Chemical diversity of ginseng saponins from Panax ginseng.

Ginseng, a perennial plant belonging to the genus Panax of the Araliaceae family, is well known for its medicinal properties that help alleviate pathological symptoms, promote health, and prevent potential diseases. Among the active ingredients of ginseng are saponins, most of which are glycosides of triterpenoid aglycones. So far, numerous saponins have been reported as components of Panax ginseng, also known as Korean ginseng. Herein, we summarize available information about 112 saponins related to P. ginseng; >80 of them are isolated from raw or processed ginseng, and the others are acid/base hydrolysates, semisynthetic saponins, or metabolites.

Introduction

Ginseng has been one of the most important components in a number of East Asian herbal remedies. In fact, the term ginseng, without any modifier, refers particularly to the species Panax ginseng Meyer or sometimes even more specifically to the root of the plant species. As the name ginseng carries authority and veneration in East Asian medicine, other plants that have some properties in common with P. ginseng have been allegedly called “ginseng”. Eventually, ginseng has become a blanket term that encompasses >10 species of perennial plants belonging to the genus Panax of the family Araliaceae [1], [2]. Currently, 14 plants, including 12 species and two infraspecific taxa, have been recognized as members of the genus Panax, as shown in Table 1 [3]. Some of the Panax plants have common names, which stem from their countries of origin: P. ginseng, Panax japonicus, Panax notoginseng, Panax quinquefolius, and Panax vietnamensis are also called Korean ginseng, Japanese ginseng, Chinese ginseng, American ginseng, and Vietnamese ginseng, respectively. Of the Panax plants, Korean ginseng, Chinese ginseng, and American ginseng have been commercially cultivated; Vietnamese ginseng has recently been introduced for agriculture. Most ginseng species are native to Asia, especially East Asia. Thus, the use of equivocal names, such as Asian ginseng that often refers to P. ginseng, is discouraged.

Table 1

Scientific and common names of panax plants

Scientific name	Rank	Common name
Panax bipinnatifidus Seem	Species
Panax bipinnatifidus var. angustifolius	Infraspecific taxon
Panax bipinnatifidus var. bipinnatifidus	Infraspecific taxon
Panax ginseng C. A. Mey.	Species	Korean ginseng, Ginseng
Panax japonicus (T. Nees) C. A. Mey.	Species	Japanese ginseng
Panax notoginseng (Burkill) F. H. Chen	Species	Chinese ginseng, sanchi
Panax pseudoginseng Wall.	Species
Panax quinquefolius L.	Species	American ginseng
Panax sokpayensis Shiva K. Sharma & Pandit	Species
Panax stipuleanatus H. T. Tsai & K. M. Feng	Species
Panax trifolius L.	Species
Panax vietnamensis Ha & Grushv.	Species	Vietnamese ginseng
Panax wangianus S. C. Sun	Species
Panax zingiberensis C. Y. Wu & Feng	Species

While the variety of species renders some pharmacological effects specific to certain species, ginseng, in general, displays restorative, tonic, and revitalizing properties [4]. Thus far, >6,000 articles regarding the traditional uses, chemical constituents, and biological and pharmacological effects of ginseng have been published since Petkov [5] reported the pharmacological properties of P. ginseng extracts in the 1950s. Such pharmacological activities of ginseng have been found to be mainly attributed to ginseng saponins, also known as ginsenosides [6], [7], [8], [9], [10], [11].

Since the first isolation of six ginsenosides from P. ginseng in the 1960s [12], plenty of ginsenosides have been isolated and identified from the species. In this review, we recapitulate the chemical structures, molecular masses, and monoisotopic masses of saponins from various parts of P. ginseng, including roots, flower buds, fruits, and leaves. In addition, we furnish available information about artifactual saponins formed during physicochemical and/or biological treatment and compounds synthesized from saponins isolated from P. ginseng.

Classification of ginseng saponins according to their genin structures

Most ginseng saponins are believed to be biosynthesized from 2,3-oxidosqualene, which is also the precursor of β-sitosterol, a steroid commonly found in plants [13]. It has been suggested that the action of three different enzymes on 2,3-oxidosqualene leads to the formation of cycloartenol, dammarenediol-II, and β-amyrin, the latter two of which are eventually biotransformed into ginseng saponins. Fig. 1 shows the proposed biosynthetic pathway of ginseng saponins and β-sitosterol. Dammarenediol-II is the precursor of dammarane-type saponins, including ginsenosides Rb1, Rb2, Re, and Rg1, which account for a significant portion of saponins found in ginseng species. Dammarane-type saponins are further classified into various groups. By contrast, oleanane-type saponins are biosynthesized from β-amyrin. In P. ginseng, however, oleanane-type saponins other than ginsenoside Ro are rare and often practically undetectable.

Fig. 1

Biosynthetic pathways of ginseng saponins. 2,3-Oxidosqualene may be cyclized into three different compounds, two of which are dammarenediol-II and β-amyrin, the precursor of dammarane-type saponins and oleanane-type saponins, respectively.

Table 2 [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] displays the molecular formulas, molecular masses, monoisotopic masses, and parts of ginseng saponins, isolated from or related to P. ginseng, that are used. We categorize the ginseng saponins based upon the position of hydroxyl group(s) and/or double bond(s) of their genins.

Table 2

Useful information about saponins isolated from p. ginseng, synthetic saponins, and saponin metabolites

No.	Saponin	Formula	Backbone (Fig. 2)	Molecular mass (u) 1)	Monoisotopic mass (u) 1)	Plant part (process)	Refs
	Saponins from Panax ginseng
1	Protopanaxadiol	C30H52O3	A	460.73	460.3916	(Hydrolysis)	[14], [15]
2	Ginsenoside F2	C42H72O13	A	785.01	784.4973	Leaves	[16]
3	Ginsenoside Ra1	C58H98O26	A	1,211.38	1,210.6346	Roots	[17]
4	Ginsenoside Ra2	C58H98O26	A	1,211.38	1,210.6346	Roots	[17]
5	Ginsenoside Ra3	C59H100O27	A	1,241.41	1,240.6452	Roots	[18]
6	Ginsenoside Rb1	C54H92O23	A	1,109.29	1,108.6029	Roots	[19], [20], [21], [22]
7	Ginsenoside Rb2	C53H90O22	A	1,079.27	1,078.5924	Roots	[19], [20], [21]
8	Ginsenoside Rb3	C53H90O22	A	1,079.27	1,078.5924	Roots	[23]
9	Ginsenoside Rc	C53H90O22	A	1,079.27	1,078.5924	Roots	[19], [20], [21]
10	Ginsenoside Rd	C48H82O18	A	947.15	946.5501	Roots	[19], [20], [21], [24]
11	Ginsenoside Rg3	C42H72O13	A	785.01	784.4973	Steamed roots	[20], [25]
12	Ginsenoside Rh2	C36H62O8	A	622.87	622.4445	Steamed roots	[25]
13	Ginsenoside Rs1	C55H92O23	A	1,121.31	1,120.6029	Roots	[20]
14	Ginsenoside Rs2	C55H92O23	A	1,121.31	1,120.6029	Roots	[20]
15	Ginsenoside Rs3	C44H74O14	A	827.05	826.5079	Steamed roots	[26]
16	Malonylginsenoside Ra3	C62H102O30	A	1,327.46	1,326.6456	Roots	[27]
17	Malonylginsenoside Rb1	C57H94O26	A	1,195.34	1,194.6033	Roots	[28]
18	Malonylginsenoside Rb2	C56H92O25	A	1,165.31	1,164.5928	Roots	[28]
19	Malonylginsenoside Rc	C56H92O25	A	1,165.31	1,164.5928	Roots	[28]
20	Malonylginsenoside Rd	C51H84O21	A	1,033.20	1,032.5505	Roots	[28]
21	Malonylnotoginsenoside R4	C62H102O30	A	1,327.46	1,326.6456	Roots	[29]
22	Protopanaxatriol	C30H52O4	A	476.73	476.3866	(Hydrolysis)	[30]
23	Floralginsenoside M	C53H90O22	A	1,079.27	1,078.5924	Flower buds	[31]
24	Floralginsenoside N	C53H90O22	A	1,079.27	1,078.5924	Flower buds	[31]
25	Floralginsenoside P	C53H90O23	A	1,095.27	1,094.5873	Flower buds	[31]
26	Ginsenoside F1	C36H62O9	A	638.87	638.4394	Leaves	[16]
27	Ginsenoside F3	C41H70O13	A	770.99	770.4816	Leaves	[16]
28	Ginsenoside Re	C48H82O18	A	947.15	946.5501	Roots	[20], [21], [24], [32]
29	Ginsenoside Rf	C42H72O14	A	801.01	800.4922	Roots	[20], [32]
30	Ginsenoside Rg1	C42H72O14	A	801.01	800.4922	Roots	[20], [21], [33]
31	Ginsenoside Rg2	C42H72O13	A	785.01	784.4973	Roots	[25], [32], [34], [35]
32	Ginsenoside Rh1	C36H62O9	A	638.87	638.4394	Steamed roots	[21], [25], [34]
33	20-Glucoginsenoside Rf	C48H82O19	A	963.15	962.5450	Roots	[23]
34	Floralginsenoside H	C50H84O21	B-(a)	1,021.19	1,020.5505	Flower buds	[36]
35	Floralginsenoside Tc	C53H90O24	B-(a)	1,111.27	1,110.5822	Flower buds	[37]
36	Floralginsenoside Td	C53H90O24	B-(a)	1,111.27	1,110.5822	Flower buds	[37]
37	Ginsenoside I	C48H82O20	B-(a)	979.15	978.5400	Flower buds	[38]
38	Ginsenoside II	C48H82O20	B-(a)	979.15	978.5400	Flower buds	[38]
39	Floralginsenoside A	C42H72O16	B-(a)	833.01	832.4820	Flower buds	[39]
40	Floralginsenoside C	C41H70O15	B-(a)	802.99	802.4715	Flower buds	[39]
41	Floralginsenoside J	C48H82O20	B-(a)	979.15	978.5400	Flower buds	[36]
42	Floralginsenoside Ka	C36H62O11	B-(a)	670.87	670.4292	Flower buds	[40]
43	Ginsenoside SL1	C36H62O11	B-(a)	670.87	670.4292	Steamed leaves	[41]
44	Ginsenoside Rg7	C36H60O9	B-(b)	636.86	636.4237	Leaves	[42]
45	Floralginsenoside La	C48H82O19	B-(b)	963.15	962.5450	Flower buds	[36]
46	Floralginsenoside Lb	C48H82O19	B-(b)	963.15	962.5450	Flower buds	[36]
47	Floralginsenoside Ta	C36H60O10	B-(c)	652.86	652.4187	Flower buds	[37]
48	Floralginsenoside E	C42H72O15	C-(a)	817.01	816.4871	Flower buds	[39]
49	Floralginsenoside F	C42H72O15	C-(a)	817.01	816.4871	Flower buds	[39]
50	Floralginsenoside G	C50H84O21	C-(a)	1,021.19	1,020.5505	Flower buds	[36]
51	Floralginsenoside K	C48H82O21	C-(a)	995.15	994.5349	Flower buds	[36]
52	Floralginsenoside O	C53H90O22	C-(a)	1,079.27	1,078.5924	Flower buds	[31]
53	Floralginsenoside B	C42H72O16	C-(a)	833.01	832.4820	Flower buds	[39]
54	Floralginsenoside D	C41H70O15	C-(a)	802.99	802.4715	Flower buds	[39]
55	Floralginsenoside I	C48H82O20	C-(a)	979.15	978.5400	Flower buds	[36]
56	Ginsenoside Rh6	C36H62O11	C-(a)	670.87	670.4292	Leaves	[42]
57	Ginsenoside ST2	C36H62O10	C-(b)	654.87	654.4343	Steamed leaves	[43]
58	Ginsenoside Ki	C36H62O10	C-(c)	654.87	654.4343	Leaves	[44]
59	Ginsenoside Km	C36H62O10	C-(c)	654.87	654.4343	Leaves	[44]
60	Floralginsenoside Kb	C45H76O19	D-(a)	921.07	920.4981	Flower buds	[40]
61	Floralginsenoside Kc	C45H76O20	D-(a)	937.07	936.4930	Flower buds	[40]
62	Floralginsenoside Tb	C35H62O11	D-(b)	658.86	658.4292	Flower buds	[37]
63	25-Hydroxyprotopanaxadiol	C30H54O4	E	478.75	478.4022	Fruits	[45]
64	25-Hydroxyprotopanaxatriol	C30H54O5	E	494.75	494.3971	Fruits	[45]
65	Dehydroprotopanaxadiol I	C30H50O2	F-(a)	442.72	442.3811	Steamed roots	[46]
66	Ginsenoside Rg5	C42H70O12	F-(a)	767.00	766.4867	Steamed roots	[47], [48]
67	Ginsenoside Rh3	C36H60O7	F-(a)	604.86	604.4339	Steamed roots	[47], [49]
68	Ginsenoside Rs4	C44H72O13	F-(a)	809.03	808.4973	Steamed roots	[46]
69	Dehydroprotopanaxatriol I	C30H50O3	F-(a)	458.72	458.3760	Steamed roots	[46]
70	Ginsenoside F4	C42H70O12	F-(a)	767.00	766.4867	Leaves	[50]
71	Ginsenoside Rh4	C36H60O8	F-(a)	620.86	620.4288	Steamed roots	[47], [51]
72	Ginsenoside Rs6	C38H62O9	F-(a)	662.89	662.4394	Steamed roots	[46]
73	Ginsenoside Rz1	C42H70O12	F-(b)	767.00	766.4867	Steamed roots	[52]
74	Dehydroprotopanaxadiol II	C30H50O2	F-(c)	442.72	442.3811	Steamed roots	[46]
75	Ginsenoside Rk1	C42H70O12	F-(c)	767.00	766.4867	Steamed roots	[47]
76	Ginsenoside Rk2	C36H60O7	F-(c)	604.86	604.4339	Steamed roots	[47]
77	Ginsenoside Rs5	C44H72O13	F-(c)	809.03	808.4973	Steamed roots	[46]
78	Dehydroprotopanaxatriol II	C30H50O3	F-(c)	458.72	458.3760	Steamed roots	[46]
79	Ginsenoside Rg6	C42H70O12	F-(c)	767.00	766.4867	Steamed roots	[53]
80	Ginsenoside Rk3	C36H60O8	F-(c)	620.86	620.4288	Steamed roots	[47]
81	Ginsenoside Rs7	C38H62O9	F-(c)	662.89	662.4394	Steamed roots	[46]
82	Panaxadiol	C30H52O3	G-(a)	460.73	460.3916	(Hydrolysis)	[54], [55]
83	Panaxatriol	C30H52O4	G-(a)	476.73	476.3866	(Hydrolysis)	[30]
84	Ginsenoside Rh9	C36H60O9	G-(b)	636.86	636.4237	Leaves	[42]
85	12,23-Epoxyginsenoside Rg1	C42H70O14	G-(b)	799.00	798.4766	Leaves	[56]
86	Panaxadione	C30H48O5	G-(c)	488.70	488.3502	Seeds	[57]
87	Ginsenoside Rh5	C36H60O9	H-(a)	636.86	636.4237	Steamed roots	[42]
88	Ginsenoside Rh7	C36H60O9	H-(b)	636.86	636.4237	Leaves	[42]
89	Ginsenoside Rh8	C36H60O9	H-(c)	636.86	636.4237	Leaves	[42]
90	Ginsenoside Ro	C48H76O19	H-(d)	957.11	656.4981	Roots	[19], [22], [58]
91	Ginsenoside SL2	C42H70O14	I-(a)	799.00	798.4766	Steamed leaves	[41]
92	Ginsenoside ST1	C36H60O10	I-(a)	652.86	652.4187	Steamed leaves	[43]
93	Ginsenoside SL3	C42H70O14	I-(b)	799.00	798.4766	Steamed leaves	[41]
94	Hexanordammaran	C24H40O4	I-(c)	392.57	392.2927	Leaves	[59]
95	Isoprotopanaxadiol	C30H52O3	I-(d)	460.73	460.3916	(Hydrolysis)	[60]
	Synthetic saponins
96	Ginsenoside DM1	C48H84O9	J-(a)	805.18	804.6115	(Synthesis)	[61]
97	Ginsenoside PM1	C52H92O9	J-(a)	861.28	860.6741	(Synthesis)	[61]
98	Ginsenoside SM1	C54H96O9	J-(a)	889.33	888.7054	(Synthesis)	[61]
99	C-X1	C53H90O23	J-(a)	1,095.27	1,094.5873	(Synthesis)	[62]
100	C-Y1	C53H90O23	J-(a)	1,095.27	1,094.5873	(Synthesis)	[62]
101	C-Y2	C42H72O14	J-(a)	801.01	800.4922	(Synthesis)	[62]
102	Ginsenoside ORh1	C44H76O10	J-(a)	765.07	764.5439	(Synthesis)	[63]
103	Ocotillol derivative 3a	C36H62O10	J-(b)	654.87	654.4343	(Synthesis)	[64]
104	Ocotillol derivative 3b	C36H62O10	J-(b)	654.87	654.4343	(Synthesis)	[64]
105	Ginsenoside Rp1	C42H74O12	J-(c)	771.03	770.5180	(Synthesis)	[65]
	Saponin metabolites
106	M1 (Compound K)	C36H62O8	K	622.87	622.4445	(Metabolization)	[66]
107	M2 (Compound Y)	C41H70O12	K	754.99	754.4867	(Metabolization)	[66]
108	M3 (Ginsenoside Mc)	C41H70O12	K	754.99	754.4867	(Metabolization)	[66]
109	M6	C47H80O17	K	917.13	916.5396	(Metabolization)	[66]
110	M7 (Ginsenoside Mb)	C47H80O17	K	917.13	916.5396	(Metabolization)	[66]
111	M9 (Gp-LXXV)	C48H82O18	K	947.15	946.5501	(Metabolization)	[66]
112	M13 (Gp-XVII)	C42H72O13	K	785.01	784.4973	(Metabolization)	[66]

The calculations are based upon the latest atomic mass data from the International Union of Pure and Applied Chemistry (IUPAC) [67].

Protopanaxadiol, protopanaxatriol, and their glycosides

As shown in Fig. 1, dammarenediol-II is hydroxylated to protopanaxadiol (PPD), 3β,12β,20-trihydroxydammar-24-ene. Ultimately, a number of saponins are biosynthesized by O-glycosylation of PPD that involves the attachment of saccharide(s) to C-3 and/or C-20. Typical PPD-type saponins include ginsenosides Rb1, Rb2, Rc, and Rd, which are found in the roots [19], [20], flower buds [21], and leaves [21] of P. ginseng.

PPD may further be hydroxylated to protopanaxatriol (PPT), 3β,6α,12β,20-tetrahydroxydammar-24-ene. A variety of saponins are biosynthesized by O-glycosylation of PPT that involves the attachment of saccharide(s) to C-6 and/or C-20. Typically, the hydroxyl group at C-3 remains free in PPT-type ginsenosides. The two most abundant PPT-type saponins in P. ginseng are ginsenosides Re and Rg1.

Fig. 2A illustrates the structures of PPD- and PPT-type saponins. While most naturally occurring ginsenosides are of the (S)-configuration at C-20, some artifactual ginsenosides exist in two epimeric forms at the carbon.

Fig. 2

Structures of ginseng saponins. A. Structures of ginseng saponins whose genin is 3β,12β,20-trihydroxydammar-24-ene (protopanaxadiol)/3β,6α,12β,20-tetrahydroxydammar-24-ene (protopanaxatriol); B. Structures of ginseng saponins whose genin is (a) 3β,12β,20-trihydroxy-24-hydroperoxydammar-25-ene/3β,6α,12β,20-tetrahydroxy-24-hydroperoxydammar-25-ene; (b) 3β,12β,20,24-tetrahydroxydammar-25-ene/3β,6α,12β,20,24-pentahydroxydammar-25-ene; (c) 3β,6α,12β,20-tetrahydroxydammar-24-one-25-ene; C. Structures of ginseng saponins whose genin is (a) (E)-3β,12β,20-trihydroxy-25-hydroperoxydammar-23-ene/(E)-3β,6α,12β,20-tetrahydroxy-25-hydroperoxydammar-23-ene; (b) (E)-3β,6α,12β,20,25-pentahydroxydammar-23-ene; (c) 3β,6α,12β,26-tetrahydroxydammar-24-ene/3β,6α,12β,27-tetrahydroxydammar-24-ene; D. Structures of ginseng saponins whose genin is (a) 3β,12β,20-trihydroxy-25,26,27-trinordammar-24-al/3β,12β,20,23-tetrahydroxy-25,26,27-trinordammar-24-al; (b) 3β,6α,12β,20-tetrahydroxy-24,24-dimethoxy-25,26,27-trinordammarane; E. Structures of ginseng saponins whose genin is 3β,12β,20,25-tetrahydroxydammarane/3β,6α,12β,20,25-pentahydroxydammarane; F. Structures of ginseng saponins whose genin is (a) (E)-3β,12β-dihydroxydammar-20(22),24-diene/(E)-3β,6α,12β-trihydroxydammar-20(22),24-diene; (b) (Z)-3β,12β-dihydroxydammar-20(22),24-diene; (c) 3β,12β-dihydroxydammar-20(21),24-diene/3β,6α,12β-trihydroxydammar-20(21),24-diene; G. Structures of ginseng saponins whose genin is (a) 3β,12β-dihydroxy-20,25-epoxydammarane (panaxadiol)/3β,6α,12β-trihydroxy-20,25-epoxydammarane (panaxatriol); (b) 3β,6α,20-trihydroxy-12,23-epoxydammar-24-ene; (3) 6α,25-dihydroxy-20,24-epoxydammar-3,12-dione; H. Structure of a ginseng saponin whose genin is (a) 3β,6α,12β,24-tetrahydroxydammar-20(22),25-diene; (b) 3β,7β,12β,20-tetrahydroxydammar-5,24-diene; (c) 3β,6α,20-trihydroxydammar-12-one-24-ene; (d) oleanolic acid; I. Structures of ginseng saponins whose genin is (a) 3β,6α,12β-trihydroxy-24-hydroperoxydammar-20(22),25-diene; (b) 3β,6α,12β-trihydroxy-23-hydroperoxydammar-20(21),24-diene; (c) 3β,6α,12β-trihydroxy-22,23,24,25,26,27-hexanordammar-20-one; (d) (E)-3β,12β,25-trihydroxydammar-20(22)-ene; J. Structures of synthesized saponins whose genin is (a) 3β,12β,20-trihydroxydammar-24-ene (protopanaxadiol)/3β,6α,12β,20-tetrahydroxydammar-24-ene (protopanaxatriol); (b) 3β,12β,25-trihydroxy-20,24-epoxydammarane/3β,6α,12β,25-tetrahydroxy-20,24-epoxydammarane; (c) 3β,12β-dihydroxydammarane; K. Structures of ginseng saponin metabolites whose genin is 3β,12β,20-trihydroxydammar-24-ene (protopanaxadiol)/3β,6α,12β,20-tetrahydroxydammar-24-ene (protopanaxatriol).

Peroxidation products of PPD- and PPT-type saponins

Some saponins isolated from the flower buds of P. ginseng have an aglycone that is believed to be produced via the peroxidation of PPD or PPT [68]. In most cases, the peroxidation occurs at or around the double bond between C-24 and C-25, and eventually leads to various structures. Fig. 2B, C show the structures of ginsenosides whose genin appears to be produced via the peroxidation of PPD or PPT. Fig. 2B-(a) shows the structures of some saponins that have a hydroperoxyl group at C-24 and a double bond between C-25 and C-26. Fig. 2B-(b) contains the genin structure that has a hydroxyl group at C-24, which would be reduced from the hydroperoxyl group shown in Fig. 2B-(a). In addition, Fig. 2B-(c) shows the structure of floralginsenoside Ta, a glycoside of 3β,6α,12β,20-tetrahydroxydammar-24-one-25-ene, which may be considered to be formed by the dehydration of floralginsenoside Ka, whose structure is illustrated in Fig. 2B-(a).

In a similar fashion, Fig. 2C-(a,b) show the structures of ginseng saponins whose genin has a hydroperoxyl group and a hydroxyl group, respectively, at C-25 and a double bond between C-23 and C-24. While geometric isomerism is possible in compounds with a double bond between C-23 and C-24, most of those reported are the (E)-form isomers rather than the (Z)-form. In addition, Fig. 2C-(c) illustrates the structures of ginsenosides whose genin has a hydroxyl group either at C-26 or at C-27, which would be reduced from the hydroperoxyl group formed around the double bond between C-24 and C-25.

Cleavage products of PPD- and PPT-type saponins

The oxidative cleavage of the double bond of some saponins yields an aldehyde with three fewer carbon atoms, that is, 3β,12β,20-trihydroxy-25,26,27-trinordammar-24-al, and its derivatives, which are found mainly in the flower buds of ginseng.

Fig. 2D-(a) shows the structures of ginsenosides whose genin is considered to be formed by the oxidative cleavage of the double bond of PPD or 23-hydroxyprotopanaxadiol. Fig. 2D-(b) shows the structure of floralginsenoside Tb, whose genin is an acetal of 3β,6α,12β,20-tetrahydroxy-25,26,27-trinordammar-24-al, which appears to be formed from PPT.

Hydration and dehydration products of PPD- and PPT-type saponins

The hydration of the double bond of PPD or PPT yields a dammarane derivative with a hydroxyl group at C-25 and no double bond. Fig. 2E illustrates the structures of the saponins 25-hydroxyprotopanaxadiol and 25-hydroxyprotopanaxatriol.

Most PPD- and PPT-type ginsenosides tend to be deglycosylated and dehydrated at C-20 when steamed or heat processed. The resultant double bond is formed either between C-20 and C-21 or between C-20 and C-22. In the latter case, the (E)/(Z) geometric isomerism exists. Fig. 3 illustrates the probable pathways of the formation of artifactual saponins owing to heating. Fig. 2F shows the structures of saponins that are considered to be the dehydration products of the PPD- and PPT-type saponins shown in Fig. 2A.

Fig. 3

Probable pathways of the formation of artifactual saponins owing to heating. Deglycosylation and dehydration may occur at C-20 when a PPD- or PPT-type ginsenoside is steamed or heat-processed. The resultant double bond is formed either between C-20 and C-21 or between C-20 and C-22, leading to positional and geometric isomerism. PPD, protopanaxadiol; PPT, protopanaxatriol.

Saponins with an epoxy group

The acid hydrolysis of a PPD-type and a PPT-type saponin leads to the formation of a six-membered ring containing oxygen, yielding panaxadiol, 3β,12β-dihydroxy-20,25-epoxydammarane, and panaxatriol, 3β,6α,12β-trihydroxy-20,25-epoxydammarane, respectively. Fig. 2G-(a) shows the structures of panaxadiol and panaxatriol. Moreover, some saponins are derivatives of 3β,6α,20-dihydroxy-12,23-epoxydammar-24-ene or 6α,25-dihydroxy-20,24-epoxydammar-3,12-dione. Fig. 2G-(b,c) show the structures of saponins with an epoxy group between C-12 and C-23 and between C-20 and C-24, respectively.

Saponins isolated from P. ginseng with other aglycones

The genins of some saponins isolated from P. ginseng are different from those aforementioned. Fig. 2H, I illustrate the structures of ginsenosides with other backbones.

Synthetic saponins

Synthetic compounds whose structures are related to saponins isolated from P. ginseng have been reported. In most cases, derivatives of dammarane are synthesized from isolated ginsenosides to enhance biological activity. Indeed, several acylated saponins have been found to have antitumor activity [61], [63]. In addition, some derivatives of ocotillol have shown myocardial ischemia protective effect [64]. Fig. 2J illustrates the structures of some synthetic saponins.

Saponin metabolites

Most ginsenosides are metabolized by intestinal bacteria. Fig. 4 shows the suggested metabolic pathways of PPD- and PPT-type ginsenosides. The former is deglycosylated at C-3 and transformed to either M1 (compound K) or PPD. By contrast, the latter is deglycosylated at C-6 and/or C-20, and eventually transformed to PPT. Fig. 2K shows the structures of the saponin metabolites that have not been reported as being present in raw or processed ginseng.

Fig. 4

Suggested metabolic pathways of PPD- and PPT-type ginsenosides. PPD-type ginsenosides tend to be deglycosylated at C-3, and M1 (compound K) may result. PPT-type ginsenosides are deglycosylated at C-6 and/or C-20. PPD, protopanaxadiol; PPT, protopanaxatriol.

Concluding remarks

Ginseng is well known for its beneficial biological effects on the human body. While the plant contains various ingredients, ginsenosides play a more significant role in exerting pharmacological actions than any other constituents. Of the great number of ginsenosides present in P. ginseng, fewer than 10 account for most ginsenoside contents. In particular, ginsenosides Rb1, Rb2, Rc, Rd, Re, Rf, and Rg1 are most abundant in the roots of raw ginseng. Intriguingly, chemical reactions during the processing of ginseng, such as oxidation, hydrolysis, and/or dehydration, lead to the formation of artifactual compounds, which often have enhanced biological activities. Besides, orally administered ginsenosides undergo biotransformations in the gastrointestinal tract, and some metabolites produced by the action of bacteria have structures different from those of naturally occurring ginsenosides. Here, >100 ginsenosides have been classified according to their structural features.

Conflicts of interest

The authors declare no conflict of interest.