Research progress on chemical constituents in Sophora alopecuroides L.and their pharmacological activities
2021-11-05BohanYangJingWangXiaoxuGaoJingmingJiaAnhuaWang
Bohan Yang†,Jing Wang†,Xiaoxu Gao,Jingming Jia,Anhua Wang
School of Traditional Chinese Materia Medica,Shenyang Pharmaceutical University,Shenyang 110016,People’s Republic of China
Abstract Sophora alopecuroides L.,a perennial plant belonging to Leguminosae family,is used as medicinal materials to treat a variety of skin diseases.Its chemical components are complex and diverse,mainly including alkaloids and flavonoids.Modern pharmacological studies have found that the isolated compounds from S.alopecuroides have a variety of pharmacological activities.In particular,alkaloids represented by matrine,aloperine and oxymatrine have significant anti-inflammatory,anti-viral,anti-tumor,anti-bacterial and immunomodulatory activities.This paper summarized the chemical constituents and pharmacological activities of S.alopecuroides,aiming to provide the basis for further research.
Keywords:Sophora alopecuroides L.;chemical components;pharmacological activities
1 Introduction
Sophora alopecuroides
L,a perennial plant belonging to Leguminosae family,is often planted on both sides of the Yellow River to consolidate soil and sand due to its strong salt and alkali resistance,and it is also used as a medicinal material to treat sore throat,acute dysentery,stomachache,eczema and stubborn ringworm in folk [1-4].Previous phytochemical research onS.alopecuroides
revealed the presence of alkaloids [5-8] and flavonoids [9].Alkaloid,which accounts for the largest portion,is also the main active component ofS.alopecuroides
.Modern pharmacological studies have found that the isolated compounds fromS.alopecuroides
have a wide range of pharmacological activities,such as anti-inflammatory [10],anti-tumor [11],and immunoregulation activities [12].In particular,alkaloids fromS.alopecuroides
have remarkable biological activity.This review systematically summarized the chemical components identified fromS.alopecuroides
and their pharmacological activities by searching Chinese and English databases,in order to provide a reference for the further development and the improvement of quality standards inS.alopecuroides
.2 Chemical constituents
Most of the reports on the chemical constituents ofS.alopecuroides
focus on alkaloids and flavonoids,while a few pay attention to steroids,polysaccharide,and volatile oil.Literature shows that a total of 121 compounds have been isolated fromS.alopecuroides
,which are roughly divided into 6 categories.2.1 Alkaloids
Most alkaloids inS.alopecuroides
are quinolisidine alkaloids,which are divided into matrine-type,aloperine-type,cytisine-type,lupininetype and other type alkaloids according to the number of piperidine rings [13].2.1.1 Matrine-type Alkaloids
24 matrine-type alkaloids were isolated fromS.alopecuroides
,and identified as matrine (1
) [14],oxymatrine (2
) [14],(+)-9α
-hydroxymatrine (3
) [15],14β
-hydroxymatrine (4
) [16],lehmannine (5
) [17],sophoramine (6
) [18],7α
-hydroxysophoramine(7
) [16],9α
-hydroxysophoramine (8
) [19],neosophoramine (9
) [20],isosophoramine (10
) [21],sophocarpine (11
) [22],oxysophocarpine (12
) [23],12β
-hydroxysophocarpine (13
) [16],sophoridine(14
) [16],oxysophoridine (15
) [24],3α
-hydroxysophoridine (16
) [21],N
-hydroxy-sophoridine(17
) [1],(-)-13,14-dehydrosophoridine (18
) [25],sophaline A (19
) [26],sophaline B (20
) [26],sophaline C (21
) [26],sophaline D (22
) [26],sophaline F(23
) [27] and sophaline I (24
) [27] (Fig.1).
Fig.1 Matrine-type alkaloids isolated from S.alopecuroides
2.1.2 Aloperine-type Alkaloids
Eight aloperine-type alkaloids were isolated fromS.alopecuroides
,and the structures of them were identified as sophaline E (25
) [27],aloperine(26
) [21],N
-methyl-aloperine (27
) [21],N
-allylaloperine (28
) [1],Δ～(11)-dehydroaloperine(29
) [1],baptifoline (30
) [16],(-)-O
-acetylbaptifoline(31
) [28] and anagyrine (32
) [21] (Fig.2).
Fig.2 Aloperine-type alkaloids isolated from S.alopecuroides
2.1.3 Cytisine-type Alkaloids
Only three cytisine-type alkaloids were isolated fromS.alopecuroides
,and identified as cytisine(33
) [21],N
-methyl-cytisine (34
) [21] andN
-2-hydroxyethyl-cytisine (35
) [1] (Fig.3).
Fig.3 Cytisine-type alkaloids isolated from S.alopecuroides
2.1.4 Lupinine-type Alkaloids
Only four lupinine-type alkaloids were isolated fromS.alopecuroides
,and identified as adenocarpine(36
) [21],nicotine (37
) [21],lamprolobine (38
) [21]and anabasine (39
) [29] (Fig.4).
Fig.4 Lupinine-type alkaloids isolated from S.alopecuroides
2.1.5 Other type Alkaloids
In addition to the above structural types,three other type alkaloids were isolated fromS.alopecuroides
,and identified as sophaline G(40
) [27],sophaline H (41
) [27] and alopecurin A(42
) [30] (Fig.5).
Fig.5 Other alkaloids isolated from S.alopecuroides
2.2 Flavonoids and flavonoid glycosides
Flavonoid is the second most abundant active ingredient inS.alopecuroides
,including isoflavones,dihydroflavones,chalcone and many kinds of flavonoid glycosides.It is worth mentioning that most of the flavonoids from
S.alopecuroides
were replaced by isopentenyl group to enhance the biological activities of these compounds to a certain degree.The structures of the 63 compounds were identified as 3’,4’-dihydroxyisoflavones-7-O
-β
-Dglucopyranoside (43
) [31],7,3’-dihydroxyflavanone-4’-O
-β
-D-glucopyranoside (44
) [31],rutin(45
) [31],6-β
-D-glucopyranosy-5,7-dihydroxy-2-(4-hydroxyphenyl)-8-[7-hydroxy-2-(4-hydroxyphenyl)-5-methoxy-6-β
-D-xylopyranosyl-4-oxo-4H-1-benzopyran-8-yl-4H-1-benzopyran-4-one (46
)[32],5,6-dihydroxy-3,7,3’,4’-tetramethoxyflavone(47
) [33],3’-methoxyluteolin (48
) [33],alopecurone A (49
) [34],alopecurone B (50
) [34],alopecurone C (51
) [34],alopecurone D (52
) [34],alopecurone E (53
) [34],alopecurone F (54
) [34],alopecurone G (55
) [34],alopecurone H (56
) [35],alopecurone I (57
) [35],alopecurone J (58
) [35],alopecurone K(59
) [35],alopecurone L (60
) [35],alopecurone M(61
) [36],alopecurone N (62
) [36],alopecurone O(63
) [36],kurarinone (64
) [36],sophoraflavanone G (65
) [36],5,4’-di-O
-methylsophoraflavanone G (66
) [36],lehmanin (67
) [36],leachianone A (68
) [36],2’-O
-methyl-sophoraflavanone K(69
) [36],2’-demethoxyleachianone B (70
) [36],8-prenylnaringenin (71
) [36],4’-O
-methyl-8-prenylnaringenin (72
) [36],isobavachin (73
) [36],ammothamnidin (74
) [36],cudraxanthone D (75
) [36],trifolirhizin (76
) [36],trifolirhizin (77
) [37],7-hydroxy-3’,4’-methylenedioxyisoflavone (78
) [37],butein (79
) [38],butein 4’-O
-(2’’-feruloyl)-glucoside (80
) [38],butein 4’-O
-glucoside(81
) [38],butin (82
) [38],butin-O
-glucoside(83
) [38],7,3’,4’-trihydroxyisoflavone(84
) [38],5,7,3’,4’-tetrahydroxyisoflavone(85
) [38],7,4’-dihydroxyisoflavone (86
) [38],7,3’-dihydroxy-4’-methoxyisoflavone (87
) [38],7,3’,4’-trihydroxyisoflavoneO
-(2’’-coumaroyl)-glucoside (88
) [38],7,4’-dihydroxyisoflavone-7-O
-(2’’-feruloyl)-glucoside (89
) [38],5,7,3’,4’-tetrahydroxyisoflavoneO
-(2’’-feruloyl)-glucoside (90
) [38],5,7,3’,4’-tetrahydroxyisoflavoneO
-(2’’-coumaroyl)-glucoside (91
) [38],7,4’-dihydroxy-3’-methoxyisoflavone7-O
-(coumaroyl)-glucoside(9 2
) [3 8],4’-hydroxy-3’-methoxyisoflavone (93
) [38],7,3’,4’-trihydroxyisoflavoneO
-(2’’-feruloyl)-glucoside (94
) [38],7,4’-dihydroxy-3’-methoxyisoflavone (95
) [38],7,4’-dihydroxy-3’-methoxyisoflavone 4’-O
-(2’’-feruloyl)-glucoside(96
) [38],7,3’,4’-trihydroxyflavoneO
-(2’’-caffeoyl)-glucoside (97
) [38],7,3’,4’-trihydroxyflavone(98
) [38],4’-feruloyl-3,5,7,4’-tetrahydroxy-3’-methoxyflavone (99
) [38],4’,7-dihydroxyflavanone-7-O
-β
-D-glucopyranoside (100
) [35],7-O
-β
-D-glucosyl-4’-O
-methylisoflavone (101
) [35],2’,4’,5,7-tetrahydroxy-6-prenylisoflavone (102
) [35],3’,4’,5,7-tetrahydroxyflavone (103
) [35],liquiritin(104
) [39] and hydroxyflavanone (105
) [40] (Fig.6).
Fig.6 Flavonoids and flavonoid glycosides isolated from S.alopecuroides
Continued fig.6
Continued fig.6
2.3 Steroids
In addition to alkaloids and flavonoids,six steroid compounds were also isolated fromS.alopecuroides
,probably because of the presence of isopentyltransferase in this plant [33,41].The structures were identified as 19-norpregn-4-ene-3,20-dione (106
) [41],stigmastan-3-ol,5-chloro-,acetate(3β
,5α
) (107
) [41],ergost-5-en-3-ol(3β
)(108
) [41],stigmasterol (109
) [41],γ
-sitosterol(110
) [41],andβ
-daucosterol (111
) [33] (Fig.7).
Fig.7 Steroids isolated from S.alopecuroides
2.4 Others compounds
Phenylpropanin and some analogues were isolated fromS.alopecuroides
.The structures were identified as 1,2-diferuloyl-glucose (112
) [38],piscidic acid (113
) [38],(-)-maackiain-3-O
-β
-Dglucoside (114
) [35],2-(4-hydroxyphenyl)-2,3-dihydrobenzofuran-3,4,6-triol (115
) [35],ferulic acid (116
) [37],dihydrophaseic acid (117
) [37],sophoratonkin (118
) [17],6-(2,2-dimethyl-4-chromanone)acrylic acid (119
) [36] leachianol D(120
) [36] and pallidol (121
) [36] (Fig.8).
Fig.8 Other compounds isolated from S.alopecuroides
3 Pharmacological activity
Alkaloids isolated fromS.alopecuroides
are the main active components.Studies have shown that the alkaloids represented by matrine,aloperine and oxymatrine have significant antiinflammatory,anti-viral,anti-tumor,anti-bacterial and immunomodulatory activities.Flavonoids are also one of the main chemical components ofS.alopecuroides
,but the pharmacological effects are relatively less reported and need to be further explored.3.1 Matrine (1)
Matrine (1
),one of the main components ofS.alopecuroides
,has been clinically developed as matrine-injection,-tablets,and -capsules.Current studies have shown that it has anti-tumor,antiinflammatory,antibacterial,antiviral,anti-fibrosis,anti-ischemia reperfusion,analgesia and other pharmacological activities.With MTT,Hochest staining,flow cytometry and western blot,Miu Dongying determined the inhibition ratio,the pro-apoptotic effect,and the expression of Akt,p-Akt proteins of matrine against colon cancer cell SW480 [42].The results showed that the growth inhibition rate of SW480 cells in the experimental group was 68.27±10.83% at the mass concentration of 2.0 g/L after 24 h culture with,statistically significant compared with the control group (P
<0.05),and it could promote the apoptosis of SW480 cell through Akt signaling pathway.Lin Xingzhen found that matrine had inhibitory effects on cell Tca8113 proliferation,inducing cell apoptosis and arresting cell cycle in the G0/G1 phase [43].Wang Ying found that matrine could significantly inhibit the proliferation,clone formation and lateral and longitudinal migration of MGC-803,induce cell cycle arresting in G0/G1 phase,down-regulate the protein expression levels of Vimentin,Snail,MMP2,MMP9 and up-regulate the protein expression level of E-cadherin [44].Sun Panpan established a mouse model of inflammation co-stimulated by porcine reproductive,respiratory syndrome virus and liposolysaccharide [45].After matrine was given,IL-1β
mRNA expression was significantly inhibited,but TNF-α
mRNA expression was not significantly changed.Lu Yinghong established the atherosclerosis model of human aortic vascular smooth muscle cells,and the results showed that matrine could significantly improve abnormal lipid metabolism,regulate inflammatory factors and anti-inflammatory factors,inhibit cell proliferation ability,reduce cell apoptosis,and inhibit the activation of JAK/STAT3 pathway [46].Liu Junfeng tested the bacteriostatic effect of matrine onEscherichia coli
,Staphylococcus aureus
,Bacillus subtilis
andPhytophthora solani
by using the bacteriostatic zone method,and the results showed that matrine had good inhibitory effect on them and the minimum inhibitory concentrations were 12.5 μg/mL,25.0μ
g/mL,12.5μ
g/mL,100μ
g/mL,respectively [47].Liu Xiaqiong investigated the effect of matrine combined with thymopeptide on HepG2.2.15 cells,and the results showed that this combination was significantly superior to that of any of the two alone [48].The survival rate of HepG2.2.15 cells was above 90% with the combination of thymopeptide 0.025-0.4 g/L and 0.2 mM matrine,indicating that the selected concentration had no significant inhibitory effect on normal cells.After the combined administration,the expression level of IFN-α
significantly increased,and the expression of HBV DNA and HBeAg in the supernatant was inhibited.3.2 Aloperine (26)
Zhang Li compared the inhibition rates of total alkaloids with aloperine,sophoridine,sophocarpine,matrine,cytisine,lehmannine,oxymatrine,and oxysophocarpine on 8 kinds of digestive cancer cells by MTT method,and found that the inhibition rates of aloperine on 8 kinds of cancer cells were better than other alkaloids with the ICvalue comparable to pentafouracil [49].Microscopic observation of cell morphology showed that there were early apoptotic cells in the aloperine group and the apoptosis was dose-dependent.It was further inferred that aloperine could block cell cycle and inhibit cell proliferation by inhibiting Ras/Raf/ERK pathway.Finally,the tumor-bearing experiment in nude mice showed that aloperine could reduce the phosphorylation level of ERK1/2.
Zhou Haifeng established a mouse model of psoriasis induced by imiquimod,and found that aloperine could reduce skin damage and keratinocyte proliferation,inhibit the infiltration of Th1 and Th17 cell subsets,promote the increase of Treg subsets,decrease the expression levels of inflammatory factors such as IL-6,IL-17 and IL-23,and increase the expression levels of cytokines such as IL-10 [50].It also inhibited LPS-induced dendritic cell activation,suggesting that the anti-inflammatory mechanism of aloperine might be related to IL-23/Th17 axis and enhanced Treg cell stability.
Huang Ziming tested the inhibitory effects of aloperine and matrine onNeisseria catanisseria
,Neisseria xanthobacteria
,Escherichia coli
,Dysentery bacillus
andSalmonella typhimurium
,and found that aloperine had better bacteriostasis effects than matrine,especially againstNeisseria catanisseria
,and the same antibacterial effect as penicillin when its concentration reached 5.0 mg/mL,with the diameter of the inhibition zone being 21 mm [51].3.3 Oxymatrine (2)
Ma Lin investigated the inhibitory effect of oxymatrine on the proliferation of human gastric cancer cell line SGC-7901 and human umbilical vein endothelial cell line ECV304in
vitro
and found that oxymatrine had a significant inhibitory effect since SGC-7901 underwent middle late apoptosis (IC,660.07μ
g/mL),while ECV304 cell underwent early apoptosis (IC,1555.17μ
g/mL),indicating that it could inhibit the proliferation of gastric cancer cells and angiogenesis [52].Han Yunyang found that oxymatrine could inhibit the auricle swelling of mice,weaken the torsion response and reduce the swelling of rats’feet [53].Huang Xiumei investigated the effect of oxymatrine on IL-6,IL-8 and TNF-α
in
vivo
andin
vitro
and found that it could inhibit the secretion of IL-6,IL-8 and TNF-α
in LPS-induced macrophages [54].Zhang Aijun found that oxymatrine had inhibitory effect on both methicillin-resistant and methicillin sensitiveStaphylococcus aureus
(MRSA and MSSA),and the minimum inhibitory concentrations of oxymatrine against MRSA and MSSA were 50 g/L and 32.5 g/L,respectively [55].This finding indicated that it had the prospect of further developing into anti-drug resistant bacteria.3.4 Other Monomeric Alkaloids
Quan Xiaoyan tested the antibacterial effect of sophoridine and oxysophoridinein vitro
,and found that sophoridine had good inhibitory effect onEscherichia coli
,Proteusbacillus vulgaris
,pseudomonas aeruginosa
andStaphylococcus epidermidis
with the MIC values of 8.0,8.0,8.0 and 4.0 mg/mL,respectively [56].However,oxysophoridine exhibited weak activity and had certain inhibitory effect onS.epidermidis
at a high concentration with the MIC values at 128 mg/mL.Yang Xiaoyi investigated the pharmacokinetics of sophocarpine and its inhibitory effect on human cervical cancerin
vivo
andin
vitro
,and found that the metabolism of sophocarpinein
vivo
conformed to the two-compartment model [57].The absorption of sophocarpine in stomach and small intestine showed linear kinetic characteristics from low dose to medium dose and nonlinear kinetic characteristics from medium dose to high dose in an obvious dosedependent manner.In
vitro
cytotoxicity test showed that sophocarpine had a good inhibitory effect on HeLa cells and SiHa cells.Wang Wenwen found that oxysophoridine could reduce the expression levels of urinary anhydride,urea nitrogen and malondialdehyde in model mice,down-regulate the expressions of TNF-α
and IL-1β
,increase the activities of SOD and CAT,regulate apoptotic proteins and inhibit cell apoptosis,indicating that renal injury is alleviated after administration [58].3.5 Total Alkaloids and flavonoids of S.alopecuroides
Gao Li investigated the toxicity of total alkaloids fromS.alopecuroides
on pheochromocytoma PC12in
vitro
,and found that it had significant inhibitory effect on PC12 cells and the growth inhibition rate of PC12 cells in the experimental group was 73.17±5.34% at the mass concentration of 2.0 g/L after 24 h culture,increasing the leakage rate of LDH,inducing apoptosis of cells,and inhibiting the cells in theS
phase [59].Jiao Heling investigated its therapeutic effect on S180 tumor-bearing mice,and found that the tumor volume of mice significantly decreased,while the serum levels of TNF-α
and IL-6 increased [60].Zhou Yi demonstrated that total alkaloids fromS.alopecuroides
had a significant therapeutic effect on rats with ulcerative colitis,and up-regulated IL-10 in colonic mucosal tissues and peripheral blood after administration [61].He Wenying tested the antioxidant activity of total flavonoids fromS.alopecuroides
,and the results showed that total flavonoids had good DPPH radical scavenging activity and certain scavenging activities for superoxide anion radical and hydroxyl radical [62].Zhang Shuyu investigated the effect of flavonoids on isolated guinea pig atrial muscles,and found that it could inhibit the contraction frequency of right atrial muscles,enhance myocardial contractility,prolong the function of left atrial muscles,and improve automaticity and arrhythmia [63].Zhao Yiyong found that it had the activity of inhibiting HBV-DNA replication and could significantly interfere with hepatitis B virus replication [64].Zhao Dehua firstly established a rat model of arrhythmia induced by aconitine,a guinea pig model of arrhythmia induced by wabain,a rabbit model of cardiac arrhythmias induced by chloroform-adrenaline,a mouse model of ventricular fibrillation induced by chloroform and a rat model of ventricular fibrillation induced by calcium dichloride,then found that total flavonoids had different degrees of therapeutic effects on these models and had the prospect of further development [65].4 Conclusion
In this review,the chemical constituents and biological activities ofS.alopecuroides
were systematically summarized.The chemical compositions ofS.alopecuroides
include alkaloids,flavonoids,steroids and some phenylpropanoid analogues,among them,alkaloids account for the largest proportion and should be considered as the characteristic compounds ofS.alopecuroides.
In particular,the application of matrine in all aspects is worthy of attention.Meanwhile,these compounds have exhibited anti-inflammatory,anti-viral,antitumor and antibacterial activities.However,the mechanism underlying the therapeutical effects remains to be elucidated,and further studies are needed to promote the better development ofS.alopecuroides
.Flavonoids,as another major active ingredient inS.alopecuroides
,have not received enough attention over the years,and their potential value might be greater and worth exploring.Funding
This work was supported by the College Student Innovation and Entrepreneurship Training Program (X202010163166).
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