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Chinese Journal of
Natural Chinese Journal of Natural Medicines 2016, 14(5): 03210334 Medicines
doi: 10.3724/SP.J.1009.2016.00321
Recent advances in phytochemistry and pharmacology of
C21 steroid constituents from Cynanchum plants
GU Xiao-Jie*, HAO Da-Cheng
Biotechnology Institute, School of Environment, Dalian Jiaotong University, Dalian 116028, China
Available online 20 May, 2016
[ABSTRACT] Cynanchum is one of the most important genera in Asclepiadaceae family, which has long been known for its therapeutic effects. In this genus, 16 species are of high medicinal value. The extracts of the root and/or rhizome parts have been
applied in traditional Chinese medicines (TCM) for the prevention and treatment of various illnesses for centuries. C21 steroids, as the typical constituents of Cynanchum species, possess a variety of structures and pharmacological activities. This review summarizes the
comprehensive information on phytochemistry and pharmacology of C21 steroid constituents from Cynanchum plants, based on reports published between 2007 and 2015. Our aim is to provide a rationale for their therapeutic application, and to discuss the future trends in research and development of these compounds. A total of 172 newly identified compounds are reviewed according to their structural classifications. Their in vitro and in vivo pharmacological studies are also reviewed and discussed, focusing on antitumor, antidepressant, antifungal, antitaging, Na+/K+-ATPase inhibitory, appetite suppressing and antiviral activities. Future research efforts
should concentrate on in vitro and in vivo biological studies and structure activity relationship of various C21 steroid constituents.
[KEY WORDS] Asclepiadaceae; Cynanchum; C21 steroid constituents; Phytochemical studies; Pharmacological actions [CLC Number] R284 [Document code] A [Article ID] 2095-6975(2016)05-0321-14
immune deficiency, and other illnesses. A survey of the Introduction literature shows that C21 steroids are typical constituents of [2] Cynanchum species have long been used in traditional Cynanchum species . Phytochemical studies of Cynanchum Chinese medicine (TCM). This genus comprises of about 200 species have resulted in the isolation of numerous biologically species in Asclepiadaceae family and is distributed worldwide, active C21 steroidal compounds. Most of them possess a including east Africa, the Mediterranean region, the tropical variety of pharmacological actions, e.g. antitumor, antiaging, zone of Europe, and the subtropical and temperate zones of antidepressant, antifungal, and antiviral activities, and also [3] Asia. There are 53 species and 12 varieties are native to appetite suppressing ability . Due to their relatively rich southwestern region of China. Among them, 16 species, medicinal value, C21 steroids deserve more research than they including C. auriculatum, C. atratum, C. glaucescens, C. have received. Several monographs on Cynanchum species bungei, C. chekiangense, C.vincetoxicum, C. saccatumi, C. have been published. Wu et al and Liu et al have summarised inamoenum, C. mongolicum, C. otophyllum, C. paniculatum, the chemistry and pharmacological activities of Cynanchum [4-5] C. stauntonii, C. decipines, C. wallichii, C. wilfordii, and C. plants in two consecutive reviews . Wu and Zhou have [1] versicolor, are of high medicinal value . The extracts of the contributed a review on the chemical constituents of C21 root and/or rhizome parts have long been used in folk steroids, alkaloids, flavonoids, terpenoids, phenols, and other [6] medicine to treat rheumatalgia, phlegm, geriatric diseases, ingredients in plants of Cynanchum . The classification, NMR spectral characteristics and structure determination of Cynanchum C21 steroid constituents are covered in the monograph by Bai et al [7]. Ni and Ye have reviewed the [Received on] 04-Jun.-2015 distribution and pharmacological activities of C steroidal [Research funding] This work was financially supported by the 21 [8] National Natural Science Foundation of China (No. 21502014). glycosides in in plants of Asclepiadaceae . Although five [*Corresponding author] Tel: 86-411-84105506, E-mail: guxiaojie review articles on certain aspects of C21 steroids have [email protected] appeared, no recent review has been published since. The These authors have no conflict of interest to declare. purpose of this comtribution was to review the up-to-date
– 321 – GU Xiao-Jie, et al. / Chin J Nat Med, 2016, 14(5): 321334 literatures covering phytochemical and pharmacological of hydroxyls at C-3, can be grouped into four types, viz., aspects of naturally occurring plant C21 steroids and to discuss types B, C, D, and E. According to the different pregnane the future directions as well. skeletons, these compounds can be finally divided into five types: the normal four-ring pregnane type (A), 14,15-seco- Phytochemistry pregnane type (B), 13,14:14,15-diseco-pregnane type (C), the aberrant 14,15-seco-pregnane type (D), and 12,13-seco-14, C21 steroid constituents possess a tetracyclic pregnane carbon skeleton and differ in the number and nature of 18-nor-pregnane type (E) (Fig. 1). In C21 steroidal glycosides, substituents and sometimes in the degree of unsaturation, the sugar moiety is linked most frequently at C-3 to a which are found in Cynanchum species either in free states hydroxyl group of the pregnane aglycone, containing one to or as glycosides. They can be classified into two groups on seven sugar units with the mode of 1→4, and generally is the basis of the carbon framework: typical C21 steroids and composed of a linear rather than a branched oligosaccharide modified C21 steroids. The former, usually designated as chain. The most common sugar residues are hexose type A, is characterized by the common pregnane skeleton. (glucose), 6-deoxyhexose (thevetose), and 2,6-dideoxyhexoses The latter, containing the unusual modified pregnane (cymarose, oleandrose, digitoxose, diginose, sarmentose, and skeleton and fewer hydroxy groups except for the location canarose) (Fig. 2).
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Fig. 1 Basic skeletons of C21 steroidal glycosides from Cynanchum species
Fig. 2 Chemical structures of sugar moieties
Normal four-ring pregnane type substituted by a cinnamoyl group [14]. Type A, including compounds 1−59, can be further 14, 15-Seco-pregnane type classified into three subtypes, based on different oxidation Type B, including 14 new steroidal glycosides, is patterns and specific substituent groups at C-8, C-12, C-17 characterized by a tetrahydrofuran unit as the D-ring and and C-20 (Table 1). Substituents at C-12, C-17 and C-20 C-16 and C-18 are joined to C-20 through a five-membered are always esters, with the hydroxyl groups of the cyclic ether linkage (Table 2). According to the number and aglycone at these positions esterified with six different position of unsaturated groups and hydroxyls, type B is acyl groups (Fig. 3). Type A1 is the largest group and further classified into four subtypes. Type B1, including currently comprises of 50 new compounds. These 60−65, possesses the common deoxyamplexicogenin A [26-28] members consist of six different aglycones on the basis of skeleton ; type B2, including 66−71, is anhydro- six different acyl groups at C-12 and C-17, viz., kidjoranin hirundigenin derivatives [26, 29]; and aglycones of the other
(1−9), metaplexigenin (10 and 11), deacylmetaplexigenin types, 72 (type B3) and 73 (type B4), are stauntogenins A (12−16), 17-O-acetyl-kidjoranin (17), qinyangshengenin and B, respectively [26]. (18−32), and caudatin (33−50) [9-24]. The different 13,14:14,15-Diseco-pregnane type oxidation patterns on C-20 make A1 distinguish from A2. Steroid constituents of type C have nine-membered
Type A2 consists of 6 new compounds: 51−53 from kidjoranin unsaturated lactone ring with the oxidation and the breakdown steroidal aglycone [14], 54 and 55 from 20-O-acetylpenupogenin of C- and D-rings, and contain 59 new examples (Table 3). steroidal aglycone [24], and 56 from 2′,3′-Z-gagaminine Because of the different configurations and positions of [15] steroidal aglycone . Type A3 (57) differs from A2 in a hydroxyl groups, a total of 49 new steroids from type C1 have hydroxy group at C-8 that is oxidized into a carbonyl [15]. been described: 74−90 from glaucogenin C, 91−116 from
Type A4 (58) differs from A1 in a hydroxy group at C-3 glaucogenin A, 117−119 from 2-epi- glaucogenin A, 120 that is eliminated to form double bonds [14]. The formation from glaucogenin E, 121 from neocynapanogenin F, and 122 [26, 27, 29-39] of type A5 (59) is due to elimination of H2O by the two from hancopregnane . Type C2 consists of 4 new hydroxyl groups at C-12 and C-20, and its hydroxyl group compounds, and is based on the amplexicogenin B (123 [40] [33, 41] of C-17, a commonly free group in pregnane sapogenin, is and 124) and C (125 and 126) skeletons . Type C3
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Table 1 C21 steroid constituents isolated from Cynanchum species (A type) No. Type Compound Substitutional group Taxon Ref.
1 A1 Cynauricoside A R1 = RC1 R2 = RX1 R3 = H a 9
2 A1 Cynauricoside B R1 = RE1 R2 = RX1 R3 = H a 9
3 A1 Cynauricoside C R1 = RE2 R2 = RX1 R3 = H a 9
4 A1 Wilfoside K1GG R1 = RF1 R2 = RX1 R3 = H b 10 Rostratamine-3-O-β-D-oleandropyranosyl-(1→4)-β- 5 A R = RC R = RX R = H d 11 1 D-cymaropyranosyl-(1→4)-β-D-cymaropyranoside 1 3 2 1 3
6 A1 Auriculoside Ⅲ R1 = RG5 R2 = RX1 R3 = H a 12
7 A1 Auriculoside Ⅳ R1 = RF1 R2 = RX1 R3 = H a 12
8 A1 Kidjoranin 3-O-α-diginopyranosyl-(1→4)-β-cymaropyranoside R1 = RB3 R2 = RX1 R3 = H a 13
9 A1 Kidjoranin 3-O-β-digitoxopyranoside R1 = RA1 R2 = RX1 R3 = H a 13
10 A1 Cynauricoside D R1 = RE1 R2 = RX2 R3 = H a 9
11 A1 Cynauricoside E R1 = RE2 R2 = RX2 R3 = H a 9
12 A1 Cynauricoside F R1 = RE1 R2 = H R3 = H a 9
13 A1 Cynauricoside G R1 = RE2 R2 = H R3 = H a 9
14 A1 Cynauricoside H R1 = RD1 R2 = H R3 = H a 9
15 A1 Cynauricoside I R1 = RD2 R2 = H R3 = H a 9
16 A1 12-O-Vanilloyl-deacymetaplexigenin R1 = H R2 = RX7 R3 = H b 14
17 A1 Cyanoauriculoside F R1 = RD5 R2 = RX1 R3 = RX2 a 15
18 A1 Otophylloside N R1 = RD3 R2 = RX4 R3 = H c 16
19 A1 Otophylloside O R1 = RD4 R2 = RX4 R3 = H c 16
20 A1 Otophylloside P R1 = RE3 R2 = RX4 R3 = H c 16
21 A1 Cynanauriculoside C R1 = RB1 R2 = RX4 R3 = H a 17
22 A1 Cynanauriculoside D R1 = RE4 R2 = RX4 R3 = H a 17 Qinyangshengenin-3-O-β-D-oleandropyranosyl-(1→4)-β- 23 A R = RB R = RX R = H d 18 1 D-cymaropyranoside 1 1 2 4 3 Qinyangshengenin-3-O-β-D-oleandropyranosyl-(1→4)-β-D- 24 A R = RC R = RX R = H d 18 1 oleandropyranosyl-(1→4)-β-D-cymaropyranoside 1 2 2 4 3 Qinyangshengenin-3-O-β-D-cymaropyranosyl-(1→4)-β-D- 25 A R = RB R = RX R = H d 11 1 digitoxopyranoside 1 2 2 4 3 Qinyangshengenin-3-O-β-D-oleandropyranosyl-(1→4)-β-D-cymar 26 A R = RC R = RX R = H d 11 1 opyranosyl-(1→4)-β-D-digitoxopyranoside 1 $ 2 4 3
27 A1 Otophylloside H R1 = RE5 R2 = RX4 R3 = H c 19
28 A1 Otophylloside I R1 = RD6 R2 = RX4 R3 = H c 19
29 A1 Otophylloside J R1 = RE6 R2 = RX4 R3 = H c 19
30 A1 Otophylloside K R1 = RD7 R2 = RX4 R3 = H c 19
31 A1 Qinyangshengenin-3-O-β-D-digitoxopyranoside R1 = RA1 R2 = RX4 R3 = H c 20 Qinyangshengenin-3-O-β-D-cymaropyranosyl-(1→4)-β- 32 A R = RB R = RX R = H c 20 1 D-digitoxopyranoside 1 2 2 1 3
33 A1 Wilfoside C1GG R1 = RF1 R2 = RX3 R3 = H b 10
34 A1 Otophylloside Q R1 = RF2 R2 = RX3 R3 = H c 16
35 A1 Otophylloside R R1 = RG1 R2 = RX3 R3 = H c 16
36 A1 Otophylloside S R1 = RG2 R2 = RX3 R3 = H c 16
37 A1 Cynanauriculoside E R1 = RE5 R2 = RX3 R3 = H a 17 Caudatin-3-O-β-D-cymaropyranosyl-(1→4)-β- 38 A R = RB R = RX R = H d 21 1 D-digitoxopyranoside 1 2 2 3 3 Caudatin-3-O-β-D-oleandropyranosyl-(1→4)-β- 39 A R = RB R = RX R = H d 21 1 D-cymaropyranoside 1 1 2 3 3
40 A1 Otophylloside L R1 = RE7 R2 = RX3 R3 = H c 19
41 A1 Otophylloside M R1 = RE8 R2 = RX3 R3 = H c 19
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Continue Substitutional No. Type Compound Taxon Ref. No. Type group Caudatin-3-O-α-L-cymaropyranosyl-(1→4)-α-D-oleandropyranos yl-(1→4)-α-L-cymaropyranosyl-(1→4)-β-D-glucopyranosyl- 42 A R = RG R = RX R = H c 22 1 (1→4)-α-D-oleandropyranosyl-(1→4)-β-D-oleandropyranosyl- 1 3 2 3 3 (1→4)-β-D-diginopyranoside Caudatin-3-O-β-D-cymaropyranosyl-(1→4)-α-D-oleandropyranos yl-(1→4)-α-L-cymaropyranosyl-(1→4)-β-D-glucopyranosyl- 43 A R = RG R = RX R = H c 22 1 (1→4)-β-D-oleandropyranosyl-(1→4)-β-D-cymaropyranosyl- 1 4 2 3 3 (1→4)-β-D-diginopyranoside
44 A1 Auriculoside Ⅰ R1 = RG5 R2 = RX3 R3 = H a 12
45 A1 Auriculoside Ⅱ R1 = RF3 R2 = RX3 R3 = H a 12 Caudatin-3-O-α-L-cymaropyranosyl-(1→4)-β-D-cymaropyranosyl 46 A R = RC R = RX R = H c 23 1 -(1→4)-β-D-cymaropyranoside 1 21 2 3 3 Caudatin-3-O-β-D-oleandropyranosyl-(1→4)-β-D-oleandropyrano 47 A R = RD R = RX R = H c 23 1 syl-(1→4)-β-D-cymaropyranosyl-(1→4)-β-D-cymaropyranoside 1 21 2 3 3 Caudatin-3-O-β-D-glucopyranosyl-(1→4)-β-D-oleandropyranosyl 48 A R = RD R = RX R = H d 24 1 -(1→4)-β-D-cymaropyranosyl-(1→4)-β-D-digitoxopyranoside 1 6 2 3 3 Caudatin-3-O-β-D-glucopyranosyl-(1→4)-β-D-cymaropyranosyl- 49 A1 (1→4)-β-D-oleandropyranosyl-(1→4)-β-D-cymaropyranosyl- R1 = RE6 R2 = RX3 R3 = H d 24 (1→4)-β-D-digitoxopyranoside
50 A1 3-O-Methyl-caudatin R1 = CH3 R2 = RX3 R3 = H b 14
51 A2 20-O-Salicyl-kidjoranin R1 = H R2 = RX1 R3 = RX8 b 14
52 A2 20-O-(4-Hydroxybenzoyl)-kidjoranin R1 = H R2 = RX1 R3 = RX4 b 14
53 A2 20-O-Vanilloyl-kidjoranin R1 = H R2 = RX1 R3 = RX7 b 14
54 A2 Cyanoauriculoside A R1 = RF1 R2 = RX1 R3 = RX2 a 25
55 A2 Cyanoauriculoside B R1 = RE9 R2 = RX1 R3 = RX2 a 25
56 A2 Cyanoauriculoside G R1 = RD5 R2 = RX5 R3 = RX6 a 15
57 A3 Cyanoauriculoside F R = RD5 a 15 12β-O-(4-Hydroxybenzoyl)-8β,14β,17-trihydroxypregn-2, 58 A R = RX b 14 4 5-diene-20-one 4
59 A5 17β-O-Cinnamoyl-3β,8β,14β-trihydroxypregn-12,20-ether R = RX1 b 14
Fig. 3 Chemical structures of substitutional groups
(127−130), C4 (131) and C5 (132) are derived from stauntogenin, comprises of 31 new constituents. These members consist of amplexicogenin D and 5β,6β-epoxy-glaucogenin skeletons, five different carbon skeletons on the basis of the difference [26, 33, 42, 43] respectively . of the number and position of hydroxyls and substituent of R4. Aberrant 14,15-seco-pregnane type The aglycones of 133−137, 138−153, 154−158, 159−162, and Type D belongs to the aberrant 14,15-seco-pregnane 163 have 13-hydroxycynajapogenin A, cynajapogenin A, 13-epi- skeleton with D-ring completely oxidized and broken into cynajapogenin A, atratogenin A, and 1β-hydroxyatratogenin A furan-ring side chain, and includes 39 new steroidal carbon skeletons, respectively [29, 30, 35, 44-45]. The structures of [44] glycosides (Table 4). According to the number and position of 164−166 (type D2) are based on atratogenin B with the unsaturated groups and hydroxyls, type D is further divided substituent of a carbonyl group at C-2. Type D3 (167−171), into three types, D1-D3. Type D1 is the largest group and characterized by the presence of a butenolide moiety at C-13
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Table 2 C21 steroid constituents isolated from Cynanchum species (B type) No. Type Compound Substitutional group Taxon Ref.
60 B1 Stauntoside C R = RA2 e 26
61 B1 Stauntoside J R = RC5 e 26
62 B1 Stauntoside K R = RC6 e 26
63 B1 Stauntoside N R = RA3 e 27
64 B1 Stauntosaponin A R = RA2 e 28
65 B1 Stauntosaponin B R = RA3 e 28
66 B2 Stauntoside I R = RC7 a 26
67 B2 Sublanceoside E4 R = RC8 f 29
68 B2 Sublanceoside F4 R = RD10 f 29
69 B2 Sublanceoside G4 R = RC9 f 29
70 B2 Sublanceoside J4 R = RD11 f 29
71 B2 Sublanceoside K4 R = RE10 f 29
72 B3 Stauntoside G R = RD8 e 26
73 B4 Stauntoside H R = RD9 e 26
Table 3 C21 steroid constituents isolated from Cynanchum species (C type) No. Type Compound Substitutional group Taxon Ref.
74 C1 Stauntoside D R1 = RC10 R2 = H R3 = H R4 = H e 26
75 C1 Cynaforroside K R1 = RF4 R2 = H R3 = H R4 = H h 30
76 C1 Cynaforroside L R1 = RF5 R2 = H R3 = H R4 = H h 30
77 C1 Cynaforroside M R1 = RF6 R2 = H R3 = H R4 = H h 30
78 C1 Cynaforroside N R1 = RF7 R2 = H R3 = H R4 = H h 30
79 C1 Cynaforroside Q R1 = RC11 R2 = H R3 = H R4 = H h 30
80 C1 Stauntoside L R1 = RC5 R2 = H R3 = H R4 = H e 27
81 C1 Stauntoside M R1 = RD12 R2 = H R3 = H R4 = H e 27 Glaucogenin C 3-O-α-L-cymaropyranosyl- 82 C1 (1→4)-β-D-digitoxopyranosyl-(1→4)-β-D- R1 = RC12 R2 = H R3 = H R4 = H e 31 canaropyranoside
83 C1 Inamoside E R1 = RD13 R2 = H R3 = H R4 = H i 32
84 C1 Inamoside F R1 = RE11 R2 = H R3 = H R4 = H i 32
85 C1 Inamoside G R1 = RE12 R2 = H R3 = H R4 = H i 32
86 C1 Cynanoside H R1 = RB4 R2 = H R3 = H R4 = H l 33
87 C1 Cynanoside I R1 = RB5 R2 = H R3 = H R4 = H l 33
88 C1 Cynanoside J R1 = RC22 R2 = H R3 = H R4 = H l 33
89 C1 Cynanoside K R1 = RC23 R2 = H R3 = H R4 = H l 33
90 C1 Cynanoside L R1 = RC22 R2 = H R3 = H R4 = H l 33
91 C1 Amplexicoside A R1 = RC13 R2 = α-OH R3 = H R4 = H g 34
92 C1 Amplexicoside B R1 = RC14 R2 = α-OH R3 = H R4 = H g 34
93 C1 Amplexicoside C R1 = RC13 R2 = α-OH R3 = H R4 = H g 34
94 C1 Amplexicoside D R1 = RC14 R2 = α-OH R3 = H R4 = H g 34
95 C1 Amplexicoside E R1 = RC15 R2 = α-OH R3 = H R4 = H g 34
96 C1 Amplexicoside F R1 = RC16 R2 = α-OH R3 = H R4 = H g 34
97 C1 Amplexicoside G R1 = RA2 R2 = α-OH R3 = H R4 = H g 34
98 C1 Chekiangensoside B R1 = RD15 R2 = α-OH R3 = H R4 = H j 35
99 C1 Sublanceoside A2 R1 = RA1 R2 = α-OH R3 = H R4 = H f 29
100 C1 Sublanceoside B2 R1 = RB4 R2 = α-OH R3 = H R4 = H f 29
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Continue No. Type Compound Substitutional group Taxon Ref.
101 C1 Sublanceoside C2 R1 = RC17 R2 = α-OH R3 = H R4 = H f 29
102 C1 Sublanceoside D2 R1 = RD16 R2 = α-OH R3 = H R4 = H f 29
103 C1 Cynanoside J R1 = RC8 R2 = α-OH R3 = H R4 = H f 29
104 C1 Glaucoside H R1 = RD10 R2 = α-OH R3 = H R4 = H f 29
105 C1 Sublanceoside H2 R1 = RD20 R2 = α-OH R3 = H R4 = H f 29
106 C1 Sublanceoside J2 R1 = RD11 R2 = α-OH R3 = H R4 = H f 29
107 C1 Sublanceoside K2 R1 = RE10 R2 = α-OH R3 = H R4 = H f 29
108 C1 Sublanceoside L2 R1 = RF8 R2 = α-OH R3 = H R4 = H f 29
109 C1 Cynanoside A R1 = RB1 R2 = α-OH R3 = H R4 = H l 33
110 C1 Cynanoside B R1 = RB6 R2 = α-OH R3 = H R4 = H l 33
111 C1 Cynanoside C R1 = RB5 R2=α-OH R3 = H R4 = H l 33
112 C1 Cynanoside D R1 = RC24 R2=α-OH R3 = H R4 = H l 33
113 C1 Cynanoside E R1 = RC25 R2=α-OH R3 = H R4 = H l 33
114 C1 Cynanoside F R1 = RC23 R2=α-OH R3 = H R4 = H l 33
115 C1 Cynanoside G R1 = RD22 R2=α-OH R3 = H R4 = H l 33
116 C1 Cynanside B R1 = RC26 R2 = α-OH R3 = H R4 = H k 36
117 C1 Inamoside A R1 = RD13 R2 = β-OH R3 = H R4 = H i 37
118 C1 Inamoside B R1 = RD14 R2 = β-OH R3 = H R4 = H i 37
119 C1 Inamoside C R1 = RE11 R2 = β-OH R3 = H R4 = H i 37
* 120 C1 Glaucogenin E R1 = H R2 = α-OH R3 = OH R4 = H e 38
121 C1 Neocynapanogenin F 3-O-β-D-thevetoside R1 = RA3 R2 = H R3 = H R4 = OH k 39
122 C1 Cynanoside M R1 = RA4 R2 = α-OH R3 = H R4 = OH l 33
123 C2 Amplexicogenin B-3-O-β-D-cymaropyranoside R1 = RA4 R2 = H g 40 Amplexicogenin B 3-O-β-D-cymaropyranosyl- 124 C2 (1→4)-α-L-cymaropyranosyl-(1→4)-β-D- R1 = RC20 R2 = OH g 40 cymaropyranoside
125 C2 Amplexicogenin C-3-O-β-D-cymaropyranoside R1 = RA4 R2 = OH g 41
126 C2 Cynanoside O R1 = RA5 R2 = H l 33
127 C3 Stauntoside E R = RD8 e 26
128 C3 Stauntoside F R = RC8 e 26
129 C3 Cynanoside N R = RC22 l 33 Stauntogenin-3-O-α-L-oleandropyranosyl- 130 C3 (1→4)-O-β-D-digitoxopyranosyl-(1→4)-O- R = RC19 g 42 β-D-oleandropyranoside
131 C4 Amplexicogenin D-3-O-β-D-cymaropyranoside R = RA4 g 42
132 C5 Inamoside D R = RE14 i 43 "*" Compound 120 has been isolated from the rhizome part. Apart from this, other compounds have been isolated from the root part of the (20S)-cynanogenin C nucleus [44], is the first example in Tables 1-4. This review is concerned with the scientific of a C21 steroid constituent from Cynanchum species. literature on C21 steroids published between 2007 and 2015. A 12,13-Seco-14,18-nor-pregnane type total of 172 new compounds are listed, and 59 references are
Type E is a special class of C21 steroid with the oxidative cited. cleavage of the bond between C-8 and C-14 of the C-ring, Pharmacology resulting in the absence of ring C. Only one novel compound (172), characterized as the 12,13-seco-14,18-nor-pregnane The scientific world’s particular interest in the genus [44] derivative of cynanogenin D has been reported thus far Cynanchum and thetherapeutic properties originates from C21 (Table 4). steroids. These constituents have exhibited a wide spectrum Phytochemical studies on Cynanchum species are summarized of pharmacological activities, but the literature has focussed
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Table 4 C21 steroid constituents isolated from Cynanchum species (D and E types) No. Type Compound Substitutional group Taxon Ref.
133 D1 Cynanoside Q1 R1 = RD17 R2 = OH R3 = H R4 = β-OH l 44
134 D1 Cynanoside Q2 R1 = RC18 R2 = OH R3 = H R4 = β-OH l 44
135 D1 Cynanoside Q3 R1 = RD18 R2 = OH R3 = H R4 = β-OH l 44
136 D1 Sublanceoside E3 R1 = RC8 R2 = OH R3 = H R4 = β-OH f 29
137 D1 Sublanceoside G3 R1 = RC9 R2 = OH R3 = H R4 = β-OH f 29
138 D1 Cynanoside K R1 = RD17 R2 = OH R3 = H R4 = β-H l 45
139 D1 Cynanoside L R1 = RE13 R2 = OH R3 = H R4 = β-H l 45
140 D1 Sublanceoside A1 R1 = RA1 R2 = OH R3 = H R4 = β-H f 29
141 D1 Sublanceoside B1 R1 = RB4 R2 = OH R3 = H R4 = β-H f 29
142 D1 Sublanceoside C1 R1 = RC17 R2 = OH R3 = H R4 = β-H f 29
143 D1 Sublanceoside D1 R1 = RD16 R2 = OH R3 = H R4 = β-H f 29
144 D1 Sublanceoside E1 R1 = RC8 R2 = OH R3 = H R4 = β-H f 29
145 D1 Cynascyroside C R1 = RD10 R2 = OH R3 = H R4 = β-H f 29
146 D1 Sublanceoside H1 R1 = RD20 R2 = OH R3 = H R4 = β-H f 29
147 D1 Sublanceoside I1 R1 = RC1 R2 = OH R3 = H R4 = β-H f 29
148 D1 Sublanceoside J1 R1 = RD11 R2 = OH R3 = H R4 = β-H f 29
149 D1 Sublanceoside K1 R1 = RE10 R2 = OH R3 = H R4 = β-H f 29
150 D1 Sublanceoside L1 R1 = RF8 R2 = OH R3 = H R4 = β-H f 29
151 D1 Cynaforroside O R1 = RF9 R2 = H R3 = H R4 = β-H h 30
152 D1 Cynaforroside P R1 = RE11 R2 = H R3 = H R4 = β-H h 30
153 D1 Chekiangensoside A R1 = RD15 R2 = OH R3 = H R4 = β-H j 35
154 D1 Cynanoside M R1 = RC1 R2 = OH R3 = H R4 = α-H l 45
155 D1 Sublanceoside E5 R1 = RC8 R2 = OH R3 = H R4 = α-H f 29
156 D1 Sublanceoside F5 R1 = RD10 R2 = OH R3 = H R4 = α-H f 29
157 D1 Sublanceoside H5 R1 = RD20 R2 = OH R3 = H R4 = α-H f 29
158 D1 Sublanceoside L5 R1 = RF8 R2 = OH R3 = H R4 = α-H f 29
159 D1 Cynanoside N R1 = RD19 R2 = OH R3 = H R4 = β-CH3 l 45
160 D1 Cynanoside O R1 = RD17 R2 = OH R3 = OH R4 = β-CH3 l 45
161 D1 Sublanceoside F6 R1 = RD10 R2 = OH R3 = H R4 = β-CH3 f 29
162 D1 Sublanceoside H6 R1 = RD20 R2 = OH R3 = H R4 = β-CH3 f 29
163 D1 Sublanceoside L6 R1 = RF8 R2 = OH R3 = H R4 = β-CH3 f 29
164 D2 Cynanoside R1 R1 = RC1 R2 = H l 44
165 D2 Cynanoside R2 R1 = RC1 R2 = OH l 44
166 D2 Cynanoside R3 R1 = RD17 R2 = OH l 44
167 D3 Cynanoside P1 R1 = RC1 R2 = H R3 = CH3 l 44
168 D3 Cynanoside P2 R1 = RD17 R2 = H R3 = CH3 l 44
169 D3 Cynanoside P3 R1 = RC1 R2 = CH3 R3 = H l 44
170 D3 Cynanoside P4 R1 = RD17 R2 = CH3 R3 = H l 44
171 D3 Cynanoside P5 R1 = RD17 R2 = OCH3 R3 = CH3 l 44
172 E Cynanoside S R = RC1 l 44 primarily on antitumor activity. An overview of the Antitumor/Anticancer activity pharmacological evaluations carried out on these species has The search for effective antitumor agents has been one of been described in a great detail by a large number of the most important areas in cancer research. There are several researchers (Table 5). natural plants used in clinical therapy for cancer that belong to
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Table 5 Overview on the current status of modern pharmacological evaluations of Cynanchum species Antitumor Antidepressant Antifungal Antitaging Na+/K+-ATPase Appetite Antiviral Taxon Ref. activity activity activity activity inhibitory activity suppressing activity activity a + + + + 5,8-9,13,17,46-58 b + + + 5,8,10,14 k + + + + + 5,8,59 m + 5 n + 5 o + 5 p + 5 q + + 4 r + + 4 i + + + 4,6 e + + + 8,28,38-39 d + 8,18 l + + 8 s + + 8 j + 8 c + + + 8 "+" indicates Cynanchum species possess a variety of pharmacological actions
Cynanchum species as TCM. In bioassays, kidjoranin human cervical carcinoma cells (HeLa) and human 3-O-α-diginopyranosyl-(1→4)-β-cymaropyranoside 8, kidjoranin breast cancer cells (MCF-7) [13]. All of them have 3-O-β-digitoxopyranoside 9 and caudatin 3-O-β-cymaro- displayed markedly cytotoxic activities against pyranoside, isolated from the same plant, have been SMMC-7721 and HeLa cells with IC50 values ranging tested for their in vitro inhibitory activity against the from 8.6 to 58.5 µmol·L−1, but no activity against MCF-7 growth of human hepatoearcinoma cells (SMMC-7721), cells was detected (Table 6).
Table 6 Activities of C21 steroid constituents isolated from Cynanchum species against human tumor cell lines
−1 Compound IC50 value (µmol·L ) Taxon Ref. Kidjoranin 3-O-α-diginopyranosyl-(1→4)- 14.2 ± 1.6 (SMMC-7721); 3.5 ± 3.4 (HeLa); ＞200 (MCF-7) a 13 β-cymaropyranoside, 8 Kidjoranin 3-O-β-digitoxopyranoside, 9 19.6 ± 1.9 (SMMC-7721); 19.5 ± 2.0 (HeLa); ＞200 (MCF-7) a 13 Caudatin 3-O-β-D-cymaropyranoside 8.6 ± 1.2 (SMMC-7721); 58.5 ± 4.4 (HeLa); ＞200 (MCF-7) a 13 Qinyangshengenin-3-O-β-D-oleandropyranosyl- 11.71 ± 1.36 (HL-60); 43.77 ± 7.03 (PC-3) d 18 (1→4)-β-D-cymaropyranoside, 23 Qinyangshengenin-3-O-β-D-oleandropyranosyl- (1→4)-β-D-oleandropyranosyl-(1→4)-β- 9.94 ± 0.73 (HL-60); 16.01 ± 3.87 (PC-3) d 18 D-cymaropyranoside, 24 20-O-Salicyl-kidjoranin 51 6.72 (HL-60); 2.89 (MCF-7) b 14 Rostratamin 2.49 (HL-60) b 14 Qingyangshengenin 6.72 (K-562) b 14 ＞150 (HeLa); ＞150 (Bel-7402); ＞150 (SGC-7901); ＞150 Glaucogenin E 120 e 38 (BGC-823) Neocynapanogenin F 3-O-β-D-thevetoside 121 ＞150 (HeLa); 4.0 (Bel-7402); ＞150 (SGC-7901); ＞150 (BGC-823) e 38, 39 Glaucogenin C-mono-D-thevetoside 6.1 (HeLa); 98 (Bel-7402); 100 (SGC-7901); ＞150 (BGC-823) e 38 120 (HeLa); ＞150 (Bel-7402); ＞150 (SGC-7901); ＞150 Glaucogenin A e 38 (BGC-823) 170.52 (HepG-2, 24 h); 84.51 (HepG-2, 48 h); 55.50 (HepG-2, 72 h); Caudatin a 46,52 13.49 (SMMC-7721)
Wilfoside C1N 46.07 ± 4.2 (A549) a 49
Wilfoside C3N 33.02 ± 5.7 (A549) a 49
Wilfoside K1N 59.92 ± 4.6 (A549) a 49,51 Caudatin-2,6-dideoxy-3-O-methy-β-D- 24.95 (SMMC-7721) a 52 cymaropyranoside Auriculoside A 24.10 (MCF-7); 23.21 (HO-8910); 26.55 (Bel-7402) a 54 Caudatin 3-O-β-D-cymaropyranosyl-(1→4)-β-D- 12.2 ± 0.6 (HepG-2); 16.4 ± 2.1 (HT-29); 12.6 ± 0.5 (SGC-7901) a 55 cymaropyranosyl-(1→4)-β-D-oleandropyranoside
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Taxon: a: C. auriculatum; b: C. wilfordii; c: C. otophyllum; d: C. wallichii; e: C. stauntonii; f: C. sublanceolatum; g: C. amplexicaule; h: C. Forrestii; i: C. inamoenum; j: C. chekiangense; k: C. paniculatum; l: C. atratum; m: C.vincetoxicum; n: C. bungei; o: C. mongolicum; p: C. glaucescens; q: C. saccatum; r: C. decipines; s: C. versicolor Oligosaccharide chain:
RA1 = β-D-Dit; RA2 = β-D-ole; RA3 = β-D-The; RA4 = β-D-Cym; RA5 = β-L-Dig
RB1 = β-D-Cym-β-D-Ole; B2 = β-D-Dit-β-D-Cym; RB3 = β-D-Cym-α-L-Dig; RB4 = β-D-Cym-β-D-Dit; RB5 = β-D-Cym-β-D-Glc; RB6 = β-L-Cym-β-D-Dit
RC1 = β-D-Cym-α-L-Dig-β-D-Cym; RC2 = β-D-Cym-β-D-Ole-β-D-Ole; RC3 = β-D-Cym-β-D-Cym-β-D-Ole; RC4 = β-D-Dit-β-D-Cym-β-D-
Ole; RC5 = β-D-The-β-D-Dit-β-D-Cym; RC6 = β-D-Ole-β-D-Dit-α-L-Cym; RC7 = β-D-The-β-D-Cym-β-L-Dig; RC8 = β-D-Cym-β-D-Dit-α-L-
Cym; RC9 = β-D-Cym-β-D-Cym-α-L-Cym; RC10 = β-D-The-β-D-Cym-β-D-Cym; RC11 = β-D-The-β-D-3-Demethyl-2-deoxythe-β-D-Ole;
RC12=β-D-Can-β-D-Dit-α-L-Cym; RC13 = β-D-Ole-β-D-3-Demethyl-2-deoxythe-β-D-Ole; RC14 = β-D-Ole-β-D-Dit-α-L-Ole; RC15 = β-D-
Ole-β-D-3-Demethyl-2-deoxythe-β-D-Cym; RC16 = β-D-Ole-β-D-Cym-α-L-Ole; RC17 = β-D-Dit-β-D-Dit-α-L-Cym; RC18 = β-D-Cym-β-D-
Dit-α-L-Ole; RC19=β-D-Ole-β-D-Dig-α-L-Ole; RC20=β-D-Cym-α-L-Cym-β-D-Cym; RC21=β-D-Cym-β-D-Cym-β-D-Cym; RC22 = β-D-Cym-
β-D-Dit-α-L-Dig; RC23 = β-D-Cym-β-D-Dit-α-D-Ole; RC24 = β-D-Cym-α-L-Dig-β-D-Ole; RC25 = β-D-Cym-β-D-3-Demethyl-2-deoxythe-α-
D-Ole; RC26 = β-D-Ole-β-D-Cym-α-L-Cym
RD1 = β-D-Dit-β-D-Dit-α-L-Cym-β-D-Cym; RD2 = β-D-Dit-β-D-3-O-Acetyldit-α-L-Cym-β-D-Cym; RD3 = β-D-Dit-β-D-Cym-β-D-Ole-β-D-
Cym; RD4 = β-D-Cym-β-D-Cym-β-D-Ole-β-D-Cym; RD5 = β-D-Cym-α-L-Dig-β-D-Cym-α-L-Cym; RD6 = β-D-Dit-β-D-Cym-β-D-Ole-β-D-
Glc; RD7 = β-D-Dit-β-D-Cym-β-D-The-β-D-Glc; RD8 = β-D-The-β-D-Cym-β-D-Cym-α-L-Dig; RD9 = β-D-The-β-D-Cym-β-D-Cym-α-L-
Cym; RD10 = β-D-Cym-β-D-Dit-α-L-Cym-β-D-Glc; RD11 = β-D-Cym-α-L-Sar-β-D-Dit-β-D-Cym; RD12 = β-D-The-β-D-Dit-β-D-Cym-α-L-
Cym; RD13=β-D-Ole-β-D-Dit-β-D-Ole-β-D-Glc; RD14=β-D-Ole-β-D-Dit-α-L-Cym-β-D-Glc; RD15=β-D-Cym-α-L-Cym-β-D-Cym-β-D-Glc;
RD16 = β-D-Dit-β-D-Dit-α-L-Cym-β-D-Glc; RD17 = β-D-Cym-α-L-Dig-β-D-Cym-β-D-Glc; RD18 = β-D-Cym-β-D-Dit-α-L-Ole-β-D-Glc; RD19
= β-D-Cym-α-L-Dig-β-D-Glc-β-D-Glc; RD20 = β-D-Cym-β-D-Cym-α-L-Cym-β-D-Glc; RD21 = β-D-Cym-β-D-Cym-β-D-Ole-β-D-Ole; RD22 = β-D-Cym-β-D-Dit-α-D-Ole-β-D-Glc
RE1 = β-D-Dit-β-D-Dit-α-L-Cym-β-D-Cym-α-L-Cym; RE2 = β-D-Dit-β-D-3-O-Acetyldit-α-L-Cym-β-D-Cym-α-L-Cym; RE3 = β-D-Cym-β-
D-Cym-β-D-Ole-β-D-Glc-β-D-Glc; RE4 = β-D-Cym-β-D-Ole-α-L-Cym-β-D-Glc-β-D-Glc; RE5 = β-D-Dit-β-D-Ole-β-D-Cym-β-D-Glc-β-D-
Glc; RE6 = β-D-Dit-β-D-Cym-β-D-Ole-β-D-Cym-β-D-Glc; RE7 = β-D-Cym-β-D-Ole-β-D-Cym-β-D-Glc-β-D-Glc; RE8 = β-D-Cym-β-D-
Cym-β-D-Ole-β-D-Cym-β-D-Glc; RE9 = β-D-Cym-α-L-Dig-β-D-Cym-α-L-Cym-β-D-Glc; RE10 = β-D-Cym-α-L-Sar-β-D-Dit-β-D-Cym-α-L-
Cym; RE11 = β-D-Ole-β-D-Dit-α-L-Cym-β-D-Glc-β-D-Glc; RE12=β-D-3-Demethyl-2-deoxythe-β-D-Dit-α-L-Cym-β-D-Glc-β-D-Glc; RE13 =
β-D-Cym-β-D-Dit-α-L-Cym-β-D-Glc-β-D-Glc; RE14=β-D-Ole-β-D-Ole-β-D-Cym-β-D-Glc-β-D-Glc
RF1 = β-D-Cym-α-L-Dig-β-D-Cym-α-L-Cym-β-D-Glc-β-D-Glc; RF2 = β-D-Cym-β-D-Cym-β-D-Ole-β-D-Cym-β-D-Glc-β-D-Glc; RF3 = β-D-
Dit-α-L-Cym-β-D-Dit-β-D-Cym-α-L-Cym-β-D-Glc; RF4 = β-D-Ole-β-L-Cym-β-L-Cym-β-D-Ole-β-D-Glc-β-D-Glc; RF5 = β-D-Ole-β-D-Ole-
β-D-Ole-β-D-Ole-β-D-Glc-β-D-Glc; RF6 = β-D-Ole-β-D-3-Demethyl-2-deoxythe-β-L-Cym-β-D-Ole-β-D-Glc-β-D-Glc; RF7 = β-D-3-
Demethyl-2-deoxythe-β-L-Cym-β-D-Ole-β-D-Ole-β-D-Glc-β-D-Glc; RF8 = β-D-Cym-α-L-Sar-β-D-Dit-β-D-Cym-α-L-Cym-β-D-Glc; RF9 = β-D-Ole-β-D-Ole-β-L-Cym-β-D-Ole-β-D-Glc-β-D-Glc
RG1 = β-D-Cym-β-D-Ole-α-L-Cym-β-D-Cym-β-D-Cym-β-D-Ole-β-D-Glc; RG2 = β-D-Cym-β-D-Ole-α-L-Cym-β-D-Cym-β-D-Cym-α-L-
Cym-β-D-Glc; RG3 = β-D-Dig-β-D-Ole-α-D-Ole-β-D-Glc-α-L-Cym-α-D-Ole-α-L-Cym; RG4 = β-D-Dig-β-D-Cym-β-D-Ole-β-D-Glc-α-L-
Cym-α-D-Ole-α-L-Cym; RG5=β-D-Cym-α-L-Dig-β-D-Cym-α-L-Cym-β-D-Cym-α-L-Cym-β-D-Glc
The extraction of the roots of C. wallichii has resulted in two 6.72 μmol·L−1 (Table 6). new compounds, qinyangshengenin-3-O-β-D- oleandropyranosyl- The cytotoxicity assay of glaucogenin E (120), (1→4)-β-D-cymaropyranoside 23 and qinyangshengenin-3-O- neocynapanogenin F 3-O-β-D-thevetoside (121), glaucogenin β-D-oleandropyranosyl-(1→4)-β-D-oleandropyranosyl-(1→4)- C-mono-D-thevetoside (GCT) and glaucogenin A (GA) β-D-cymaropyranoside 24 [18]. Both of them produce isolated from C. stauntonii has been performed in various cytotoxicity towards human breast cancer cells (HL-60) and human cancer cells such as HeLa, human hepatocellular prostatic carcinoma cells (PC-3), with the IC50 values being carcinoma cells (Bel-7402), human gastric cancer cells 11.71 ± 1.36 and 9.94 ± 0.73 µmol·L−1 for HL-60, and 43.77 (SGC-7901) and human gastric cancer cells (BGC-823) by ± 7.03 and 16.01 ± 3.87 µmol·L−1 for PC-3,, respectively microculture tetrazolium (MTT) test, with docetaxel as the (Table 6). reference compound. GCT showes cytotoxicity against HeLa,
The extraction of roots of C. wilfordii has yielded three Bel-7402 and SGC-7901 cells with IC50 values being 6.1, 98, −1 C21 steroids, namely 20-O-salicyl-kidjoranin (51), rostratamin and 100 µmol·L , respectively GA and 121 are cytotoxic [14] and qingyangshengenin . Compound 51 showes significant towards HeLa and Bel-7402 cells with IC50 values bieng 120 inhibitory activity against the proliferation of HL-60 and and 4.0 µmol·L−1 [38], respectively. The cytotoxic activities MCF-7 cells, compared with positive control Adriamycin (P against SMMC-7721, BGC-823, HL-60 and A-549 (human −1 < 0.05), with IC50 values being 6.72 and 2.89 μmol·L , lung adenocarcinoma cells) of 121 and neocynapanogenin F respectively. Rostratamin showes a significant cytotoxicity (NF) have also been measured by MTT assay (Table 6). −1 on HL-60 with IC50 value being 2.49 μmol·L and Significant cytotoxic effect on HL-60 cells with the inhibitory qingyangshengenin showes cytotoxicity on human immortalised rate of 98.14% bieng observed at 10 µg·mL−1 of NF [39]. myelogenous leukemia line (K-562) with IC50 value being Caudatin, a C21 steroidal aglycone from the roots of C.
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auriculatum, exhibits anticancer activity against human mechanism of C3N-induced apoptosis in ECA109 cells is hepatoma cells (HepG-2). The in vitro bioassay results show dependent on the overexpression of activated caspase-2 and that caudatin possesses inhibition of cell proliferation in a the decreased expression of Bcl-2, which induces cytochrome dose- and time-dependent manner, with IC50 values being c release, up-regulates caspase-9 expression, and initiats the 170.52, 84.51, and 55.50 µmol·L−1 at 24, 48, and 72 h, subsequent events, leading to apoptosis. respectively (Table 6). Activation of extracellular-signal Six C21 steroid constituents, viz., wilfoside C1G, caudatin, regulating kinase (ERK) and c-Jun N-terminal kinase (JNK) cynauriculoside A, cynauriculoside C, metaplexigenin, and could be involved in caudatin-induced HepG-2 cell apoptosis. caudatin-2,6-dideoxy-3-O-methy-β-D-cymaropyranoside The preliminary observation indicates that caudatin arrests (CDMC) have been isolated from the roots of C. auriculatum. cell proliferation and induces cell apoptosis, at least partially, They are administered in combination with the chemother- via caspase-dependent apoptotic pathway and phosphorylation apeutic agent 5-fluorouracil (5-FU) to test their inhibitory of the ERK and JNK [46]. These signal transduction pathways action against human tumor cell lines SMMC-7721, MCF-7 might also be regulated by other structurally related and Hela by the MTT method [52]. Of them, caudatin and compounds. CDMC show the highest effects against SMMC-7721 cells −1 The total C21 steroidal glycosides (TSG) from the with IC50 values being 13.49 and 24.95 μmol·L , chloroform extract of C. auriculatum causes a reduction in rat respectively. Moreover, CDMC inhibits the growth of glioma C6 cells viability and the enhancement of apoptosis in SMMC-7721 cells in a dose- and time-dependent manner a dose- and time-dependent manner. TSG has the potent (Table 6). It also induces apoptosis rather than necrosis in growth-inhibiting and apoptosis-inducing effects on C6 SMMC-7721 cells, through caspase 3 activation. It is [47] cells in vivo . The total C21 steroidal glycosides (TGB) demonstrated that the anticancer activity of CDMC could be from the butanol extract of the same plant exhibits moderate attributed partially to induction of apoptosis associated with antihepatocarcinoma activity against Heps cells. After caspase 3-dependent pathway [53]. In addition, CDMC and treatment with 10, 20, and 40 mg·kg−1 of TGB, tumor caudatin significantly inhibit the growth of transplantable inhibition rates on the transplanted Heps are 34.79%, 47.08% hepatoma-22 (H22) in mice, compared to 5-FU as positive and 50.23%, respectively. TGB also exhibits an ablility to control [52]. Whether other similar compounds regulate pro- induce apoptosis in Heps by downregulating B-cell apoptotic pathways should also be investigated in the future. lymphoma- leukemia-2 gene (Bcl-2) expression. It is Auriculoside A (AA), isolated from the roots of C. presumed that inhibition on excessive expression of Bcl-2 auriculatum, has been found to inhibit the growth of several gene to promote apoptosis might be one of the major human tumor cells and to induce apoptosis in MCF-7 cells in antitumor mechanisms for TGB [48]. vitro. AA also exhibits considerable antitumor activity in
Wilfosides C1N, C3N, and K1N are abundant and active mice transplanted with implanted sarcoma-180 (S180). constituents in C. auriculatum. They inhibit the proliferation Compared with negative controls, the inhibitory rates increase of A549 cells in dose-dependent manner. In that study (MTT in a dose-dependent manner both in vitro and in vivo. AA has assay), A549 cells were exposed to these compounds at been evaluated for its cytotoxicity against MCF-7, HO-8910 different concentrations (5, 10, 20, 40, 60, 80, and 100 and Bel-7402 cells with IC50 values being 24.10, 23.21 and −1 −1 μmol·L ) for 48 h , and IC50 values were showen to be 46.07 26.55 μmol·L , respectively (Table 6). Moreover, AA ± 4.2, 33.02 ± 5.7, 59.92 ± 4.6 μmol·L−1, respectively [49] showes a clear apoptosis-inducing effect on MCF-7 cells in a −1 (Table 6). Although C3N showed a much better absorption time-dependent manner. When treated with 40 µg·mL of than C1N, virtually no study had been conducted to elucidate AA for 24, 48 and 72 h, the apoptotic rates of the cells are 5, its mechanism [50]. Liu et al [51] have described the effects of 8 and 18.5%, respectively [54]. Although AA has a potential to
C3N on the esophageal carcinoma cell lines (ECA109) and be developed into an active chemotherapeutic agent against the mechanism of C3N-induced apoptosis in these cells. C3N human cancers, the underlying mechanisms of action has not inhibits the proliferation of ECA109 cells moderately in a been fully elucidated. dose- and time-dependent manner and induces apoptosis in Caudatin 3-O-β-D-cymaropyranosyl-(1→4)-β-D-cymaro- ECA109 cells. The percentages of apoptotic ECA109 cells pyranosyl-(1→4)-β-D-oleandropyranoside (CG), isolated from −1 treated with C3N at 2, 4, 8, and 16 mg·mL for 48 h were roots of C. auriculatum, inhibits the growth of HepG-2, (3.6 ± 0.5)%, (10.2 ± 0.9)%, (18.9 ± 1.2)% and (21.3 ± 2.7)%, HT-29 and SGC-7901 cells in a dose- and time-dependent respectively, compared to negative control (1.5 ± 0.6)%. C3N manner in vitro. The IC50 values of CG, ranging between 12.2 induces apoptosis in ECA109 through a mitochondrial and 16.4 μmol·L−1, are lower than that of AA, demonstrating pathway by triggering cytochrome c released from the greater cytotoxic effects than AA (Table 6). Furthermore, CG mitochondria, with caspase-2 functioning upstream of induces cancer cell apoptosis at a lower concentration than a [54] caspase-9 rather than association with Fas and caspase-8. number of other C21 steroidal glycosides . As analyzed by −1 Furthermore, C3N-driven apoptotic events are also associated assay, treatment with 21.6 μmol·L of CG for only 24 h with downregulation of Bcl-2. These results indicate that the induces apoptosis in > 40% cells, which is consistent with its
– 331 – GU Xiao-Jie, et al. / Chin J Nat Med, 2016, 14(5): 321334 strong cytotoxicity observed in cancer cells [55]. malonaldehyde content, and increase the superoxide Antidepressant activity dismutase activity of serum, heart, liver and brain in
Total C21 steroidal glycosides (TGC), from 80% ethanol D-galactose induced aging model mice as well as the extract of C. auriculatum, and its CHCl3/MeOH (10 : 1) telomerase activity of serum and heart tissues, but not of fractions (TGC-D and TGC-E) display potential antide- liver and brain tissues [57]. pressant activity in mice. TGC, TGC-D, and TGC-E (80 Na+/K+-ATPase inhibitory activity mg·kg−1) decrease the immobility times by 61.7%, 64.5%, Two Na+/K+-ATPase inhibitors stauntosaponin A (64) and 61.9% in tail suspension test, respectively. TGC (80 and stauntosaponin B (65), isolated from the roots of C. mg·kg−1), TGC-D (80 mg·kg−1), and TGC-E (20 mg·kg−1) stauntonii,show moderate inhibitory activities against + + −1 decrease the immobility times by 32.6, 47.3, and 48.7% in Na /K -ATPase with IC50 values being 21 and 29 μmol·L , forced swimming test, respectively. TGC (80 mg·kg−1) and respectively, whereas ouabain as a positive control that −1 −1 [28] TGC-E (20 and 40 mg·kg ) decrease the crossing distances displays an IC50 value of 3.5 μmol·L . by 28.8, 29.5, and 36.2% in locomotor activity test, Appetite suppressing activity respectively. TGC, TGC-D, and TGC-E (10 mg·L−1) inhibit Obesity has become a serious concern because it serotonin reuptake by 7.4%, 4.5%, and 71.1% in rat brain increases the risk of cardiovascular disease, type 2 diabetes synaptosomes, respectively, and the IC50 value of TGC-E is and other health problems. To reduce food intake is an 5.2 mg·L−1, further revealing that TGC-E may at least efficient way to control both obesity and overweight. The two [56] partly inhibits serotonin reuptake . Additionally, other most abundant compounds wilfoside K1N and C1N, isolated five C21 steroidal glycosides, viz., cynanauriculoside C 21, from the roots of C. auriculatum, possess the potential cynanauriculoside D 22, cynanauriculoside E 37, otophylloside, anti-obesity action [58]. They up-regulate hypothalamic ATP and cynauricuoside C from the same plant, show significant level and affect the sense of satiety to stop eating because antidepressant effect at the dosage of 50 mg·kg−1 (i.g.) and the their structures resemble that of P57 (3β-[β-D- most potent one is 22, which is close to the positive control thevetopyranosyl-(1→4)-β-D-cymaropyranosyl-(1→4)-β-D-c fluoxetine (20 mg·kg−1) [17]. ymaropyranosyloxy]-12β-tigloyloxy-14β-hydroxypregn-5-en- Antifungal activity 20-one), a natural appetite suppressant [58]. The presence of
Six C21 steroidal glycosides isolated from the roots of C. two compounds is responsible for appetite suppressing effect [9] wilfordii, viz, wilfoside K1GG 4, wilfoside C1GG 33, with a concomitant overall decrease in body weight . wilfoside C1N, K1N, C1G, and cynauricuoside A (CA) have Antiviral activity been tested for their antifungal activities against barley Paniculatumosides C, D, and E (PC-PE), isolated from C. powdery mildew,compared with polyoxin B [10]. The caudatin paniculatum, show potent antiviral activities. They are glycosides (C1N, C1G and 33) exhibit stronger in vivo antifungal effective and selective inhibitors to alphavirus-like activities than polyoxin B, with disease-control values being > positive-strand RNA viruses including plant-infecting tobacco 77% at a concentration of 63 μg·mL−1, whereas the kidjoranine mosaic virus (TMV), animal-infecting Sindbis virus (SINV), glycosides (K1N, CA and 4) have weaker activities than eastern equine encephalitis virus (EEEV), and Getah virus −1 polyoxin B. The IC50 values are 3.24 μg·mL for C1N, (GETV), but not other unrelated RNA or DNA viruses, yet −1 −1 [59] 12.90 μg·mL for C1G, and 28.35 μg·mL for 33, they are not toxic to host cells . PC-PE show inhibition of −1 compared to polyoxin B (IC50 71.36 μg·mL ). The TMV infection with IC50 values being each about 25 structural difference between the two groups is the substituent nmol·L−1. PC is an effective inhibitor of SINV, GETV and −1 at C-12; caudatin glycosides have an ikemaoyl group, while EEEV, with EC50 values bieng 1.5, 1, and 2 nmol·L , kidjoranine glycosides have a cinnamoyl group. Among three respectively. In vivo administration of PC-PE protects caudatin glycosides, the tetraglycoside (C1N) most effectively BALB/c mice from lethal SINV infection without adverse controls barley powdery mildew, followed by the effects. The mechanism of action for the antiviral activities is pentaglycoside (C1G) and the hexaglycoside (33). Structure- that compounds specifically suppress the expression of viral activity relationship studies have revealed that the antifungal subgenomic (sg) RNA without affecting the expression of activities of pregnane glycosides may be attributed to the viral genomic RNA. Thus, PC-PE have the potential for polarity of the glycosidic linkage and to the nature of the further development as antiviral agents against alphavirus hydrophobic ester linkage at C-12. Moreover, the antifungal superfamily and other positive-strand RNA virus infections in [59] activities of C21 steroidal glycosides could be increased by the humans and in plants as well . removal of the C-3 glycone moiety, indicating that the sugar Conclusion moiety may play a key role in antifungal activity [10].
Antitaging activity The phytochemical studies on C21 steroid constituents
Total C21 steroidal glycosides (CSG) from the roots of from Cynanchum species are initially motivated by their C. auriculatum show satisfactory antiaging activity in widespread clinical use in Chinese folk medicines. Modern mice. CSG antagonize free radical injury, decrease the pharmacological investigations of these constituents indicate
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Cite this article as: GU Xiao-Jie, HAO Da-Cheng. Recent advances in phytochemistry and pharmacology of C21 steroid constituents from Cynanchum plants [J]. Chin J Nat Med, 2016, 14(5): 321-324
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