by single crystal X-ray crystallographic analysis. In vitro activity assays showed that 1 exhibited moderate cytotoxicity against HL-60 with IC50 value at 14.59 μM.
Lignans are secondary metabolites synthesized by plants and exhibit a wide range of remarkable biological activities. In this chapter, the biosynthesis, metabolism, and the role of lignans in plant defense are extensively treated. All these details have been developed according to structures of main families and types in order to signify, when possible, the relationship between structures and biological activities . A special attention has been paid to podophyllotoxin and related substances due to their remarkable antitumoral properties.
Lignans are polyphenols spread in a wide variety of plant-based foods, including seeds, whole grains,
legumes, fruit, and vegetables. When consumed, lignan precursors are converted to the enterolignans, enterodiol and enterolactone, by bacteria that normally colonize the human intestine. Lignans have attracted considerable attention due to their pharmacological and biological activities. This review article is a survey on the molecular structure of about 276 new naturally occurring lignans obtained from different plant families. We classified seven main types according to their structural features, and provided a number of review reports published recently about lignans. A tabular compilation of the molecular structures of known lignans is presented at the end of this survey report. A total of 111 references were considered for this survey report.
NAtural Deep Eutectic Solvents (NADES) are chemically simple but physiologically important plant constituents that exhibit unique solubilizing properties of other metabolites, including bioactive constituents. The high polarity of NADES introduces a challenge in the ability of conventional solid-support based chromatography to recover potential bioactive metabolites. This complicates the systematic explanation of the NADES' functions in botanical extracts. The present study utilizes countercurrent separation (CCS) methodology to overcome the recovery challenge. To demonstrate its feasibility, Glucose-Choline chloride-Water (GCWat, 2:5:5, mole/mol) served as a model NADES, and four widely used marker flavonoids with different polarities (rutin, quercetin, kaempferol, and daidzein) were chosen as model target analytes. In order to prepare GCWat with high consistency, a water drying study was performed. The unique capabilities of the recently introduced CherryOne system, offering volumetric phase metering, were used to monitor the CCS operations. The collected fractions were analyzed using UHPLC and NMR/quantitative NMR. CCS was able to recover the analytes from the NADES matrix with quantitative recovery efficiencies of 95.7%, 94.6%, 97.0%, and 96.7% for rutin, quercetin, kaempferol, and daidzein respectively. The CCS strategy enables recovery of target metabolites from NADES-containing crude extracts as well as from other chemical mixtures, and moreover offers a means of using NADES as environmentally friendly extraction solvents.
Wuweizi, Fructus Schisandrae, is the dry fruits of Schisandra chinensis (Turcz.) Baill. or S. sphenanthera Rehd. et Wils. (Magnoliaceae) collected in the fall when the fruits have become ripe. It is officially listed in the Chinese Pharmacopoeia and is used as a tonic and sedative.
A series of schisantherin A (1) derivatives were efficiently synthesized utilizing Yamaguchi esterification (2, 4, 6-trichlorobenzoyl chloride, Et3N, THF, DMAP, Toluene) at the C-7' position of the schisantherin A core. The synthesized derivatives were evaluated for their anti-cancer activities against SIHA, PANC 1, MDA-MB-231, IMR-32, DU-145, and A-549 cancer cell lines using sulphorodamine B assay. Within the new series tested, compound 29 displayed most promising cytotoxic effect against human cervical cancer cell line (SIHA) with GI50 value of <0.01µM, which is comparable to the standard drug, doxorubicin. Mechanism of action studies validated that 29 functions as a microtubule inhibitor. Additionally, several of the other analogues exhibited potent activity against the tested cell lines. Based on the results obtained structure activity relationship (SAR) were established and a correlation between the activities was also observed and discussed.
The family Schisandraceae (Magnoliiadae) contains approximately sixty species which are disjunctly distributed in the southeast of Asia and North America. It was divided into two genera, Schisandra and Kadsura, represented by 29 species in China, 19 in Schisandra and 10 in Kadsura. This paper reviews current knowledge about the chemistry, ethnopharmacology and pharmacology of the family in an attempt to present a preliminary study into the pharmacophylogenetics of the family as a whole. Dibenzocyclooctadiene lignans (I) are considered to be the main chemical components of the family. Despite their traditionally recognized hepatoprotective function, they also exhibit anti-oxidant, anti-cancer and anti-HIV potential. Those dibenzocyclooctadiene lignans (I) possessing hydroxyl or angeloyloxy groups at C-6 or C-9 in the ethylidene-cyclooctane ring tend to exhibit a higher anti-cancer activity. Spirobenzofuranoid dibenzocyclooctadienes (II), mostly present in Kadsura, contain a special tetrahydrofuran ring spanning the biphenyl linkage and these demonstrate particular anti-PAF activities. This supports the traditional use of Kadsura to improve blood circulation and "remove dampness". Spirobenzofuranoid dibenzocyclooctadienes (II) could be considered as the bioactive marker compounds in Kadsura and hence markers for assessing quality. The distribution of all known lignans in the family showed that Kadsura is relatively advanced in evolution. Cycloartanone triterpenes occur in both Schisandra and Kadsura. Those with the A-ring open (II) tend to exhibit greater anti-cancer and anti-HIV activity. 7/7/5/6 triterpene lactones (IV), showing strong cytotoxicity, have only recently been discovered in Kadsura longipedunculata and as such have potential as anticancer agents. Recently, novel nortriterpenoids possessing a unique skeleton were found in S. lancifolia and S. micrantha; some exhibited clear anti-cancer or anti-HIV activity and are the subject of separate studies.
A method for the preparative purification of lignans from Schisandra chinensis was established using a combination of high-speed counter-current chromatography (HSCCC) and preparative high-performance liquid chromatography (HPLC). The crude extracts obtained from S. chinensis by using 70% ethanol were separated on a macroporous resin column and then eluted with a graded ethanol series. A two-phase solvent system consisting of n-hexane-ethyl acetate-methanol-water (1:1:1:1, v/v) was used for HSCCC, and a mobile phase of acetonitrile-water (50:50, v/v) was used for preparative HPLC. The results obtained using HSCCC were compared with those obtained using preparative HPLC, and their advantages were further integrated to improve the separation efficiency. Six known lignans were identified by electrospray ionisation mass spectrometry and (1)H nuclear magnetic resonance (NMR) and (13)C NMR analyses; the purities of all the compounds were more than 91%.
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In a previous study, we showed that a series of homoisoflavonoids from the stems of Haematoxylon campechianum possess potent protein tyrosine kinase inhibitory activity. In a further chemical investigation of the heartwood of H. campechianum, three new homoisoflavonoids, epihematoxylol B (2), 10-O-methylhematoxylol B (3), and 10-O-methylepihematoxylol B (4), were isolated and identified, together with 15 known compounds, including three homoisoflavonoids, three flavonoids, six lignans, and three unsaturated fatty acids. The structures of the new compounds were established on the basis of 1D- and 2D-NMR and other spectroscopic analyses.
The pressurized liquid extraction and HPLC-DAD was developed for extraction and determination of bioactive lignans in Schisandra chinensis. The efficient PLE conditions employed methanol as extraction solvent, 125°C of extraction temperature, 5min of static extraction time and only one cycle. A rapid HPLC-DAD method was described for simultaneous determination of nine lignans, including schisandrol A, gomisin J, schisandrol B, tigloylgomisin H, angeloylgomisin H, schisandrin A, γ-schisandrin, gomisin N and schisandrin C. The extraction efficiency of PLE was observed to be comparable with reflux and sonication. In addition, the contents of nine lignans in S. chinensis from different regions were analysed by PLE and HPLC-DAD method.
Five new dibenzocyclooctane lignans, schisanwilsonins K-O (1-5), together with eighteen known lignans (6-23) were isolated from the stems of Schisandra wilsoniana. The structures of these new compounds were elucidated by spectroscopic methods, including 2D-NMR techniques. Several compounds were found to show anti-HIV and anti-HBV activity.
A new dibenzocyclooctane lignan, schisanbicolorin A, together with fifteen known lignans, were isolated from the stems of Schisandra bicolor Cheng. Their structures were identified as (aS,6R,7S)-5,6,7,8-tetrahydro-2,3,13-trimethoxy-6,7-dimethyldibenzo[3,4]cycloocta [1,2-f][1,3]benzodioxol-1-ol (1), neglschisandrin C (2), angeloylgomisin R (3), schisantherin D (4), gomisin F (5), schisantherin B (6), tigloylgomisin Q (7), gomisin G (8), interiotherin B (9), schisandrin (10), angeloylgomisin H (11), benzoylgomisin H (12), gomisin H (13), angeloyl−(+)−gomisin K3 (14), deoxyschizandrin (15), and (+)-gomisin K3 (16), respectively, based on spectroscopic analysis and by comparison of their spectral data with those reported previously in the literature.
Summary The fruits ofSchisandra chinensis were extracted with supercritical carbon dioxide under various conditions of temperature (40–80 C) and pressure (13.6–34.0
MPa) and each extract was analyzed by high-performance liquid chromatography for the main bioactive lignans schisandrol A
(1), schisandrol B (2), schisandrin A (3), schisandrin B (4), and schisandrin C (5). When the extraction time was sufficient (30 min/100 mg plant material) the temperature and pressure of the supercritical
carbon dioxide had no distinct effect on the extraction yields of the targetted lignans. If, however, the extraction time
was 6 min, increasing the pressure greatly enhanced the yields of the lignans. The extraction efficiency of supercritical
fluid extraction (SFE) was compared with that of conventional extraction with organic solvent. The efficiency of extraction
ofS. chinensis lignans by SFE was approximately 80% that by methanol extraction but was superior to that achievable by use of other solvents
such as chloroform-methanol (2:1),n-hexane, and petroleum ether. The results obtained suggest that in terms of efficiency and selectivity SFE could be used as
an alternative to conventional extraction with organic solvent.
An electrospray high-performance liquid chromatography-mass spectrometry interface coupled with a photodiode-array detector has been applied successfully to the identification of a number of lignan constituents from an ethanol extract of the fruits of Schisandra chinensis Baill. A total of fifteen peaks were identified, six of them unambiguously identified as schisandrin (1), schisantherin A (19), schisantherin B (20), schisanhenol (4), deoxyschisandrin (3) and γ-schisandrin (11), based on their abundant [M+H]+, [M+Na]+ ions, UV spectra and retention times, compared with those data of reference compounds. Another nine peaks were tentatively identified, based on their intense [M+H]+ and [M+Na]+ ions and UV spectra.
Gomishi is the dried fruit of Schisandra chinensis Baillon (Fructus Schisandrae chinensis, FSC) and has been used in Japanese Kampo medicine to treat inflammatory and liver diseases. However, it is unclear which constituent of FSC is primarily responsible for its pharmacological effects. FSC was extracted with methanol, fractionated by hydrophobicity, and further purified. We measured the effects of each fraction or constituent thereof on the induction of the inflammatory mediator nitric oxide (NO), which was induced by interleukin 1β in primary cultured rat hepatocytes. The hydrophobic fraction markedly suppressed NO induction and reduced the expression of inducible nitric oxide synthase (iNOS) in interleukin 1β-treated hepatocytes. Gomisin N and γ-schizandrin, two major constituents of the hydrophobic fraction, significantly reduced NO production and the levels of the iNOS protein, mRNA, and antisense transcript. Gomisin N and γ-schizandrin also decreased the transcription of interleukin 1β and inflammatory chemokines. The overexpression of the p65 subunit of nuclear factor κB or CCAAT/enhancer-binding protein β increased the promoter activity of the iNOS gene in the firefly luciferase assay, whereas gomisin N decreased the promoter activity. The anti-inflammatory activity of FSC and its constituents were analysed, and we demonstrated that gomisin N and γ-schizandrin are involved in the hepatoprotective effect of the FSC extract, which has therapeutic potential for liver disease.
For the first time a simple, rapid, and specific liquid chromatographic–mass spectrometric (LC–MS) method for simultaneous
quantification of 15 lignans from Schisandra chinensis (Turcz.) Baill. fruit has been developed and fully validated. Samples were ultrasonically extracted with methanol. Chromatographic
separation was performed on a C18 column with methanol–0.1% aqueous acetic acid 72:28 (v/v) as mobile phase at a flow rate of 0.8mLmin−1; the run time was 40min. The analytes were monitored by selected ion monitoring (SIM) with electrospray ionization (ESI).
Fifteen regression equations revealed good linear relationships (r
2>0.99) between peak area and concentration. Within-batch and between-batch precision of the method for the 15 lignans was
<9.5% and accuracy was 93.1–107.5%. The validated method was successfully used to determine the 15 compounds in the fruits
of Schisandra
chinensis procured from different regions of China. The results indicated the method could be used for quality control of Schisandra chinensis fruit and might also useful for further studies of lignans.
Glucose uptake assay-guided fractionations of the methanol extract of Schisandra chinensis led to the isolation of the dibenzocyclooctadiene lignans: gomisin J (1), gomisin N (2), wuweizisu B (3), wuweizisu C (4), gomisin C (5), gomisin D (6), (+)-schisandrin A (7), schisandrin C (8), schisandrol A (9), gomisin H (10), angeloylgomisin H (11), gomisin A (12), and schizandrin (13). Among these, 1, 2, 7, and 8 significantly improved basal glucose uptake in HepG2 cells. Their improving effects were concentration-dependent. Compound 2 exhibited a stronger effect than that of rosiglitazone, which has been used as an anti-diabetic drug. The results suggest that these lignans may partially contribute to the anti-diabetic activity of Fructus Schisandrae Chinensis in traditional use by stimulating the glucose uptake into peripheral tissue, which may be responsible for reducing the level of blood glucose in circulation. Thus, these findings show the potential of these lignans for development as hypoglycemic drugs.
Four derivatives of schisandrin, a major dibenzo[a,c]cyclooctadiene lignan of Schisandra chinensis (Turcz.) Baillon were synthesized and structurally characterized by means of NMR and mass spectroscopy. Furthermore, axial chirality of the biphenyl system was determined by comparison of calculated with measured circular dichroism (CD) spectra. Three of the obtained derivatives showed a ring contraction during chemical modification. While the original lignans were inactive on the performed bioassays, the compounds which showed the cycloheptadiene skeleton revealed remarkable activities. For the inhibition of LTB(4) production the IC(50) values of aR-6,7-dihydro-6-(1'-hydroxyethyl)-3,9-dimethoxy-6-methyl-5H-dibenzo[a,c]cycloheptene-1,2,10,11-tetraol (6) and aR-6-(1'-iodoethyl)-1,2,3,9,10,11-hexamethoxy-6-methyl-5H-dibenzo[a,c]cycloheptene (8) were 4.2+/-0.3microM and 4.5+/-0.2microM, respectively. aR-6,7-Dihydro-6-(1'-hydroxyethyl)-6-methyl-5H-dibenzo[a,c]cycloheptene-1,2,3,9,10,11-hexaol (5) revealed dual inhibition on COX-2 (IC(50) 32.1+/-2.5microM) and on LTB(4) production (37.3+/-5.5% inhibition at 50microM).
Seven new dibenzocyclooctane lignans, schisanwilsonins A-G (1-7), were isolated from the fruits of Schisandra wilsoniana, together with five known lignans (8-12). The structures of these new compounds were elucidated by spectroscopic methods including 2D-NMR techniques. The 12 lignans were tested for anti-hepatitis B virus (HBV) activity in vitro. Schisanwilsonin D (4), schisantherin C (9), deoxyschizandrin (10) and (+)-gomisin K(3) (11) showed anti-HBV activity. 9 exhibited the most potent anti-HBV activity with potency against HBsAg and HBeAg secretion by 59.7% and 34.7%, respectively, at 50 microg/mL.
Dibenzocyclooctadiene lignans are bioactive constituents in Schisandra chinensis (Turcz.) Baill. They are often present as isomers and this makes structural discrimination difficult.
To develop a rapid approach towards the characterisation and identification of isomeric dibenzocyclooctadiene lignans from S. chinensis using HPLC-PAD-ESI-MS(n).
The fragmentation behaviours of seven dibenzocyclooctadiene lignans from S. chinensis were studied using ion trap mass spectrometry with positive electrospray ionisation and loop injection. The fragmentation patterns of angeloylgomisin H, tigloylgomisin H, benzoylgomisin H and gomisin D were supported by high-resolution mass spectrometric analysis of some characteristic ions using a time-of-flight mass spectrometer. Combined with high-performance liquid chromatography and photodiode array detection, the established approach to the structural identification of dibenzocyclooctadiene lignans by ion trap mass spectrometry was applied to the analysis of extracts of S. chinensis.
According to the HPLC retention behaviour, the diagnostic UV spectra and the molecular structural information provided by multistage mass spectrometry spectra and the literature, a total of 25 dibenzocyclooctadiene lignans, including seven groups of lignan isomers, were identified or tentatively characterised in S. chinensis rapidly. One of these was reported as a constituent of S. chinensis for the first time.
This study has shown that HPLC-PAD-ESI-MS(n) may be used as an effective and rapid method for the characterisation and identification of isomeric dibenzocyclooctadiene lignans from S. chinensis.
The absorption and excretion of gomisin A (TJN-101) in rats whose livers were injured by carbon tetrachloride (CCl4) were investigated. After intravenous administration of TJN-101 at a dose of 5 mg/kg, the terminal elimination half-life was 1.5 h in the CCl4-treated rats, which was two times that in normal rats. The mean area under the blood concentration-time curve (AUC) value of TJN-101 in the CCl4-treated rats was twice that in normal rats, and this difference was significant (p less than 0.05). Therefore, the total body clearance of TJN-101 in the CCl4-treated rats decreased less than half of that in normal rats. Similar results were observed when it was administered orally. In the CCl4-treated rats, the serum concentration of Met. B, which was identified as a demethylenated substance and one of major metabolites, tended to decrease more than that in normal rats. On the other hand, the cumulative biliary excretion ratio of TJN-101 in 24 h after dosing in the CCl4-treated rats was 2.5 times that in normal rats. The excretion rate of Met. B in the bile in the CCl4-treated rats tended to be delayed. However, the quantitative variance of biliary excretion of Met. B was not found in both groups. The urinary excretion of TJN-101 or Met. B in 72 h after dosing in the CCl4-treated rats was lower than that in normal rats. Similar results were also observed in excretion in the feces.(ABSTRACT TRUNCATED AT 250 WORDS)
Gomisin A (TJN-101) is one of the lignan components isolated from Schisandra Fruits. A high sensitive and precise method for the determination of TJN-101 and its major metabolite (Met. B) in the rat serum was developed by selected ion monitoring (SIM) with gas chromatography-mass spectrometry (GC/MS) using a fused silica capillary column (SPB-1, Supelco). A 100 microliter serum sample was used for the solid phase extraction. The calibration curves of TJN-101 and Met.B both showed a good linearity between 2.0 and 2000.0 ng/ml. The analytical precision (intra-assay, C.V. less than 4.7%), recoveries (98.4 +/- 10.1%), and detection limit (2 ng/ml) of TJN-101 indicated that this system was suited for the determination of TJN-101 in biological fluid. In case of Met.B, the same results as TJN-101, were obtained. After oral administration of TJN-101 at a dose of 10 mg/kg to male rats, the average values of the maximal serum concentration of TJN-101 and Met.B were 1446.1 +/- 131.8 and 317.4 +/- 18.5 ng/ml, respectively. The serum concentrations of these substances could be monitored sufficiently for 8 h after dosing.
Lignans in the fruits of Schizandra (syn. Schisandra MICHX.) chinensis BAILL. (Schisandraceae) were quantitatively analysed by high performance liquid chromatography using a reversed-phase stationary phase. It was found that the commercially available samples considered to be collected in central and northern parts in Korea or China contained schizandrin (I), gomisin N (IX) and gomisin A (IV) as main components, while those in the samples collected in Japan were schizandrin (I) and deoxyscizandrin (VII). Seasonal variations of lignan contents in the fruits of S. chinensis collected in Nagano prefecture were also investigated. It became clear that all of the lignans were produced in the seed with its formation and that the contents gradually decreased in the same constituent ratio.
Schizandrin (SZ) is one of the lignan components from Schisandra fruits. A highly sensitive and precise method for the determination of SZ in human plasma was developed involving selected-ion monitoring with gas chromatography-mass spectrometry using a fused-silica capillary column. A 0.1-ml plasma sample was used for solid-phase extraction. A good linear relationship was obtained in the concentration range studied (2.0-500 ng/ml) and the method was sufficiently accurate and precise to support clinical pharmacokinetic studies. After oral administration of SZ at a dose of 15 mg to healthy male subjects, the average value of the maximum plasma concentration of SZ was 96.1 +/- 14.1 ng/ml. The plasma concentration of this substance could be monitored for 8 h after administration.
The biaryl axis is the joint central structural element of a broad variety of structurally (in particular stereochemically) and biosynthetically interesting as well as pharmacologically promising natural products. The increasing importance of this challenging class of secondary metabolites, its widespread occurrence, its pharmacological implications, and, in particular, the phenomenon of axial chirality, have so far been largely underestimated, if not neglected. This is reflected by the fact that there is as yet no true comprehensive review on naturally occurring biaryls in the literature. By this article, we do not intend to provide such a fully comprehensive review, but still want to draw the attention of the scientific community on the manifold rewarding facets of this exciting class of natural products, which is rapidly growing now, with more and more sophisticated analytical and synthetic tools becoming available.
The drug Wuweizi (dried fruits of Schisandra chinensis or S. sphenantherd) is one of important medicinal means used in the Oriental medicine. The lignans of dibenzo[a,c]cyklooctadiene type are major constituents, a volatile oil with mono- and ses-quiterpens, an oil, organic acids and small amounts of additional compounds are also present. The content of major lignans (schizandrin, deoxyschizandrin, gomisin A, gomisin N, gamma-schizandrin, wuweizisu C) in commercially available drugs ranges usually between 3 and 5%. The present paper biefly comments the isolation and biological activity of the lignans and is especially concerned with analytical methods (TLC and HPLC) for the determination of the drug fingerprint and methods for the determination of constituents in drugs, mixtures and biological materials. HPLC methods using RP-silica bonded phases and diluted methanol, acetonitrile (or a mixture of both), are most important for these purposes. Electromigration methods are less suitable and the importance of hyphenation procedures is practically negligible.
Synthetic methodologies for dibenzocyclooctadiene lignans is divided into intermolecular and intramolecular biaryl couplings. The former requires multiple linear steps which generate the lignans in low overall yields. In contrast, biomimetic inspired intramolecular approach, in which two or more relatively advanced fragments are used to make a fully functionalized intermediate, realizes a reduction in synthetic steps and an increase in overall yields. In addition, spectral characteristics of these lignans are analyzed by nuclear magnetic resonance (NMR), infrared (IR), ultraviolet (UV), mass spectrometry (MS), and circular dichroism (CD) spectroscopy. Alternative strategy for obtaining optically active dibenzocyclooctadiene lignans is by chromatographic separation of diastereomeric acyclic biphenyl derivatives.
Two new dibenzocyclooctadiene lignans angeloyl-(+)-gomisin K(3) (1) and methylisogomisin O (2), together with six known ones, isogomisin O, angeloylisogomisin O, gomisin O, angeloygomisin O, benzoylgomisin O, epigomisin O, and four 1,4-bis(phenyl)-2,3-dimethylbutane type lignans, pregomisin, meso-dihydroguaiaretic acid, isoanwulignan, and sphenanlignan were isolated from the aerial parts of Schisandra propinqua var. propinqua. The structures of 1 and 2 were elucidated by spectroscopic methods including extensive 1D- and 2D-NMR techniques.
A new dibenzocyclooctadiene lignan, intermedin A (1), and a new natural bisabolane sesquiterpenoid, intermedin B (2), were isolated from the aerial parts of Schisandra propinqua var. intermedia. Their structures were elucidated on the basis of extensive spectroscopical analysis.
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