Biological Activities and Secondary Metabolites from Sophora tonkinensis and Its Endophytic Fungi

Abstract

The roots of Sophora tonkinensis Gagnep., a traditional Chinese medicine, is known as Shan Dou Gen in the Miao ethnopharmacy. A large number of previous studies have suggested the usage of S. tonkinensis in the folk treatment of lung, stomach, and throat diseases, and the roots of S. tonkinensis have been produced as Chinese patent medicines to treat related diseases. Existing phytochemical works reported more than 300 compounds from different parts and the endophytic fungi of S. tonkinensis. Some of the isolated extracts and monomer compounds from S. tonkinensis have been proved to exhibit diverse biological activities, including anti-tumor, anti-inflammatory, antibacterial, antiviral, and so on. The research progress on the phytochemistry and pharmacological activities of S. tonkinensis have been systematically summarized, which may be useful for its further research.

1. Introduction

Sophora tonkinensis Gagnep. belongs to the Sophora genus of the Leguminosae family, which is widely distributed in the southwest provinces of China [1,2]. As a famous folk medicine of the Miao people, the roots of S. tonkinensis were known as Shan Dou Gen or Guang Dou Gen in the Miao ethnopharmacy [3,4]. The early medicinal records of Shan Dou Gen were contained in the classics “Kai Bao Ben Cao”, in which S. tonkinensis showed the effect of anti-sore throat diseases [5,6]. A large number of previous studies have suggested the usage of S. tonkinensis in the folk treatment of upper respiratory tract infection, including lung and throat diseases. Meanwhile, S. tonkinensis is also highly effective in the treatment of liver and skin diseases [7,8]. Moreover, the roots of S. tonkinensis can also be combined with other medicines to form dozens of clinical and marketing Chinese patent medicines, such as Kai Hou Jian throat spray, Shuyanqing Spray, and Watermelon Frost Spray, which is usually used for treatment of pharyngitis, tonsillitis, and aphthous ulcers [9,10,11]. Existing phytochemical works reported more than 300 compounds with various structural skeleton types from different parts and endophytic fungi of S. tonkinensis. Some of the isolated monomer compounds from S. tonkinensis have been proved to exhibit diverse biological activities, including anti-tumor, anti-inflammatory, antibacterial, antiviral, and so on [12,13,14,15,16,17]. Herein, the research progress on the phytochemistry and pharmacological activities of S. tonkinensis have been systematically summarized, which may be useful for its further research.

2. Phytochemistry

Previous studies have shown that alkaloids, flavonoids, triterpenoids, and triterpenoid saponins were the main chemical components isolated from S. tonkinensis. To date, 78 (1–78) alkaloids, 115 (79–193) flavonoids, 46 (194–239) triterpenes and triterpenoid saponins, and 37 (240–276) other compounds have been isolated from S. tonkinensis, and it is worth mentioning that 40 (277–316) compounds were also isolated from the endophytic fungi produced by S. Tonkinensis (Table 1, Figure 1).

Table 1.

The comprehensive list of the compounds from S. tonkinensis and its Endophytic fungus.

NO	Compounds	Molecular Formula	Parts of Plant	References
Matrine-Type alkaloids
1	Matrine	C15H24N2O	Roots	[12]
2	5α,14β-Dihydroxymatrine	C15H24N2O3	Roots	[12]
3	(+)-5α-Hydroxyoxymatrine	C15H24N2O3	Roots	[12]
4	(+)-Oxymatrine	C15H24N2O2	Roots	[18]
5	(+)-5α-Hydroxymatrine ((+)-Sophoranol)	C15H24N2O2	Roots	[12]
6	(−)- 14β-Hydroxyoxymatrine	C15H24N2O3	Roots	[18]
7	Sophtonseedline E	C17H26N2O4	Seeds	[19]
8	Sophtonseedline F	C17H28N2O3S	Seeds	[19]
9	Sophtonseedline G	C15H24N2O3	Seeds	[19]
10	Sophtonseedline H	C16H26N2O2	Seeds	[19]
11	(+)-9α-Hydroxymatrine	C15H24N2O2	Seeds	[19]
12	(+)-5α-9α-Dihydroxymatrine	C15H24N2O3	Seeds	[19]
13	(+)-Allomatrine (Sophoridine)	C15H24N2O	Roots	[20]
14	(+)-Lehmannine	C15H24N2O	Roots	[20]
15	(+)-12α-Hydroxysophocarpine	C15H24N2O2	Roots	[20]
16	(−)-13,14-Dehydrosophoridine (12,13-Dehydrosophoridine)	C15H24N2O	Roots	[20]
17	(+)-5α-Hydroxyoxysophocarpine	C15H22N2O3	Roots	[14]
18	(−)-12β-Hydroxyoxysophocarpine	C15H22N2O3	Roots	[14]
19	(−)-12β-Hydroxysophocarpine	C15H22N2O2	Roots	[14]
20	(+)-Oxysophocarpine	C15H22N2O2	Roots	[14]
21	Sophtonseedline B	C15H22N2O3	Seeds	[19]
22	Sophtonseedline C	C17H24N2O4	Seeds	[19]
23	Sophtonseedline D	C17H26N2O3S	Seeds	[19]
24	(−)-5α-Hydroxysophocarpine (13,14-Dehydrosophoranol)	C15H22N2O2	Seeds	[19]
25	(−)-9α-Hydroxysophocarpine	C15H22N2O2	Seeds	[19]
26	(−)-14β-Acetoxymatrine	C17H26N2O3	Leaves	[21]
27	(+)-14α-Acetoxymatrine	C17H26N2O3	Leaves	[21]
28	(−)-14β-Hydroxymatrine	C15H24N2O2	Leaves	[21]
29	(+)-14α-Hydroxymatrine	C15H24N2O2	Leaves	[21]
30	Sophtonseedline I	C17H24N2O4	Seeds	[19]
31	6,7-Dehydro-matrine	C15H22N2O	Seeds	[19]
32	5-Hydroxy-6,7-dehydro-matrine	C15H22N2O2	Seeds	[19]
33	(+)-13,14-Dehydrosophoranol	C15H22N2O2	Roots	[22]
34	(−)-Sophocarpine	C15H22N2O	Roots	[12]
35	(+)-5α-Hydroxylemannine	C15H22N2O2	Roots	[14]
36	13α-Hydroxymatrine	C15H24N2O2	Roots	[23]
37	13β-Hydroxymatrine	C15H24N2O2	Roots	[23]
38	11,12-Dehydroallmatrine	C15H22N2O	Roots	[1]
39	11,12-Dehydromatrine	C15H22N2O	Roots	[1]
40	(+)-Matrine N-oxide	C15H24N2O	Leaves	[21]
41	(+)-Sophoranol N-oxide	C15H24N2O2	Leaves	[21]
42	(+)-7,11-Dehydromatrine	C15H22N2O	Roots	[22]
43	Alopecurin A	C15H22N2O4	Seeds	[19]
44	Sophtonseedline J	C15H20N2O3	Seeds	[19]
45	Sophtonseedline K	C15H20N2O3	Seeds	[19]
46	Sophtonseedline A	C15H22N2O2	Seeds	[19]
47	5,6-Dehydro-matrine	C15H22N2O	Seeds	[19]
48	Isosophocarpine	C15H22N2O	Roots	[23]
49	(+)-Sophoramine (7β-Sophoramine)	C15H20N2O	Roots	[14]
Cytisine-type alkaloids
50	(−)-Cytisine	C11H14N2O	Seeds	[19]
51	N-Methylcytisine	C12H16N2O	Seeds	[19]
52	(−)-N-Formylcytisine	C12H14N2O2	Seeds	[19]
53	N-Acylcytisine	C13H16N2O2	Seeds	[19]
54	(−)-N-Methylcytisine	C12H16N2O	Roots	[18]
55	(−)-N-Hexanoylcytisine	C17H24N2O2	Roots	[24]
56	(−)-N-Ethylcytisine	C13H18N2O	Roots	[24]
57	(−)-N-Propionylcytisine	C14H18N2O2	Roots	[24]
58	Tonkinensine A	C28H26N2O6	Roots	[25]
59	Tonkinensine B	C28H26N2O6	Roots	[25]
Anagyrine-type alkaloids
60	17-Oxo-α-isosparteine	C15H24N2O	Leaves	[21]
61	(−)-Anagyrine	C15H20N2O	Roots	[12]
62	(−)-Thermopsine	C15H20N2O	Roots	[12]
63	(−)-Baptifoline	C15H20N2O2	Leaves	[21]
64	(−)-Clathrotropine	C17H22N2O4	Roots	[26]
65	Lanatine A	C22H29N3O3	Roots	[26]
Lupine-types and other alkaloids
66	Lamprolobine	C15H24N2O2	Leaves	[21]
67	Jussiaeiine B	C16H24N2O2	Roots	[26]
68	Jussiaeiine A	C13H20N2O2	Roots	[26]
69	Senepodine H	C14H26NO+	Roots	[26]
70	Cermizine C	C11H21N	Roots	[26]
71	Senepodine G	C11H20N+	Roots	[26]
72	Harmine	C13H12N2O	Roots	[1]
73	Tonkinensine C	C16H16N2O2	Roots	[1]
74	Perlolyrine	C16H12N2O2	Roots	[1]
75	3-(4-Hydroxyphenyl)-4-(3-methoxy-4-hydroxyphenyl)-3,4-dehydroquinolizidine	C22H25NO3	Roots	[26]
76	1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)ethanone	C8H10N2O	Roots	[27]
77	Cyclo (Pro-Pro)	C10H14N2O2	Roots	[27]
78	Nicotinic acid	C6H5NO2	Roots	[27]
Flavonoids
79	4′,7-Dihydroxyflavone	C15H10O4	Roots	[28]
80	Wogonin	C16H12O5	Roots	[29]
81	Luteolin	C15H10O4	Roots	[29]
82	Luteolin-7-glucoside	C21H20O11	Roots	[30]
83	Baicalein 7-O-β-Ⅾ-glucuronide	C21H18O11	Roots	[31]
84	Bayin	C21H20O9	Roots	[15]
85	Swertisin	C22H22O10	Roots	[31]
86	Sophoraflavone B	C21H20O9	Roots	[32]
87	Sophoraflavone A	C27H30O13	Roots	[32]
Flavonols
88	Quercetin	C15H10O7	Roots	[33]
89	Morin	C15H10O7	Roots	[31]
90	6,8-Diprenylkaempferol	C25H26O6	Roots	[34]
91	8-C-prenylkeamferol	C20H18O6	Roots	[35]
92	Dehydrolupinifolinol	C25H24O6	Roots	[33]
93	Tonkinensisol	C25H24O6	Roots	[15]
94	Isoquercitrin	C21H20O12	Roots	[36]
95	Quercitrin	C21H20O11	Roots	[37]
96	Rutin (Quercetin-3-O-β-D-rutinoside)	C27H30O16	Roots	[31]
97	Isorhamnetin-3-O-β-D-rutinoside	C28H32O16	Roots	[31]
Isoflavones and Dihydroisoflavones
98	8,4′-Dihydroxy-7-methoxyisoflavone	C16H12O5	Roots	[38]
99	5,7,2′,4′-Tetrahydroxyisoflavone	C15H10O6	Roots	[38]
100	Calycosin	C16H12O5	Roots	[38]
101	7,3′-Dihydroxy-5’-methoxyisoflavone	C16H12O5	Roots	[38]
102	7,4′-Dihydroxy-3′-methoxyisoflavone	C16H12O5	Roots	[38]
103	Daidzein (7,4’-Dihydroxyisoflavone)	C15H10O4	Roots	[38]
104	7,3′-Dihydroxy-8,4′-dimethoxyisoflavone	C17H14O6	Roots	[38]
105	7,8-Dihydroxy-4′-methoxyisoflavone	C16H12O5	Roots	[38]
106	7,3′,4′-Trihydroxyisoflavone	C15H10O5	Roots	[38]
107	Formononetin	C16H12O4	Roots	[39]
108	Genistein	C15H10O5	Roots	[39]
109	Wighteone	C20H18O5	Roots	[40]
110	8-Methylretusin	C17H14O5	Roots	[41]
111	7-Methoxyebenosin	C22H22O4	Roots	[42]
112	Tectorigenin	C16H12O6	Roots	[43]
113	Butesuperin A	C26H22O8	Roots	[44]
114	Butesuperin B -7′-O-β-glucopyranoside	C33H34O14	Roots	[44]
115	Genistin	C21H20O10	Roots	[33]
116	Ononin (Formononetin-7-O-β-D-glucoside)	C22H22O9	Roots	[33]
117	Daidzein-4′-glucoside-rhamnoside	C27H30O13	Roots	[37]
118	Sophorabioside	C27H30O14	Roots	[37]
Dihydroflavones
119	6,8-Diprenyl-7,4′-Dihydroxyflavanone	C25H28O4	Roots	[45]
120	Sophoranone	C30H36O4	Roots	[45]
121	Glabrol	C25H28O4	Roots	[45]
122	6,8-Diprenyl-7,2′,4′-trihydroxyflavanone	C25H28O5	Roots	[45]
123	Lespeflorin B4	C30H36O6	Roots	[33]
124	(2S)-7,4′-Dihydroxy-5′-aldehyde-8,3′-(3′′-methylbut-2′′-enyl) flavanone	C26H28O5	Roots	[34]
125	(2S)-7,2′,4′-Trihydroxy-8,3′,5′-(3′′-methyl- but-2′′-enyl) flavanone	C30H36O5	Roots	[34]
126	Tonkinochromane J	C25H28O5	Roots	[46]
127	Shandougenine C	C30H36O5	Roots	[40]
128	Shandougenine D	C25H28O5	Roots	[40]
129	Sophoratonin F	C35H44O4	Roots	[42]
130	Lonchocarpol A	C25H28O5	Roots	[42]
131	2′-Hydroxyglabrol	C25H28O5	Roots	[47]
132	8,5′-Diprenyl-7,2′,4′-trihydroxyflavanone	C25H28O5	Roots	[45]
133	Sophoratonin A	C27H28O4	Roots	[42]
134	Sophoratonin B	C30H32O4	Roots	[42]
135	Tonkinochromane I	C30H36O5	Roots	[35]
136	Tonkinochromane G	C30H36O5	Roots	[34]
137	Sophoratonin C	C30H30O4	Roots	[42]
138	Sophoratonin D	C30H36O4	Roots	[42]
139	Flemichin D	C25H26O5	Roots	[45]
140	5-Dehydroxylupinifolin	C25H26O4	Roots	[34]
141	Lupinifolin	C25H26O5	Roots	[40]
142	2-(2′,4′-Dihydroxyphenyl)-8,8-dimethyl-1′-(3-methyl-2-butenyl)-8H-pyrano[2,3-d] chroman-4-one	C25H26O5	Roots	[48]
143	Tonkinochromane A	C30H36O4	Roots	[45]
144	Sophoranochromene	C30H34O4	Roots	[33]
145	2-[{2-(1-Hydroxy-1-methylethyl)-7-(3-methyl-2-butenyl)-2′,3-dihydrobenzofuran}-5-yl]-7-hydroxy-8-(3-methyl-2-butenyl)-chroman-4-one	C30H36O5	Roots	[49]
146	Sophoratonin E	C30H32O4	Roots	[42]
147	Tonkinochromane D	C30H38O5	Roots	[50]
148	Tonkinochromane E	C32H42O5	Roots	[50]
149	2-[{2′-(1-Hydroxy-1-methylethyl)-7′-(3-methyl-2-butenyl)-2′,3′-dihydrobenzofuran}-5′-yl]-7-hy-droxy-8-(3-methyl-2-butenyl) chroman-4-one	C30H36O5	Whole	[51]
150	Euchrenone A2	C25H26O5	Roots	[33]
151	Sophoratonin G	C27H28O4	Roots	[42]
152	Tonkinochromane K	C30H36O6	Roots	[46]
153	2-[{3′-Hydroxy-2′,2′-dimethyl-8′-(3-methyl-2-butenyl)} chroman-6′-yl]-7-hydroxy-8-(3-methyl-2-butenyl)-chroman-4-one	C30H36O5	whole	[51]
154	2-[{3-Hydroxy-2′,2-dimethyl-8-(3-methyl-2-butenyl)} chroman-6-yl]-7-hydroxy-8-(3-methyl-2-butenyl)-chro-man-4-one	C31H38O4	Roots	[49]
155	Tonkinochromane H	C30H34O5	Roots	[52]
156	Tonkinochromane B	C30H36O4	Roots	[53]
157	Kushenol E	C25H28O6	Roots	[46]
158	Naringenin 7-O-neo-hesperidoside	C27H32O14	Roots	[31]
Chalcones and Dihydrochalcones
159	Isoliquiritigenin	C15H12O4	Roots	[47]
160	Sophoradin	C30H36O4	Roots	[34]
161	Xanthohumol	C21H22O5	Roots	[54]
162	7,9,2,4-Tetrahydroxy-8-isopentenyl-5-methoxychalcone	C21H22O6	Roots	[54]
163	Tonkinochromane C	C28H30O4	Roots	[53]
164	Tonkinochromane F	C32H42O5	Roots	[50]
165	Kuraridine	C26H30O6	Roots	[54]
166	Sophoradochromene	C30H34O4	Roots	[42]
167	Tonkinochromane L	C21H24O4	Roots	[46]
Pterostanes
168	(−)-Maackiain	C16H12O5	Roots	[33]
169	Pisatin	C17H14O6	Roots	[39]
170	Maackiain-3-O-glucoside 6′’-acetate	C24H24O11	Roots	[47]
171	(−)-Maackiain 3-sulfate	C16H11O8S	Roots	[55]
172	6aR,11aR-1-hydroxy-4-isoprenyl-maackiain	C21H20O6	Roots	[48]
173	(6aR,11aR) - 2-hydroxy-3-methoxy-1-isopentenyl- maackiain	C22H22O6	Roots	[47]
174	Sophotokin	C21H20O6	Roots	[34]
175	(−)-Pterocarpin	C17H14O5	Seeds	[56]
176	Medicarpin	C16H14O4	Roots	[39]
177	(6aR, 11aR)-3-O-β-D-Glucopyranosylmedicarpin	C22H24O9	Roots	[24]
178	Medicarpin-3-O-glucoside 6″-acetate	C24H26O10	Roots	[47]
179	Demethylmedicarpin	C15H12O4	Roots	[40]
180	Homopterocarpin	C17H16O4	Roots	[42]
181	Dehydromaackiain	C16H10O5	Roots	[42]
182	Flemichapparin B	C17H12O5	Roots	[42]
183	Maackiapterocarpan B	C21H18O6	Roots	[57]
184	3-Methylmaackiapterocarpan B	C22H20O6	Roots	[47]
185	Erybraedin D	C25H26O4	Roots	[42]
186	Maackiapterocarpan A	C21H20O6	Roots	[42]
187	Medicagol	C16H8O6	Seeds	[56]
188	Sophtonseedlin B	C28H28O13	Seeds	[56]
189	Sophoratonkin	C26H26O11	Roots	[28]
190	(−)-Trifolirhizin	C22H22O10	Seeds	[56]
191	(−)-Trifolirhizin-6′′-monoacetate	C24H24O11	Seeds	[56]
Flavanols
192	7,2’-Dihydroxy-4’-methoxy-isofiavanol	C16H16O5	Roots	[58]
193	(3S,4R)-4-hydroxy-7,4′-dimethoxyisoflavan 3′-O-β-D-glucopyranoside	C23H28O10	Roots	[24]
Triterpenoids and Triterpenoid saponins
194	Subprogenin A	C30H48O4	Roots	[59]
195	Subprogenin B	C30H48O5	Roots	[59]
196	Subprogenin C	C30H46O4	Roots	[59]
197	Subprogenin C methylester	C31H48O4	Roots	[59]
198	Subprogenin D	C30H46O4	Roots	[59]
199	Subprogenin D methylester	C31H48O4	Roots	[59]
200	Abrisapogenol H	C30H48O3	Roots	[59]
201	Wistariasapogenol A	C30H48O4	Roots	[59]
202	Melilotigenin	C30H46O5	Roots	[59]
203	Abrisapogenol I	C30H46O5	Roots	[59]
204	Sophoradiol	C30H50O2	Roots	[59]
205	Cantoniensistiol	C30H50O3	Roots	[59]
206	Soyasapogenol B	C30H50O3	Roots	[59]
207	Soyasapogenol A	C30H50O4	Roots	[59]
208	Abrisapogenol C	C30H50O4	Roots	[59]
209	Abrisapogenol D	C30H50O3	Roots	[59]
210	Abrisapogenol E	C30H50O4	Roots	[59]
211	Kudzusapogenol A	C30H50O5	Roots	[59]
212	Abrisapogenol A	C30H50O3	Roots	[59]
213	Lupeol	C30H50O	Roots	[60]
214	Stigmasterol	C29H48O	Roots	[60]
215	β-Sitosterol	C29H50O	Roots	[60]
216	Daucosterol	C35H60O6	Roots	[60]
217	Subproside Ⅰ	C48H78O19	Roots	[61]
218	Subproside Ⅰ methylester	C49H80O19	Roots	[61]
219	Subproside Ⅱ	C47H76O19	Roots	[61]
220	Subproside Ⅱ methylester	C48H78O19	Roots	[61]
221	Soyasaponin A3 methylester	C49H80O19	Roots	[62]
222	Kuzusapogenol A methylester	C49H80O20	Roots	[62]
223	Soyasaponin I methylester	C49H80O18	Roots	[62]
224	Kaikasaponin Ⅲ methylester	C49H80O17	Roots	[62]
225	Soyasaponin Ⅱ methylester	C48H78O17	Roots	[62]
226	Kaikasapomn I methylester	C49H80O17	Roots	[62]
227	Kudzusaponin A3	C47H76O19	Roots	[61]
228	Soyasaponin II	C47H76O17	Roots	[61]
229	Dehydrosoyasaponin I	C48H76O18	Roots	[61]
230	Subproside Ⅶ	C59H96O27	Roots	[63]
231	Subproside Ⅶ methylester	C60H98O27	Roots	[63]
232	Subproside Ⅳ	C54H88O23	Roots	[63]
233	Subproside Ⅳ methylester	C55H90O23	Roots	[63]
234	Subproside Ⅴ	C54H88O24	Roots	[63]
235	Subproside Ⅴ methylester	C55H90O24	Roots	[63]
236	Subproside Ⅲ	C54H86O24	Roots	[61]
237	Subproside Ⅲ methylester	C55H88O24	Roots	[61]
238	Subproside Ⅵ	C54H88O24	Roots	[63]
239	Subproside Ⅵ methylester	C55H90O24	Roots	[63]
Other compounds
240	Tyrosol	C8H10O2	Roots	[64]
241	4-(3-Hydroxypropyl) phenol	C9H12O2	Roots	[64]
242	Vanillin alcohol	C8H10O3	Roots	[64]
243	(±)-4-(2-Hydroxypropyl) phenol	C9H12O2	Roots	[64]
244	3,4,5-Trihydroxybenzoic acid	C7H6O5	Roots	[31]
245	3,4-Dihydroxybenzoic acid	C7H6O4	Roots	[31]
246	4-Hydroxy-3-methoxybenzoic acid	C8H8O4	Roots	[31]
247	p-Hydroxybenzonic acid	C7H6O3	Roots	[31]
248	Venillic acid	C8H8O4	Roots	[41]
249	p-Methoxybenzonic acid	C8H8O3	Roots	[27]
250	Salicylic acid	C7H6O3	Roots	[43]
251	Benzamide	C7H7NO	Roots	[64]
252	4-Methoxybenzamide	C8H9NO2	Roots	[64]
253	Docosyl caffeate	C31H52O4	Roots	[4]
254	Maltol	C6H6O3	Roots	[41]
255	(±)-3-( p-Methoxyphenyl) -1,2-propanediol	C9H12O4	Roots	[64]
256	3,4-Dimethoxybenzeneacrylic acid methyl ester	C12H14O4	Roots	[39]
257	Sophoratonin H	C22H26O5	Roots	[42]
258	Piscidic acid monoethyl ester	C13H16O7	Roots	[41]
259	2′,4′, 7-trihydroxy-6,8-bis(3-methyl-2-butenyl) flavanone	C25H28O5	Roots	[40]
260	2-(2′, 4′-dihydroxylphenyl)-5,6-methylenedioxybenzoftiran	C15H10O5	Roots	[56]
261	bolusanthin IV	C15H12O4	Roots	[40]
262	7,2′-Dihydroxy-4′,5′-methylenedioxyisoflavan	C16H14O5	Roots	[40]
263	Shandougenine A	C30H18O10	Roots	[40]
264	Shandougenine B	C30H18O10	Roots	[40]
265	(−)-Syringaresinol-4,4’-di-O-β-D-glucopyranoside	C34H46O18	Roots	[27]
266	(−)-Syringaresinol-4-O-β-D-glucopyranoside	C28H36O13	Roots	[27]
267	(−)-Pinoresinol-4,4’-di-O-β-D-glucopyranoside	C32H42O16	Roots	[27]
268	Pinoresinol	C20H22O6	Roots	[28]
269	Syringaresinol	C22H26O8	Roots	[28]
270	Medioresinol	C21H24O7	Roots	[28]
271	Coniferin	C16H22O8	Roots	[27]
272	4-Hydroxymethyl-2,6-dimethoxyphenol-1-O-β-D-glucopyranoside	C15H22O9	Roots	[27]
273	Syringin	C17H24O9	Roots	[29]
274	Sophtonseedlin A	C23H14O9	Roots	[56]
275	(6S,9R) -Roseoside	C19H30O8	Roots	[27]
276	(−)-Secoisolariciresinol-4-O-β-D-glucopyranoside	C25H33NO9	Roots	[27]
Compounds produced by endophytic fungi
277	2-Methoxy-6-methyl-1,4-benzoquinone	C8H8O3	Endophytic Fungus Xylaria sp. GDG-102	[65]
278	1-Methyl emodin	C16H12O5	Endophytic Fungus Penicillium macrosclerotiorum	[66]
279	Isorhodoptilometrin	C17H14O6	Endophytic Fungus Penicillium macrosclerotiorum	[66]
280	(−)-5-Carboxylmellein	C11H10O5	Endophytic Fungus Xylaria sp. GDG-102	[65]
281	(−)-5-Methylmellein	C11H12O3	Endophytic Fungus Xylaria sp. GDG-102	[67]
282	Xylariphilone	C11H16O4	Endophytic Fungus Xylaria sp. GDG-102	[65]
283	Xylarphthalide A	C11H10O6	Endophytic Fungus Xylaria sp. GDG-102	[65]
284	2-Anhydromevalonic acid	C6H10O3	Endophytic Fungus Xylaria sp. GDG-102	[65]
285	(2S,5R)-2-Ethyl-5-methylhexanedioic acid	C9H16O4	Endophytic Fungus Xylaria sp. GDG-102	[65]
286	6-Heptanoyl-4-methoxy-2H-pyran-2-one	C13H18O4	Endophytic Fungus Xylaria sp. GDG-102	[65]
287	Xylareremophil	C15H18O3	Endophytic Fungus Xylaria sp. GDG-102	[68]
288	1α,10α-Epoxy-13-hydroxyeremophil-7(11)-en-12,8-β-olide	C15H20O4	Endophytic Fungus Xylaria sp. GDG-102	[68]
289	1α,10α-Epoxy-3α-hydroxyeremophil-7(11)-en-12,8-β-olide	C15H20O5	Endophytic Fungus Xylaria sp. GDG-102	[68]
290	Mairetolide B	C15H20O4	Endophytic Fungus Xylaria sp. GDG-102	[68]
291	Mairetolide G	C15H22O5	Endophytic Fungus Xylaria sp. GDG-102	[68]
292	1β,10α,13-Trihydroxyeremophil-7(11)-en-12,8-olide	C16H24O4	Endophytic Fungus Xylaria sp. GDG-102	[65]
293	(−)-3-Carboxypropyl-7-hydroxyphthalide	C12H12O5	Endophytic fungus Penicillium vulpinum	[69]
294	(−)-3-Carboxypropyl-7-hydroxyphthalide methyl ester	C13H14O5	Endophytic fungus Penicillium vulpinum	[69]
295	Sulochrin	C17H16O7	Endophytic fungus Penicillium macrosclerotiorum	[66]
296	Monoacetylasterric acid	C18H16O9	Endophytic fungus Penicillium macrosclerotiorum	[66]
297	Methyl dichloroasterrate	C18H16Cl2O8	Endophytic Fungus Penicillium macrosclerotiorum	[66]
298	Penicillither	C18H17 ClO8	Endophytic fungus Penicillium macrosclerotiorum	[66]
299	Methyl asterrate	C18H18O8	Endophytic fungus Penicillium macrosclerotiorum	[66]
300	Asterric acid	C17H16O8	Endophytic fungus Penicillium macrosclerotiorum	[66]
301	Xylapeptide A	C30H45N5O5	Endophytic Fungus Xylaria sp. GDG-102	[70]
302	Xylapeptide B	C29H43N5O5	Endophytic Fungus Xylaria sp. GDG-102	[70]
303	21-Acetoxycytochalasin J2	C30H37NO4	Endophytic fungus Diaporthe sp.GDG-118	[71]
304	21-Acetoxycytochalasin J3	C30H39NO3	Endophytic fungus Diaporthe sp.GDG-118	[71]
305	Cytochalasin J3	C32H41NO4	Endophytic fungus Diaporthe sp.GDG-118	[71]
306	Cytochalasin H	C30H39NO5	Endophytic fungus Diaporthe sp.GDG-118	[71]
307	7-Acetoxycytochalasin H	C32H41NO6	Endophytic fungus Diaporthe sp.GDG-118	[71]
308	Cytochalasin J	C28H37NO4	Endophytic fungus Diaporthe sp.GDG-118	[71]
309	Geomycin A	C35H32O15	Endophytic fungus Penicillium macrosclerotiorum	[66]
310	Cytochalasin E	C28H33NO7	Endophytic fungus Diaporthe sp.GDG-118	[71]
311	Cytochalasin K	C28H33NO7	Endophytic fungus Xylaria sp. GDG-102	[65]
312	Diaporthein B	C20H28O6	Endophytic fungus Xylaria sp. GDGJ-368	[72]
313	Piliformic	C11H18O4	Endophytic fungus Xylaria sp. GDGJ-368	[72]
314	Cytochalasin C	C30H37NO6	Endophytic fungus Xylaria sp. GDGJ-368	[72]
315	Cytochalasin D	C30H37NO6	Endophytic fungus Xylaria sp. GDGJ-368	[72]
316	(22E)-ergosta-6,22-diene-3β,5β,8α-triol	C28H46O3	Endophytic fungus Xylaria sp. GDGJ-368	[72]

Figure 1.

Structures of compounds 1–316 from S. tonkinensis.

2.1. Alkaloids

The alkaloids isolated in S. tonkinensis were mainly quinolizidine-type alkaloids [73]. To date, 78 alkaloids have been identified and isolated, of which 49 (1–49) are matrine type alkaloids. Sophtonseedline A (46) was isolated from the seeds of S. tonkinensis, which featured an unprecedented 5/6/6/6 tetracyclic skeleton [19]. Meanwhile, tonkinensines A (58) and B (59) with the rare multi group bridging structures were isolated from S. tonkinensis also [25].

2.2. Flavonoids

Flavonoids generically referred to the compounds with C6-C3-C6 structure skeleton. The flavonoids were rich in S. tonkinensis, and more than 115 flavonoids have been reported as far as we know. Their structural types can be classified as flavonoids (79-87), flavonols (88–97), isoflavones and dihydroisoflavones (98–118), dihydroflavones (119–158), chalcones and dihydrochalcones (159–167), pterostanes (168–191), and flavanols (192–193). Interestingly, tonkinochromanes A (143) and B (156) may ring-fused in the isoprenyl substituents [53]. Meanwhile, sophoraflavones A (87) and B (86) were the rare 5-deoxyflavonoids from the roots of S. tonkinensis [32]. Among the eighteen flavonoids identified using UPLC-ESI-LTQ/MS methods, formononetin (107), quercetin (88), rutin (96), isoquercitrin (94), and quercitrin (95) were suggested as the major quality markers of S. tonkinensis roots [37].

2.3. Triterpenoids and Triterpenoid Saponins

As far as we know, more than 46 (194–239) triterpenoids and triterpenoid saponins have been isolated from S. tonkinensis. Isolated triterpenoids are mainly of the oleanane type with carbonyl substitution at position C-22 [30,74]. Compared with flavonoids and alkaloids, the triterpenoids and triterpenoid saponins of S. tonkinensis were rarely reported [59,61,62].

2.4. Other Compounds

In addition to alkaloids, flavonoids, and triterpenoids, a total of 37 (240–276) phenolic acids, sterols, and other compounds were reported from S. tonkinensis. Two new 2-arylbenzofuran dimers, shandougenines A (263) and B (264), were isolated from the roots of S. tonkinensis. It is noteworthy that shandougenine A (263) has the unique dimeric 2-Arylbenzofuran with a C-3\C-5 bond, and shandougenine B (264) was the natural dimeric 2-arylbenzofuran with a novel C-3/C-3 bond [40]. Meanwhile, a new propenyl phenylacetone was also isolated from S. tonkinensis and named sophoratonin H (257) [42].

2.5. Compounds Produced by Endophytic Fungi

The endophytic fungus Xylaria sp.GDG-102, Penicillium macrosclerotiorum, Penicillium vulpinum, Diaporthe sp.GDG-118, and Xylaria sp. GDGJ-368 [65,66,69,71] were isolated from S. tonkinensis, and some compounds produced by these endophytic fungi were interesting. More than 40 (277–316) compounds have been isolated from its endophytic fungi. Xylapeptide A (301) identified from the associated fungus Xylaria sp. GDG-102 was the first example of cyclopentapeptide with an L-Pip of terrestrial origin [70].

3. Pharmacological Activities

3.1. Anti-Inflammatory Effect

Reported studies have shown the anti-inflammatory activities of S. tonkinensis (Table 2) [45,75]. Some novel compounds, including 12,13-dehydrosophoridine (16) from S. tonkinensis, showed significant activity against inflammatory cytokines TNF-α and IL-6 on LPS-induced RAW264.7 macrophages [23]. Moreover, 6,8-diprenyl-7,4’-dihydroxyflavanone (DDF) (119) inhibited the production of NO and the expression of TNF-α, IL-1β, and IL-6 [45]. Meanwhile, the compounds 2′-hydroxyglabrol (131), glabrol (121), maackiain (168), and bolusanthin IV (261) showed strong inhibitory effects on IL-6 [47]. Sophotokin (174) dose-dependently inhibited the lipopolysaccharide (LPS)-stimulated production of NO, TNF-α, PGE₂, and IL-1β in microglial cells [34]. Moreover, the orally administered roots extract of S. tonkinensis attenuated the total leukocytes, eosinophil infiltration, and IL-5 level in BAL fluids [76]. Another study also showed S. tonkinensis were able to reduce TNF-α, NO, and IL-6 contents in rat paw edema induced by carrageenan [77].

Table 2.

The comprehensive list of the pharmacological activities from S. tonkinensis.

Detail	Extracts/Compounds	In Vivo/In Vitro	Active Concentration/Dose	References
Anti-inflammatory activity
Reduce TNF-α	(−)-Anagyrine (61)	In vitro	50 µM	[12]
	Sophocarpine (34)	In vitro	50 µM	[12]
	14β-Hydroxymatrine (28)	In vitro	50 µM	[12]
	7β-Sophoramine (49)	In vitro	50 µM	[12]
	Matrine (1)	In vivo	50 µM	[12]
	(+)-5α-Hydroxymatrine (5)	In vivo	50 µM	[12]
	12,13-Dehydrosophoridine (16)	In vitro	50 µM	[23]
	13α-Hydroxymatrine (36)	In vitro	50 µM	[23]
	13β-Hydroxymatrine (37)	In vitro	50 µM	[23]
	Isosophocarpine (48)	In vitro	50 µM	[23]
	Sophoridine (13)	In vitro	50 µM	[23]
	Water extract of roots	In vivo	0.3 g/kg	[75]
Inhibit the production of NO	sophoratonkin (189)	In vitro	IC50 = 33.0 µM	[28]
	Maackiain (168)	In vitro	IC50 = 27.0 µM	[28]
	Sophoranone (120)	In vitro	IC50 = 28.1 µM	[28]
	Sophoranochromene (144)	In vitro	IC50 = 13.6 µM	[28]
	Tonkinochromane A (143)	In vitro	20 µM	[45]
	Flemichin D (139)	In vitro	20 µM	[45]
	6,8-Diprenyl-7,4′-dihydroxyflavanone (119)	In vitro	IC50 = 12.21 µM	[45]
	Water extract of roots	In vivo	100 mg/kg	[13]
	Non-alkaloid extracts of roots	In vivo	400 mg/kg	[13]
Reduce IL- 6	2′-Hydroxyglabrol (131)	In vitro	IC50 = 1.62 µM	[47]
	Glabrol (121)	In vitro	IC50 = 0.73 µM	[47]
	Maackiain (168)	In vitro	IC50 = 3.01 µM	[47]
	Bolusanthin IV (261)	In vitro	IC50 = 4.02 µM	[47]
	Ethanol extract of roots	In vivo	100 mg/kg	[7]
	(−)-Anagyrine (61)	In vitro	50 µM	[12]
	Sophocarpine (34)	In vitro	50 µM	[12]
	14β-Hydroxymatrine (28)	In vitro	50 µM	[12]
	7β-Sophoramine (49)	In vitro	50 µM	[12]
	Matrine (1)	In vitro	50 µM	[12]
	(+)-5α-Hydroxyoxymatrine (3)	In vivo	50 µM	[12]
	(+)-5α-Hydroxymatrine (5)	In vivo	50 µM	[12]
	12,13-Dehydrosophoridine (16)	In vitro	50 µM	[23]
	13α-Hydroxymatrine (36)	In vitro	50 µM	[23]
	13β-Hydroxymatrine (37)	In vitro	50 µM	[23]
	Isosophocarpine (48)	In vitro	50 µM	[23]
	Sophoridine (13)	In vitro	50 µM	[23]
	Water extract of roots	In vivo	0.3 g/kg	[75]
Reduce IL-5	50% (v/v) ethanol-water mixture	In vivo	100 mg/kg	[76]
Reduce IL-10	Ethanol extract of roots	In vivo	100 mg/kg	[7]
Reduce IL-1β	Water extract of roots	In vivo	0.3 g/kg	[75]
Reduced the hyperplasia of goblet cell	50% (v/v) ethanol-water mixture	In vivo	10 mg/kg	[76]
Inhibit xylene induced auricle swelling in mice	Oxymatrine (4)	In vivo	40 mg/kg	[78]
	(−)-Cytisine (50)	In vivo	40 mg/kg	[78]
	S. tonkinensis particles	In vivo	1.75 g/kg	[79]
Inhibit pain induced by acetic acid stimulation of the celiac mucosa	Matrine (1)	In vivo	40 mg/kg	[78]
	Sophoridine (13)	In vivo	30 mg/kg	[78]
	Sophocarpine (34)	In vivo	40 mg/kg	[78]
	S. tonkinensis particles	In vivo	3.5 g/kg	[79]
Inhibit croton oil induced ear swelling in mice	Water extract of roots	In vivo	0.35–1.12 g/kg	[80]
	Ethanol extract of roots	In vivo	0.35–1.12 g/kg	[80]
	Water extract of roots	In vivo	0.39 g/kg	[81]
Anti-tumor activity
Inhibit A549	(−)-N-hexanoylcytisine (55)	In vitro	IC50 = 31.64 µM	[24]
	(−)-N-Formylcytisine (52)	In vitro	IC50 = 22.05 µM	[24]
	(6aR, 11aR)-Maackiain (168)	In vitro	IC50 = 24.58 µM	[24]
	Water extracts of roots	In vitro	6.5 µg/µL	[82]
	1-(6,7-Dihydro-5H-pyrrolo [1,2-a] imidazol-3-yl) ethenone (76)	In vitro	IC50 = 23.05 ± 0.46 µM	[27]
Inhibit HL-60	Tonkinensisol (93)	In vitro	IC50 = 36.48 μg/mL	[15]
	Sophoranol (5)	In vitro	10.00 µg/mL	[83]
	13,14-Dehydrosophoranol (24)	In vitro	1.00 µg/m L	[83]
Inhibit HepG2	Tonkinensine C (73)	In vitro	IC50 = 87.4 ± 7.1 µM	[1]
	Perlolyrine (74)	In vitro	IC50 = 91.8 ± 3.5 µM	[1]
	Harmine (72)	In vitro	IC50 = 48.9 ± 5.2 µM	[1]
	Alkaloids	In vitro	IC50 = 9.04 g/L	[84]
	Non-alkaloids extract of roots	In vitro	IC50 = 0.98 g/L	[84]
	Water extracts of roots	In vitro	6.5 µg/µL	[82]
Inhibit SH-SY5Y	Sophoranone (120)	In vitro	IC50 = 18.49 µM	[85]
	Matrine (1)	In vitro	IC50 = 60.81 µM	[85]
	Oxymatrine (4)	In vitro	IC50 = 42.56 µM	[85]
	(−)-Trifolirhizin (190)	In vitro	IC50 = 72.11 µM	[85]
	(−)-Maackiain (168)	In vitro	IC50 = 65.62 µM	[85]
Inhibit B16-BL6	Extract of roots	In vitro	400 µg/mL	[86]
Inhibit CNE-1, CNE-2	Chloroform extract of roots	In vitro	25 µg/mL	[87]
Inhibit U937	Sophoranone (120)	In vitro	IC50 = 3.8 ± 0.9 µM	[88]
Inhibit HeLa	Tonkinensine B (59)	In vitro	IC50 = 24.3± 0.3 µM	[25]
Inhibit MDA-MB-231	Tonkinensine B (59)	In vitro	IC50 = 48.9± 0.5 µM	[25]
	Water extract of roots	In vitro	6.5 µg/µL	[82]
Inhibit ESC solid tumor cell	Total alkaloids of roots	In vivo	100 mg/kg	[89]
Inhibit H22 ascites tumor cells	Total alkaloids of roots	In vivo	100 mg/kg	[89]
Inhibit S180 solid tumor cell	Total alkaloids of roots	In vivo	75 mg/kg	[89]
Inhibit BV2 glioma cell lines	Sophotokin (174)	In vitro	10 µM	[34]
	Maackiain (168)	In vitro	10 µM	[34]
	Medicarpin (176)	In vitro	10 µM	[34]
Inhibit Hep3B and KG-1 cells	Water extract of roots	In vitro	6.5 µg/µL	[82]
Decrease the number of cancer nodules in tumor tissue and reduce AFP in serum	Alkaloids extract of roots	In vivo	0.036 g/kg	[90]
Effects on the liver
Protect HepG2 cell against acetaminophen (APAP)- induced damage	4-Methoxybenzamide (252)	In vitro	10 µmol/L	[64]
	7,3’-Dihydroxy-8,4’-dimethoxyisoflavone (104)	In vitro	10 µmol/L	[64]
	7,4’-Dihydroxy-3’-methoxyisoflavone (102)	In vitro	10 µmol/L	[64]
	(±)-3-(p-Methoxyphenyl)-1,2-propanediol (255)	In vitro	10 µmol/L	[64]
Enhance L-02 hepatocytes	Matrine (1)	In vivo and vitro	10 µM	[91]
	Oxymatrine (4)	In vivo and vitro	10 µM	[91]
Increase SOD and GSH	Non-alkaloids extract of roots	In vivo	400 mg/kg	[13]
	Water extract of roots	In vivo	400 mg/kg	[13]
Increase ALT and AST	Water extract of roots	In vivo	0.59 g/kg	[92]
Increase CPT 1A activity	Water extract of roots	In vivo	25 μg/mL	[91]
Reduce nonestesterified fatty acid Induce cellular lipids accumulation in hepatocytes	Matrine (1)	In vivo	10 µM	[91]
	Oxymatrine (4)	In vivo	10 µM	[91]
Reduce immune liver injury	Oxymatrine (4)	In vivo	60 mg/kg	[93]
	Sophocarpine (34)	In vivo	60 mg/kg	[93]
	Oxymatrine (4)	In vivo	120 mg/kg	[94]
Inhibite acetaminophen-induced hepatic oxidative damage in mice	STRP1 (Polysaccharide part)	In vivo	200 mg/kg	[95]
	STRP2 (Polysaccharide part)	In vivo	200 mg/kg	[95]
Alleviate non-alcoholic fatty liver disease of mice	Water extract of roots	In vivo	90 mg/kg	[91]
Inhibit the production of tyrosinase	Formononetin-7-O-β-D-glucoside(116)	In vitro	IC50 = (7.82 ± 0.28) × 10−4 mol/L	[43]
	Tectorigenin (112)	In vitro	IC50 = (3.73 ± 0.45) × 10−4 mol/L	[43]
	8-Prenylkeamferol (91)	In vitro	IC50 = (1.58 ± 0.31) × 10−5 mol/L	[43]
Reduce AST and ALT	Oxymatrine (4)	In vivo	120 mg/kg	[93]
	Sophocarpine (34)	In vivo	120 mg/kg	[93]
	Water extract of roots	In vivo	0.25 g/kg	[96]
Reduce AST	Non-alkaloid extract of roots	In vivo	100 mg/kg	[13]
	Water extract of roots	In vivo	200 mg/kg	[13]
Reduce ALT	Non-alkaloid extracts of roots	In vivo	400 mg/kg	[13]
	Water extract of roots	In vivo	200 mg/kg	[13]
Anti-viral activity
Anti-Coxsackie virus B3	(−)-12β-Hydroxyoxysophocarpine (18)	In vitro	IC50 = 26.62 µM	[14]
	(−)-9α-Hydroxysophocarpine (25)	In vitro	IC50 = 197.22 µM	[14]
	(+)-Sophoranol (5)	In vitro	IC50 = 252.18 µM	[14]
	(−)-14β-Hydroxymatrine (28)	In vitro	IC50 = 184.14 µM	[14]
	3-(4-Hydroxyphenyl)- 4- (3- methoxy- 4-hydroxyphenyl)-3,4-dehydroquinolizidine (75)	In vitro	IC50 = 6.40 µM	[26]
	Cermizine C (70)	In vitro	IC50 = 3.25 µM	[26]
	Jussiaeiine A (68)	In vitro	IC50 = 4.66 µM	[26]
	Jussiaeiine B (67)	In vitro	IC50 = 3.21 µM	[26]
	(+)-5α-Hydroxyoxysophocarpine (17)	In vitro	IC50 = 0.12 µM	[26]
	(−)-12β-Hydroxyoxysophocarpine (18)	In vitro	IC50 = 0.23 µM	[26]
	(−)-Clathrotropine (64)	In vitro	IC50 = 1.60 µM	[26]
Anti-tobacco mosaic virus (TMV)	Sophtonseedlin B (188)	In vitro	100 µg/mL	[56]
	(−)-Trifolirhizin (190)	In vitro	100 µg/mL	[56]
	Sophtonseedline B (21)	In vitro	100 µg/mL	[19]
	Sophtonseedline D (23)	In vitro	100 µg/mL	[19]
	Sophtonseedline F (8)	In vitro	100 µg/mL	[19]
	(−)-N-Formylcytisine (52)	In vitro	100 µg/mL	[19]
	Alkaloid extracts of seeds	In vitro	0.5 mg/mL	[19]
	Methanol extracts of seeds	In vitro	0.5 mg/mL	[19]
Anti-hepatitis B virus (HBV)	(+)-Oxysophocarpine (20)	In vitro	0.4 µmol/mL	[20]
	(−)-Sophocarpine (34)	In vitro	0.4 µmol/mL	[20]
	(+)-Lehmannine (14)	In vitro	0.4 µmol/mL	[20]
	(−)-13,14-Dehydrosophoridine (16)	In vitro	1.6 µmol/mL	[20]
	(−) -14β-Hydroxyoxymatrine (6)	In vitro	0.4 µmol/mL	[18]
	(+)-Sophoranol (5)	In vitro	0.2 µmol/mL	[18]
	(−)-Cytisine (50)	In vitro	0.2 µmol/mL	[18]
Anti-mouse hepatitis virus	Methanol extracts of plant	In vitro	EC50 = 27.5 ± 1.1 µg/mL	[97]
Inhibited influenza virus A/Hanfang/359/95	(+)-12α-Hydroxysophocarpine (15)	In vitro	IC50 = 84.70 µM	[14]
	(−)-12β-Hydroxysophocarpine (19)	In vitro	IC50 = 242.46 µM	[14]
	(+)-Sophoramine (49)	In vitro	IC50 = 63.07 µM	[14]
Anti-oxidant capacity
ABTS free radical scavenging ability	Chloroform extract of roots	In vitro	EC50 = 1.08 mg/mL	[98]
	Ethyl acetate extract of roots	In vitro	EC50 = 0.55 mg/mL	[98]
	N-butanol extract of roots	In vitro	EC50 = 1.27 mg/mL	[98]
	Ethanol extract of roots	In vitro	EC50 = 3.08 mg/mL	[98]
	Shandougenines A (263)	In vitro	IC50 = 0.532 ± 0.076 mM	[40]
	Shandougenines B (264)	In vitro	IC50 = 0.18 ± 0.032 mM	[40]
	Bolusanthin IV (261)	In vitro	IC50 = 0.3 ± 0.025 mM	[40]
	2-(2′,4′-Dihydroxyphenyl)-5,6-methylenedioxybenzofuran (260)	In vitro	IC50 = 0.726 ± 0.041 mM	[40]
	Shandougenine C (127)	In vitro	IC50 = 0.382 ± 0.055 mM	[40]
	Shandougenine D (128)	In vitro	IC50 = 0.341 ± 0.058 mM	[40]
	Demethylmedicarpin (179)	In vitro	IC50 = 0.503 ± 0.036 mM	[40]
Scavenging of DPPH radicals	Ethyl acetate extract of roots	In vitro	0.5 mg/mL	[98]
	Ethanol extract of roots	In vitro	0.5 mg/mL	[98]
	Chloroform extract of roots	In vitro	0.5 mg/mL	[98]
	N-butanol extract of roots	In vitro	0.5 mg/mL	[98]
	Water extract of aerial parts	In vitro	IC50 = 0.1434 g/L	[17]
	N-butyl alcohol extract of aerial parts	In vitro	IC50 = 0.0754 g/L	[17]
	Ethyl acetate extract of aerial parts	In vitro	IC50 = 0.0693 g/L	[17]
	Dichloromethane of aerial parts	In vitro	IC50 = 0.0494 g/L	[17]
	Petroleum ether extract of aerial parts	In vitro	IC50 = 0.1218 g/L	[17]
	STRP1 (Polysaccharide part)	In vitro	1.0 mg/mL	[95]
	STRP2 (Polysaccharide part)	In vitro	1.0 mg/mL	[95]
	Tonkinensisol (93)	In vitro	IC50 = 0.616 ± 0.021 mM	[40]
	Bolusanthin IV (261)	In vitro	IC50 = 0.502 ± 0.101 mM	[40]
	2-(2′,4′-Dihydroxyphenyl)-5,6-methylenedioxybenzofuran (260)	In vitro	IC50 = 0.527 ± 0.054 mM	[40]
	Shandougenines A (263)	In vitro	IC50 = 1.213 ± 0.101 mM	[40]
	Shandougenines B (264)	In vitro	IC50 = 0.327 ± 0.022 mM	[40]
	WRSP-A2b (Polysaccharide part)	In vitro	IC50 = 19.95 ± 0.25 mg/mL	[99]
	WRSP-A3a (Polysaccharide part)	In vitro	IC50 = 5.99 ± 0.20 mg/mL	[99]
Reducing power	Chloroform extract of roots	In vitro	EC50 = 0.60 mg/mL	[98]
	Ethyl acetate extract of roots	In vitro	EC50 = 0.64 mg/mL	[98]
	N-butanol extract of roots	In vitro	EC50 = 0.51 mg/mL	[98]
	Ethanol extract of roots	In vitro	EC50 = 0.84 mg/mL	[98]
Hydroxyl radical scavenging ability	Chloroform extract of roots	In vitro	EC50 = 1.33 mg/mL	[98]
	Ethyl acetate extract of roots	In vitro	EC50 = 2.80 mg/mL	[98]
	N-butanol extract of roots	In vitro	EC50 = 5.00 mg/mL	[98]
	WRSP-A2b (Polysaccharide part)	In vitro	IC50 = 19.78 ± 0.47 mg/mL	[99]
	WRSP-A3a (Polysaccharide part)	In vitro	IC50 = 8.38 ± 0.18 mg/mL	[99]
Superoxide anion radical scavenging ability	WRSP-A2b (Polysaccharide part)	In vitro	IC50 = 4.24 ± 0.11 mg/mL	[99]
	WRSP-A3a (Polysaccharide part)	In vitro	IC50 = 1.94 ± 0.05 mg/mL	[99]
Toxicity
Respiratory depression, muscle fibrillation, convulsions, spasms, and death	Hydroalcoholic extract from the roots	Mice (i.g.)	LD50 = 9.802 ± 2.0067 g/kg	[100]
Convulsions, hair erection, rapid abdominal contraction and excitement, depression, abdominal breathing and eye closure, and death	(−)- Cytisine (50)	Mice (i.g.)	LD50 = 48.16 mg/kg	[101]
Irritability, hyperactivity, shortness of breath, and convulsions	Water extract of roots	Mice (i.g.)	LD50 = 17.469 g/kg	[102]
	90% Ethanol extract of roots	Mice (i.g.)	LD50 = 27.135 g/kg	[102]
	Alkaloids of roots	Mice (i.g.)	LD50 = 13.399 g/kg	[102]
	Water and 70% Ethanol extract mixture of roots	Mice (i.g.)	MTD = 36 g/kg	[103]
	All-component of of roots	Mice (i.g.)	MTD = 10.68 g/kg	[102]
Slow heartbeat, bent trunk of zebrafish, accelerated movement frequency, and abnormal movement track, Hepato renal, pericardial enlargement, death.	Sophoranone (120)	Zebrafish (p.o.)	LC50 = 22.45 µmol/L	[104]
To cause hepatomegaly	Sophoranone (120)	Zebrafish (p.o.)	3.86 µmol/L	[104]
The zebrafish liver lost transparency and became dark or brown, and liver blood flow was no longer observable	Dealkalized water extract of roots	Zebrafish (p.o.)	LC10 = 1009.1 µg/mL	[105]
	Ethanol sedimentation extract of roots	Zebrafish (p.o.)	LC10 = 4367.6 µg/mL	[105]
	N-Butyl ethanol extract of roots	Zebrafish (p.o.)	MNLC = 700.0 µg/mL	[105]
Slowed heart rate, reduced blood flow, and absence of circulation in the cardiotoxic phenotype, neurotoxic, and presents with behavioral abnormalities, bent trunk.	Sophoranone (120)	Zebrafish (p.o.)	11.59 µmol/L	[104]
Induced pericardial edema and slowed the blood circulation, heart rate lower	Diethyl ether extract of roots	Zebrafish (p.o.)	LC10 = 93.6 µg/mL	[105]
	N-Butyl ethanol extract of roots	Zebrafish (p.o.)	LC10 = 538.3 µg/mL	[105]
Pericardial edema, a misshaped atrium and ventricle as well as reduced number of endothelial cells and cardiomyocytes	Dichloromethane extract of roots	Zebrafish (p.o.)	MNLC = 450.0 µg/mL	[105]
Delayed yolk sac resorption in the hepatotoxic phenotype and Intestinal dysplasia	Sophoranone (120)	Zebrafish (p.o.)	1.29 µmol/L	[104]
To cause renal and pericardial edema	Sophoranone (120)	Zebrafish (p.o.)	15.57 µmol/L	[104]
Other pharmacological activities
Inhibit Pseudomonas aeruginosa	2’,4’,7-Trihydroxy-6,8-bis(3-methyl-2-butenyl) flavanone (259)	In vitro	MIC = 125.0 µg/mL	[16]
	Genistin (115)	In vitro	MIC = 15.6 µg/mL	[16]
Inhibit Bacillus megaterium	2-Methoxy-6-methyl-1,4-benzoquinone (277)	In vitro	MIC = 3.125 µg/mL	[65]
	Xylariphilone (282)	In vitro	MIC = 12.5 µg/mL	[65]
	Xylarphthalide A (283)	In vitro	MIC = 25 µg/mL	[67]
	(−)-5-Carboxylmellein (280)	In vitro	MIC = 25 µg/mL	[67]
	(−)-5-Methylmellein (281)	In vitro	MIC = 25 µg/mL	[67]
Inhibit Escherichia coli	Lanatine A (65)	In vitro	MIC = 1.0 g/L	[26]
	Jussiaeiines A (68)	In vitro	MIC = 3.2 g/L	[26]
	Jussiaeiines B (67)	In vitro	MIC = 0.8 g/L	[26]
	(−)-5-Carboxylmellein (280)	In vitro	MIC = 25 µg/mL	[67]
	21-Acetoxycytochalasin J3 (304)	In vitro	MIC = 12.5 µg/mL	[71]
	2-(2’,4’-Dihydroxy)-5,6-dioxomethylbenzofuran (260)	In vitro	MIC = 31.3 µg/mL	[16]
	Xylarphthalide A (283)	In vitro	MIC = 25 µg/mL	[67]
	(−)-5-Methylmellein (281)	In vitro	MIC = 25 µg/mL	[67]
	6-Heptanoyl-4-methoxy-2H-pyran-2-one (286)	In vitro	MIC = 50 µg/mL	[106]
Inhibit Staphylococcus aureus	3-(4-Hydroxyphenyl)-4-(3-methoxy-4-hydroxyphenyl) -3,4-dehydroquinolizidine (75)	In vitro	MIC = 8.0 g/L	[26]
	Cermizines C (70)	In vitro	MIC = 3.5 g/L	[26]
	Jussiaeiines B (67)	In vitro	MIC = 6.0 g/L	[26]
	Cytochalasin K (311)	In vitro	MIC = 12.5 µg/mL	[65]
	6-Heptanoyl-4-methoxy-2H-pyran-2-one (286)	In vitro	MIC = 50 µg/mL	[106]
	(−) -N-methylcytisine (54)	In vitro	MIC = 12.0 g/L	[26]
	Xylarphthalide A (283)	In vitro	MIC = 25 µg/mL	[67]
	(−)-5-Carboxylmellein (280)	In vitro	MIC = 25 µg/mL	[67]
	(−)-5-Methylmellein (281)	In vitro	MIC = 12.5 µg/mL	[67]
	Cytochalasin K (311)	In vitro	MIC = 12.5 µg/mL	[65]
	2’,4’,7-Trihydroxy-6,8-bis(3-methyl-2-butenyl) flavanone (259)	In vitro	MIC = 62.5 µg/mL	[16]
	Ethyl acetate extract of roots	In vitro	MIC = 0.313 mg/mL	[98]
Inhibit Shigella dysenteriae	Xylarphthalide A (283)	In vitro	MIC = 25 µg/mL	[67]
	(−)-5-Methylmellein (281)	In vitro	MIC = 25 µg/mL	[67]
	(−)-3-Carboxypropyl-7-hydroxyphthalide (293)	In vitro	MIC = 12.5 µg/mL	[69]
Inhibit Proteus vulgaris	Xylareremophil (287)	In vitro	MIC = 25 µg/mL	[68]
	Mairetolide G (291)	In vitro	MIC = 25 µg/mL	[68]
Inhibit Micrococcus luteus	Mairetolide G (291)	In vitro	MIC = 50 µg/mL	[68]
	Mairetolide B (290)	In vitro	MIC = 50 µg/mL	[68]
	Xylareremophil (287)	In vitro	MIC = 25 µg/mL	[68]
Inhibit Micrococcus lysodeikticus	Mairetolide B (290)	In vitro	MIC = 100 µg/ml	[68]
	Mairetolide G (291)	In vitro	MIC = 100 µg/mL	[68]
	Xylareremophil (287)	In vitro	MIC = 100 µg/mL	[68]
Inhibit Bacillus subtilis	(−)-5-Carboxylmellein (280)	In vitro	MIC = 12.5 µg/mL	[67]
	Mairetolide B (290)	In vitro	MIC = 100 µg/mL	[68]
	Mairetolide G (291)	In vitro	MIC = 100 µg/mL	[68]
	Xylarphthalide A (283)	In vitro	MIC = 25 µg/mL	[67]
	(−)-5-Methylmellein (281)	In vitro	MIC = 12.5 µg/mL	[67]
	Xylapeptide A (301)	In vitro	MIC = 12.5 µg/mL	[70]
	(−)-3-Carboxypropyl-7-hydroxyphthalide (293)	In vitro	MIC = 25 µg/mL	[69]
	Xylareremophil (287)	In vitro	MIC = 100 µg/mL	[68]
Inhibit Bacillus anthracis	(−)-5-Carboxylmellein (280)	In vitro	MIC = 25 µg/mL	[67]
	21-Acetoxycytochalasin J3 (304)	In vitro	MIC = 12.5 µg/mL	[71]
Inhibit Alternaria oleracea	Cytochalasin E (310)	In vitro	MIC = 3.125 µg/mL	[71]
	Cytochalasin H (306)	In vitro	MIC = 6.25 µg/mL	[71]
Inhibit Colletotrichum capsici	Cytochalasin E (310)	In vitro	MIC = 1.56 µg/mL	[71]
	Cytochalasin H (306)	In vitro	MIC = 6.25 µg/mL	[71]
Inhibit Pestalotiopsis theae	Cytochalasin E (310)	In vitro	MIC = 1.56 µg/mL	[71]
	Cytochalasin H (306)	In vitro	MIC = 12.5 µg/mL	[71]
Inhibit Enterobacter areogenes	(−)-3-Carboxypropyl-7-hydroxyphthalide methyl ester (294)	In vitro	MIC = 12.5 µg/mL	[69]
	(−)-3-Carboxypropyl-7-hydroxyphthalide (293)	In vitro	MIC = 12.5 µg/mL	[69]
Inhibit Colletotriehum gloeosporioides	Methanol extract of roots	In vitro	EC50 = 1.214 mg/mLMIC = 2.5 mg/mL	[107]
Inhibit Fusarium solani	Methanol extract of roots	In vitro	EC50 = 1.169 mg/mLMIC = 2.5 mg/mL	[107]
Inhibit Ceratocystis paradoxa	Cytochalasin H (306)	In vitro	MIC = 25 µg/mL	[71]
Inhibit Bacillus cereus	Xylapeptide A (301)	In vitro	MIC = 12.5 µg/mL	[70]
Moderate activities against Aphis fabae	Sophtonseedline G (9)	In vivo	LC50 = 38.29 mg/L	[19]
	Matrine (1)	In vivo	LC50 = 18.63 mg/L	[19]
	(−)-N-Formylcytisine (52)	In vivo	LC50 = 23.74 mg/L	[19]
Decreased fasting blood glucose levels	Matrine (1)	In vivo	2.5 mg/kg	[108]
	Ethyl acetate extract of roots	In vivo	60 mg/kg	[33]
alleviate insulin resistance	Ethyl acetate extract of roots	In vivo	60 mg/kg	[33]
	Matrine (1)	In vivo	10 mg/kg	[108]
Inhibit 5-lipoxygenase	50 % (v/v) Ethanol–water mixture	In vitro	IC50 = 1.61 µg/mL	[76]
	Maackiain (168)	In vitro	IC50 = 7.9 µM	[76]
	Sophoranone (120)	In vitro	IC50 = 1.6 µM	[76]
Inhibit thromboxane synthase	50 % (v/v) Ethanol–water mixture	In vitro	IC50 = 5.56 µg/mL	[76]
Inhibit butyrylcholinesterase	Ethanol extract of roots	In vitro	IC50 = 15. 169 µg/mL	[109]

3.2. Anti-Tumor Effect

The anti-tumor effect was one of the most reported activities of S. tonkinensis (Table 2). The chloroform extracts of S. tonkinensis have been discovered its inhibitory effect on cell viability and clonal growth in a dose-dependent manner [87]. Meanwhile, the extracts of S. tonkinensis also have been reported the inhibit ability target the proliferation, adhesion, invasion, and metastasis of mouse melanoma cells [86]. The anticancer activities of compounds have also been reported [38]. The natural compounds from S. tonkinensis exhibited inhibitory effects against different tumor cells. The growth-inhibitory and apoptosis-inducing activities of sophoranone (120) for leukemia U937 cells were investigated [88].

3.3. Hepatoprotective

The components of S. tonkinensis were reported significant protective effects against immune induced liver injury (Table 2). Previous works suggested that the nonalkaloid constituents of S. tonkinensis obviously reduced the alanine aminotransferase (ALT), aspartate aminotransferase (AST) serum, malondialdehyde (MDA), and nitric oxide (NO), as well as increased the superoxide dismutase (SOD) and glutathione (GSH) in mice with immune-induced liver injury [13]. The water extract of S. tonkinensis alleviated hepatic inflammation, liver fibrosis, and hepatic lipids accumulation [91]. Compounds matrine (1) and oxymatrine (4) may be the main components contributing to the lipid-lowering activity of the water extract of S. tonkinensis [91]. Meanwhile, two purified polysaccharide fractions (STRP1 and STRP2) from the roots of S. tonkinensis have been reported to attenuate hepatic oxidative damage in vivo [95]. In addition, some compounds, including sophocarpine (34) from S. tonkinensis have been reported to significantly improve liver injury in mice [93].

3.4. Anti-Viral Activity

The compounds isolated from S. tonkinensis (Table 2), such as 3-(4-Hydroxyphenyl)-4-(3-methoxy-4- hydroxyphenyl)-3,4-dehydroquinolizidine (75), cermizine C (70), jussiaeiine A (68), jussiaeiine B (67), (+)-5α-hydroxyoxysophocarpine (17), (−)-12β- hydroxyoxysophocarpine (18), and (−)-clathrotropine (64), have reported the anti-coxsackie virus B₃ (CVB₃) activities with IC₅₀ values rang of 0.12~6.40 µmol/L [26]. The compounds sophtonseedline B (188) and (−)-trifolirhizin (190) from S. tonkinensis exhibited anti-tobacco mosaic virus (TMV) activities with the inhibition rates of 69.62% and 68.72%, respectively, at a concentration of 100 µg/mL [56]. The other compounds, including sophtonseedline D (23), sophtonseedline F (8), and (−)-N-formylcytisine (52), have been reported to have anti-TMV activities as well [19]. In addition to TMV, compounds (+)-oxysophocarpine (20), (−)-sophocarpine (34), and (−)-13,14-Dehydrosophoridine (16) have showed anti-HBV activities [20].

3.5. Anti-Antioxidant Activities

The antioxidant activities of chloroform, ethyl acetate, N-butanol, and ethanol extracts of S. tonkinensis have been tested (Table 2). The results of DPPH, ABTS, and OH radical scavenging assay showed that all extracts exhibited antioxidant activities [98]. Some compounds from S. tonkinensis exhibited antioxidant activities. It is noteworthy that shandougenine A (263), shandougenine C (127), shandougenine D (128), and 7,4’-Dihydroxyisoflavone (103) showed stronger superoxide anion radical scavenging capacity than the known flavanone luteolin. Shandougenines B (264) showed DPPH free radical and ABTS cation radical scavenging capacity. Shandougenine A (263), shandougenine C (127), shandougenine D (128), bolusanthin IV (261), 2-(2’,4’-Dihydroxyphenyl)-5,6-methylenedioxybenzofuran (260), and demethylmedicarpin (179) were reported parallel ABTS cation radical scavenging capacity to the positive control [40].

3.6. Toxicity

The roots of S. tonkinensis were the famous toxic Miao drug (Table 2) and were named Shan Dou Gen or Guang Dou Gen [4,110]. The aqueous and alcoholic parts of S. tonkinensis caused obvious liver damage in mice, which could result in both the alteration of liver function and the organelle damage of hepatocytes [111,112]. Meanwhile, the extracts of S. tonkinensis exhibited pulmonary toxicity, which may trigger pulmonary cancer, dyspnea, and oxidative stress [113]. The obvious toxicity of sophoranone (120) to zebrafish was mainly characterized as hepatotoxicity, neurotoxicity, cardiovascular toxicity, and nephrotoxicity in the acute toxicity model [104]. Besides, the alkaloids matrine (1), oxymatrine (4), cytisine (50), and sophocarpine (34) of S. tonkinensis showed significant cardiotoxicity [114].

3.7. Other Pharmacological Activities

The extracts of S. tonkinensis have the ability to reduce blood glucose and resist microbial activities (Table 2, Figure 2). Cytochalasin E (310) and H (306) inhibit a variety of plant pathogens [71]. The flavonoid-rich extracts of S. tonkinensis administrated orally to mice significantly increased sensibility to insulin, as well as reduced fasting blood-glucose levels [33]. Moreover, matrine (1) from S. tonkinensis could improve glucose metabolism and increased insulin secretion in diabetic mice, which may be used as a potential drug for diabetes treatment [108]. Methanol extracts of S. tonkinensis exhibited antidiarrheal activities [115]. Moreover, diverse anti-microbial activities of compounds from S. tonkinensis and its endophytic fungi have been reported [26,67].

Figure 2.

The biological activities of S. tonkinensis.

4. Conclusion and Future Prospective

In this review, we provide a detailed summary of the medicinal chemistry, pharmacological activities, and related toxicity research of S. tonkinensis. Structurally, more than 300 compounds have been isolated from S. tonkinensis and its endophytic fungi, including alkaloids, triterpenes and triterpenoid saponins, flavonoids, and so on. Some of the star molecules, including matrine (1) and oxymatrine (4), were documented to exhibit well biological activities [110]. For its pharmacological research, previous studies suggested the usage of S. tonkinensis in the folk treatment of upper respiratory tract infection diseases. It is generally believed that the alkaloid components of S. tonkinensis were the main active substances in the roots of S. tonkinensis [116]. Interestingly, the extracts of S. tonkinensis have been reported for hepatotoxicity, while the other related studies showed the opposite hepatoprotective effects. The in-depth toxicological or structure-activity relationship study may be worth for further research. Moreover, the roots of S. tonkinensis combined with other medicines form dozens of marketing Chinese patent medicine for the treatments of pharyngitis, tonsillitis, and aphthous ulcers [9,10,11]. However, it is rare for its prescription pharmacological research in the treatment of upper respiratory tract diseases, especially works on the drug combination mechanism, which may need to be further developed.

Author Contributions

Resources, J.-J.L.; writing—original draft preparation, J.-J.L., P.-P.Z., and W.Z.; writing—review and editing, D.S., X.Y., Y.-Q.Z., and X.W.; project administration, X.W., X.P., and Y.Z.; funding acquisition, X.P. and Y.Z. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Funding Statement

This research was funded by National Key Research and Development Program of China (2018YFC1708100), the Guiyang Science and Technology Planning Project (Zhu Ke He [2021]43-11), the National Natural Science Foundation of China (32000276), and the Doctoral Startup Funding of Guizhou University of Traditional Chinese Medicine ([2019]-17).