A,review:,Chemical,constituents,and,pharmacological,activities,of,Solanum,lyratum,Thunb.

Shuang Qiu,Qi Jia,Xiaoxiao Huang＊

Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research &Development,Liaoning Province,School of Traditional Chinese Materia Medica,Shenyang Pharmaceutical University,Shenyang 110016,China

Abstract Solanum lyratum Thunb.belonging to the family Solanaceae,is a common Chinese herbal medicine in folk.It has been used for the treatment of colds,fever,jaundice hepatitis,cholecystitis,cholelithiasis,nephritis,edema and cancer.Previous phytochemical studies on S.lyratum have led to the identification of many chemical constituents,including steroidal saponins,alkaloids,terpenoids,flavonoids,quinonoids,phenylpropanoids,organic acids and several other kinds of compounds,which showed diverse bioactivities,such as anticancer,anti-inflammatory and antioxidant activities.This paper summarized the primary chemical constituents and pharmacological effects of S.lyratum to provide reference for its further development and utilization.

Keywords: Solanum lyratum Thunb;chemical constituents;pharmacological activities;review

Solanum lyratumThunb.(S.lyratum) of the family Solanaceae,also known as “Baimaoteng”,is a perennial herb and natively distributed in China,Japan and Korea [1].This plant was first recorded in the “Shen Nong’s herbal classic” and has been used as traditional Chinese medicine (TCM) for more than 2000 years.It has been used for the treatment of colds,fever,jaundice hepatitis,cholecystitis,cholelithiasis,nephritis,edema and cancer as a folk remedy [2].

Studies on the chemical constituents ofS.lyratumcan be traced back to the 1980s [3].Previous phytochemical studies have indentified numerous chemical constituents,including steroidal saponins,alkaloids,terpenoids,flavonoids,quinonoids,phenylpropanoids,organic acids and several other kinds of compounds [2,4],which showed diverse bioactivities,such as anticancer,anti-inflammatory,antioxidant,antiallergic,hepatoprotective and other activities [5].Among them,alkaloids and steroidal saponins are the main chemical components of the plant,and many studies have proven their anticancer effects [6].This study summarized the chemical constituents and pharmacological activities ofS.lyratumaiming to provide reference for further research.

2.1 Steroidal saponins

Steroidal saponins are the main chemical components and effective components ofS.lyratum,which are commonly found inSolanum.At present,23 steroids and their saponins have been isolated fromS.lyratum,most of which are spirostanane type saponins.They were identified as diosgenin (1),diosegenin 3-O-β-D-glucopyranosiduronic acid methyl ester (2),diosegenin-3-O-β-D-glucopyranosiduronic acid(3),diosegenin-3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosiduronic acid (4),diosegenin-3-O-α-L-rhamnopyranosyl-(1→2)-β-Dglucoroniduronic acid methyl ester (5) [2],(25R)-5(6)-en-spirost-3β-ol-3-O-β-D-glucopyranosyl-(1→4)-[α-L-rhamnopyranosyl-(1→2)]-β-Dgalactopyranoside (6) [7],16-dehydropregnenolone(7),1 6-dehydropregnenolone-3-O-α-Lrhamnopyranosyl-(1→2)-β-D-glucopyranosid uronic acid (8),allopregeolone (9) [8],(25R)-26-O-β-D-glucopyranosyl-5 (6),20 (22)-dien-furost-3β,26-diol (10),(25R)-26-O-β-D-glucopyranosyl-5α-furost-3β,26-diol (11),tigogenin (12),(25R)-5αspirost-3β-ol-3-O-β-D-glucopyranosyl-(13)-[β-Dglucopyranosyl-(12)]-β-D-glucopyranosyl-(14)-β-Dgalactopyranoside (13) [7],aspidistrin (14),methyl protoaspidistrin (15),26-O-β-D-glucopyranosyl-(22ξ,25RandS)-3β,26-dihydroxy-22-methoxyfurost-5-ene-3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucuronopyranoside (16) [9],yamogenin(17) [10],9,11-dehydro ergosterol peroxide (18),ergosterol peroxide (19) [4],SL-0 (20),SL-1 (21) [3],26-O-β-D-glucopyranosyl-(22ξ,25R)-3β,22,26-trihydroxyfurost-5-ene-3-O-α-L-rhamnopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-Dglucuronopyranoside (22) [11],and (22R)-3β,16β,22,26-tetrahydroxycholest-5-ene-3-O-α-Lrhamnopyranosyl-(1→2)-β-D-glucuronopyranoside(23) [12].The structures were shown in Fig.1.

Fig.1 Steroidal saponins isolated from S.lyratum

Continued fig.1

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2.2 Alkaloids

Forty-three alkaloids have been isolated fromS.lyratum,mainly including organic amine alkaloids (I) and steroidal alkaloids (II).Organic amine alkaloids (I) includeN-transferuloyloctopamine (24),N-trans-feruloytramine(25),N-cis-feruloytramine (26) [13],N-transferuloyl-3-methyldopamine (27),paprazine(28) [14],3-(4-hydroxy-3-methoxyphenyl)-N-[2-(4-hydroxyphenyl)-2-methoxyethyl] acrylamide(29) [15],N(p-hydroxyphenethy)p-coumaramide(30) [16],uridine (31),thymidine (32),uracil(33),β-indole carboxylic acid (34) [13],N-(4-amino-butyl)-3-(3-hydroxy-4-methoxy-phenyl)-Earcylamide (35),N-(4-amino-butyl)-3-(3-hydroxy-4-methoxy-phenyl)-Z-arcylamide (36),adenoside(37) [17],strychnine (38) [18],and soyacerebroside I (39) [19].These structures were shown in Fig.2.

Fig.2 Organic amine alkaloids (I) isolated from S.lyratum

Twenty-seven steroidal alkaloids (II) have been isolated fromS.lyratum.They are soladulcidine(40) [15],solalyratine A-C (41-43) [4,6],xylosylsolamarine (44),xylosyl-solamagine (45),tomatidenol (46),α-solamarine (47),β-solamarine(48),solasodine (49),solasonine (50) [6],16,23-epoxy-22,26-epimino-cholest-22 (N),23,25-trien-3β-ol-3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-(1→6)-galactopyranoside(51) [7],SL-c (52),SL-d (53) [20],solamargine(54) [21],dihydroleptinidine (55),3-O-β-Dglucopyranosyl-(1→2)-β-D-glucopyranosyl-(1→4)-β-D-galactopyranoside-(25ξ)-solanidan-3β,23βdiol (56) [15],solalyraine A-G (57-63),(3β,22α,25R)-spirosolan-5-en-3-yl-O-β-D-glucopyranosyl-(1→2)-O-β-D-glucopyranosyl-(1→4)-β-Dgalactopyranoside (64),and 16,23-epoxy-22,26-epimino-cholest-22(N),23,25 (26)-trien-3β-ol-3-Oβ-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-(1→4)-β-D-galactopyranoside (65) [22].All the structures were shown in Fig.3.

Fig.3 Steroidal alkaloids (II) isolated from S.lyratum

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2.3 Terpenoids

A total of 21 sesquiterpenoids were isolated fromS.lyratum,including lyratol A-F(66-71) [21,23-24],solajiangxin A-E (72-76) [25,26],2-hydroxylsolajiangxin E (77) [26],solajiangxin F-I (78-81) [27,28],7-hydroxylsolajiangxin I(82) [28],dehydrovomifoliol (83),blumenol A(84) [23],atractylenollde (85),dehydrocarlssone(86) [4],solanoids A-D (87-90),solafuranone (91),lycifuranone A (92),(4R,5R,7R,10R)-4-hydroxyeudesma-2,11-dien-1-one (93),(+)-anhydro-β-rotunol (94),nardoeudesmol A (95),rishitin (96),1α-hydroxy-bisabola-2,10-dien-4-one (97) [29],1β-hydroxy-1,2-dihydro-α-santonin (98),boscialin(99),blumenol C (100),3β-hydroxy-5α,6α-epoxy-7-megastigmen-9-one (101),dehydrovomifoliol (102),(1′S,2R,5S,10R)-2-(1′,2′-dihydroxy-1′-methylethyl)-6,10-dimethylspiro [4,5] dec-6-en-8-one (103),(1′R,2R,5S,10R)-2-(1′,2′-dihydroxy-1′-methylethyl)-6,10-dimethylspiro [4,5] dec-6-en-8-one (104),and grasshopper ketone (105) [30].All the structures were shown in Fig.4.

Fig.4 Terpenoids isolated from S.lyratum

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2.4 Flavonoids

Since 2002 when Yang et al.isolated rutin fromS.lyratumfor the first time [9],17 flavonoids have been isolated fromS.lyratum.They are ononin (106),genistin (107),5-hydroxy ononin(108),formononetin (109),daidzein (110),daidzin(111) [31],quercetin (112) [7],naringenin(113) [32],5,7-diol-8-methoxy-flavone(114) [7],apigenin (115) [14],lyratin A (116-118),4,7,2-trihydroxy-4-methoxyisoflavan (119) [30],rutin (120) [9],apigenin-7-O-β-D-glucopyranoside(121),and apigenin-7-O-β-D-apiofunnosyl-(1→2)-β-D-glucopyranoside (122) [17].All the structures were shown in Fig.5.

Fig.5 Flavonoids isolated from S.lyratum

2.5 Quinonoids

There are four anthraquinone compounds isolated fromS.lyratum,including 1,3,5-trihydroxy-7-methyl-anthraquinone (123),1,5-dihydroxy-3-methoxy-7-methyl-anthraquinone (124),physcion-8-O-β-D-glucopyranoside (125) [19],and solanrubiellin A (126) [33].Among them,solanrubiellin A (126) is an anthraquinone dimer.Their structures were shown in Fig.6.

Fig.6 Quinonoids isolated from S.lyratum

2.6 Phenylpropanoids

Five coumarin compounds including scopoletin (127) [8],magnolioside (128) [13],coumestrol (129),solalyratin A (130),9-hydroxy-2′,2′-dimethylpyrano [5′,6′: 2,3]-coumestan(131) [34],and a simple phenylpropanoid syringin(132) [35] have been isolated fromS.lyratum.In 2018,Xu et al.isolated 12 lignanoids fromS.lyratum[35].They were identified as (+)-isolariciresinol (133),(+)-syringaresinol (134),zhebeiresinol (135),leptolepisol D (136),(–)-secoisolariciresinol(137),(–)-epi-syringaresinol (138),aviculin (139),ciwujiatone (140),(–)-(7′S,8S,8′R)-4,4′-dihydroxy-3,3′,5,5′-tetramethoxy-7′,9-epoxylignan-9′-ol-7-one(141),(+)-lariciresinol (142),(+)-pinoresinol (143),and (+)-medioresinol (144).The structures were shown in Fig.7.

Fig.7 Phenylpropanoids isolated from S.lyratum

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2.7 Organic acids

Seven organic acids have been isolated fromS.lyratum,identified as 4-hydroxybenzoic acid(145) [31],syringic acid (146) [36],chlorogenic acid (147) [37],protocatechuic acid (148),vanillic acid (149),caffeic acid (150) [8],and ursolic acid(151) [7].All the structures were shown in Fig.8.

Fig.8 Organic acids isolated from S.lyratum

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2.8 Other compounds

Other compounds isolated fromS.lyratuminclude solacetal A-D (152-155) [38],resveratrol(156) [17],erythritol (157),docosylferulate(158) [19],4-hydroxybenzaldehyde (159),ethylα-D-arabinofuranoside (160) [26],isovanillin(161),syringaldehyde (162),mannitol (163) [36],puerariafuran (164),and solalyratn B (165) [34](Fig.9) .

Fig.9 Other compounds isolated from S.lyratum

3.1 Anticancer effect

It has been reported that the extracts ofS.lyratumcould obviously inhibit the proliferation of human cancer cells.It has been used clinically to treat liver cancer,lung cancer,gastric cancer,esophageal cancer and cervical cancer.

Shan et al.used different concentrations ofS.lyratumextract to cultivate liver cancer Bel-7404 cells [39].They found that the treated cells showed apoptotic bodies and trapezoidal DNA,indicating thatS.lyratumextract could induce apoptosis in Bel-7404 cells.It was probably becauseS.lyratumextract inhibited the expression of Bcl-2 gene by inducing a large amount of Bax gene expression,which might result in the increase of the Bax/Bc1-2 protein ratio and finally the promotion of apoptosis.Huo et al.investigated the effects ofSolanum lyratumThunberg Alkaloid (STA) on the proliferation and apoptosis in Huh-7 cellsin vitro,and found that STA could induce apoptosis of Huh-7 and that the mechanism might be related with regulation of p38 and Caspase-3 protein.

Sun et al.isolated a series of cytotoxic compounds fromS.lyratumby activity-directed separation [40].Among them,saponins showed obvious inhibitory effect on A375-S2,HeLa,SCG-7901 and Bel-7402 cell lines.Wei et al.reported that the water extract ofS.lyratumhad strong proliferation inhibitory effect on HeLa cells,and its molecular mechanism might be related to the upregulation of Caspase-3 gene expression and downregulation of survivin gene expression [41].

Yan et al.investigated the effects of inhibition and apoptosis induction of the monomer ofS.lyratumon ovarian carcinoma cell SKOV3in vitroby using MTT assay,and found that the monomer ofS.lyratumsignificantly inhibited the growth of SKOV3,induced apoptosis,blocked cell cycle and activated Caspase-3 and Caspase-9 [42].

3.2 Anti-inflammatory effect

Zhang et al.isolated a series of 4-hydroxyisoflavans from the whole plant ofS.lyratumand evaluated their anti-inflammatory activities [43].The results showed that these compounds had inhibitory activities on the release ofβ-glucuronidase from polymorphonuclear leukocytes(PMNs) of rats induced by platelet activating-factor(PAF) and the inhibitory rates reached 30.3%-38.6%at the concentration of 10μM.

Lin et al.examined the anti-inflammatory activity of total alkaloids and total saponins ofS.lyratum[44,45].Both of them showed similar antiinflammatory activity.The effect of total alkaloids fromS.lyratumat medium dose and high dose on H2O2-induced HUVECs were similar to that of the positive control group.They could significantly reduce the swelling degree of the acute ankle model in rats and decrease the content of prostaglandin E2 (PGE2) in the toe exudate of rats and that of cyclooxygenase-2 (cox-2) in serum.

3.3 Antioxidant effect

Through 2,2-diphenyl-1-picrylhydrazyl(DPPH) radical scavenging monitoring,Ji et al.screened the antioxidant metabolites inS.lyratumand isolated 7 compounds [46].6 of the compounds showed strong antioxidant activity,and the ethyl acetate extracts also displayed DPPH scavenging activity (IC50=28.92μg/mL).

Xie et al.studied the antioxidant effect ofS.lyratum[47].They found its water extract could significantly increase peroxidase (POD) activity and superoxide dismutase (SOD) activity and reduce the content of malondialdehyde (MDA) in blood,liver and kidney tissues.Kuo et al.found the crude extracts ofS.lyratum(SLE)could protect the oxidized low-density lipoprotein (oxLDL) induced injury in endothelial cells by direct antioxidant action [48].SLE scavenged DPPH and also delayed the kinetics of LDL oxidation in a dose-dependent manner.It could also attenuate the level of oxLDLinduced reactive oxygen species (ROS) generation,diminish the expression of endothelial NO synthase(eNOS),and enhance the expression of adhesion molecules and the adherence of monocytic THP-1 cells to HUVECs.Therefore,SLE might help prevent the atherosclerotic process.

3.4 Anti-allergic effect

In 1998,Kim et al.investigated the effect of aqueous extract ofS.lyratum(SLAE) on anaphylactic reaction [49].They found that SLAE could inhibit skin mast cells-mediated anaphylactic reaction activated by anti-dinitrophenyl (DNP)-IgE.It could dose-dependently inhibit the histamine release in mouse peritoneal mast cells activated by anti-DNP-IgE or substance P,and it could inhibit the substance P-induced L-histidine decarboxylase(HDC) mRNA over-expression.

Kang et al.found SLAE could inhibit compound 48/80-induced anaphylactic shock 100%at a dose of 1 mg/g [50].When SLAE was pretreated at the concentration ranging from 0.0001 to 1.0 mg/g,the serum histamine levels were reduced in a dosedependent manner.Passive cutaneous anaphylaxis also inhibited to 69.3% by oral administration of SLAE (0.05 mg/g).The level of cAMP in preparation of rat peritoneal mast cells (RPMC) after the addition of SLAE was significantly increased compared with that of normal control.Based on these results,they concluded that SLAE possessed strong anti-allergic activity.

3.5 Hepatoprotective activity

In 1998,Kang et al.isolated a coumarin(Scopoletin) from the aerial part ofS.lyratumand firstly evaluated its hepatoprotective activity [51].The results showed that scopoletin which from the toxicity in a dose-dependent manner in the concentration range of 1μM to 50μM could significantly reduce the release of glutamic pyruvic transaminase and sorbitol dehydrogenase from the carbon tetrachloride-intoxicated primary cultured rat hepatocytes by 53% and 58%,respectively.Further studies revealed that at the concentration of 10μM,scopoletin significantly preserved glutathione content by 50% and the activity of superoxide dismutase by 36%,and also inhibited the production of malondialdehyde to the degree as seen in the control.

In 2015,Li et al.evaluated the influence ofS.lyratumethanol extract (EEST) on carbon tetrachloride (CCl4)-induced rats acute liver injury [52].They found that EEST could remarkably decrease the alanine aminotransferase (ALT),aspartate aminotransferase (AST) and alkaline phosphatase (ALP) contents compared with the model group.Hematoxylin-eosin (HE) staining showed mild lesion.SOD and catalase (CAT)activity increased in the cytoplasm,while MDA level was reduced.They concluded that EEST could remarkably reduce CCl4-induced liver injury,and it might be related to anti-lipid peroxidation effect of EEST.

3.6 Other activities

Like other Solanaceous plants,S.lyratumcontains a large number of toxic glycoside alkaloids,and when the content exceeds a certain level,there is a risk of poisoning or teratogenicity.Its mechanism of action includes the dissolution and destruction of biofilms leading to damage to the digestive system and other organs,and the inhibition of cholinesterase in the central nervous system [5].

Liu et al.evaluated the therapeutic effect of then-butanol extract fromS.lyratum(BESL) on mice transplantable tumor and immunomodulatory potentials on the immune response in tumor-bearing mice [53].The results showed that BESL could not only significantly inhibit the growth of S180 sarcoma transplanted in mice,but also remarkably promote splenocytes proliferation,natural killer (NK)cells and cytotoxic T lymphocytes (CTL) activity,interleukin-2 and interferon-γproduction from splenocytes,and serum antigen-specific antibody levels in tumor-bearing mice.This finding suggested that BESL might exhibit antitumor activity by improving immune response,and it could act as an antitumor agent with immunomodulatory activity.

S.lyratumis a traditional Chinese medicinal material commonly used in China and plays an extensive role in pharmacological research.Recent pharmacological research onS.lyratummostly focused on the activity of the extract.The research on the chemical composition of monomers inS.lyratummainly focused on steroids and sesquiterpenes.There is not much research on monomers and their pharmacological activity.This study summarized the chemical constituents and pharmacological activities ofS.lyratumbased on the previous reports,hoping to provide reference for further development and utilization ofS.lyratum.