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. 2014 Nov 17;19(11):18850–18880. doi: 10.3390/molecules191118850

A Review of Recent Research Progress on the Astragalus Genus

Xiaoxia Li 1, Lu Qu 1, Yongzhe Dong 1, Lifeng Han 2, Erwei Liu 2, Shiming Fang 2, Yi Zhang 1,*, Tao Wang 1,2,*
Editor: Derek J McPhee
PMCID: PMC6270929  PMID: 25407722

Abstract

Astragalus L., is one of the largest genuses of flowering plants in the Leguminosae family. Roots of A. membranaceus Bge. var. mongholicus (Bge.) Hsiao, A. membranaceus (Fisch.) Bge. and its processed products are listed in the China Pharmacopeia for “qi deficiency” syndrome treatment. However, more and more researches on other species of Astragalus have been conducted recently. We summarize the recent researches of Astragalus species in phytochemistry and pharmacology. More than 200 constituents, including saponins and flavonoids, obtained from 46 species of Astragalus genus were collected for this article. In pharmacological studies, crude extracts of Astragalus, as well as isolated constituents showed anti-inflammatory, immunostimulant, antioxidative, anti-cancer, antidiabetic, cardioprotective, hepatoprotective, and antiviral activities. The goal of this article is to provide an overview of chemical and pharmacological studies on the Astragalus species over the last 10 years, which could be of value to new drug or food supplement research and development.

Keywords: traditional Chinese medicines, Astragalus genus, phytochemistry, biological activities, analyses

1. Introdution

Astragalus L., is one of the largest genuses of flowering plants in the Leguminosae family. As annual or perennial herbs, subshrubs, or shrubs, the plants of Astragalus L. are widely distributed throughout the temperate and arid regions. So far, the genus has been estimated to contain 2000–3000 species and more than 250 taxonomic sections in the world [1,2,3].

Some species of Astragalus in Asia are a source of the economically important natural product, gum tragacanth. In addition, the dried roots of some species grown in East Asia are well used in Traditional Chinese Medicines (TCM) as antiperspirants, diuretics, and tonics for a wide array of diseases such as empyrosis, nephritis, diabetes mellitus, hypertension, cirrhosis, leukaemia, and uterine cancer [4,5]. For example, the root of A. membranceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao (Radix Astragali) is a precious medicine in TCM, which has the properties of intensifying phagocytosis of reticuloendothelial systems, stimulating pituitary-adrenal cortical activity, and restoring depleted red blood cell formation in bone marrow. Also, it is famed for its antimicrobial, antiperspirant, anti-inflammatory, diuretic and tonic effects [6]. Some plants in the Astragalus genus are well known for their pharmacological properties, particularly hepatoprotective, immunostimulant, and antiviral activities [7]. While, the most common use of this genus is as forage for livestock and wild animals, some plants in this genus have been recognized as being used in foods, medicines, cosmetics, as substitutes for tea or coffee, or as sources of vegetable gums.

Saponins, flavonoids, and polysaccharides are believed to be the principle active constituents of Astragalus [8]. It also includes components such as anthraquinones, alkaloids, amino acids, β-sitosterol, and metallic elements.

Here, we have undertaken this review in an effort to summarize the available literatures on these promising bioactive natural products. The review focuses on the phytochemistry, biological activities, and analysis of the Astragalus genus.

2. Phytochemistry

As the summarized results shown in Table 1, Table 2 and Table 3 and Figure 1, Figure 2, Figure 3 and Figure 4, 46 kinds of Astragalus species have been studied for their chemical constituents in recent years [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79]. Also there have been more than 200 constituents obtained from them. Though the studies were for different species, the chemical compositions in Astragalus genus appeared highly uniform, which mainly include terpenoids, flavonoids, and polysaccharides. The interesting compounds, such as terpenoids and flavonoids are always in free or glycosidic forms. Meanwhile, we found that about 40 percent of the composition researches were focused on the aerial parts of Astragalus.

Table 1.

Cycloartane-type triterpenoids from the Astragalus genus (1142).

Compound’s Name Species Resource Parts Used Reference
1 3-O-[β-d-Xylopyranosyl(1→2)-β-d-xylopyranosyl]-6-O-β-d-glucuronopyranosyl-3β,6α,16β,24(S),25-pentahydroxyxyxloartane A. erinaceus whole plant [9]
2 Hareftoside A A. erinaceus whole plant [9]
A. hareftae whole plant [10]
3 Hareftoside B A. hareftae whole plant [10]
4 Cycloquivinoside A A. chivensis aerial parts [11]
5 Astramembranosides B A. membranaceus roots [12]
6 3-O-[α-l-Rhamnopyranosyl(1→2)-β-d-xylopyranosyl]-6-O-β-d-glucopyranosyl-24-O-α-(4'-O-acetoxy)-l-arabinopyranosyl-16-O-acetoxy-3β,6α,16β,24S,25-pentahydroxycycloartane A. wiedemannianus whole plant [13]
7 3-O-[α-l-Rhamnopyranosyl(1→2)-β-d-xylopyranosyl]-6-O-β-d-glucopyranosyl-24-O-α-l-arabinopyranosyl-16-O-acetoxy-3β,6α,16β,24(S),25-pentahydroxycycloartane A. wiedemannianus whole plant [13]
8 Cyclocanthogenin A. unifoliolatus epigeal parts [14]
A. chivensis aerial parts [15]
9 3-O-β-d-Xylopyraosyl-24(S)-cycloart-3β,6α,16β,24,25-pentaol-25-O-β-d-glucopyranoside A. ernestii roots [16]
A. amblolepis roots [17]
10 Cyclocanthoside E A. hareftae whole plant [10]
A. oleifolius lower stem parts [18]
A. caucasicus leave s [19]
11 Cyclochivinoside B A. chivensis aerial parts [15]
12 Cyclochivinoside C A. chivensis aerial parts [20]
13 Caspicuside I A. caspicus roots [6]
14 Oleifoliosides A A. oleifolius lower stem parts [18]
15 Oleifoliosides B A. oleifolius lower stem parts [18]
16 3-O-[α-l-Rhamnopyranosyl(1→2)-α-l-arabinopyranosyl(1→2)-β-d-xylopyranosyl]-6-O-β-d-xylopyranosyl-3β,6α,16β,24(S),25-pentahydroxycycloartane A. aureus whole plant [21]
17 3,6-di-O-β-d-Xylopyranosyl-25-O-β-d-glucopyranosyl-3β,6α,16β,24(S),25-pentahydr-oxycycloartane A. aureus whole plant [21]
18 3-O-β-d-Xylopyranosyl-6,25-di-O-β-d-glucopyranosyl-3β,6α,16β,24(S),25-pentahydroxycycloartane A. aureus whole plant [21]
19 6-O-β-d-Glucopyranosyl-3β,6α,16β,24(S),25-pentahydroxycycloartane A. aureus whole plant [21]
20 3-O-[α-l-Arabinopyranosyl(1→2)-O-3-acetoxy-α-l-arabinopyranosyl]-6-O-β-d-glucopyranosyl-3β,6α,16β,24(S),25-pentahydroxycycloartane A. icmadophilus whole plant [22]
21 3-O-[α-l-Rhamnopyranosyl(1→2)-O-α-l-arabinopyranosyl(1→2)-O-β-d-xylopyranosyl]-6-O-β-d-glucopyranosyl-3β,6α,16β,24(S),25-pentahydroxycycloartane A. icmadophilus whole plant [22]
22 3-O-[α-l-Arabinopyranosyl(1→2)-O-3,4-diacetoxy-α-l-arabinopyranosyl]-6-O-β-d-glucopyranosyl-3β,6α,16β,24(S),25-pentahydroxycycloartane A. icmadophilus whole plant [22]
23 3-O-β-d-Xylopyranosyl-25-O-β-d-glucopyranosyl-3β,6α,16β,24(S),25-pentahydroxycycloartane A. ernestii roots [16]
A. amblolepis roots [17]
24 3-O-β-d-Xylopyranosyl-16-O-β-d-glucopyranosyl-3β,6α,16β,24(S),25-pentahydroxycycloartane A. amblolepis roots [17]
25 3-O-[β-d-Glucuronopyranosyl(1→2)-β-d-xylopyranosyl]-25-O-β-d-glucopyranosyl-3β,6α,16β,24(S),25-pentahydroxy-cycloartane A. amblolepis roots [17]
26 3-O-β-d-Xylopyranosyl-24,25-di-O-β-d-glucopyranosyl-3β,6α,16β,24(S),25-pentahydr-oxy-cycloartane A. amblolepis roots [17]
27 6-O-α-l-Rhamnopyranosyl-16,24-di-O-β-d-glucopyranosyl-3β,6α,16β,24(S),25-pentahydroxy cycloartane A. amblolepis roots [17]
28 6-O-α-l-Rhamnopyranosyl-16,25-di-O-β-d-glucopyranosyl-3β,6α,16β,24(S),25-pentahydroxy cycloartane A. amblolepis roots [17]
29 Cicerosides A A. cicer aerial parts [7]
30 Cicerosides B A. cicer aerial parts [7]
31 Cycloascidoside A. ernestii roots [16]
A. amblolepis roots [17]
A. mucidus aerial parts [23]
32 Eremophiloside A A. eremophilus aerial parts [24]
33 Eremophiloside B A. eremophilus aerial parts [24]
34 Cycloascidoside A A. mucidus aerial parts [25]
35 Cyclounifoliside C A. unifoliolatus epigeal parts [14]
A. chivensis aerial parts [15]
36 3-O-[α-l-Arabinopyranosyl(1→2)-β-d-glucopyranosyl]-24-O-β-d-glucopyranosyl-3β,6α,16β,24(R),25-pentahydroxycycloartane A. stereocalyx roots [26]
37 3-O-[α-l-Arabinopyranosyl(1→2)-β-d-glucopyranosyl]-16-O-β-d-glucopyranosyl-3β,6α,16β,24(R),25-pentahydroxycycloartane A. stereocalyx roots [26]
38 3-O-{α-l-Rhamnopyranosyl(1→4)-[α-l-arabinopyranosyl(1→2)]-β-d-glucopyranosyl}-3β,6α,16β,24(R),25-pentahydroxycycloartane A. stereocalyx roots [26]
39 3-O-[α-l-Arabinopyranosyl(1→2)-β-d-xylopyranosyl]-16-O-β-d-glucopyranosyl-3β,6α,16β,20(S),24(R),25-hexahydroxycycloartane A. stereocalyx roots [26]
A. halicacabus whole plant [27]
A. campylosema Boiss. subsp. campylosema roots [28]
40 3-O-[α-l-Arabinopyranosyl(1→2)-β-d-xylopyranosyl]-3β,6α,16β,20(S),24(R),25-hexahydroxycycloartane A. stereocalyx roots [26]
41 3-O-[α-l-Arabinopyranosyl(1→2)-β-d-glucopyranosyl]-3β,6α,16β,20(S),24(R),25-hexahdroxycycloartane A. stereocalyx roots [26]
42 3-O-β-d-Xylopyranosyl-3β,6α,16β,20(S),24(R),25-hexahydroxycycloartane A. schottianus roots [29]
43 Cyclomacrogenin B A. macropus roots [30,31]
44 Cyclomacroside E A. macropus roots [32]
45 Cyclomacroside B A. macropus roots [33]
46 Cyclomacroside D A. macropus roots [31]
47 Mongholicoside A A. membranace (Fisch.) Bge. var. mongholicus (Bge.) aerial parts [34]
48 Mongholicoside B A. membranace (Fisch.) Bge. var. mongholicus (Bge.) aerial parts [34]
49 Askendoside K A. taschkendicus roots [35]
50 Askendoside H A. taschkendicus roots [36]
51 Cycloorbicoside D A. orbiculatus aerial parts [37,38]
52 Cycloorbigenin C A. taschkendicus roots [35,36]
A. orbiculatus aerial parts [37,38]
53 Eremophiloside C A. eremophilus aerial parts [24]
54 Eremophiloside D A. eremophilus aerial parts [24]
55 Bicusposide F A. bicuspis whole plant [39]
56 Bicusposide E A. bicuspis whole plant [39]
57 Kahiricoside II A. kahiricus aerial parts [40]
58 Kahiricoside III A. kahiricus aerial parts [40]
59 Kahiricoside IV A. kahiricus aerial parts [40]
60 Kahiricoside V A. kahiricus aerial parts [40]
61 Secomacrogenin B A. macropus roots [41]
62 Orbigenin A. orbiculatus aerial parts [37,38]
63 Orbicoside A. orbiculatus aerial parts [37,38]
64 16-O-β-d-Glucopyranosyl-3β,6α,16β,25-tetrahydroxy-20(R),24(S)-epoxycycloartane A. hareftae whole plant [10]
65 Astramembranosides A A. membranaceus roots [12]
66 Cyclosiversioside F A. oldenburgii aerial parts [42]
67 Astraverrucin IV A. oldenburgii aerial parts [42]
68 Astragaloside VII A. oldenburgii aerial parts [42]
A. dissectus roots and stems [43]
A. membranace (Fisch.) Bge. var. mongholicus (Bge.) hisao roots [44]
69 3-O-[α-l-Rhamnopyranosyl(1→2)-β-d-glucopyranosyl]-16-O-hydroxyacetoxy-3β,6α,16β,25-tetrahydroxy-20(R),24(S)-epoxycycloartane A. angustifolius whole plant [45]
70 CyclolehmanosideC A. lehmannianus aerial parts [46]
71 Armatoside II A. armatus roots [47]
72 Acetylastragaloside I A. baibutensis roots [48]
73 Astragaloside III A. illyricus roots [49]
A. membracaceus roots [50]
74 Cyclounifolioside B A. illyricus roots [49]
75 Astraverrucin I A. illyricus roots [49]
76 Trigonoside II A. armatus roots [47]
A. halicacabus whole plant [27]
77 Trojanoside H A. stereocalyx roots [26]
A. armatus roots [47]
78 Armatoside I A. armatus roots [47]
79 Cyclosieversioside A A. sieversianus roots [51]
80 Cyclosieversioside G A. sieversianus roots [51]
81 Cyclosieversioside H A. sieversianus roots [51]
82 3-O-[α-l-Rhamnopyranosyl(1→2)-β-d-glucopyranosyl]-25-O-β-d-glucopyranosyl-20(R),24(S)-epoxy-3β,6α,16β,25-tetrahydroxycycloartane A. wiedemannianus whole plant [13]
83 Cyclosiversigenin A. orbiculatus aerial parts [52]
84 Brachyoside B A. wiedemannianus whole plant [13]
85 Astragaloside II A. hareftae
A. wiedemannianus
whole plant
whole plant
[10]
[13]
86 Astrasieversianin X A. wiedemannianus whole plant [13]
87 Astrasieversianin IX A. sieversianus roots [51]
88 Caspicuside II A. caspicus roots [6]
89 Baibutoside A. baibutensis roots [48]
90 Astragalosides I A. baibutensis roots [48]
A. sieversianus roots [51]
91 Astraverrucin VII A. verrucosus aerial parts [53]
92 Cycloaraloside D (Peregrinoside II) A. verrucosus aerial parts [53]
A. angustifolius whole plant [45]
93 Cycloaraloside C (Astrailienin A) A. verrucosus aerial parts [53]
94 (20R,24S)-3-O-[α-l-Arabinopyranosyl(1→2)-β-d-xylopyranosyl]-20,24-epoxy-16-O-β-d-glucopyranosyl-3β,6α,16β,25-tetrahydroxycycloartane A. halicacabus whole plant [27]
95 3-O-[α-l-Arabinopyranosyl(1→2)-β-d-xylopyranosyl]-25-O-β-d-glucopyranosyl-3β,6α,16β,25-tetrahydroxy-20(R),24(S)-epoxycycloartane A. campylosema Boiss. subsp. campylosema roots [28]
96 3-O-[α-l-Arabinopyranosyl(1→2)-O-3-acetoxy-α-l-arabinopyranosyl]-6-O-β-d-glucopyranosyl-3β,6α,16β,25-tetrahydroxy-20(R),24(S)-epoxycycloartane A. icmadophilus whole plant [22]
97 20(R),24(S)-Epoxycycloartane-3β,6α,16β,25-tetraol-3-β-O-d-(2-O-acetyl)-xylopyranoside A. bicuspis whole plant [39]
98 3-O-[α-l-Rhamnopyranosyl(1→2)-β-d-glucopyranosyl]-16-O-hydroxyacetoxy-3β,6α,16β,23α,25-pentahydroxy-20(R),24(S)-epoxycycloartane A. angustifolius whole plant [45]
99 3-O-[α-l-Rhamnopyranosyl(1→2)-β-d-glucopyranosyl]-3β,6α,25-trihydroxy-20(R),24(S)-epoxycycloartane-16-one A. angustifolius whole plant [45]
100 3-O-[α-l-Arabinopyranosyl(1→2)-β-d-xylopyranosyl]-3β,6α,16β,23α,25-pentahydroxy-20(R),24(S)-epoxycycloartane A. campylosema Boiss. subsp. campylosema roots [28]
101 3-O-[α-l-Arabinopyranosyl(1→2)-β-d-xylopyranosyl]-16-O-hydroxyacetoxy-23-O-acetoxy-3β,6α,16β,23α,25-pentahydroxy-20(R),24(S)-epoxycycloartane A. campylosema Boiss. subsp. campylosema roots [28]
102 Cyclogaleginoside E A. galegiformis stems [54]
103 Cycloascualoside D A. galegiformis stems [55]
104 Cyclogaleginoside C A. galegiformis stems [55]
105 Cyclogalegigenin A. galegiformis stems [54,55,57]
A. caucasicus leaves [56]
106 Cycloascauloside A A. caucasicus leaves [56]
107 Cyclogaleginoside D A. galegiformis stems [57]
108 20(R),25-Epoxy-3-O-β-d-xylopyranosyl-24-O-β-d-glucopyranosyl-3β,6α,16β,24α-tetrahydroxycycloartane A. schottianus roots [29]
109 20(R),25-Epoxy-3-O-[-β-d-glucopyranosyl(1→2)]-β-d-xylopyranosyl-24-O-β-d-glucopyranosyl-3-β,6α,16β,24α-tetrahydroxycycloartane A. schottianus roots [29]
110 Hareftoside C A. hareftae whole plant [10]
111 Cylotrisectoside A. dissectus roots and stems [43]
112 3-O-[α-l-Arabinopyranosyl(1→2)-β-d-xylopyranosyl]-3β,6α,16β,24α-tetrahydroxy-20(R),25-epoxycycloartane A. aureus whole plant [21]
113 6-O-β-d-Glucopyranosyl-3β,6α,16β,24α-tetrahydroxy-20(R),25-epoxycycloartane A. aureus whole plant [21]
114 6-O-β-d-Xylopyranosyl-3β,6α,16β,24α-tetrahydroxy-20(R),25-epoxycycloartane A. aureus whole plant [21]
115 3-O-[α-l-Arabinopyranosyl(1→2)-O-β-d-xylopyranosyl]-6-O-β-d-glucopyranosyl-3β,6α,16β,24α-tetrahydroxy-20(R),25-epoxycycloartane A. icmadophilus whole plant [22]
116 3-O-[α-l-Rhamnopyranosyl(1→2)-O-α-l-arabinopyranosyl(1→2)-O-β-d-xylopyranosyl]-6-O-β-d-glucopyranosyl-3β,6α,16β,24α-tetrahydroxy-20(R),25-epoxycycloartane A. icmadophilus whole plant [22]
117 Eremophiloside G A. eremophilus aerial parts [24]
118 Eremophiloside E A. eremophilus aerial parts [24]
119 Eremophiloside F A. eremophilus aerial parts [24]
120 Eremophiloside H A. eremophilus aerial parts [24]
121 Eremophiloside I A. eremophilus aerial parts [24]
122 Eremophiloside J A. eremophilus aerial parts [24]
123 Eremophiloside K A. eremophilus aerial parts [24]
124 Cyclomacroside A A. macropus roots [58]
125 Bicusposide D A. bicuspis whole plant [39]
126 3-O-[α-l-Arabinopyranosyl(1→2)-β-d-xylopyranosyl]-3β,6α,23α,25-tetrahydroxy-20(R),24(R)-16β,24;20,24-diepoxycycloartane A. campylosema Boiss. subsp. campylosema roots [28]
127 Dihydrocycloorbigenin A A. orbiculatus aerial parts [38]
128 Cycloorbigenin A. orbiculatus aerial parts [38]
129 Cycloorbigenin B A. orbiculatus aerial parts [38]
130 Cycloorbicoside A A. orbiculatus aerial parts [38]
131 Cycloorbicoside B A. orbiculatus aerial parts [38]
132 Cycloorbicoside C A. orbiculatus aerial parts [38]
133 Cycloorbicoside G A. orbiculatus aerial parts [38]
134 Tomentoside I A. tomentosus aerial parts [59]
135 Deacetyltomentoside I A. tomentosus aerial parts [59]
136 Tomentoside III A. tomentosus aerial parts [59]
137 Tomentoside IV A. tomentosus aerial parts [59]
138 Huangqiyenin E A. membranaceus leaves [60]
139 Huangqiyenin F A. membranaceus leaves [60]
140 Huangqiyegenin III A. membranaceus leaves [60]
141 Huangqiyegenin IV A. membranaceus leaves [60]
142 Trideacetylhuangqiyegenin III A. membranaceus leaves [60]

Table 2.

Oleanane triterpenoids from the Astragalus genus (143161).

Compound’s Name Species Resource Parts Used Reference
143 3-O-[α-l-Rhamnopyranosyl(1→2)-β-d-xylopyranosyl(1→2)-β-d-glucuronopyranosyl]-21-O-α-l-rhamnopyranosyl-3β,21β,22α,24-tetrahydroxyolean-12-ene A. tauricolus whole plant [61]
144 3-O-[α-l-Rhamnopyranosyl(1→2)-β-d-glucopyranosyl(1→2)-β-d-glucuronopyranosyl]-21-O-α-l-rhamnopyranosyl-3β,21β,22α,24-tetrahydroxyolean-12-ene A. tauricolus whole plant [61]
145 3-O-[α-l-Rhamnopyranosyl(1→2)-β-d-glucopyranosyl(1→2)-β-d-glucuronopyranosyl]-3β,21β,22α,24,29-pentahydroxyolean-12-ene A. tauricolus whole plant [61]
146 3-O-[α-l-Rhamnopyranosyl(1→2)-β-d-xylopyranosyl(1→2)-β-d-glucuronopyranosyl]-22-O-α-l-rhamnopyranosyl-3β,22β,24-trihydroxyolean-12-ene A. tauricolus whole plant [61]
147 3-O-[α-l-Rhamnopyranosyl(1→2)-β-d-xylopyranosyl(1→2)-β-d-glucuronopyranosyl]-3β,21β,22α,24,29-pentahydroxyolean-12-ene A. angustifolius whole plant [45]
148 3-O-[α-l-Rhamnopyranosyl(1→2)-β-d-xylopyranosyl(1→2)-β-d-glucuronopyranosyl]-3β,22β,24-trihydroxyolean-12-en-29-oic acid A. angustifolius whole plant [45]
149 3-O-[α-l-Rhamnopyranosyl(1→2)-β-d-xylopyranosyl(1→2)-β-d-glucuronopyranosyl]-22-O-α-l-arabinopyranosyl-3β,22β,24-trihydroxyolean-12-ene A. angustifolius whole plant [45]
150 29- O-β-d-Glucopyranosyl-3β,22β,24,29-tetrahydroxy-olean-12-ene A. angustifolius whole plant [45]
151 Soyasapogenol B A. caprinus roots [62]
A. bicuspis whole plant [39]
152 3-O-[β-d-Xylopyranosyl(1→2)-O-β-d-glucopyranosyl(1→2)-O-β-d-glucuronopyranosyl] soyasapogenol B A. hareftae whole plant [10]
153 3-O-α-l-Rhamnopyranosyl(1→2)-β-d-glucuronopyranosyl]-22-O-β-d-apiofuranosyl soyasapogenol B A. caprinus roots [62]
154 3-O-[α-l-Rhamnopyranosyl(1→2)-β-d-xylopyranosyl(1→2)-β-d-glucuronopyranosyl]-29-O-β-d-glucopyranosyl-3β,22β,24-trihydroxyolean-12-en-29-oic acid A. tauricolus whole plant [61]
155 3-O-[α-l-Rhamnopyranosyl(1→2)-β-d-glucopyranosyl(1→2)-β-d-glucuronopyranosyl]-29-O-β-d-glucopyranosyl-3β,22β,24,-trihydroxyolean-12-en-29-oic acid A. tauricolus whole plant [61]
156 3-O-[β-d-Xylopyranosyl(1→2)-β-d-glucuronopyranosyl]-29-O-β-d-glucopyranosyl-3β,22β,24,-trihydroxyolean-12-en-29-oic acid A. tauricolus whole plant [61]
157 3-O-[α-l-Rhamnopyranosyl-(1→2)-β-d-glucopyranosyl-(1→2)-β-d-glucuronopyranosyl]-29-O-β-d-glucopyranosyl-3β,22β,24,29-tetrahydroxyolean-12-ene A. tauricolus whole plant [61]
158 3-O-[α-l-Rhamnopyranosyl-(1→2)-β-d-glucopyranosyl-(1→2)-β-d-glucuronopyranosyl]-3β,24-dihydroxyolean-12-ene-22-oxo-29-oic acid A. tauricolus whole plant [61]
159 3-O-[β-d-Glucopyranosyl-(1→2)-β-d-glucuronopyranosyl]-29-O-β-d-glucopyranosyl-3β,22β,24,-trihydroxyolean-12-en-29-oic acid A. tauricolus whole plant [61]
160 Azukisaponin V A. cruciatus aerial parts and roots [2]
A. hareftae whole plant [10]
161 Astragaloside VIII A. flavescens roots [4]
A. cruciatus aerial parts and roots [2]
A. hareftae whole plant [10]
A. wiedemannianus whole plant [13]
A. icmadophilus whole plant [22]
A. angustifolius whole plant [45]

Table 3.

Flavonoids from the Astragalus genus (162224).

Compound’s Name Species Resource Parts Used Reference
162 Narcissin A. cruciatus aerial parts and roots [2]
A. icmadophilus whole plant [22]
A. corniculatus aerial parts [63]
163 Nicotiflorin A. cruciatus aerial parts and roots [2]
A. verrucosus aerial parts [53]
A. asper aerial parts [64]
164 Kaempferol 3-O-α-l-rhamnopyranosyl(1→4)-α-l-rhamnopyranosyl(1→6)-β-d-glucopyranoside A. cruciatus aerial parts and roots [2]
165 Microcephalin I A. microcephalus leaves [65]
166 Microcephalin II A. microcephalus leaves [65]
167 Kaempferol-3-O-α-l-rhamnoxyloside A. microcephalus leaves [66]
168 Quercetin A. asper aerial parts [64]
A. corniculatus aerial parts [63]
169 Quercimeritrin A. asper aerial parts [64]
170 Rutin A. cruciatus aerial parts and roots [2]
A. verrucosus aerial parts [53]
A. asper aerial parts [64]
171 Quercetin-3-O-β-d-glucopyranoside A. corniculatus aerial parts [63]
A. asper aerial parts [64]
172 Kaempferol A. corniculatus aerial parts [63]
A. asper aerial parts [64]
A. galegiformis leaves [67]
173 Kaempferol-3-glucoside (Astragalin) A. asper aerial parts [64]
A. galegiformis leaves [67]
A. hamosus aerial parts [68]
174 Isorhamnetin A. corniculatus aerial parts [63]
A. hamosus aerial parts [68]
175 Quercetin-3-O-galactoside A. corniculatus aerial parts [63]
176 Quercetin-3,7-di-β-d-glucopyranoside-4'-O-α-l-rhamnopyranoside A. bombycinus whole plant [8]
177 Quercetin-3,7-di-O-β-d-glucopyranoside A. bombycinus whole plant [8]
178 Quercetin 3-O-β-d-glucopyranoside-7-O-α-l-rhamnopyranoside A. bombycinus whole plant [8]
179 Flagaloside C A. galegiformis leaves [67]
180 Flagaloside D A. galegiformis leaves [67]
181 Kaempferol 3-O-robinobioside A. verrucosus aerial parts [53]
182 7-O-Methyl-kaempferol-4'-β-d-galactopyranoside A. hamosus aerial parts [68]
183 5,7,2'-Trihydroxyflavone A. cruciatus aerial parts and roots [2]
184 Salvigenin A. propinquus roots [69]
185 Apigenin A. bombycinus whole plant [8]
A. verrucosus aerial parts [53]
A. propinquus roots [69]
186 Luteolin A. bombycinus whole plant [8]
A. propinquus roots [69]
187 7-Hydroxyflavone A. microcephalus leaves [66]
188 5,2',4'-Trihydroxy-flavone-8-C-l-arabinopyranoside-7-O-β-d-glucopyranoside A. bombycinus whole plant [8]
189 Apigenin 7-O-β-d-glucopyranoside A. bombycinus whole plant [8]
190 Apigenin 7-O-gentobioside A. bombycinus whole plant [8]
191 Luteolin 7-O-β-d-glucopyranoside A. bombycinus whole plant [8]
192 Apigenin-8-C-glucoside (Vitexin) A. corniculatus aerial parts [63]
193 Luteolin-8-C-glucoside (Orientin) A. corniculatus aerial parts [63]
194 Eriodyctiol-7-O-glucoside A. corniculatus aerial parts [63]
195 Liquiritigenin A. membranaceus roots [70]
196 Odoration A. membranaceus var. mongholicus roots [71]
197 Odoration-7-O-β-d-glucopyranoside A. mongholicus aerial parts [72]
198 Calycosin-7-O-β-d-glucopyranoside A. ernestii roots [16]
A. membranaceus roots [70]
A. membranaceus var. mongholicus roots [71]
A. mongholicus roots [73]
A. membranaceus roots [74]
199 Calycosin A. membranaceus roots [70]
A. membranaceus var. mongholicus roots [71]
A. mongholicus roots [72]
A. membranaceus roots [74]
200 Ononin A. membracaceus roots [50]
A. verrucosus aerial parts [53]
A. microcephalus leaves [65]
A. mongholicus roots [73]
A. membranaceus roots [74]
201 Formononetin A. membranaceus roots [70]
A. mongholicus roots [72]
202 Calycosin 7-O-β-d-{6''-[(E)-but-2-enoyl]}-glucoside A. membracaceus roots [50]
203 Pratensein 7-O-β-d-glucopyranoside A. membranaceus var. mongholicus roots [71]
204 Pratensein A. verrucosus aerial parts [53]
A. membranaceus var. mongholicus roots [71]
205 Calycosin 7-O-β-d-(6''-acetyl)-glucoside A. membracaceus roots [50]
206 6ꞌꞌ-Acetylononin A. membracaceus roots [50]
207 Ammopiptanoside A A. membracaceus roots [50]
208 7,5'-Dihydroxy-3'-methoxy-isoflavone-7-O-β-d-glucopyranoside A. membranaceus var. mongholicus roots [71]
209 7-Hydroxy-3',5'-dimethoxyisoflavone A. peregrinus aerial parts [75]
210 Daidzein A. bombycinus whole plant [8]
A. verrucosus aerial parts [53]
211 (3R,4R)-3-(2-Hydroxy-3,4-dimethoxy-phenyl)-chroman-4,7-diol-7-O-β-d-glucopyranoside A. membranaceus roots [74]
212 (3R)-8,2'-Dihydroxy-7,4'-dimethoxyisoflavane A. membranaceus roots [76]
213 (R)-3-(5-Hydroxy-2,3,4-trimethoxyphenyl)-chroman-7-ol A. membracaceus roots [50]
214 Isomucronulatol 7-O-β-glucoside A. membracaceus roots [50]
A. membranaceus roots [70]
215 Isomucronulatol A. membracaceus roots [50]
A. membranaceus roots [70]
216 (–)-Methylinissolin 3-O-β-d-(6'-acetyl)-glucoside A. membracaceus roots [50]
217 (–)-Methylinissolin 3-O-β-d-{6'-[(E)-but-2-enoyl]}-glucoside A. membracaceus roots [50]
218 (–)-Methylinissolin 3-O-β-d-glucoside A. membracaceus roots [50]
219 Licoagroside D A. membracaceus roots [50]
220 Vesticarpan A. membracaceus roots [50]
221 (–)-Methylinissolin A. membracaceus roots [50]
222 Sulfuretin A. microcephalus leaves [66]
223 Isoliquiritigenin A. membranaceus roots [70]
224 Pendulone A. membracaceus roots [50]

Figure 1.

Figure 1

Figure 1

Figure 1

The structures of compounds 1142 obtained from the Astragalus genus.

Figure 2.

Figure 2

The structures of compounds 143161 obtained from the Astragalus genus.

Figure 3.

Figure 3

Figure 3

The structures of compounds 162224 obtained from the Astragalus genus.

Figure 4.

Figure 4

The structures of compounds 225231 obtained from the Astragalus genus.

2.1. Saponins

Saponin is the major chemical constituent type in the Astragalus genus. Cycloartane- and oleanane-type saponins from it showed interesting biological properties.

2.1.1. Cycloartane-Type Saponins

The plants of Astragalus genus have been proved to be the richest source of cycloartane-type saponins, possessing cardiotonic, hypocholesteremic, anti-depressive and antiblastic actions as well as immunomodulatory activity [7]. This promising spectrum of pharmacological effects led researchers to further search for structurally interesting cycloartane glycosides from the genus. Until now, more than 140 kinds of cycloartane-type saponins have been identified (Table 1, Figure 1). The main substituted sugar groups in them are β-d-glucopyranosyl (Glc), β-d-xylopyranosyl (Xyl), α-l-rhamnopyranosyl (Rha), or α-l-arabinopyranosyl (Ara). Additionally, β-d-glucuronopyranosyl (GlcA), β-d-fucopyranosyl (Fuc), β-d-apiofuranosyl (Api) and acetyl (Ac) groups were also found in cycloartane glycosides obtained from the Astragalus genus.

Commonly, the aglycon of cycloartane-type saponins such as 162 possess an acyclic side chain at the 17-position. For the 17-acyclic side chain substituted cycloartane-type saponins, obtained from the Astragalus genus, the 24-position is often replaced by oxygen containing groups, and there are two kinds of steric configuration constituents with 24S (128) [6,9,10,11,12,13,14,15,16,17,18,19,20,21,22] or 24R (2948) [7,14,15,16,17,23,24,25,26,27,28,29,30,31,32,33,34].

If there are hydroxyls substituted in the 20- and 24-positions, it is easy to dehydrate and form a furan ring between them. So the 20,24-epoxycycloartane-type saponins like 64107 are derived from secondary metabolic pathways. Also there are usually 20R, 24S (64101) [6,10,12,13,22,26,27,28,39,42,43,44,45,46,47,48,49,50,51,52,53] or 20S,24R (102107) [54,55,56,57] steric configurations.

Some uncommon cycloartane triterpene glycosides such as 108142 were also isolated from the Astragalus genus. For example, the eremophilosides E–I (118121) [24] are 16β,23-epoxycycloartanes. Among them, eremophilosides E (118) and F (119) are characterized as having an unusual loss of a four carbon side chain from C-24 to C-27 and a six-membered lactone ring between C-23 and C-16, while eremophilosides G–I (117, 120 and 121) show an unusual modification of the cyclic side chain. On the other hand, eremophilosides J (122) and K (123) are 16β,23; 22β,25-diepoxycycloartanes, which are highly oxygenated cycloartane triterpenes.

In the study of isoprenoid plants of the Astragalus genus like A. orbiculatus, researchers found several derivatives of 16β,23,16α,24-diepoxycycloartane (127133) from its aerial parts [38], which have been found only in this species.

Additionally, some cycloartane-type saponin ethylacetals (134142) were identified from the extracts of Astragalus genus [59,60].

2.1.2. Oleanane-Type Saponins

Apart from the cycloartane triterpene glycosides, many oleanane-type saponins shown in Table 2 were also isolated and identified from the Astragalus genus. Structure characterizations of this kind of saponin indicated they were substituted with a β-hydroxymethyl, instead of methyl in the 23-position.

2.2. Flavonoids

Just like many other herbs, Astragalus genus plants are also a rich source of flavonoids. The flavonoids in this genus include flavonols (162182) [2,8,22,63,64,65,66,67,68], flavones (183193) [2,8,53,63,66,69], flavonones (194195) [65,70] and isoflavonoids (196221) [16,50,53,65,66,70,71,72,73,74,75], which have many kinds of bioactivities.

In addition, some special flavonoids, such as sulfuretin (222) [65], isoliquiritigenin (223) [8], and pendulone (224) [50] have been obtained.

2.3. Polysaccharides

Yao et al., analyzed the monosaccharide compositions for the Radix Astragali polysaccharide by gas chromatography, and identified the monosaccharides in it as arabinose, fructose, glucose, and mannose. Their molar ratios calculated according to the equation was 1:10.309:24.667:0.462 [77]. Xu et al., isolated and purified two kinds of Astragalus polysaccharides (APS) (APS-I and APS-II) from the water extract of Radix Astragali. The research indicated that APS-I consisted of arabinose and glucose in the molar ratio of 1:3.45, with molecular weight 1,699,100 Da; meanwhile, APS-II consisted of rhamnose, arabinose and glucose in a molar ratio of 1:6.25:17.86 with molecular weight 1,197,600 Da [78].

2.4. Others

Undoubtedly, apart from the compounds mentioned above, others chemical constituents also exist in the Astragalus genus, including caffeic acid (225) [64], chlorogenic acid (226) [64], gentisin (227) [44], emodin (228) [44], 3-O-[β-d-apiofuranosyl(1→2)-O-β-d-glucopyranosyl] maltol (229) [27], β-sitosterol (230) [16,30,51,73] and β-sitosterol β-d-glycopyranoside (231) [51].

Certainly, some other constituents, such as amino acids and proteins have been obtained from Astragalus genus plants, which were also found to be rich in metal elements like Ca, Mg, Fe, Cu, Zn, and Mn [79].

3. Biological Activities of the Astragalus Genus

A. membranaceus, A. mongholicus and A. complanatus have been mainly used in folk medicine for their anti-inflammatory, immunostimulant, antioxidative, anti-cancer, antidiabetic, cardioprotective, hepatoprotective, and antiviral properties in recent years. The active constituents for the above-mentioned effects were proved to be polysaccharides, saponins, and flavonoids.

3.1. Anti-Inflammatory Activity

Astragalus extract, along with its polysaccharides, and saponins showed anti-inflammatory activity both in vitro and in vivo. Kim et al., found that the extract of A. membranaceus not only improved the atopic dermatitis skin lesions in 1-chloro-2,4-dinitrobenzene-induced mice as well as restoring nuclear factor-κB expression markedly, but also suppressed the expression of Th2 cytokines and significantly decreased the TNF-α level. They then figured out that A. membranaceus was effective for treating atopic dermatitis by regulating cytokines [80]. Ryu et al., verified that Astragali Radix had an anti-inflammatory effect mediated by the MKP-1-dependent inactivation of p38 and Erk1/2 and the inhibition of NFkappaB-mediated transcription [81]. As the main composition of Astragalus, Astragalus polysaccharides can effectively ameliorate the palmitate-induced pro-inflammatory responses in RAW264.7 cells through AMPK activity [82]. They also showed anti-inflammatory activity, along with structure protective properties for lipopolysaccharide-infected Caco2 cells [83]. On the other hand, the anti-inflammatory activity of saponins was also studied. The results, of agroastragalosides I, II, isoastragaloside II, and astragaloside IV showed the ability to inhibit lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophages [84]. Meanwhile, astragaloside IV was shown to be a promising natural product with both healing and anti-scar effects for wound treatment [85], could be used as a novel anti-inflammatory agent, and attenuated diabetic nephropathy in rats by inhibiting NF-κB mediated inflammatory gene expression [86].

3.2. Immunoregulatory Activity

Qin et al., studied the effect of A. membranaceus extract on the advanced glycation end product-induced inflammatory response in α-1 macrophages. The results suggested that it could inhibit advanced glycation end product-induced inflammatory cytokine production to down-regulate macrophage-mediated inflammation via p38 mitogen-activated protein kinase and nuclear factor (NF)-κB signaling pathways [87]. Du et al., investigated the potential adjuvant effect of Astragalus polysaccharides on humoral and cellular immune responses to hepatitis B subunit vaccine. The result suggested that it was a potent adjuvant for the hepatitis B subunit vaccine and could enhance both humoral and cellular immune responses via activation of the Toll-like receptor 4 signaling pathway and inhibit the expression of transforming growth factor β [88]. Nalbantsoy et al., studied the in vivo effects of two Astragalus saponins on the immune response cytokines by using six to eight week old male Swiss albino mice. The results showed that astragaloside VII and macrophyllosaponin B showed powerful immunoregulatory effects without stimulation of inflammatory cytokines in mice, and had no significant effect on the inflammatory cellular targets in vitro [89]. Huang et al. found that astragaloside IV could rival the suppressing effect of high mobility group box 1 protein on immune function of regulatory T cells with dose-dependent in vitro [90].

3.3. Anti-Tumor Activity

Recently, many active screening results have indicated that Astragalus polysaccharides, saponins, and flavonoids have anti-tumor activities. Tian et al., investigated the adjunct anticancer effect of Astragalus polysaccharides on H22 tumor-bearing mice, and found that it exerted a synergistic anti-tumor effect with adriamycin and to alleviate the decrease in the sizes of the spleen and thymus induced by adriamycin in H22 tumor-bearing mice [91]. As a potential anti-tumor saponin, astragaloside IV could down-regulate Vav3.1 expression in a dose- and time-dependent manner [92]. Meanwhile, astragaloside II could down regulate the expression of the P-glycoprotein and mdr1 gene, which suggested it was a potent multidrug resistance reversal agent and could be a potential adjunctive agent for hepatic cancer chemotherapy [93]. On the other hand, the experimental data showed that the total flavonoids of Astragalus and calycosin could inhibit the proliferation of K562 cells [94].

3.4. Cardioprotection Activity

Ma et al., studied the cardio protective effect of the extract of Radix Astragali on myocardial ischemia and its underlying mechanisms in ROS-mediated signaling cascade in vivo by using different rat models, and drew the conclusion that the cardio protection was due to a protection of tissue structure and a decrease in serum markers of the ischemic injury [95]. The total flavonoids of A. mongholicus are the active components, which benefit cardiovascular disease attributed to the potent antioxidant activity in improving the atherosclerosis profile [96]. Isoflavones, calycosin and formononetin from the Astragalus root, could promote dimethylarginine dimethylaminohydrolase-2 protein and mRNA expressions in Madin Darby Canine Kidney (MDCK) II cells, and up regulate the neuronal nitric oxide synthase levels [97]. Astragaloside IV could prolong the action potential duration of guinea-pig ventricular myocytes, which might be explained by its inhibition of K+ currents [98].

3.5. Antidiabetic

The study of Liu et al., indicated that Astragalus polysaccharide could regulate part of the insulin signaling in insulin-resistant skeletal muscle, and could be a potential insulin sensitizer for the treatment of type 2 diabetes [99]. Zhou et al., found Astragalus polysaccharide could up regulate the expression of galectin-1 in muscle of type I diabetes mellitus mice [100]. Saponins and astragaloside IV could exert protective effects against the progression of peripheral neuropathy in streptozotocin-induced diabetes in rats [101]. In addition, astragaloside V was found to inhibit the formation of N-(carboxymethyl)lysine and pentosidine during the incubation of bovine serum albumin with ribose, which suggested that it might be a potentially useful strategy for the prevention of clinical diabetic complication by inhibiting advanced glycation end products [102].

3.6. Anti-Oxidative Activity

The anti-oxidative activities of some flavonoids and saponins from A. mongholicus have been studied. For example, formononetin, calycosin, calycosin-7-O-β-d-glucoside could scavenge 1,1-diphenyl-2-picrylhydrazyl free radicals in vitro. Formononetin and calycosin were found to inhibit xanthine/xanthine oxidase-induced cell injury significantly. Among them, calycosin exhibited the most potent antioxidant activity both in the cell-free system and in the cell system [73]. The compound 7,2-dihydroxy-3',4'-dimethoxyisoflavan-7-O-β-d-glucoside and calycosin-7-O-β-d-glucoside from A. membranaceus showed anti-lipid peroxidative activities [103]. The saponin, astragaloside IV can inhibit hepatic stellate cells activation by inhibiting generation of oxidative stress and associated p38 MAPK activation [104].

3.7. Anti-Aging

According to the study of the anti-aging effect of astragalosides, Lei et al., suggested that the mechanism might be related to the improvement of brain function and immunomodulatory effects [105]. Gao et al., concluded that Astragalus polysaccharides could lengthen the living time of mice, improve the activity of superoxide dismutase and decrease the malonaldehyde content in mice blood serum compared with the control group, which suggested that Astragalus polysaccharides have anti-aging effects [106].

3.8. Other Biological Activities

Additionally, according to previous research, the plants of Astragalus species also have pharmacological effects such as antiviral, hepatoprotective, neuron protective, and so on.

4. Analyses

Researchers have conducted numbers of qualitatively and quantitatively analytical experiments on the plants in the Astragalus genus by different methods. Among them, the analyses of flavonoids and saponins from the radix of A. membranaceus and A. mongholicus were well done.

Han et al., studied ultra-performance liquid chromatography for quantification of flavone in A. membranaceus, the outcome of which showed that the linear ranges of calycosin glycoside, formononetin glycoside, calycosin, and formononetin were 0.1313–1.313 g/L (r = 0.9997), 0.1186–1.186 g/L (r = 0.9994), 0.0206–0.206 g/L (r = 0.9995), and 0.0150–0.150 g/L (r = 0.9995), respectively. The average recoveries were 97.07%, 97.26%, 97.45% and 96.97% respectively [107]. The research results of Zhang et al., indicated that the content of flavonoids in Radix Astragali of different growth years increased along with the growth period, and the types of flavonoids remained the same [108]. By comparing the retention time and MS data with those obtained from the authentic compounds and the published data, Ye et al., identified a total of 19 compounds including 11 isoflavonoids and eight saponins [109].

In addition, analyses for other constituents in A. membranaceus and A. mongholicus and composition analysis for other species of Astragalus were also conducted. Huang et al., studied the water extract of Radix Astragali by infrared spectroscopy, and found it contained an abundance of polyose, and the residue from it included some substances such as starch, cellulose, and lignin. The study provided an effective reference for the further analyses of chemical components and the improvement of extraction-separation technologies of TCM [110]. Using solid phase microextraction followed by GC-MS analysis, Movafeghi et al., identified the volatile organic compounds in the leaves, roots and gum of A. compactus. As a result, a range of volatile compounds were recognized in different parts of it under optimized conditions, but tetradecane 1-chloro only existed in roots [111]. Sun et al., determined the chemical components of A. hamiensis with a systematic extract method and TLC, the results showed that it contained alkaloids, polysaccharides, glucosides, amino acids, steroids, terpenoids, oils, tannins, phenols, organic acids, flavonoids-chinones, cardiac glycosides, and coumarins. Futhermore, they found the alkaloids were mainly swainsonine and analogous indolizidine. Meanwhile, A. hamiensis was found to contain small amount of ermopsine and anagyrine, which belong to quinolizidine [112].

5. Conclusions

As a TCM, the root of the Astragalus plant, Huang Qi, has been used in Chinese medicine for thousands of years. There are over two thousand species of Astragalus, among which only A. membranaceus and A. mongholicus are primarily used for medicinal purposes. In light of the considerable interest generated in the chemistry and pharmacological properties of the Astragalus plant, this review summarizes the retrieved literature published over the last 10 years dealing with several aspects including phytochemistry, bioactivity, and the research of the analysis.

In the field of phytochemistry and analysis, the chemical constituents from 46 kinds of Astragalus species have been studied. Although more than 200 compounds, including cycloartane-type saponins and flavonoids, were obtained from them, the systematic phytochemistry research needs to be improved. In addition, though the researchers conducted a number of qualitatively and quantitatively analytical experiments for flavonoids and saponins from the radix of A. membranaceus and A. mongholicus by different methods, the simultaneous analysis of two kinds of constituents was rarely found. In the field of pharmacology, the bioactivity evaluation of extracts and isolated compounds focused on anti-inflammatory, immunostimulant, antioxidative, anti-cancer, antidiabetic, cardioprotective, hepatoprotective, and antiviral, but anti-inflammation activity research of flavonoids was rare. Though a lot of results of pharmacological studies were carried out using crude extract of Astragalus species, the relationship between chemical constituents and activity is still unclear. Additionally, data on pharmacokinetics and bioavailability, especially related to the target tissue, need to be further supplemented.

Acknowledgments

This research was supported by the Program for New Century Excellent Talents in University (NCET-12-1069), Program for Tianjin Innovative Research Team in University (TD12-5033).

Author Contributions

Xiaoxia Li: Acquisition, interpretation of data and wrote the manuscript. References management; Lu Qu: Drafted the structural formulas. Classified the chemical components; Yongzhe Dong: Classified the Pharmacological literatures; Lifeng Han: Revising the review critically for important intellectual content; Erwei Liu: Drafted the structural formulas; Shiming Fang: References management; Yi Zhang: Obtained funding. Contributed to conception and design of the review; Tao Wang: Obtained funding. Overall responsibility.

Conflicts of Interest

The authors declare no conflict of interest.

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