J Nat Med (2007) 61:91–101
DOI 10.1007/s11418-006-0126-3
REVIEW
The Dioscorea genus: a review of bioactive steroid saponins
Marc Sautour Æ Anne-Claire Mitaine-Offer Æ
Marie-Aleth Lacaille-Dubois
Received: 23 October 2006 / Accepted: 10 November 2006 / Published online: 18 January 2007

The Japanese Society of Pharmacognosy and Springer 2007
Abstract This review will summarize some of the
important reports on the chemistry and the biological
activities of Dioscorea steroid saponins from the liter-
ature data of recent years (2000–2006) and from the
authors’ studies. These discoveries became possible as
a result of the scientific development of isolation,
structure elucidation, and the development of in vitro
bioassays. Over 50 steroid saponins of furostane-,
spirostane-, and pregnane-type skeleton have been
discovered and characterized from 13 Dioscorea spe-
cies, namely, D. bulbifera L., D. cayenensis Lam.-Holl,
D. colletii Hook. F. var. hypoglauca (Palib.) Pei et
Ting, D. deltoidea Wall var. orbiculata, D. futschau-
ensis R. Kunth, D. nipponica Mak., D. panthaica Prain
et Burkill, D. parviflora Ting, D. polygonoides Humb.
et Bonpl., D. pseudojaponica Yamamoto, D. spongiosa
Xi, Mizuno et Zhao, D. villosa L., D. zingiberensis
Wright. The main biological and pharmacological
properties of Dioscorea saponins concern cytotoxic and
antifungal activity, which are highlighted.
Keywords Dioscorea
Steroid saponins

Cytotoxic activity
Antifungal activity
M. Sautour
A.-C. Mitaine-Offer

M.-A. Lacaille-Dubois (&)
Laboratoire de Pharmacognosie,
Unité de Molécules d’Intérêt Biologique,
UMIB UPRES EA 3660, Faculté de Pharmacie,
Université de Bourgogne, 7, Blvd. Jeanne d’Arc,
BP 87900, 21079 Dijon Cedex, France
e-mail: m-a.lacaille-dubois@u-bourgogne.fr
Introduction
The roots of several species of the genus Dioscorea
(family of Dioscoreaceae), known as yam, contribute
to the basis of the feeding in the population of Africa,
Asia, and Tropical America. Most species contain
steroid saponins (sometimes with a yield >2%) and
also sapogenins, such as diosgenin, which is the starting
material of industrial interest in the synthesis of many
steroids which are on the market as anti-inflammatory,
androgenic, estrogenic, and contraceptive drugs. Fur-
thermore, this class of compounds are reported to
possess cytotoxic, antitumor, antifungal, immunoregu-
latory, hypoglycemic, and cardiovascular properties
[1, 2].
From a therapeutic point of view, some species of
Dioscorea are used in Traditional Chinese Medicine as
anticancer agents (D. colletii var. hypoglauca), cardio-,
cerebrovascular-, gastropathy-protective, and curative
agents (D. panthaica), and anti-rheumatism agents
(D. nipponica, D. futschauensis) [3, 4].
Consequently, this review will focus, after a botan-
ical presentation of the genus, on the significant
achievements of recent years (2000–2006) on the
chemistry and biological properties of steroid saponins
from the Dioscorea species, with particular attention to
their cytotoxic and antifungal effects. The discussion
will also focus on the understanding of their mecha-
nism of action and structure/activity relationships.
Botanical study
Dioscorea is a genus in the monocotyledonous family
Dioscoreaceae. This genus includes more than 600
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92
species widely distributed in the tropical and temperate
regions of Asia, Africa, and America [3].
Dioscorea sp. are creeping and climbing vines, typ-
ically herbaceous, that may reach up to 5 m in height,
given support from trees and shrubs. The vines twine
from left to right. Rootstock are rhizomatous or
tuberous and variable in color [3]. Stems are branched
or not, smooth or winged, glabrous or sometimes
bearing prickles. Leaves are alternate or opposite and
heart-shaped with long pointed tips. Major veins orig-
inate from the base of the leaf and curve nearly par-
allel, following the leaf shape. Finer veins form a
network between the major ones. The margins, peti-
oles, and stems are purplish to red in color. Flowers are
small, white to greenish-yellow, and may have a cin-
namon flagrance. They are unisexual (dioecious plants)
and arise from the leaf axils in spike or paniculate.
Fruits are three-angled capsules (loculicidal dehis-
cence) and contain winged seeds. Yams make up
the genus Dioscorea. The water yam is classified as
D. alata, the Chinese yam as D. batatas, the air potato
as D. bulbifera, and the wild yam as D. villosa.
Chemical study
From 2000 to 2006, steroid saponins were found in the
literature from several species of Dioscorea genus: D.
bulbifera var. sativa [5], D. cayenensis [6, 7], D. collettii
var. hypoglauca [8–13], D. deltoidea var. orbiculata
[14], D. futschauensis [15–20], D. nipponica [21], D.
panthaica [22–24], D. parviflora [25], D. polygonoides
[26, 27], D. pseudojaponica [28], D. spongiosa [29], D.
villosa [30], and D. zingiberensis [31] (Table 1). The
structures of the aglycons of the isolated saponins be-
longed to three skeleton types: furostane, a pentacyclic
ABCDE-ring system with a sixth open F ring (1–30);
spirostane, a hexacyclic ABCDEF-ring system (31–46);
and pregnane, a tetracyclic ABCD-ring system (47–58)
(Figs. 1, 2, 3).
Most of the aglycons possess a furostane-type skel-
eton and differ by the configurations of the substituents,
sometimes not determined (19–21), and by the nature
of the E ring. These saponins presented mainly a 25(R)
position (1–18, 20, 21, 26–30), or a 25(S) (22–25). About
the E ring, a satured one can be found (1–12), or with
insaturations in the positions 20(22) (13–18) or 22(23)
on the open F ring (26). A seco-furostane skeleton is
equally described (27–30). Moreover, in the same plant,
pairs of furostanol saponins can be found constituted by
the native molecule and its methyl derivative, like
protoneodioscin (24) and Me protoneodioscin (25),
protogracillin (3) and Me protogracillin (4), protone-
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J Nat Med (2007) 61:91–101
ogracillin (22) and Me protoneogracillin (23), from D.
futschauensis. The methyl derivative may be described
as an artifact [14]. In the same way, furostanol glyco-
sides and their spirostanol analogs are sometimes iso-
lated from the same plant as protodioscin (7) and
dioscin (32) from D. futschauensis, D. panthaica, and
D. villosa, asperoside (1) and parrisaponin (33) from D.
cayenensis, protogracillin (3) and gracillin (34) from D.
futschauensis and D. spongiosa, parvifloside (9) and 37,
and deltoside (11) and deltonin (38) from D. parviflora.
Among the furostanol saponins group, 2 compounds
15 and 26 possessed the same name Dioscoreside E
according to references [15] and [22], respectively, but
showed two different structures (see Fig. 1).
For the spirostanol saponins (32–46), all of their
structures are derivated from diosgenin (31) with
additional hydroxylations at the 12, 14, 17, 23, 24, and
27 positions. The pregnane group is more heteroge-
neous, presenting many variations between the differ-
ent aglycons (47–58).
For all of the molecules isolated from the Dioscorea
species described in this review, the oligosaccharidic
group linked in C-3 of the aglycon is composed by a
glucopyranosyl moiety, which is substituted at posi-
tions 2, 3, and 4 only by glucopyranosyl and rhamno-
pyranosyl moieties.
The extraction and isolation procedures described in
the literature for the steroid saponins of the Dio-
scoreaceae family are classical methods. The structural
diversity of steroid saponins was ascertained by the use
of spectroscopic techniques, including fast atom bom-
bardment mass spectrometry (FABMS) and extensive
2D nuclear magnetic resonance (NMR) experiments
(COSY, TOCSY, NOESY, HSQC, HMBC). The
assignment of the 25(R)/25(S) configuration of the 27-
methyl group in the case of furostane- and spirostane-
type steroidal saponins was supported via 1H NMR
chemical shifts of H2-26 geminal protons [32, 33]. More
recently, it has been demonstrated that ESI-QqTOF-
MS/MS with APCI-MS is a fast, effective, and practical
tool to characterize the structures of underivatized
steroid saponins in crude extracts from medicinal herbs
and to further study the structure of isomers. Such
methods were successfully used to analyze the struc-
tures of 13 steroid saponins in D. panthaica [34].
Biological study
Several pharmacological in vitro and in vivo assays
allowed researchers to characterize various pharma-
cologically active steroid saponins in Dioscorea species
having cytotoxic, immunomodulating [3], antimicrobial
J Nat Med (2007) 61:91–101 93

Table 1 Saponins from Dioscorea species (2000–2006)

Species No. Saponins Ref.

D. bulbifera var. sativa 39 Pennogenin-3-O-a-L-Rha-(1 fi 2)-[a-L-Rha-(1 fi 3)]-b-D-Glc (spiroconazole A) [5]

D. cayenensis 2 26-O-b-D-Glc-22-methoxy-3b,26-dihydroxy-25(R)-furost-5-en-3-O-a-L-Rha-(1 fi 4)- [6]
a-L-Rha-(1 fi 4)-[a-L-Rha-(1 fi 2)]-b-D-Glc (Me asperoside)
32 Dioscin [6]
33 Diosgenin-3-O-a-L-Rha-(1 fi 4)-a-L-Rha-(1 fi 4)-[a-L-Rha-(1 fi 2)]-b-D-Glc [6]
(parrisaponin)
27 26-O-b-D-Glc-3b,26-dihydroxy-20,22-seco-25(R)-furost-5-en-20,22-dione-3-O-a-L- [7]
Rha-(1 fi 4)-a-L-Rha-(1 fi 4)-[a-L-Rha-(1 fi 2)]-b-D-Glc
8 Me protodioscin [7]
1 Asperoside [7]
36 Prosapogenin A of dioscin (progenin III) [7]
D. collettii var. hypoglauca 23 Me protoneogracillin [8]
34 Gracillin [8]
4 Me protogracillin [9]
7 Protodioscin [10]
24 Protoneodioscin [11]
8 Me protodioscin [12]
25 Me protoneodioscin [13]
D. deltoidea var. orbiculata 44 Isonarthogenin-3-O-a-L-Rha-(1 fi 2)-[a-L-Rha-(1 fi 4)]-b-D-Glc (orbiculatoside B) [14]
5 Protobioside [14]
6 Me protobioside [14]
D. futschauensis 15 26-O-b-D-Glc-23(S)-methoxy-3b,26-dihydroxy-25(R)-furost-5,20(22)-dien-3-O-a-L- [15]
Rha-(1 fi 2)-[b-D-Glc-(1 fi 3)]-b-D-Glc (dioscoreside E)
16 26-O-b-D-Glc-3b,26-dihydroxy-25(R)-furost-5,20(22)-dien-3-O-a-L-Rha-(1 fi 2)- [15]
[b-D-Glc-(1 fi 3)]-b-D-Glc(pseudoprotogracillin)
17 26-O-b-D-Glc-3b,26-dihydroxy-25(R)-furost-5,20(22)-dien-3-O-a-L-Rha- [15]
(1 fi 2)-b-D-Glc
13 Pseudoprotodioscin [15]
14 26-O-b-D-Glc-23(S)-methoxy-3b,26-dihydroxy-25(R)-furost-5,20(22)-dien-3-O-a-L- [15]
Rha-(1 fi 2)-[a-L-Rha-(1 fi 4)]-b-D-Glc (dioscoreside C)
7 Protodioscin [15]
8 Me protodioscin [15]
24 Protoneodioscin [15]
25 Me protoneodioscin [15]
3 Protogracillin [15]
4 Me protogracillin [15]
22 Protoneogracillin [15]
23 Me protoneogracillin [15]
56 16a-methoxy-3b-hydroxy-pregn-5-en-20-one-3-O-a-L-Rha-(1 fi 2)-[a-L-Rha- [16]
(1 fi 4)]-b-D-Glc
52 21-methoxy-3b-hydroxy-pregn-5,16-en-20-one-3-O-a-L-Rha-(1 fi 2)-[a-L-Rha- [16]
(1 fi 4)]-b-D-Glc
47 3b-hydroxy-pregn-5,16-en-20-one-3-O-a-L-Rha-(1 fi 2)-[a-L-Rha-(1 fi 4)]-b-D-Glc [16]
(pregnadienolone-3-O-b-D-chacotrioside)
48 3b-hydroxy-pregn-5,16-en-20-one-3-O-a-L-Rha-(1 fi 2)-[b-D-Glc-(1 fi 3)]-b-D-Glc [16]
(pregnadienolone-3-O-b-D-gracillimatriose)
45 3b,27-dihydroxy-25(S)-spirost-5-en-3-O-a-L-Rha-(1 fi 2)-[b-D-Glc-(1 fi 3)]-b-D-Glc [17, 18]
36 Prosapogenin A of dioscin [17, 18]
32 Dioscin [17, 18]
34 Gracillin [17, 18]
18 26-O-b-D-Glc-23(S)-methoxy-3b,26-dihydroxy-25(R)-furost-5,20(22)-dien-3-O-a-L- [19]
Rha-(1 fi 2)-[b-D-Glc-(1 fi 3)]-b-D-Glc
7 Protodioscin [19]
3 Protogracillin [19]
14 Dioscoreside C [19]
35 Diosgenin-3-O-a-L-Rha-(1 fi 4)-b-D-Glc (progenin II) [20]
D. nipponica 19 26-O-b-D-Glc-3b,26-dihydroxy-furost-5,20(22)-diene [21]

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Table 1 Continued
Species No. Saponins Ref.

D. panthaica 26 20(R)-methoxy-3b,26-dihydroxy-25(R)-furost-5,22(23)-dien-3-O-a-L-Rha-(1 fi 2)- [22]

[a-L-Rha-(1 fi 4)]-b-D-Glc (dioscoreside E)
7 protodioscin [22]
28 26-O-b-D-Glc-3b,26-dihydroxy-20,22-seco-25(R)-furost-5-en-20,22-dione-3-O-b-D- [23]
Glc-(1 fi 3)-[a-L-Rha-(1 fi 2)]-b-D-Glc (dioscoreside A)
29 26-O-b-D-Glc-3b,23(S),26-trihydroxy-20,22-seco-25(R)-furosta-5-en-20,22-dione- [23]
3-O-a-L-Rha-(1 fi 4)-[a-L-Rha-(1 fi 2)]-b-D-Glc (dioscoreside B)
35 Progenin II (prosapogenin B of dioscin) [23]
36 Progenin III [23]
34 Gracillin [23]
32 Dioscin [23]
13 Pseudoprotodioscin [23]
14 26-O-b-D-Glc-23(S)-methoxy-3b,26-dihydroxy-25(R)-furost-5,20(22)-dien-3-O-a-L- [24]
Rha-(1 fi 2)-[a-L-Rha-(1 fi 4)]-b-D-Glc (dioscoreside C)
30 26-O-b-D-Glc-3b,26-dihydroxy-20,22-seco-25(R)-furost-5-en-20,22-dione-3-O-a-L- [24]
Rha-(1 fi 2)-[a-L-Rha-(1 fi 4)]-b-D-Glc (dioscoreside D)
48 Pregnadienolone-3-O-b-D-gracillimatriose [24]
47 Pregnadienolone-3-O-b-D-chacotrioside [24]
13 Pseudoprotodioscin [24]
D. parviflora 46 Isonarthogenin-3-O-a-L-Rha-(1 fi 2)-b-D-Glc [25]
36 Prosapogenin A of dioscin [25]
32 Dioscin [25]
38 Deltonin [25]
11 Deltoside [25]
12 Me deltoside [25]
37 Diosgenin-3-O-b-D-Glc-(1 fi 3)-b-D-Glc-(1 fi 4)-[a-L-Rha-(1 fi 2]-b-D-Glc [25]
9 Parvifloside [25]
10 Me parvifloside [25]
31 Diosgenin [25]
D. polygonoides 40 Diospolysaponin A [26]
36 Progenin III [26]
41 3b,23,24-trihydroxy-23(S),24(R),25(R)-spirost-5-en-3-O-a-L-Rha-(1 fi 2)-b-D-Glc [27]
42 3b,12a,17a,23-tetrahydroxy-23(S),25(R)-spirost-5-en-3-O-a-L-Rha-(1 fi 2)-b-D-Glc [27]
43 3b,14a,17a,23-tetrahydroxy-23(S),25(R)-spirost-5-en-3-O-a-L-Rha-(1 fi 2)-b-D-Glc [27]
D. pseudojaponica 2 26-O-b-D-Glc-22a-methoxy-3b,26-dihydroxy-25(R)-furost-5-en-3-O-a-L-Rha- [28]
(1 fi 4)-a-L-Rha-(1 fi 4)-[a-L-Rha-(1 fi 2)]-b-D-Glc
33 3b-hydroxy-25(R)-spirost-5-en-3-O-a-L-Rha-(1 fi 4)-a-L-Rha-(1 fi 4)-[a-L-Rha- [28]
(1 fi 2)]-b-D-Glc (=parrisaponin)
8 Me protodioscin [28]
32 Dioscin [28]
4 Me protogracillin [28]
34 Gracillin [28]
D. spongiosa 49 Spongipregnoloside A [29]
50 Spongipregnoloside B [29]
51 Spongipregnolosides C [29]
55 Spongipregnolosides D [29]
53 Spongioside A [29]
54 Spongioside B [29]
57 Hypoglaucin G [29]
8 Me protodioscin [29]
48 Pregnadienolone-3-O-b-gracillimatriose [29]
47 Pregnadienolone-3-O-b-chacotrioside [29]
32 Dioscin [29]
36 Prosapogenin A of dioscin [29]
44 Isonarthogenin-3-O-a-L-Rha-(1 fi 2)-[a-L-Rha-(1 fi 4)]-b-D-Glc [29]
(= orbiculatoside B)
34 Gracillin [29]
3 Protogracillin [29]
20 Trigofoenoside D-1 [29]
5 Glycoside D (= protobioside) [29]
58 Dumoside [29]

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J Nat Med (2007) 61:91–101 95

Table 1 Continued
Species No. Saponins Ref.

D. villosa 7 Protodioscin [30]

8 Me protodioscin [30]
33 Parrisaponin [30]
32 Dioscin [30]
36 Prosapogenin A of dioscin (= progenin III) [30]
35 Progenin II [30]
D. zingiberensis 37 3b-spirost-5-en-3-O-b-D-Glc-(1 fi 3)-b-D-Glc-(1 fi 4)-[a-L-Rha-(1 fi 2]-b-D-Glc [31]
32 Dioscin [31]
b-D-Glc=-b-D-Glucopyranosyl, a-L-Rha=a-L-Rhamnopyranosyl

GlcO 26 GlcO O O
26
21 R2 O 2 3 21 23 25 F CH2 OH
20 25 27 20 27 27
22 22
17 E O
24
17
24 E O O
O
C D 16 16
19 C D

B GlcO
A 2 26 A B
6 21 RO 23
R 1O 3 5 HO 3 5 25 27
1 4 4 6 22 RO 3 5 RO 3 5
R = Rha Rha Glc 20 24 6 6
1 2 2 17 O
R = H Rha 16
4 4
31 R= H
1 3 4
2 R = Rha Rha Glc2 20 R = Glc Glc
1 4
2
R = CH3 Rha 2 32 R = Rha Glc 44 R = Rha G lc
2 2
R = CH3 Rha 2
3 R1 O 3 5
6 2 Rha Rha
1 1
3 R = Glc Glc 21 R = Rha Glc 4 4
2 3
2
R = H Rha
2
R = H 33 R = Rha Rha Glc
Glc Glc
2 45 R= 2
3 27 Rha
4 R 1= Glc Glc
2 GlcO Rha
26 3
R 2= CH3 Rha 21 R 2O 23
2
1 2 25 34 R = Glc Glc2 46 R= Rha Glc
R = Rha Glc 22
5 20 24
2 17 O Rha
R= H
2 16 4
6 R 1= Rha Glc 35 R = Rha Glc
2 3
R = CH3 22 R 1= Glc Glc 2
2
1 4 R1 O 3 5 2 Rha 36 R = Rha Glc
7 R = Rha Glc2 6 R= H
2 Rha 3 4
R = H 1 3
23 R = Glc Glc2 37 R = Glc Glc Glc
1 4 2
2
8 R = Rha Glc2 R = CH3 Rha Rha
4
R 2= CH3 Rha
4 38 R = Glc Glc 2
1
1 3 4 24 R = Rha Glc
9 R = Glc Glc Glc 2
2 2
R= H Rha Rha
R 2= H Rha
4
3 4
10 R 1= Glc Glc Glc2 25 R 1= Rha Glc O
2
R 2= CH3 Rha R 2= CH3 Rha
4 17
11 R 1= Glc Glc2 GlcO O
2 26
R = Rha H 21 OCH3 23 OH
4 25 27
1
12 R = Glc Glc2 20 22 24
17 O
R 2= CH 3 Rha
16 4
GlcO 26 R = Rha Glc RO 3 5
26 2 6
21 23 25 Rha
20 22 27
24 5
3
R2 RO 3
6 GlcO 39 R = Rha Glc
26
17 O
23
25 2
21
16 O O 27 Rha
20 22
R2 24
O
17
6 16 O
R 1O 3 5 4 R
4
13
1
R = Rha Glc 2 R1 23
OH 24
R 2= H Rha 17
O
4 R1 O 3 5
6 1 4 4 12
14
1
R = Rha Glc2 27 R= Rha Rha Glc R3
2 14
R 2= OCH3 Rha R 2= H Rha
3 2
1 R
15 R = Glc Glc
2 28 R1= Glc 3Glc
2 RO 3 5
R 2= OCH3 Rha 2
R = H Rha 6
1 3
16 R = Glc Glc2 1
29 R = Rha Glc2
4
2 Rha
R =H
2 R 2= OH
Rha R R1 R2 R3 R4
1
17 R = Rha Glc 2
1 4 40 Rha Glc OH OH OH H
R 2= H 30 R = Rha Glc
2
3 2
18 1
R = Glc Glc R = H Rha 2
2 41 Rha Glc H H H OH
R 2= OCH3 Rha 2
42 Rha Glc OH H OH H
2
Fig. 1 Furostane-type saponins from Dioscoreaceae 43 Rha Glc H OH OH H

Fig. 2 Spirostane-type saponins from Dioscoreaceae

[3], anabolizing [3], hormonal [3], anti-osteoporotic
[29], anti-inflammatory [35], and anti-allergic activities
[36]. In the last few years, the most relevant biological Cytotoxic activity
studies on the steroid saponins of Dioscorea species
described in the literature are related to cytotoxic/ It was reported that Dioscorea membranacea was used
antitumor and antifungal properties that will be in drug formulas to treat cancer in Thailand [37]. Some
summarized in the following sections. water extracts were found to be specifically active on

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21
O 21
O
urinary bladder, and renal tumors for centuries. Sev-
20
17
20
17
OCH3
eral steroid saponins isolated from this plant were
16
C D 16
tested by the National Cancer Institute’s (NCI) anti-
A B cancer drug discovery screen [9]. This is an in-vitro-
RO 5 5
3 RO
6 3
6 disease-oriented screening system with a panel of 60
47 R=
4
Rha Glc 55 R= Rha
4
Glc human cancer cell lines, including the subpanels of
2 2
Rha Rha leukemia, non-small cell lung cancer (NSCLC), colon,
3
48 R= Glc Glc
2 21
central nervous system (CNS), prostate, melanoma,
Rha O
2
20
17
ovary, renal, and breast cancers, most of them being
OCH3
49 R= Rha Glc
16 from solid tumors, and a few from leukemia. As shown
4
50 R= Rha Glc in Table 2, methyl protogracillin (4) exhibited cyto-
Rha
4
RO 3 5
6
toxicity against all of the test cell lines from leukemia
51 R= Glc Glc
3 2
4 and solid tumors with GI50<100 lM by using a colori-
Rha 56 R= Rha Glc
2
Rha
metric assay [9]. It showed particular selectivity against
21
H3 COH2C
20
O
21

20
O one colon cancer line (KM 12), one CNS cancer line (U
17
16
17
16
O 251), two melanoma lines (MALME-3M and M-14),
O OGlc two renal cancer lines (786-0 and UO-31), and one
5 RO 3 5
breast cancer line (MDA-MB-31) with GI50£2 lM [9].
RO 3
6 6

4 4
The selectivity between these seven most sensitive
52 R= Rha Glc 57 R= Rha Glc
2
Rha
2
Rha
lines and least sensitive line (CCRF-CEM, belonging
OH
to leukemia subpanel) ranged from 26- to 56-fold. In
2 O
R
the same cancer subpanel, the authors observed a
OR3 O
16 selectivity of more than 15-fold between MDA-MB-
231 and MCF-7, NCI-ADR-RES, BT-549 in breast
R1O 3 5
6 RO 3 5
6 cancer. Me protoneogracillin (23) was cytotoxic against
4 4
all of the test cell lines with GI50<100 lM, particularly
1
53 R = Rha Glc 58 R= Rha Glc
2 2 selectively against two leukemia lines (CCRF-CEM
R = 2
H2 Rha Rha
and RPMT-8226), one colon cancer line (KM12), two
R 3= Glc

54 1
R = Rha Glc
4 CNS cancer lines (SF-539 and U 251), one melanoma
2
R =
2
O Rha line (M14), one renal cancer line (786-0), one prostate
3 6
R = Glc Ac cancer line (DU-145), and one breast cancer line
(MDA-MB-435) with GI50£2 lM [8]. Leukemia, CNS
Fig. 3 Pregnane-type saponins from Dioscoreaceae
cancer, and prostate cancer were the most sensitive
subpanels, while ovarian cancer was the least sensitive
breast cancer cells (IC50 7.7 lg/ml), with little activity panel. Gracillin (34) was cytotoxic against most cell
on normal cells (IC50 78.4 lg/ml). No data relative to lines with GI50 at micromolar levels, except EKVX
the cytotoxic components has been reported, but the (NSCLC), HT 29 (colon cancer), OVCAR-5 (ovarian
prosapogenin A of dioscin (36) was reported later as the cancer), and SN12C (renal cancer). On the basis of
active principle for no inhibitory activity of Dioscorea structure/activity relationships, the C-25 (R)/(S) con-
membranacea [35]. On the contrary, other species of figuration was critical for leukemia selectivity between
Dioscorea were reported as sources of cytotoxic steroid methyl protoneogracillin (23) and methylprotogracillin
saponins in many cancer cell lines, as listed in Tables 2 (4). The F ring was critical to the selectivity between
and 3. The following species were principally studied: furostanol-(23, 4) and spirostanol- (34) saponins [8].
D. collettii var. hypoglauca, which was used in China for Protodioscin (7) was cytotoxic against most cell lines
the treatment of solid tumors, D. panthaica, D. futs- from leukemia and solid tumors, especially selectively
chauensis, and, to a lesser extent, D. polygonoides. against one leukemia line (MOLT-4), one NSCLC line
(A-549/ATCC), two colon cancer lines (HCT-116 and
D. collettii var. hypoglauca SW-620), one CNS cancer line (SNB-75), one mela-
noma line (LOX IMV), and one renal cancer line
This species, belonging to some versions of the Phar- (786-0) with GI50£2 lM. Leukemia, colon, and pros-
macopeia of the People’s Republic of China, have tate cancers are the most sensitive subpanels, while
been used as a Traditional Chinese Medicine for the ovarian cancer is the least sensitive subpanel [10].
treatment of cervical carcinoma, carcinoma of the Methyl protodioscin (8) showed strong cytotoxicity

123
J Nat Med (2007) 61:91–101 97

Table 2 Cytotoxicity of saponins from Dioscorea colettii var. hypoglauca (GI50 lM)
Compound Panel/cell
Leukemiaa NSCLCb Colon CNS Prostate Melanomaf Ovarian Renal Breast Ref.
cancerc cancerd cancere cancerg cancerh canceri

Me protogracillin (4) 4.25–25.6 2.68–15.6 1.74–9.24 1.50–12.4 3.70–7.28 1. 68–15.7 4.02–16.2 1.90–16.5 0.89–17.9 [8]
Protodioscin(7) 2.02–3.77 1.64–19.1 1.72–4.02 1.69–5.73 2.70–3.63 2. 03–10.5 2.64–18.6 1.94–<100 4.05–33.1 [10]
Me protodioscin(8) 16.7–27.4 2.88–19.0 1.93–19.7 2.11–3.41 2.39–3.88 2. 70–9.73 8.19–16.1 2.10–12.6 1.69–7.79 [12]
Me protoneo-gracillin 1.57–4.59 2.61–19.4 1.73–12.9 1.91–16.9 1.99–5.96 1. 73–16.7 10.3–19.9 1.94–22 1.43–19.2 [8]
(23)
Protoneodioscin (24) 0.49–4.16 2.35–22.3 1.92–>100 1.93–4.51 1.74–5.32 1. 77–15.4 2.87–29.4 1.62–>100 1.50–12.3 [11]
Me protoneo-dioscin 2.82–5.52 1.99–3.11 1.80–13.4 1.69–4.45 1.77–3.77 1. 75–8.95 2.82–6.17 1.48–23.5 1.65–13.3 [13]
(25)
Gracillin (34) 1.68–2.20 1.56–65.2 1.40–78.0 1.53–2.13 1.61–1.86 1. 64–2.18 0.58–81.3 1.43–44.2 1.68–2.44 [8]
a
Leukemia: CCRF-CEM, K-562, MOLT-4, RPMT-8226, SR
b
Non small cancer lung cell (NSCLC): A-549/ATCC, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, NCI-H460, NCI-
H522
c
Colon cancer: COLO 205, HCC-2998, HCT-116, HCT-15, HT-29, KM 12, SW-620
d
Central nervous system (CNS) cancer: SF-268, SF-295, SF-539, SNB-19, SNB-75, U 251
e
Prostate cancer: PC-3, DU-145
f
Melanoma: LOX IMVI, MALME-3M, M14, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257, UACC-62
g
Ovarian cancer: OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, SK-OV-3
h
Renal cancer: 786-0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10, UO-31
i
Breast cancer: MCF-7, NCI/ADR-RES, MDA-MB-231, HS 578T, MDA-MB-435, MDA-N, BT-549, T-47

Table 3 Cytotoxicity of
Compound Panel/cell
saponins from Dioscorea
panthaica (GI50 lM) A 375-S2 L-929 HeLa Ref.

Protodioscin (7) 4.79 5.89 4.23 [22]

Pseudoprotodioscin (13) 5.73/5.73 5.50/5.09 6.2/3.32 [23, 24]
Dioscoreside C (14) 6.37 6.20 4.61 [24]
Dioscoreside E (26) 11.79 10.09 8.30 [22]
Dioscoreside A (28) 8.4 8.6 7.9 [23]
Dioscoreside B (29) 7.1 6.7 6.9 [23]
Dioscoreside D (30) 8.23 10.22 5.47 [24]
Dioscin (32) 2.2 1.8 2.1 [23]
Gracillin (34) 3.4 3.3 2.8 [23]
Progenin II (35) 2.6 4.5 4.2 [23]
Progenin III (36) 2.7 3.1 2.7 [23]
Pregnadienolone-3-O-b-D-chacotriose (47) 21.55 12.24 12.30 [24]
Pregnadienolone-3-O-b-D-gracillimatriose (48) 17.92 17.33 15.56 [24]

against most cell lines from solid tumors with
GI50£10 lM, selectively against one colon cancer line
(HCT-15) and one breast cancer line (MDA-MB-435)
with GI50£2 lM, but moderate cytotoxicity against
leukemia cell lines with GI50 10–30 lM [12]. These
data are consistent with the fact that the rhizome of
Dioscorea collettii var. hypoglauca has been employed
for the treatment of solid tumors rather than leukemia
in China for centuries. The cytotoxicity spectrum of
protoneodioscin (24) showed that the more sensitive
subpanels were leukemia, CNS cancer, and prostate
cancer, whereas melanoma, ovarian, and renal cancers
are less sensitive [11]. Another study showed that CNS
cancer was the most sensitive subpanel to methyl
protoneodioscin (25), whereas renal cancer was the
least sensitive subpanel. The selectivity between the
nine most sensitive lines and the least sensitive line
(TK-10) was from 22- to 30-fold [13].
Dioscorea panthaica
The cytotoxicity of dioscoreside A (28) and B (29)
and five known saponins, progenin II (35), Progenin
III (36), dioscin (32), gracillin (34), and pseudopro-
todioscin (13), was evaluated against human mela-
noma A375-S2, murine pneumoepithelial carcinoma

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98
L929, and human cervicoma Hela cell lines by using
the MTT test [23]. All of the compounds showed a
good activity, as shown in Table 3 (IC50 1.8–8.6 lg/
ml), dioscin (32) being the most active against three
cell lines with IC50 of 2.2, 1.8, and 2.1 lg/ml and
dioscoreside A (28) the least active lines with IC50 of
8.4, 8.6, and 7.9 lg/ml, respectively [23]. In another
experiments, the cytotoxicity was evaluated on the
three cancer cell lines A 375-S2, L 929, HeLa and
compared with the positive control anticancer drug
cyclophosphamide (IC50 1.28–2.57 lM) [24]. Dio-
scoreside C (14) (IC50 4.61–6.37 lM) and pseudo-
protodioscin (13) (IC50 3.32–5.73 lM) showed
stronger cytotoxicity than that of Dioscoreside D (30)
(IC50 5.47–10.22 lM), whereas the pregnadienolone
3-O-b-D-chacotriose (47) and pregnadienolone-3-O-b-
D-gracillimatriose (48) inhibited all of the cell lines
moderately (IC50 10–20 lM) [24]. Furthermore,
comparison of the data obtained from three cancer
cells lines A 375-S2, L 929, HeLa and a normal hu-
man liver cell line HL-7702 showed that Dioscoreside
E (26) (IC50 8.30–11.79 lM) and protodioscin (7)
(IC50 4.23–5.89 lM) exhibited selective cytotoxic
activities against tumor cells and were inactive on
normal cells (IC50>50 lM) [22].
Dioscorea futschauensis
A bioguided fractionation of the n-BuOH soluble frac-
tion of the ethanol extract of D. futschauensis yielded
four saponins: prosapogenin A of dioscin (36), dioscin
(32), gracillin (34), and 3b,27-dihydroxy-25(S)-spirost-
5-en-3-O-a-L-rhamnopyranosyl-(1 fi 2)-[b-D-glucopyr-
anosyl-(1 fi 3)]-b-D-glucopyranoside (45) [17]. They
were evaluated for cytotoxicity against a mouse ts-
FT210 cell line, which is a temperature-sensitive p34
cdc2 mutant isolated from the mouse mammary carci-
noma cell line FM3A. In the bioassay carried out by
morphological observation with the aid of flow cytom-
etry, the four saponins showed cytotoxic activity with
MIC ranging from 3.46 to 4.32 lM, the most active
being compound 45.
Prosapogenin B of dioscin (35) was shown to be
more cytotoxic than the positive control cisplatin. It
inhibited the proliferation of human cancer cells,
A431 (human epidermoid carcinoma), A2780 (human
ovarian adenocarcinoma), A549 (human lung adeno-
carcinoma), K562 (human erythroleukemia), and
HCT-15 (human colon carcinoma) with IC50 ranging
from 5.86 lM (HCT-15) to 18.7 lM (A2780). In
addition, the HCT-15 cells were more sensitive to this
compound than the other cells tested. It was then
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J Nat Med (2007) 61:91–101
found by morphological observation, DNA ladder
detection, and flow cytometric analysis, that com-
pound 35 exerts its anticancer activity through the
induction of apoptosis on HCT-15 cells [20]. Further
experiments demonstrated that this saponin induced
apoptosis on HCT-15 cells via a mitochondria-con-
trolled apoptotic pathway involving the reduction of
mitochondrial membrane potential, the release
of cytochrome c into the cytosol, and the down-regu-
lation of the ratio of Bcl-2/Bax expression level, which
should be at the origin of the cytochrome release to
induce apoptosis [20].
Dioscorea polygonoides
Diospolysaponin A (40) did not show any apparent
cytotoxicity against HSC-2 human oral squamous car-
cinoma cells, even at the sample concentration of
100 lg/ml, whereas the prosapogenin A of dioscin (36)
was shown to be cytotoxic to HSC-2 cells (IC50 3.4 lg/
ml) and as potent as doxorubicin (IC50 2.5 lg/ml) used
as a positive control.
The polyhydroxylated spirostanol saponins (41–43)
did not exhibit cytotoxic activities against HSC-2 and
HL-60 human promyelocytic leukemia cells (IC50>
200 lM), respectively [27].
Antitumor activity
The in vivo antitumor studies have been made only
on the steroid saponins from D. collettii var. hypo-
glauca. After the determination of the non-toxicity
with minimum tolerated dose >600 mg/kg, methyl
protogracillin (4) and methyl protoneogracillin (23)
are in the list for NCI’s in vivo hollow fiber assay in
nude mice [9, 8], whereas gracillin (34) was not
pursued due to the lack of selectivity. The methyl
protodioscin (8), having passed the in vivo hollow
fiber assay in nude mice, is under evaluation in a
subcutaneous human tumor xenograft assay [12]. The
preliminary animal studies showed that the maximum
tolerated dose of protoneodioscin (24) and methyl
protoneodioscin (25) was more than 600 mg/kg in
mice. As a result of their non-toxicity, these mole-
cules have also been on the list for the in vivo hollow
fiber assay in nude mice [11, 13].
Antifungal activity
The continuous search for antimycotic drugs is a
consequence of the broad use of immunosuppressive
drugs and antibiotics, the high number of AIDS pa-
tients, and widespread dermatophyte infection. Each
J Nat Med (2007) 61:91–101 99

drug class, such as polyenes, allylamines, azole
derivatives, and echinocandins, suffers from dose-
limiting toxicities, rapid development of resistance, or
the lack of effectiveness [4]. This has highlighted the
need to discover new antifungal agents [4]. Steroid
saponins are an important source of antifungal com-
pounds [1, 2] and numerous patents on the thera-
peutic potentials of steroid saponins against fungal
infections have been released [4]. In Table 4, we
summarize new findings on the steroid saponins of
Dioscoreaceae as potent antifungal agents.
A new screening bioassay detecting deformation of
mycelia germinated from the conidia of Pyricularia
oryzae was recently developed for application to
screen antifungal agents [14, 15, 17]. This bioassay is
quick, easy to perform, and has been used in recent
years for the screening of antifungal saponins isolated
from D. futschauensis [15, 17] and D. deltoidea var.
orbiculata [14]. The minimum morphologic deforma-
tion concentrations (MMDC) was between 28.4 and
265 lM (Table 4). The strongest activity was observed
for spirostanol saponins (compounds 32, 34, 35, 36, 38,
44, and 45, MMDC 2–12 lM), whereas pregnane gly-
cosides exhibited weak activity (52, 56, MMDC 250–
265 lM).
Another test was performed using the broth dilution
test [38]. For this bioassay, three human pathogenic
yeasts (Candida albicans, C. glabrata, and C. tropicalis)
were used to assess the minimum inhibitory concen-
tration (MIC) of some saponins isolated from D. cay-
enensis [6, 7] (MICs 12.5–200 lg/ml) and D. villosa
[30]. Compounds producing no inhibition at concen-
tration >200 lg/ml were considered to be inactive.
Regarding the oligosaccharidic chain, it was observed

Table 4 Antifungal activities of steroid saponins from Dioscorea ssp.

Compound Source Fungus Concentration Ref.

Asperoside (1) D. cayenensis Candida albicans MIC>200 lg/ml [7]

Candida tropicalis MIC>200 lg/ml
Candida glabrata MIC>200 lg/ml
Me asperoside (2) D. cayenensis Candida albicans MIC>200 lg/ml [6]
Candida tropicalis MIC>200 lg/ml
Candida glabrata MIC>200 lg/ml
Protobioside (5) D. deltoida Wall var. orbiculata Pyricularia oryzae MMDC 15.3 lM [14]
Me protobioside (6) D. deltoida Wall var. orbiculata Pyricularia oryzae MMDC 12.1 lM [14]
Protodioscin (7) D. villosa Candida albicans MIC>200 lg/ml [30]
Candida tropicalis MIC>200 lg/ml
Candida glabrata MIC>200 lg/ml
Me protodioscin (8) D. villosa Candida albicans MIC>200 lg/ml [7, 30]
D. cayenensis Candida tropicalis MIC>200 lg/ml
Candida glabrata MIC>200 lg/ml
(27) D. cayenensis Candida albicans MIC>200 lg/ml [7]
Candida tropicalis MIC>200 lg/ml
Candida glabrata MIC>200 lg/ml
Dioscin (32) D. villosa Candida albicans MIC 12.5 lg/ml [7, 17, 30]
D. cayenensis Candida glabrata MIC 12.5 lg/ml
Candida tropicalis MIC 25 lg/ml
Pyricularia oryzae MMDC 2 lM
Parrisaponin (33) D. futschauensis Candida albicans MIC 100 lg/ml [6, 30]
D. villosa Candida tropicalis MIC 200 lg/ml
D. cayenensis Candida glabrata MIC>200 lg/ml
Gracillin (34) D. futschauensis Pyricularia oryzae MMDC 10 lM [17]
Prosapogenin B of dioscin (35) D. villosa Candida albicans MIC 12.5 lg/ml [30]
Candida tropicalis MIC 12.5 lg/ml
Candida glabrata MIC 25 lg/ml
Prosapogenin A of dioscin (36) D. villosa Candida albicans MIC 20.8 lg/ml [7, 17, 30]
D. cayenensis Candida tropicalis MIC 25 lg/ml
Candida glabrata MIC 25 lg/ml
Pyricularia oryzae MMDC 6 lM
Deltonin (38) D. futschauensis Candida albicans MIC 10 lg/ml [4]
D. parviflora Candida glabrata MIC 5.0 lg/ml
Orbiculatoside (44) D. deltoida Wall var. orbiculata Pyricularia oryzae MMDC 28.4 lM [14]
(45) D. futschauensis Pyricularia oryzae MMDC 12 lM [17]
(52) D. futschauensis Pyricularia oryzae MMDC 265 lM [16]
(56) D. futschauensis Pyricularia oryzae MMDC 250 lM [16]

123
100
that an increasing sugar number decreases the anti-
fungal properties [6]. For example, compound 33, the
analog of 32 with a longer oligosaccharidic chain,
showed weaker inhibition capacity and a narrower
spectrum of activity. Regarding the aglycone structure,
only antifungal activity with spirostanol saponins was-
observed (compounds 32, 33, 35, and 36), whereas none
was observed with furostanol saponins (compounds 1,
2, 7, 8, and 27). These results were in good agreement
with those found by Takechi and Tanaka [39] in a
comparative study between the activities of diosgenyl
and cholesteryl monoglycosides, where it was clearly
shown that the E and F rings of diosgenin play a key
role in the antifungal properties.
Conclusion
The study of saponins from plants belonging to the
Dioscorea genus has led to the isolation of more than
50 steroid saponins during the last five years having
furostane-, spirostane-, and pregnane-type aglycons,
the first being the most widely distributed. Isolation
was carried out according common procedures,
whereas structure elucidation was achieved by the use
of advanced mass spectrometry (MS) and 2D nuclear
magnetic resonance (NMR) techniques.
In some cases, saponins have been subjected to
pharmacological assays and showed cytotoxic, antitu-
mor, antifungal, anti-inflammatory, and anti-osteopo-
rotic activity. The cytotoxic and antifungal activities
are the most relevant studies made during the last
years. Seven furostane-type steroid saponins from D.
colettii var. hypoglauca were tested in an in-vitro-dis-
ease-oriented screening system with a panel of 60 hu-
man cancer lines according to the National Cancer
Institute’s (NCI) anticancer drug discovery screen.
Among them, five compounds (4, 8, 23–25) were not
toxic to animals up to 600 mg/kg, and were selected as
potential anticancer candidates for hollow fiber assay
in nude mice (Table 2). Another cytotoxic study on
tumor cell lines A 375-2, L929, HeLa showed that
spirostane-type saponins 32, 35, 36 were the most
cytotoxic compounds (IC50 1.8–4.5 lg/ml), followed by
furostane-type saponins 7, 13 (IC50 4.23–6.2 lg/ml) and
secofurostane-type saponins 14, 15, 28–30 (IC50 4.61–
11.79 lg/ml), whereas the less active were the pregn-
ane-type saponins 47, 48 (IC50 12.30–21.55 lg/ml)
(Table 3).
If we consider the results of the antifungal activity
against three Candida species and Pyricularia orizae,
the most active compounds were the four spirostane-
type saponins 32, 35, 36, 38 (MIC 5–25 lg/ml)
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J Nat Med (2007) 61:91–101
(Table 4), whereas the furostane-type derivatives were
inactive (MIC>200 lg/ml).
These observations indicate that the antifungal
activity of dioscin (32), progenin II (35), and progenin
III (36) might be correlated with their cytotoxicity to
mamalian cells and led to the assumption of a similar
mechanism of action, such as the well known mem-
brane effect of saponins. These three compounds might
be considered as lead compounds for further preclini-
cal studies in cancerology and microbiology.
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