Botanical Studies (2006) 47: 339-368.
*
Corresponding author: E-mail:
wfang@imm.ac.cn; Tel: +86-10-63036794; Fax: +86-10-63017757.
review paper
Structure-activity relationships of oleanane- and ursane-
type triterpenoids
Hua SUN
1,2,3
, Wei-Shuo FANG
1,3,
*, Wen-Zhao WANG
1,3
, and Chun HU
2
1
Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, P.R. China
2
Shenyang Pharmaceutical University, Shenyang, Liaoning province, 110016, P.R. China
3
Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine (Peking Union Medical
College), Ministry of Education, P.R. China
(Received September 21, 2005; Accepted March 2, 2006)
ABSTRACT. The chemistry of oleanane- and ursane-type triterpenoids has been actively explored in recent
years, and their biological and pharmacological activities of these compounds have been found to span a
variety of properties. These include antitumor, anti-viral, anti-inflammatory, hepatoprotective, gastroprotective,
antimicrobial, antidiabetic, and hemolytic properties as well as many others. This review summarizes the
isolation and structure modifications of these triterpenoids as well a s the biological and pharmacologica l
activities discovered in the past ten years, with an emphasis on their structure-activity relationships.
Keywords: Antidiabets; Anti-inflammatory; Antimicrobial; Antitumor; Antiviral; Gastroprotective;
Hepatoprotective; Oleanane; Structure-activity relationship; Ursane.
Abbreviations: GI
50
, concentration required to inhibit tumor cell growth by 50%; ED
50
, concentration
caused 50% inhibition of cell proliferation in vitro; CC
50
, 50% cytotoxic concentration; LC
50,
50% lethal
concentration; TI, in vitro therapeutic index; MIC, minimum inhibitory concentration; PKC, protein kinase
C; HLE, human leukocyte elastase; UISO-SQC-1, squamous cervix carcinoma; OVCAR-5, human ovarian
cancer; fMLP; N-formyl-methionyl-leucyl-phenylalanine; PMA, phorbol-12-myristate-13-acetate; AA,
arachidonic acid; A LT , alanine aminotransferase; ID
50
, doses inhibiting the oedematous response by 50%.
CONTeNTS
INTRODUCTION ............................................................................................................................................................. 340
ANTITUMOR ACTIVITIES
............................................................................................................................................. 340
ANTI-VIRAL ACTIVITIES
.............................................................................................................................................. 347
ANTI-INFLAMMATORY ACTIVITIES
.......................................................................................................................... 350
In vivo studies
.............................................................................................................................................................. 350
Inhibition of cyclooxygenase (COX) activity
............................................................................................................. 350
Inhibition of complement activity
............................................................................................................................... 353
Inhibition of elastase
................................................................................................................................................... 354
Inhibition of intercellular adhesion molecule (ICAM-1) expression induced by TNF-£\
........................................... 354
HEPATOPROTECTIVE ACTIVITIES
............................................................................................................................. 355
GASTROPROTECTIVE ACTIVITIES
............................................................................................................................ 356
ANTIMICROBIAL ACTIVITIES
..................................................................................................................................... 356
ANTI-DIABETES ACTIVITIES
....................................................................................................................................... 358
HEMOLYTIC ACTIVITIES
.............................................................................................................................................. 360
MISCELLANEOUS .......................................................................................................................................................... 362
Spasmolytic activity
................................................................................................................................................... 362
Antipruritic activity
.................................................................................................................................................... 362
Anti-thrombotic activity
............................................................................................................................................. 362
Inhibitory activity of ethanol absorption
.................................................................................................................... 363
Effects on nonmalignant prostate cell proliferation
................................................................................................... 363
LITERATURE CITED.
...................................................................................................................................................... 364
pg_0002
340
Botanical Studies, Vol. 47, 2006
iNTrODUCTiON
Oleanolic acid (OA) (3£]-hydroxy-olea-12-en-28-oic
acid) and its isomer, ursolic acid (UA) (3£]-hydroxy-urs-
12-en-28-oic acid) are triterpenoid compounds which
exist widely in nature in free acid form or as aglycones
for oleanane- and ursane-type triterpenoid saponins (Liu,
1995). Oleanane and ursane are also called £]-amyrane
and £\-amyrane, respectively. Saponins glycosylated at
either C-3 or C-28 are termed monodesmosides, and
those glycosylated at both C-3 and C-28 are termed
bisdesmosides. These types of triterpene saponins
exhibit diverse activities, which may be attributable to
the different substructures in the A-, C-, E-rings or other
positions. Many comprehensive reviews of two type
triterpenoids have been published covering different areas
of interest, such as isolation and structure determination
(Joseph, 1999; 2000; 2001a; 2001b; 2002; 2003; 2005a;
2005b), and pharmacological activities (Liu, 1995;
Safayhi et al., 1997; Setzer and Setzer, 2003; Rios et al.,
2000; Baglin et al., 2003), but reviews of structure-activity
relationships are scarce. In this review, our discussion
will focus mainly on the chemistry and pharmacology
of oleanane- and ursane-type triterpenoids discovered in
the past ten years, with an emphasis on the relationships
between their structures and activities. These triterpenoids
are often mentioned simultaneously because they share
similar structural features and pharmacological activities.
In addition, other pentacyclic triterpenoids such as those
of the lupane type are often cited in order to compare their
structures and activities with those of oleanane and ursane
type triterpenoids.
HO
COOH
1
2
3
4 5
6
7
8
9
10
1 1
1 2
1 3
1 4
15
16
17
1 8
19 2 0 21
22
23 24
25 26
2 7
28
2 9 30
A B
C D
E
OA
HO
COOH
1
2
3
4 5 6
7
8
9
1 0
11
1 2
13
1 4
1 5
16
1 7
18
1 9 2 0 21
22
23 24
2 5 26
27
2 8
29
3 0
A B
C
E
D
UA
aNTiTUMOr aCTiviTieS
U A has been reported to be effective at different
stages for tumor prevention and inhibition, e.g. inhibiting
tumorigenesis (Huang et al., 1994), differentiation
(Lee et al., 1994), and promotion (Tokuda et al., 1986),
Moreover, UA and OA have exhibited potent activity
against human leukemia and lymphoma cells. For
example, UA was effective against P3HR1 cells (IC
50
=2.5
£gg/mL) and chronic myelogenous leukemia cells K562
(IC
50
=17.8 £gg/mL), while OA inhibited the growth of
P3HR1 cells (IC
50
=26.74 £gg/mL) (Chiang et al., 2003).
They also showed anti-angiogenic activities, with UA
(IC
50
=5 £gM) found more active than OA (IC
50
=20 £gM)
(Sohn et al., 1995). Bioassay-guided fractionation of
Polylepis racemosa led to the isolation of four cytostatic
triterpenoids UA and 1-3 (GI
50
=6.9~>250 £gg/mL), in
which the 19-OH substituted compound 1 was the most
active (GI
50
=6.9~25 £gg/mL) (Neto et al., 2000).
Six triterpenes UA, OA and 4-7 were isolated from
stem bark of Physocarpus intermedius, and their ED
50
values against five different tumor cells are shown in
Table 1 (Kim et al., 2000). While introduction of 2£\-OH
substituents showed almost no influence on their activity,
9£\-OH in the UA series was detrimental to activity.
Coffemoylation of 3£]-OH enhanced antitumor activity by
several times.
Compound 6, Corosolic acid, has also been isolated
from the fruit of Crataegus pinnatifida var. psilosa. It
displayed both cytotoxicity and PKC inhibition. The ED
50
values of 6 and UA are shown in Table 2. Both compounds
were selectively more potent against solid cancer cells
HeLa S
3
and SNU C
4
. Besides, it incompletely inhibited
rat brain PKC activity in vitro by concentrations higher
than 20 £gg/mL (Ahn et al., 1998).
R
4
R
3
R
1
R
2
COOH
1 R
1
=OH R
2
=H R
3
=H R
4
=OH
2 R
1
=OAc R
2
=H R
3
=H R
4
=OH
3 R
1
=OH R
2
=R
3
=O R
4
=OH
R
1
O
COOH
R
2
O
HO
HO
4 R
1
=
R
2
=H
7 R
1
=H R
2
=OH
R
2
R
1
COOH
HO
5 R
1
=
B
-OH R
2
=OH
6 R
1
=
A
-OH R
2
=H
pg_0003
SUN
et al. ¡X Structure-activity relationships of oleanane- and ursane-type triterpenoids
341
Table 3. Cytotoxic activity was determined by the MTT.
CC
50
(£gg/mL)
HSC-2
HSG
HGF
UA
29
48
25
OA
130
230
>500
6
10
12
12
7
21
26
24
13
21
25
24
14
102
148
184
15, 16
22
30
50
H SC -2 : hu m a n o ra l s q ua m o u s c e l l c ar c i no m a ; HS G:
human salivary gland tumor; HGF: human normal gingival
fibroblasts.
It is interesting to note that the cinnamoyl substituent
can be found in oleanane and ursane type triterpenoids that
exhibit antitumor activity. Compounds 4, 8, 9, and 10 were
reported to inhibit both free radical and cyclooxygenase
I activity (IC
50
=0.9~4.6 £gg/mL) (Hamburger et al.,
2003). Cis-3-O-p -hydroxycinnamoyl ursolic acid (11)
(GI
50
=18.8~46.4 £gM) was slightly more effective than
its trans-isomer (12) (GI
50
=40~25-100 £gM) in inhibiting
tumor growth against nine different tumor cell lines
(Murphy et al., 2003).
However, the presence of the cinnamoyl segment might
not always increase antitumor activity. Callus cultures
induced from an axenic leaf of Eriobotrya japonica
(Rosaceae) produced nine triterpenes OA, UA, 6, 7, 13,
14, 15 and 16. All of these triterpenes exhibited significant
activity in terms of CC
50
against HSC-2, HSG and HGF
(Table 3), but the activity of the mixture of cinnamoyl
esters 15 and 16 was weaker than either non esterified 6 or
13 (Taniguchi et al., 2002). Moreover, when UA, 27-p-Z-
coumaroyloxy UA (17) and 27-p-E-coumaroyloxy UA
(18) were isolated through a bioactivity-guided fraction
from aerial parts of Viburnum jucundum Morton, only UA
exhibited cytotoxic activity with ED
50
values of ca. 3 £gg/
mL against HCT-15, UISO-SQC-1 and OVCAR-5 (Rios
et al., 2001).
Table 1. Inhibition ED
50
(£gg/m L) of tumor cell proliferation
with UA, OA and 4-7.
A549 SK-OV-3 SK-MEL-3 XF498 HCT15
UA
4.2 3.6 4.6
4.5 4.4
OA 16.4 12.4 18.5 >30 12.1
4
1.6 1.6 1.7
19.8 1.7
5 >30 18.4 >30
30 >30
6
4.4 3.9 5.1
5.5 4.7
7 19.4 18.4 19.8 >30 15.3
Cisplantin 1.4 0.9 0.8
0.9 2.2
A549: non sm all ce ll lung; SK-OV-3: ovary; SK-ME L-3:
me lanoma; XF498: central nerve s ystem ; HCT15: colon;
Cisplantin was positive control.
Table 2. ED
50
(£gg/mL) of corosolic acid and UA against tumor
cells.
Hep G
2
SNU-C
4
HeLa S
3
K-562
6
4.8
0.4
1.0
4.3
UA
3.0
1.4
1.5
12.5
Hep G
2
: hum an hepatocellular carcinoma; SUN-C
4
: human
colorectal cancer; HeLa S
3
: human cervix carcinoma.
R=
O
HO
OH
RO
COOH
8
RO
9
RO
10
HO
COOH
O
O
OH
18
HO
COOH
O
O
OH
17
RO
COOH
O
HO
HO
11 R=
O
HO
HO
12 R=
R
COOH
HO
HO
O
HO
15 R=
O
HO
16 R=
13 R=OH
14 R=O=
pg_0004
342
Botanical Studies, Vol. 47, 2006
Due to its ability to repair damaged DNA (Narayan
and Wilso, 1996), DNA polymerase is a potential target
for adjuvant antitumor therapy, i.e., selective inhibition of
this enzyme by other noncytotoxic agents could possibly
potentiate chemotherapeutic effects of other DNA-
damaging agents. UA at 100 £gM was tested for inhibitions
of calf DNA polymerase £\, rat DNA polymerase £], plant
DNA polymerase I (£\-like), and DNA polymerase II
(£]-like). The percent inhibitions were 92%, 86%, 0%,
and 9%, respectively (Mizushina et al., 2000). Four
triterpenoids (OA, UA, 19 and 20) were isolated from
Baeckea gunniana, and all showed inhibition of DNA
polymerase £] (IC
50
=2.5~4.8 £gM). Because 19 and 20
displayed slightly more potent inhibitory activity than that
of UA and OA, it is proposed that the exocyclic double
bond on their E-ring might contribute to this improvement
(Deng et al., 1999).
A new polyacylated oleanane triterpene 21 and OA
were isolated from Couepia polyandra. They inhibited
the lyase activity of DNA polymerase £], with IC
50
values
of 13.0 and 8.8 £gM, respectively (Chaturvedula et al.,
2003a).
Three acetyl-boswellic acid analogues 22, 23 and
24 were investigated for their topoisomerase inhibitory
activity, and the relative activity 22>23>24 was observed.
The IC
50
values for the inhibition of topoisomerase I
and II£\ catalytic activities by 22 were 3 £gM and 1 £gM,
respectively. Other structurally related pentacyclic
triterpenes, ¡Xincluding OA, UA, £\-amyrin (25), £]-amyrin
(26), betulinic acid (27), and 18-£]-glycyrrhetinic acid
( 28), ¡Xwere tested for both types of topoisomerase
inhibition. However, neither the amyrin isoforms nor
2 8 had significant effects at the concentration range
observed for 22. Of all the compounds, 27 was the
most effective with IC
50
values of 43 £gM and 5 £gM for
topoisomerase I and II£\, respectively. An analysis of their
structural features concluded that the shared pentacyclic
ring architecture was important but not sufficient for the
inhibition of topoisomerases. Moreover, the combination
of carboxyl group at C-4 and two methyl groups at C-20
were important for enhancing the inhibitory activity of
the molecule toward both topoisomerases (Syrovets et al.,
2000).
A/B¡Vring partial analogues (29-33) of OA were
enantioselectively synthesized. These compounds showed
cytotoxicity against human malignant melanoma cell SK-
MEL (IC
50
=112~ 484 £gM), except for 31, which was not
active (Assefa et al., 2001). Some partial analogous e.g.
32 and 33 had activity almost comparable to OA.
Tritepene saponins have been extensively explored
as antitumor agents. Pentacyclic triterpene glycosides
have been reported to be active against various tumors.
Considering the diverse structures of both aglycones and
attached sugars among various species, one can expect
that they will play important roles in anticancer drug
discovery.
HO
COOH
19
HO
COOH
20
CH
3
COO
COOH
OCOCH
3
CH
3
COO
21
AcO
COOH
22
AcO
COOH
23
AcO
COOH
O
24
HO
25
HO
26
27
HO
COOH
28
HO
COOH
O H
pg_0005
SUN
et al. ¡X Structure-activity relationships of oleanane- and ursane-type triterpenoids
343
Triterpene saponins 34-37 from Polyscias amplifolia,
together with two monoglycosides 38 and 39 formed
by the partial hydrolysis of 34 and 35, exhibited
cytotoxicity against A2780 ovarian cancer cells (Table 4)
(Chaturvedula et al., 2003b). The isolated cinnamoylated
compounds 40 (IC
50
=13.5 £gg/mL) and 41 (IC
50
=13.0 £gg/
mL) from Acacia tenuifolia also showed weak activity
against A2780 ovarian cancer. Moreover, saponins 42
and 43, which possess unique aminosugar moieties, were
isolated along with 40 and 41. These exhibited significant
activity against the M109 lung cancer cell line, with
IC
50
values of 1 £gM (Seo et al., 2002). Compound 4 3
was synthesized and tested for cytotoxic activity against
the A2780 and M109 lung cancer cell lines with the
IC
50
0.8 and 1.0 £gg/mL, respectively (Sun et al., 2003).
The above results clearly indicated the importance of
3-O-aminosugar, and the activity was compromised by the
presence of C-16 and C-21 substituents in 40 and 41, as
compared to 43.
Nine triterpenes (44-52) containing OA or hederagenin
aglycones were isolated from the roots of Pulsatilla
chinensis and tested for their cytotoxic activity against
HL-60 human leukemia cells (IC
50
=2.3~>10 £gg/mL).
Compound 46 was the only one that differed in C-3
sugar substituents in these saponins and no activity
was detected. The results suggested that the glycoside
HO
COOCH
3
H
H
31
HO
H
H
CN
32
HO
COOH
29a p-COOH
29b m-COOH
29c o-COOH
30a p-COOH
30b m-COOH
30c o-COOH
HO
COOH
33a p-COOH
33b m-COOH
33c o-COOH
O
H
3
CO
COOH
Table 4. Cytotoxicity against A2780 of compounds 35-43.
IC
50
(£gg/mL)
OA
20.4
35
6.7
36
9.2
37
10.8
38
9.6
39
8.9
40
8.6
41
13.5
42
13.0
43
0.8
O
COOH
O
OH
O
O
O
HO
OH
R
O
NHCOCH
3
HO
HO
O
40 R=
O
OH
HO
HO
41 R=
O
OH
HO
HO
O
O
HO
OH
R
HO
HO
O
RO
COOH
O
OH
OH
HO
OH
O O
OH
HO
34 R=
35 R=
O
OH
OH
HO
OH
O
O
HO
OH
O
OH
OH
HO
OH
36 R=
37 R=
O
OH
HO
O
O
OH
OH
HO
OH
38 R=
O
HO
HO OH
39 R=
O
HO OH
OH
O
COOR
2
O
O
HO
OR
3
O
Me
HO
OH
R
4
O
R
1
R
1
R
2
R
3
R
4
44 H H H H
45 OH H H H
47 H H H
B
-D-Glc
48 OH H H
B
-D-Glc
48aOH Me H
B
-D-Glc
49 H H
B
-D-Glc H
50 OH H
B
-D-Glc H
O
HO
HO OH
Glc=
OH
O
OH
HO
HO
O
HO
HO
O
COOH
O
OH
O
O
O
HO
OH
R
O
NHCOCH
3
HO
HO
O
40 R=
O
OH
HO
HO
41 R=
O
OH
HO
HO
O
COOH
O
O
HO
OH
R
O
NHCOCH
3
HO
HO
O
O
OH
HO
HO
42 R=
43 R=
O
OH
HO
HO
RO
COOH
O
OH
OH
HO
OH
O O
OH
HO
34 R=
35 R=
O
OH
OH
HO
OH
O
O
HO
OH
O
OH
OH
HO
OH
36 R=
37 R=
O
OH
HO
O
O
OH
OH
HO
OH
38 R=
O
HO
HO OH
39 R=
O
HO OH
OH
COOR
2
pg_0006
344
Botanical Studies, Vol. 47, 2006
moiety attached to C-3 of the aglycone was essential for
cytotoxicity (Mimaki et al., 1999). In addition, there was
no significant difference in activity between the OA-based
and hederagenin-based saponins. The presence of a C-28
methyl ester imposed no influence on the activity.
Compound 49 (Hederacolchisid A
1
) was also isolated
from Hedera colchica K. Koch, and exhibited moderate
in vitro antiproliferative activities against six human cell
lines as well as normal human fibroblasts. Comparison
of the cytotoxicity of 49 (IC
50
4.5~12 £gM) with 44 (IC
50
9~15 £gM), 4 5 (IC
50
24~36 £gM), 50 (IC
50
24~32 £gM),
53 (IC
50
18~41 £gM), and 54 (IC
50
26~47 £gM) from the
same plant offers some new information about structure-
activity relationships. The sugar sequence OA-3-O-
£\-
L
-rhamnopyranosyl (1¡÷2)-£\-
L
-arabinopyranoside
at C-3 appears essential for antitumor activity of OA
monodesmosides. Unlike the previous results (Mimaki et
al., 1999), monodesmesides with OA as aglycone were
more active in this study than those with hederagenin
(Barthomeuf et al., 2002).
A study of the synergistic effect of saponins on an
additional anticancer drug cisplatin showed that the
triterpene saponins jenisseensosides A, B, C, and D
(55-58) increased the accumulation and cytotoxicity of the
anticancer agent cisplatin in human colon tumor cells. In
contrast, the saponin 59 without the acyl moiety (trans-
or cis-p-methoxycinnamoyl acid) attached to sugar did
not exert such an effect (Gaidi et al., 2002). This agrees
with recent findings that acylating groups might be crucial
substructures due to their assumed pore-forming capacity.
Saponins 60-67 were tested for any observed difference in
the cytotoxic activity between acylated and non-acylated
states. It was concluded that the number and structure
of sugar chains did not play an important role in their
cytotoxic properties, and that acylated saponins were more
toxic than non-acylated ones (Barbato et al., 1997).
Superoxide generation can cause DNA damage
and thereby initiate tumor-genesis (Gerhauser et al.,
2003). Five compounds (UA, 1, 25, 68, 69) isolated
from Diospyros kaki were tested for stimulus-induced
superoxide generation. Compound 1 inhibited fMLP, PMA
and AA-induced superoxide generation more effectively
than its 24-hydroxy derivative 69.
The hydroxyl group at
R
3
and carboxyl group at R
2
appear to decrease superoxide
generating activity by the three stimuli (Chen et al., 2002).
Moreover, the effects of six compounds (OA, O A
3-acetate, 44, 49, 70, 71) isolated from Anemone raddeana
on fMLP, PMA, and AA-induced superoxide generations
were investigated. A methyl group at C-14 caused stronger
suppression of the fMLP-induced superoxide generation
than a hydroxylmethyl at this position. Diglycoside
7 0 more strongly suppressed PMA and AA-induced
superoxide generation than triglycoside 71 (Lu et al.,
2001).
40 R=
O
OH
HO
HO
41 R=
O
OH
HO
HO
O
OH
HO
HO
42 R=
43 R=
O
OH
HO
HO
O
COOR
2
O
O
HO
OR
3
O
Me
HO
OH
R
4
O
R
1
R
1
R
2
R
3
R
4
44 H H H H
45 OH H H H
47 H H H
B
-D-Glc
48 OH H H
B
-D-Glc
48aOH Me H
B
-D-Glc
49 H H
B
-D-Glc H
50 OH H
B
-D-Glc H
O
HO
HO
OH
Glc=
OH
RO
COOH
OH
O
OH
HO
HO
O
OH
HO
HO
OH
53 R=
54 R=
O
OH
HO
O
OH
HO
O
O
COOH
OH
HO
HO
46
R
O
HO
R
O
O
OH
OHO
HO
O
O
O
OH
HO O
HO
O
O
OH
HOHO
HO
O
R
1
R
2
51 H H
51a Me H
52 H
B
-D-Glc
pg_0007
SUN
et al. ¡X Structure-activity relationships of oleanane- and ursane-type triterpenoids
345
O
HO
HO
O
HO
HO
O
O
O
HO
HOOC
OH
OH
OH
O
O
HOOC
O
O
O
O
HO
OH
O
HO
HO
OH
OH
O
O H
3
C
O
O
HO
O CH
3
O
H
3
C
OH
O
R
61 R=H
62 R=Xyl
O
HO
HO
OH
Xyl=
O
OH
HO
HO
O
HO
HO
HOOC
O
OH
O
O
CHO
O
O
Me
OR
2
OH
O
OH
O
Me
HO
HO OR
1
55 R
1
=Glc R
2
=
MeO
O
56 R
1
=Glc R
2
=
O
MeO
57 R
1
=H R
2
=
MeO
O
58 R
1
=H R
2
=
O
MeO
O
OH
HO
HO OH
O
O
O
O
OH
HO
HO OH
59
O
OH
HO
HO OH
O
O
O
O
OH
HO
HO OH
60
O
O
CH
2
OH
O
OH
HO
O
H
3
C
OH
O
O
HO
OH
O
O H
3
C
O
O
HO
R
2
OH
3
C
OH
HO
HO
HO
O
R
1
O
HO
HOH
2
C
OH
63 R
1
=H R
2
=H
64 R
1
=H R
2
=I
65 R
1
=Glc R
2
=H
65 R
1
=Glc R
2
=I
66 R
1
=Glc R
2
=II
O
O
OH
H
3
C
O
H
3
C
O
O
O
OH
H
3
C
O
H
3
C
O
H
3
C
II =
I =
R
1
R
2
R
3
HO
R
1
R
2
R
3
68 CH
3
CH
2
OH H
69 CH
2
OH COOH OH
COOH
OH
O
O
O
HO
RO
O
Me
HO
OH
HO
70 R=H
71 R=Glc
pg_0008
346
Botanical Studies, Vol. 47, 2006
Table 5. NO inhibitory activities of olean- and urs-12-ene triterpenoids with various 1-en-3-one functionalities.
R
2
O
R
1
O
R
2
O
R
1
U
R
2
O
R
1
D
Type
R
1
R
2
IC
50
(£gM)
72
O
H
CO
2
Me
31
73
O
H
CO
2
H
5.6
74
D
H
CO
2
Me
>40
75
D
H
CO
2
H
13
76
U
H
CO
2
H
13
77
O
OH
CO
2
H
27
78
O
CONH
2
CO
2
Me
14
79
O
OMe
CO
2
H
30
80
O
CO
2
Me
CO
2
Me
0.9
81
O
CO
2
Me
CO
2
H
2.2
82
O
CO
2
H
CO
2
Me
0.8
83
O
CO
2
H
CO
2
H
0.07
84
O
CHO
CO
2
Me
Toxic
85
O
CHO
CO
2
H
Toxic
86
O
Br
CO
2
Me
>40
87
O
Br
CO
2
H
7.3
88
O
Cl
CO
2
Me
>40
89
O
Cl
CO
2
H
>40
90
O
CN
CO
2
Me
0.7
91
O
CN
CO
2
H
0.6
92
U
CN
CO
2
Me
5.1
93
U
CN
CO
2
H
6.2
OA
>40
UA
Toxic
Figure 1. St ruct ure-a cti vity re la tions hi ps of 1 -en-3-one
derivatives of oleanane triterpenoids.
R
2
O
R
3
R
1
R
4
23 2 4
A
E
1
2
3
4
ursane type
oleanane type
R
3
=CH
3
, R
4
=H
R
3
=H, R
4
=CH
3
Inhibitors of nitric oxide (NO) production in
macrophages are potential cancer chemopreventive
and anti-inflammatory drugs (Ohshima and Bartsch,
1994). Gribble et al. synthesized a series of OA and UA
derivatives as inhibitors of NO production induced by
interferon-£^ in mouse macrophages (Honda et al., 1997;
1999; 2000a, b and 2002). Some structures and activities
were summarized as shown below in Figure 1 and Tables
5-7.
Generally, (1) oleanane and ursane triterpenoids with
various enone functionalities in A-ring showed stronger
activity. More specifically, a 1-en-3-one functionality in
A-ring was important for significant activity (Table 5).
(2) Carboxyl, methoxycarbonyl, and nitrile groups at
pg_0009
SUN
et al. ¡X Structure-activity relationships of oleanane- and ursane-type triterpenoids
347
C-2 enhanced activity, while hydroxyl, aminocarbonyl,
methoxy, chloride, and bromide groups decreased it. A
formyl group did not confer activity but only toxicity. (3)
23, 24-Dimethyl groups were also important for significant
activity, as 73 was more potent than 23, 24-dinorolean-
1-en-3-one derivative 75. (4) The effect of a free acid or
ester form at C-28 was ambiguous. For some analogues,
triterpenoids bearing C-28 the carboxyl group were more
potent than C-28 methyl; esters, but for others similar
activity or even less potent activities were observed when
C-28 was carboxylic acid. (5) The oleanane skeleton was
usually more potent than the ursane skeleton.
The SARs of modified ring-C oleanane and ursane
triterpenoids with .
12
functionality (Table 6) were also
summarized as follows:
(1) A 9(11)-en-12-one functionality in ring C could
enhance activitiy about 10-100 times; (2) 12-en-11-
one,
13(18)-en-11-one, and 12-one functionalities also
enhanced potency, and a 9(11)-ene functionality showed
similar potency to the original 12-ene; (3) The saturated
ring C, 11, 13(18)-diene, and 9, 11-epoxide were less
potent than the original 12-ene; as indicated in compounds
110-112. (4) The combination of a 9(11)-en-12-one
functionality with nitrile and carboxyl groups at C-2
enhanced the potency in a synergistic way; Triterpenoids
such as 115, 116 and 119 (IC
50
=0.1 nM level) were about
10,000 times more potent than 73. (5) The combination
of a 9(11)-en-12-one functionality with amide and formyl
groups at C-2 did not enhance potency as strongly as
a nitrile or carboxyl group; (6) The combination of a
12-en-11-one and 13(18)-en-11-one functionalities with
nitrile group at C-2 also strongly enhanced the potency as
9(11)-en-12-one series by two orders of magnitude.
CDDO (11 6) showed almost the strongest NO
inhibitory activity (Table 6) among those synthetic
derivatives of OA. Moreover, it could also inhibit
proliferation of many tumor lines at sub M level and
induced cell differentiation of human myeloid leukemia
(Suh et al., 2000).
Based on structures of highly active triterpenoids
CDDO, 115 and 11 9 (Table 6), a series of oleanane
triterpenoids (123-148) with various substituents at
the C-28 were synthesized (Table 7). Some important
SARs regarding substituents at C-17 were also provided:
(1) Nitrile group enhanced potency and ester moieties
decreased potency. The less polar the ester, the less was
its potency. (2) The carbonyl pyrazole was much less
potent than that of 28-COOH, while carbonyl imidazole
had higher potency, which might have arisen from high
reactivity of imidazole with nucleophiles.
Moreover, many tricyclic compounds (149-157), as
simplified CDDO with same A, B, and C ring architecture,
were synthesized and tested for NOS inhibitory activity,
the IC
50
values were between 0.002 and 1.6 £gM, in which
(¡Ó)-80 showed the most potential (IC
50
=0.002 £gM). It was
found that the most active compound 157 was only about
one-fourth as potent as CDDO, so a nitrile group at this
position enhanced potency among the typical electron-
withdrawing groups such as in compounds 154 and 156 at
C-13. Since 151 and 152 were more potent than 149 and
150, the bis-enone structure for high potency in relatively
small molecules is important (Favaloro et al., 2002).
aNTi-viraL aCTiviTieS
Saponins 158 and 159 were isolated from Gymnoladus
chinensis (Nakashima et al., 1989) and Gleditsia japonica,
respectively. Both compounds exhibited potent anti-
HIV effects against HIV replication in H-9 cells. Their
derivatives (160-173) were prepared and evaluated for
anti-HIV activity (Table 8). The monoterpenyl moieties
in 158 and 159 were found to play an important role in
modulating the anti-HIV activity of these compounds.
In addition, methylation of 28-COOH increased activity
while introduction of n-butyryl or valeryl groups to the
C-3 and/or C-16 hydroxy group decreased it compared to
that of 167 (Konoshima et al., 1995).
A series of natural and semi-synthetic OA, UA and
betulinic acid (27) derivatives have been isolated (Ma et
al., 2002; Kashiwada et al., 1998) or synthesized. Some
relationships of anti-HIV activities and structures were
summarized in Table 9.
(1) Esters especially dicarboxylic acid hemiesters of
3-OH in OA, tended to increase inhibitory activity (Ma et
al., 1999). For the 3-acyl chains within five carbons, the
HIV-1 PR inhibitory activity of the compounds increased
as the lengths of the 3-acyl chains increased (Ma et al.,
2000). (2) Methylation of the 28-COOH or the carboxyl
OR
O
NC
149 R=H
150 R=Ac
151 R=Ac
152 R=H
OR
O
NC
O
O
NC
O
153
154 R=CO
2
CH
3
155 R=COOH
156 R=CONH
2
157 R=CN
O
NC
O
R
pg_0010
348
Botanical Studies, Vol. 47, 2006
Table 6. NO inhibitory activity of olean-1-en-3-one and urs-1-en-3-one triterpenoids with various C-ring functionalities.
R
2
O
R
1
O
R
2
O
R
1
U
Type
Structure of ring C
R
1
at C-2
R
2
at C-17
IC
50
(£gM)
94
O
H
CO
2
Me
2.8
95
O
H
CO
2
H
1.1
96
U
H
CO
2
Me
8.9
97
U
H
CO
2
H
5.1
98
O
H
CH
2
OAc
>40
99
O
H
CH
2
OH
3.0
100
O
H
CHO
3.8
101
O
CN
CO
2
Me
0.02
102
O
CN
CO
2
H
0.04
103
U
CN
CO
2
Me
0.1
104
U
CN
CO
2
H
0.8
105
O
H
CO
2
H
2.6
106
O
CN
CO
2
H
0.07
107
O
H
CO
2
Me
14
108
O
H
CO
2
H
3.3
109
O
H
CO
2
H
5.2
110
O
H
CO
2
H
8.5
111
O
H
CO
2
H
9.7
112
O
H
CO
2
H
36
113
O
H
CO
2
Me
0.7
114
O
H
CO
2
H
0.2
115
O
CN
CO
2
Me
0.0001
116
O
CN
CO
2
H
0.0002
117
O
CO
2
Me
CO
2
Me
Toxic
118
O
CO
2
Me
CO
2
H
0.1
119
O
CO
2
H
CO
2
Me
0.0008
120
O
CO
2
H
CO
2
H
0.2
121
O
CONH
2
CO
2
Me
0.1
122
O
CHO
CO
2
Me
0.1
H
O
H
H
O
H
H
O
O
H
O
H
O
H
H
O
H
H
O
O
H
O
H
O
H
H
O
H
H
O
O
H
O
H
O
H
H
O
H
H
O
O
H
O
H
O
H
H
O
H
H
O
O
H
O
H
O
H
H
O
H
H
O
O
H
O
H
O
H
H
O
H
H
O
O
H
O
H
O
H
H
O
H
H
O
O
H
O
pg_0011
SUN
et al. ¡X Structure-activity relationships of oleanane- and ursane-type triterpenoids
349
Table 7. NO inhibitory activities of compounds 123-148.
O
R
1
R
2
O
R
1
R
2
IC
50
(£gM)
123 CN
CN 0.0035
124
CN
CO
2
H 1.68
125
CO
2
Et
CN
0.80
126
CO
2
Et
CO
2
H 7.93
127 CO
2
CH
2
CH=CH
2
CN
1.33
128
CO
2
(CH
2
)
3
CH
3
CN
6.65
129
CO
2
CN
4.45
130 CO
2
CH
2
Ph
CN
4.35
131
CO
2
(CH
2
)
7
CH
3
CN
60.4
132 CO-
D
-Glc(OAc)
4
CN
0.07
133
CO-
D
-Glc
CN
10.1
134
CONH
2
CN
0.098
135
CONHNH
2
CN
0.26
136
CONHMe
CN
0.58
137 CONH(CH
2
)
2
CH
3
CN
1.50
138
CONH(CH
2
)
5
CH
3
CN
14.9
139
CONHPh
CN
28.6
140
CONHCH
2
Ph
CN
9.2
141
CONMe
2
CN
1.55
142 CON(n-Pr)
2
CN
32.9
143
CON
CN
0.80
144
CON
CN
0.95
145
CON N
CN
1.00
146
O
CON
CN
2.4
147
N
CON
CN
0.014
148
N
CON
CN
12.0
group in the C-3 hemiester chain decreased the inhibitory
activity against HIV-1 PR significantly (Kashiwada et al.,
1998). Methylation at both sites led to complete loss of
activity, e.g. 210 (Ma et al., 1999). (3) Replacement of the
28-COOH with a methyl group resulted in a significant
loss of activity (25 vs UA; 26 vs OA) (Kashiwada et al.,
1998). (4) The structure of E-ring might play an important
role in anti-HIV potency. Derivatives of betulinic acid, 27,
were more potent than those of UA and OA (Kashiwada
et al., 2000). (5) Saturation of the C
12
-C
13
double bond
could be a major cause of anti-HIV activity enhancement
(238-240), while a C-3 acyl side chain was essential for
optimal activity. In addition, changing the C
28
-carboxyl
to aminomethyl could significantly enhance anti-HIV
activity (241, 242) (Zhu et al., 2001). (6) Replacement of
C-3 hemiester in the OA series with hemi-amide retained
activity (219-223 vs 204-205) (Ma et al., 1999).
Oleanane-type triterpenoid saponins (243-258) were
examined for the anti-herpes virus (anti-HSV-1) activity
(Table 10). It has been found that (1) the trisaccharide
glycosides were more potent than the disaccharide
glycosides. The order of activity was 247> 250>>253.
(2) The saponins having a glucosyl unit in the central
sugar moiety seemed to show greater action. Among
the trisaccharide group, the order of activity was
245>244>246>>243. (3) The carbonyl group at C-22
would be more effective than the hydroxyl group in anti-
HSV-1 activity, while the hydroxyl group at C-24 could
reduce the activity. Comparing the activities of a group
having the same trisaccharide, the order of potency was
254>247>243 (Kinjo et al.,
2001).
Table 8. HIV inhibitory effects for 158-173.
Compd
ED
50
(£gM)
IC
50
(£gM)
158
1.1
9.8
159
2.7
14
160
>100
43
161
>100
37
161a
9.9
22
162
13
50
163
95
63
164
100
>100
165
42
74
166
8
40
167
3.1
4.9
168
5.1
7.6
169
2.3
13
170
27
27
171
15
>160
172
30
180
173
31
54
pg_0012
350
Botanical Studies, Vol. 47, 2006
aNTi-iNFLaMMaTOrY aCTiviTieS
in vivo studies
OA and UA inhibited the Croton oil-induced ear
oedema in mice in a dose-dependent manner, and UA
(ID
50
=0.14 £gMoles/cm
2
) was twofold more
potent than
O A (ID
50
=0.36 £gMoles/cm
2
) and indomethacin (ID
50
=0.26
£gMoles/cm
2
), which was used as a reference non-steroidal
anti-inflammatory drug (NSAID) (Ismaili et al., 2001 and
2002; Baricevic et al., 2001).
The anti-inflammatory activities of ten triterpenoids
[ 25, 26, 68, 259, 260,
OA, Hederagenin ( 261) , 28,
£\-glycyrrhetinic acid (262), and lupeol (263)] were
evaluated. It was found that the basic carbon skeletons
had no influence on the activity; the presence of a C-28
or C-30 carboxylic group and an alcoholic group at C-28
increased the activity in carrageenan and TPA-induced
edemas in mice (Recio et al., 1995).
The following mechanistic aspects of anti-inflammatory
activities of OA and U A derivatives have been
investigated.
inhibition of cyclooxygenase (COX) activity
UA was a selective inhibitor of COX-2 catalyzed
prostaglandin biosynthesis, with IC
50
value of 130 £gM and
a COX-2/COX-1 selectivity ratio of 0.6. OA (IC
50
295
£gM) was found to be less active than UA, but showed a
similar selectivity ratio (0.8). Furthermore, no significant
inhibition on COX-2 or COX-1 was observed by 28
(Ringbom et al., 1998). 1 £gM or less of CDDO (116)
blocked expression of both iNOS and COX-2 protein
(Syrovets et al., 2000). Compounds 247, 260 and 3-epi-
UA (264) (assayed at 10 £gM) blocked the inductive effect
of lipopolysaccharide on the production of PGE
2
, while
OA and UA did not substantially suppress the production
of PGE
2
(Suh et al., 1998). Compounds 5 and 9 strongly
O
OH
OH
OH
HOCH
2
O
O
O
OH
O
CH
3
OH
OH OH
O
OH
OH
OH
O
CH
3
OH OH
O
O
CH
2
OH
OH
O
O O
O
OH
OH
OH
O
OH
OH
O
O
CH
2
OH
OH
OH
O O
CH
2
OH
O
O
O
OH
OH
HO
OH
O
O
O
O
158
O
CH
3
OH
O O
O
OH
OH
OH
O
CH
3
OH OH
O
O
CH
2
OH
OH
O
O O
O
OH
OH
OH
O
OH
OH
O
O
CH
2
OH
OH
OH
O O
O
O
O
OH
OH
HOH
2
C
HO
O O
CH
3
OH
OH
159
RO
CH
2
OH
OH
O
O
HO
164 R=Glc
6
-Ara
2
-Xyl
165 R=H
O
OH
OH
OH
O
OH
OH OH
CH
3
Ara=
Rham=
R
1
O
OR
2
COOR
3
Glc
6
-Ara
2
-Xyl H Glc
2
-Rham
Glc
6
-Ara
2
-Xyl H H
Glc
6
-Ara
2
-Xyl H Me
Glc
6
-Gra H H
Glc
H H
H
H H Me
Ac H Me
Ac Ac H
Butyryl H Me
Butyryl Butyryl Me
Valeryl H Me
Valeryl Valeryl Me
H H
160
161
161a
162
163
165
167
168
169
170
171
172
173
pg_0013
SUN
et al. ¡X Structure-activity relationships of oleanane- and ursane-type triterpenoids
351
Table 9. HIV inhibitory effects for derivatives of OA, UA and 28.¡@
R
2
R
1
O
R
2
R
1
U
R
2
R
1
L
Type
R
1
R
2
IC
50
(£gM)
25
U
CH
3
OH
80
UA
U
COOH
OH
8
174
U
COOCH
3
OH
14
175
U
COOH
OCOCH
3
13
176
U
COOH
OCOCOOH
7
177
U
COOH
OCOCH
2
COOH
6
178
U
COOH
OCO(CH
2
)
2
COOH
6
179
U
COOH
OCO(CH
2
)
3
COOH
4
180
U
COOCH
3
OCO(CH
2
)
3
COOCH
3
>50
181
U
COOH
OCOC(CH
3
)
2
CH
2
COOH
30.7
182
U
COOH
OCOCH
2
C(CH
3
)
2
COOH
49.5
183
U
COOH
OCOCH
2
C(CH
3
)
2
CH
2
COOH
7
184
U
COOH
OCOCH
2
OCH
2
COOH
48.2
185
U
COOH
OCOCH
2
CH(CH
3
)
2
>18.5
186
U
COOH
OCOCH
2
C(CH
3
)
3
>18
187
U
COO
-
K
+
OH
1.8
27
L
COOH
OH
9
188
L
COOCH
3
OH
>25
189
L
COOH
COCOOH
7
190
L
COOH
OCOCH
2
COOH
6
191
L
COOH
OCO(CH
2
)
2
COOH
6
192
L
COOH
OCO(CH
2
)
3
COOH
4
193
L
COOH
OCOCH
2
C(CH
3
)
2
CH
2
COOH
4
194
L
COOCH
3
OCO(CH
2
)
2
COOCH
3
40
195
L
COOH
OCOCH
2
C(CH
3
)
2
COOH
7.0
26
O
CH
3
OH
>100
OA
O
COOH
OH
8
196
O
COOCH
3
OH
20
197
O
COOH
OCOCH
3
9
198
O
COOH
OCOCOOH
20
199
O
COOH
OCOCH
2
COOH
8
200
O
COOH
OCO(CH
2
)
2
COOH
4
201
O
COOH
OCO(CH
2
)
3
COOH
4
202
O
COOCH
3
OCO(CH
2
)
3
COOCH
3
>50
203
O
COOH
OCOCH
2
C(CH
3
)
2
COOH
19.2
204
O
COOH
OCO(CH
2
)
4
COOH
3.0
205
O
COOCH
3
OCO(CH
2
)
4
COOH
7.5
206
O
COOH
OCO(CH
2
)
6
COOH
3.0
pg_0014
352
Botanical Studies, Vol. 47, 2006
Type
R
1
R
2
IC
50
(£gM)
207
O
COOH
OCO(CH
2
)
8
COOH
4.0
208
O
COOH
OCOCH
2
C(CH
3
)
2
CH
2
COOH
3.8
209
O
COOH
OCO(CH
2
)
4
COOCH
3
5.6
210
O
COOCH
3
OCO(CH
2
)
4
COOCH
3
>20
2 11
O
COOH
OCO(CH
2
)
4
CH
3
>20
212
O
COOH
=O
5.5
213
O
COOCH
3
=O
20
214
O
COOH
=NOH
5.5
215
O
COOCH
3
=NOH
9.5
216
O
COOCH
3
£\-NH
>20
217
O
COOCH
3
£]-NH
>20
218
O
COOH
=NOCO(CH
2
)
4
COOH
5.5
219
O
COOCH
3
=NOCO(CH
2
)
4
COOH
4.0
220
O
COOH
£]-NHCO(CH
2
)
4
COOH
3.0
221
O
COOCH
3
£]-NHCO(CH
2
)
4
COOH
3.0
222
O
COOH
£\-NHCO(CH
2
)
4
COOH
2.1
223
O
COOCH
3
£\-NHCO(CH
2
)
4
COOH
3.5
224
O
COOCH
3
£]-NHCO(CH
2
)
4
CONH(CH
2
)
3
COOH
6.0
225
O
COOCH
3
£]-NHCO(CH
2
)
4
CONH(CH
2
)
3
COOCH
3
>20
226
O
COOH
£]-NHCO(CH
2
)
4
CONH-£]-OA-28-OH
3.3
227
O
COOCH
3
£]-NHCO(CH
2
)
4
CONH-£]-OA-28-OCH
3
>20
228
O
CONH(CH
2
)
5
COOH
COOH
1.7
229
O
CONH(CH
2
)
5
COOH
OCO(CH
2
)
4
COOH
1.7
Type
R
1
R
2
IC
50
(£gg/mL)
230
O
COOH
OCOC(CH
3
)
2
CH
2
COOH
9.7
231
O
COOH
OCOCH
2
OCH
2
COOH
22.1
232
O
COOH
OCOCH
2
CH(CH
3
)CH
2
COOH
27.5
233
O
COOH
O
COOH
O
4.4
234
O
COOH
O
COOH
O
4.7
235
O
COO
-
K
+
OH
34.3
RO
COOH
R
EC
50
(£gg/mL)
EC
50
(£gg/mL)
236
H
0.5
OA
1.7
237
2.6
201
7.1
238
0.1
232
8.3
239
0.1
208
1.5
240
0.1
234
1.2
Table 9. (Continued)
C O O H
O
C O O H
O
C O O H
O
C O O H
O
pg_0015
SUN
et al. ¡X Structure-activity relationships of oleanane- and ursane-type triterpenoids
353
RO
CH
2
NHR
R
EC
50
(£gg/mL)
241
0.1
242
0.1
Table 9. (Continued)
C OOH
O
COOH
O
RO
CH
2
OH
OH
243 R=S
1
244 R=S
3
245 R=S
2
246 R=S
4
249 R=S
5
251 R=S
6
252 R=S
7
256 R=H
247 R=S
1
248 R=S
3
250 R=S
5
253 R=S
7
257 R=H
RO
CH
3
OH
254 R=S
1
255 R=S
4
RO
CH
2
OH
O
258 R=H
O
COOH
OH
OH
O
O
OH
O
OH
HO
O
OH
OH
Me
OH
S
5
S
1
=
O
COOH
OH
OH
O
O
OH
O
HO
O
OH
OH
Me
OH
OH
S
6
O
COOH
OH
OH
O
O
OH
O
O
OH
OH
Me
OH
OH
O
COOH
OH
OH
O
O
OH
O
O
OH
OH
Me
OH
OH
S
7
S
2
=
S
3
= S
4
=
inhibited the formation of 6-keto-PGF
1£\
with an IC
50
value of approximately 0.12 £gM, and synthesis of TXB
2
catalyzed by COX-2 with an IC
50
value in the range of
0.4~2.5 £gM (Hamburger et al., 2002). Platycodin D (265),
isolated from the root of Platycodon grandiflorum A. DC.
(Campanulaceae), suppressed PGE
2
production at 10 £gM
in rat peritoneal macrophages stimulated by TPA (Kim et
al., 2001).
inhibition of complement activity
Complement plays a role in various functions of
the adaptive immune response. Yet overactivation of
complement is implicated in various inflammatory
diseases. A/B¡Vring partial analogues (29a-c, 30a-c
and 33b) of OA also showed complement inhibitory
activity (IC
50
=72.3~633 £gM). The lack of complement
inhibitory activity with compounds 31 and 32 showed the
importance of the free carboxylic group for complement
inhibition. The lack of complement inhibitory activity
with compounds 33a and 33c while the compound 33b
retained
the activity may indicate that the meta position of
the carboxylic group was more favorable for complement
inhibitory activity (Assefa et al., 2001).
Some semisynthetic analogues of OA (Table 11) were
evaluated for their complement inhibitory and cytotoxic
activities. The amide derivatives (268 and 269), OA-11-
oxo 273, and the 3-acyl derivatives (203, 208 and 231)
have retained the complement inhibitory activity. Among
these, compounds 269 and 231 showed potency superior
to OA. Both showed a moderate improvement in vitro TI
in comparison with OA (Assefa et al., 1999).
pg_0016
354
Botanical Studies, Vol. 47, 2006
inhibition of elastase
The hydrolysis of blood vessel elastin by HLE
promotes the transendothelial migration of stimulated
proinflammatory cells. The IC
50
values for elastase
inhibition by UA and O A were 4.4 and 6.4 £gM,
respectively (Ying et al., 1991). The £\-boswellic acid
(274), acetyl-11-keto-£]-boswellic acid (AKBA) ( 275),
25, 26, UA, and 28 were tested for the inhibitory activity
of HLE. Dual inhibition of 5-lipoxygenase and HLE
was unique to boswellic acid series. UA and amyrins,
which possessed no 5-LO inhibitory properties, blocked
the activity of HLE, but 28 had no inhibitory effects at
concentrations up to 20 £gM (Safayhi and Sailer, 1997).
The presence of an 11-keto group and hydrophilicity on
the A-ring of the pentacyclic ring system was crucial for
AKBA¡¦s potent 5-LO inhibitory activity (Sailer et al.,
1996).
In another report, UA, 27, 263, and 276 were evaluated
as potential inhibitors of HLE. Among these triterpenes,
UA and 263 showed marked HLE inhibitory activity
with IC
50
values of 4.4 and 1.9 £gM, respectively. The
appearance of HLE inhibition may depend on the presence
and the orientation of two reactive groups in the tested
molecules (Mitaine-Offer et al., 2002).
inhibition of intercellular adhesion molecule
(iCaM-1) expression induced by TNF-£\
ICAM-1 is a member of the immunoglobulin
superfamily of adhesion molecules, and appears to lead to
acute and chronic inflammation. The inhibitory effects of
oleanane-type triterpenoids from fabaceous plants on the
TNF-£\-induced expression of ICAM-1 on THP-1 human
monocytic leukemia cells were reported. The activity
Table 11. Classical complement inhibition and cytotoxicity of
OA, 196, 197, 203, 208, 212, 231, and 266-273.
Complement inhibition
IC
50
(£gM)
Cytotoxicity
IC
50
(£gM) TI
OA
72.3
112
1.55
197
NA
NA
0.06
266
NA
70
267
NA
NA
268
146.6
115
0.78
269
31.8
127
3.99
270
NA
NA
271
NA
105
196
NA
103
272
NA
NA
273
233.7
131
0.56
203
108.3
77
0.71
231
31.4
93
2.96
208
103.0
86
0.83
212
NA
31
Table 10. Anti-HSV-1 activity, cytotoxicity and selectivity index of 243-258.
Anti-HSV-1 activity (IC
50
, £gM)
Cytotoxicity (CC
50
, £gM)
Selectivity index (CC
50
/IC
50
)
243
>75.0
¡V
¡V
244
27.4
115
4.2
245
21.0
>332
>15.8
246
43.0
>343
>13.7
247
43.2
119
2.8
248
22.3
698
31.3
249
>75.0
¡V
¡V
250
64.1
641
10.0
251
54.0
>393
>7.3
252
>75.0
¡V
¡V
253
>75.0
¡V
¡V
254
19.1
>332
>17.4
255
25.1
>343
>13.7
256
5.6
116
20.7
257
37.8
>141
>3.7
258
61.4
504
8.2
pg_0017
SUN
et al. ¡X Structure-activity relationships of oleanane- and ursane-type triterpenoids
355
of oleanane saponins and sapogenins against ICAM-1
expression appears to be dependent upon the position of
the hydroxyl group, in particular upon the status of the
C-21 and C-24 positions, and of the glycosyl group at C-3
position (Ahn et al., 2002).
HepaTOprOTeCTive aCTiviTieS
OA has been successfully used as an oral drug to treat
human acute and chronic liver diseases in China (Qu,
1981). UA has been observed to be more potent than OA
in decreasing chemically induced liver injury in mice (Liu
et al., 1994).
O A 3£]-phthalic monoester disodium salt (277) w as
synthesized in order to increase the solubility of OA in
water. Compound 277 inhibited the rising of serum ALT
caused by D-galactosamine and CCl
4
, and dramatically
decreased liver fat storage, in addition to alleviating the
condition of the degeneration of hepatic cells and necrosis
(Wan et al., 1998).
OA sodium salt (278) obviously inhibited the rising
of ALT and serum phosphatase caused by CCl
4
when
hypodermically injected (100, 50, and 30 mg/kg) (Zhang
et al., 2000). When cadmium is administered as CdCl
2
to animals, most of it accumulates initially in the liver.
Accordingly, the acute toxic effects of cadmium are
observed mainly in the liver. Several triterpenes were
investigated for the effect on cadmium toxicity in Hep
G2 cells. Among them, 18£\-glycyrrhetinic acid (262) and
18£]-glycyrrhetinic acid (28) had no protective effects,
OA, UA, and glycyrrhizin (279) exhibited weak effects,
and betulin (280) and uvaol (281) were more effective in
HO
R
5
R
2
R
4
R
1
R
3
R
1
=OH, R
2
=COOH,
R
3
=CH
3
, R
4
=OH, R
5
=CH
3
259
R
1
=H, R
2
=CH
2
OH,
R
3
=H, R
4
=CH
3
, R
5
=CH
3
260
R
1
=H, R
2
=COOH,
R
3
=H, R
4
=CH
3
, R
5
=CH
2
OH
261
HO
COOH
O
H
262
HO
263
HO
COOH
264
CH
2
OH
OH OH
OH
O
CH
2
OH
OH OH
O
Me
OH OH
O
O
OH
OH
O
O
O
OH
OH
O
HOH
2
C CH
2
OH
HO
OH O
O
265
266 R
1
=COCH
3
, R
2
=CONH
2
267 R
1
=H, R
2
=CONH
2
271 R
1
=H, R
2
=CH
2
OH
R
2
R
1
O
268 X=1
269 X=4
270 X=10
CONH(CH
2
)
X
COOH
HO
272 R=COCH
3
273 R=H
COOH
RO
O
HO
COOH
274
O
O
276
HO
d=11.2
263
AcO
COOH
O
275
pg_0018
356
Botanical Studies, Vol. 47, 2006
reducing the toxicity of CdCl
2
. Betulin (280), in particular,
almost completely abolished the cytotoxicity of CdCl
2
at
concentrations as low as 0.1 £gg/mL (Miura et al., 1999).
GaSTrOprOTeCTive aCTiviTieS
OA displayed gastroprotective effects in three different
experimentally induced gastric ulcer models in rats
(Astudillo et al., 2001). Five semi-synthetic derivatives
of OA (OA-28-methyl ester, 282, OA-3-acetyl, OA-
3-oxo, an d OA-3-oxo-28-methyl ester) were assessed
for gastroprotective effects in the HCl/ethanol ulcer
model in mice. The lesion index was 15.7~39.3 mm.
Oxidation of the OH at C-3 reduced the activity of OA
and its derivatives, while methylation of the 28-COOH
with or without acetylation at C-3 did not affect the
gastroprotective activities of the compounds (Astudillo et
al., 2001).
Eight glycosides (283-290) of OA were examined for
the effects on ethanol- or indomethacin-induced gastric
mucosal lesions in rats. Saponins 283, 284 and 287 were
effective on ethanol- or indomethacin-induced lesions,
but 285, 286, 288, 290 and their aglycone O A did not
show such effects. Diglycoside 289 did not inhibit the
indomethacin-induced lesions, but 288 (50 mg/kg) did
have gastroprotective effect. The results demonstrated that
the 3-O-glycoside moiety was essential for the activity,
and the 28-ester glucoside reduced the activity (Matsuda
et al., 1998b).
aNTiMiCrOBiaL aCTiviTieS
O A was reported to have antimicrobial activity
against B. subtilis (MIC=8 £gg/mL), methicillin-sensitive
(MIC=8 £gg/mL) and resistant (MIC=64 £gg/mL) S. aureus.
In this study, 3-O -(E)-hydroxycinnamoyl OA (5) d id
not show antimicrobial activity (Woldemichael et al.,
2003b). In a separate study OA-28-methyl ester showed
weak antibacterial activity against M. luteus and E. coli
(Weimann et al., 2002).
RO
COOH
O
H
279 R=
A
-D-Glc(1 2)
B
-D-Glc(1
HO
COONa
278
O
COONa
ONa
O
O
277
HO
CH
2
OH
280
HO
CH
2
OH
281
AcO
COOCH
3
282
COOH
OR
3
OR
4
OR
2
O
COOR
1
H
R
1
R
2
R
3
R
4
283 H H H H
284 H H Xyl H
285 Glc H Xyl H
286 Glc H H Ara(f)
287 H H H Ara(f)
288 Glc Glc H H
289 H Glc H H
HO
O
O
OH
OH
CH
2
OH
OH
H
290
pg_0019
SUN
et al. ¡X Structure-activity relationships of oleanane- and ursane-type triterpenoids
357
E. coli. Only compound 303, a monodesmosidic saponin
with OA as aglycone, showed inhibitory activity. The
MIC values of 303 were 64 ppm against C. albicans,
and 128 ppm against S. epidermidis and B. cereus. The
MIC value of reference chloramphenicol was 16 ppm
for S. epidermidis and B. cereus. The other saponins
(54, 304-307) showed no inhibitory activity. Thus, it
was presumed the antibacterial activity was related to
the presence of a monodesmosidic saponin with OA as
aglycone (Bedir et al., 2000).
OA and UA also showed trypanocidal activity. UA
stopped the movement of all T. cruzi epimastigotes at
the minimum concentration (MC
100
) of 88 £gM after 48
h of incubation. OA was less active (MC
100
=550 £gM),
and 27 was inactive (Abe et al., 2002). In contrast, the
methyl esters (UA- and OA-28-methyl ester) and acetates
(UA- and OA-3-acetyl) of UA and OA were not active,
but OA-3-oxo (IC
50
=294.9 £gM), 308 (IC
50
=402.3 £gM)
and 309 (IC
50
=56.6 £gM) retained the activity. These
results suggested the importance of the polar groups to
trypanocidal activity (Cunha et al., 2003).
Two OA saponins, 290 and 310, from Viguiera
decurrens showed insecticidal activity, and their LC
50
values were 1380 and 80 £gg/mL against Epilachna
varivestis larvae, respectively (Marquina et al., 2001).
3-epi-OA (300) possessed antiprotozoal activity
(IC
50
=18.8 £gM against L. donovani promastigotes; and
28.3 £gM against P. falciparum)
(Camacho et al., 2000).
Four saponins (49, 50, 311 and 312) were isolated from
Serjania salzmanniana and were mollusicidal, causing
70-100% mortality at 10 ppm against Biomphalaria
alexandrina. The saponins also showed antifungal activity
against Cryptococcus neoformans and Candida albicans
with MIC at inhibitory concentrations of 8 and 16 £gg/mL,
respectively (Ekabo and Farnsworth, 1996).
OA, UA, 25, £\-amyrin acetate (291), UA-3-acetyl,
and 292-295 were isolated from Alyxia insularis Kanehira
& Sasaki, and examined for antimicrobial activity. Only
two compounds, both of which contained an 11-carbonyl
group (292, 293), showed inhibitory activity on the growth
of S. epidermidis, M. luteus, S. aureus, B. subtilis, and
S. faecium (at 100 and 50 £gg/mL) (Wang et al., 1993).
Compounds 296-299 were isolated from Dillenia papuana
and showed antibacterial activity (Table 12). It was
presumed that the carboxylic group and £G
12, 13
double bond
played an important role in antibacterial activity (Nick et
al., 1994). The MICs of OA, OA-3-oxo, 3-epi-OA (300),
28, 301, and 302 against M. tubercular were 50, 16, 16,
128, 64 and 64, respectively. It was concluded that the low
polarity pentacyclic triterpenes with a hydroxyl or keto
group in the A or B ring and an acid group in the E ring
possess moderate antitubercular activity (Caldwell et al.,
2000).
3-epi-UA (264) and 300 showed antimycobacterial
activity with MIC values of 8 and 16 £gg/mL, respectively
(Woldemichael et al., 2003a). Six triterpene saponins 54,
and 303-307, were isolated from Hedera helix L., and
tested against C. albicans, B. cereus, S. epidermidis and
Table 12. Antibacterial activity of 296-299.
Minimum growth inhibition (£gg)
B. subtilis E. coli M. luteus
296
2.4
2.4
1.2
297
2.0
1.0
1.0
298
2.0
5.0
2.0
299
1.0
1.0
1.0
Positive control: Chloramphenicol MGI=0.1, 0.04, and 0.04
£gg, respectively.
AcO
291
292 R
1
=Ac, R
2
=COOH, R
3
=O
293 R
1
=H, R
2
=COOH, R
3
=O
294 R
1
=Ac, R
2
=CH
3
, R
3
=O
R
1
O
R
2
R
3
HO
O
O
295
O
HOOC
HO
296
HO
HOOC
O
297
O
HOOC
OH
298
HO
COOH
300
O
O
COOH
O
HOOC
299
pg_0020
358
Botanical Studies, Vol. 47, 2006
Various dosages (1.9 to 3.0 g/kg) of OA could affect
the survival, growth, and development of the larvae of
heliothis zea. This might be one of the plant¡¦s defense
mechanisms against phytophagous insects (Argandona
and Faini, 1993). OA, UA, and their synthesized 3-O-fatty
acid ester analogues (313-318) were examined for
antifeedant activity against the agricultural pest tobacco
caterpillar S. litura larvae. At the dosages of 150, 100, 50
£gg/mL, all of the compounds showed antifeedant activity.
At 150 £gg/mL dose, all the tested compounds showed
more than 50% activity, except compounds OA and 318.
At 100 £gg/mL dose, the compounds showed 40~78%
activity, while compound 318 again showed the lowest
activity. Even at 50 £gg/mL, compounds
314-317
exhibited
more than 50% activity. Compounds 316 (74%) and
317
(71%) were found to exhibit exceptionally potent activity
at 50 £gg/mL (Mallavadhani et al., 2003).
aNTi-DiaBeTeS aCTiviTieS
Many late complications of diabetes are associated
with hypoglycemia. OA glycosides (283, 286, 287,
and 319-324) from the root of Aralia elata, which has
been used for treating diabetes, were examined for
hypoglycemic activity in the oral sucrose tolerance in
rats (Table 13). It was concluded the 3-O-glycoside
moiety was essential to the activity, while the 28-ester
glucosidal moiety significantly reduced the activity. In the
3-O-oligoglycoside structure, the 3¡¦-O-glucopyranosyl
moiety tended to decrease the activity, while the 4¡¦
-O-arabinofuranosyl moiety increase it (Yoshikawa et
al., 1994; 1996a, b; Fujimura et al., 1996). The 6¡¦-methyl
ester of the glucuronic acid (325) moiety strongly reduced
the activity (Matsuda et al., 1998c). The above summaries
for SARs were substantiated further by bioassay results
of compounds (326-329) from Beta vulgaris L., among
which 327 and 329 showed hypoglycemic activity, 328
showed weaker activity, and 326 was inactive (Yoshikawa
et al., 1996c). O A sodium salt (278) (s.c. 20 mg/kg¡Pd)
obviously reduced blood sugar (Zhang et al., 2000).
Table 13. Inhibitory effects of 283, 286, 287, 319-324,
326-329 (100 mg/kg, p.o.) on the rise in plasma glucose level
by oral sucrose tolerance test.
Plasma glucose concentration (mg/dl)
0.5 h
1 h
2 h
319
18.2
18.7
15.5
320
76.6
44.9
18.9
321
27.7
33.4
36.4
323
71.4
45.4
32.4
322
31.9
28.1
29.5
287
18.0
23.0
16.6
283
26.9
24.4
28.6
324
55.2
37.4
20.0
286
36.0
17.7
20.6
OA
82.8
58.1
30.8
326
81.1
48.9
23.4
327
36.1
41.9
31.2
328
66.9
39.3
12.4
329
39.1
30.0
23.4
HO
O
297
O
298
HO
300
HO
O
O
301
HO
COOH
302
O
OH
HO
HO
OH
303 R
1
=H, R
2
=
, R
3
=H
O
OH
HO
HO
OH
304 R
1
=OH, R
2
=
, R
3
=H
OH
O
OH
HO
OH
O
OH
HO
O
CH
2
OH
305 R
1
=OH, R
2
=H, R
3
=
O
OH
HO
HO
OH
306 R
1
=OH, R
2
=
, R
3
=
OH
O
OH
HO
OH
O
OH
HO
O
CH
2
OH
O
OH
HO
HO
OH
307 R
1
=H, R
2
=
, R
3
=
OH
O
OH
HO
OH
O
OH
HO
O
CH
2
OH
O
COOR
3
R
1
O
OR
2
HO
HO
OH
HO
R
1
COOH
R
2
308 R
1
=CH
3
, R
2
=OH
309 R
1
=COOH, R
2
=H
O
299
pg_0021
SUN
et al. ¡X Structure-activity relationships of oleanane- and ursane-type triterpenoids
359
manner, similar to the dose-dependent insulin production
by glucose in INS-1 cells. OA-28-aldehyde also enhanced
insulin secretion by about 4ng/mg in those concentrations
(Zhang et al., 2004).
Slowing gastric emptying will prolong the postprandial
absorption of food, with a resultant improvement in blood
glucose control. OA and its oligoglycosides (283-290,
333) were examined for their effects on gastric emptying
in mice, and the 3-O-glycosides moiety was found to be
essential. The 2¡¦-O-£]-D-glucopyranosyl moiety of the
glucuronic acid reduced the activity, and the 28-ester
glucose moiety markedly reduced it (Matsuda et al.,
1999).
Inhibition of £\-glucosidase can prevent late
complications of diabetes by decreasing the postprandial
rise in blood glucose (Bischoff, 1994). OA and its five
synthetic derivatives (OA-28-methyl ester, OA-3-acetyl,
330, 331 and 332) were found to inhibit £\-glucosidase,
with IC
50
values of 11.16, 55.097, 19.012, 7.97, 89.71
and 21.63 £gM, respectively. Compound 330 was the most
potent among them (Ali et al., 2002).
OA and OA-28-aldehyde were reported to stimulate
insulin production in INS-1 cells. At 12.5 £gg/mL, O A
increased insulin production by 87.97 ng/mg of protein
in INS-1 cells. At 25 and 50 mg/ml of OA, the secretion
of insulin was reduced considerably in a dose-dependent
O
O
O
OH
O
OH
HO
OH
O
OH
HO
HO
MeOOC
310
313 R
1
=CH
3
, R
2
=H, R
3
=CH
3
, n=10
314 R
1
=CH
3
, R
2
=H, R
3
=CH
3
, n=12
315 R
1
=CH
3
, R
2
=H, R
3
=CH
3
, n=14
316 R
1
=CH
3
, R
2
=H, R
3
=CH
3
, n=16
317 R
1
=H, R
2
=R
3
=CH
3
, n=14
318 R
1
=H, R
2
=R
3
=CH
3
, n=16
CH
3
(CH
2
)
n
COO
COOH
R
3
R
2
R
1
311 R
1
=CHO, R
2
=H
312 R
1
=CH
2
OH, R
2
=
O
O
HO
O
O
Me
HO
OH
R
2
O
O
OH
OH
OH
OH
O
R
1
COOH
O
OH
HO
OH
O
OH
OH
H
OH
O
CH
2
OH
OH
OH
OH
H
O
O
O
H
OH O
COOR
319 R=H
320 R=Glc
R
1
R
2
R
3
R
4
Xyl Gal H H
H Gal H H
Xyl Gal H Glc
H Gal Ara Glc
H Ara(p) H H
321
322
323
324
333
O
OR
2
H
O
COOR
4
COOH
OR
1
OR
3
O
OH
OH
OH
H
O
O
H
O
COOH
COOCH
3
OH
OH
325
COOR
pg_0022
360
Botanical Studies, Vol. 47, 2006
HeMOLYTiC aCTiviTieS
Hemolytic activity is one of the well known
characteristics of triterpene saponins. Monodesmosidic
OA disaccharides and trisaccharides (335-355) were
prepared and their hemolytic activity compared (Table 14).
The authors concluded that for lactosides of glycyrrhetic
acid, its 11-deoxo and 18£\-derivatives, and their methyl
esters (335-341), it was found that 28-COOH might
be a basic requirement for strong hemolytic activity of
lactosides. Compound 357, which possessed no detectable
hemolytic properties, differed from the highly active 341
only by interchanged positions of a methyl. Esterification
increased the hemolytic activity, but esterification of the
most OA lactoside 341 led to the almost non-hemolytic
compound 340. The linkage between rings D and E
had remarkable influenced on the activity of esters of
glycyrrhetic acid lactosides (Ullah et al., 2002). A separate
study showed that the connectivity between the sugar
units strongly influenced the hemolytic activity of OA
disaccharides (341-346). The 1¡÷4 linked saponin 341
showed the highest activity. £]-configuration of the outer
anomeric position showed higher potency in the 1¡÷6
linked saponins, while 1¡÷2 linked glycosides exhibited
very low hemolytic properties. Linkage positions 3 or 4
were structural requirements for higher hemolytic activity.
The 1¡÷3 linked saponin was more active than the 1¡÷
4 linked one, but the hemolytic activities of 1¡÷6 and 1
¡÷2 linked analogues were less active (Seebacher et al.,
2000). It was also found that OA trisaccharides (347-350)
usually proved to be less potent than the corresponding
disaccharides. A £\-configuration of the terminal sugar
residue was able to enhance hemolytic activity (Seebacher
et al., 1999).
Glycyrrhetic acid disaccharides (351-355) were not
found to possess detectable hemolytic properties, so the
influence of the structure of the aglycon on the hemolytic
activity is crucial (Ullah et al., 2000).
Table 14. Hemolytic index (HI) of compounds 335-350.
Saponin
Class
HI
335
Monosacchride
<1000
336
Monosacchride
<1000
337
Monosacchride
<1000
338
Monosacchride
135000
339
Monosacchride
19500
340
Monosacchride
10000
341
Monosacchride
150700
342
Disacchride
100100
343
Disacchride
3400
344
Disacchride
3400
345
Disacchride
22000
346
Disacchride
35000
347
Trisacchride
22000
348
Trisacchride
11000
349
Trisacchride
19500
350
Trisacchride
<2000
OH
H
OH
319 R=H
320 R=Glc
H Gal H H
Xyl Gal H Glc
H Gal Ara Glc
H Ara(p) H H
322
323
324
333
OH
325
HOOC O
O
O
O
COOR
COOH
OH
O
HOOC
HO
H
326 R=Glc
327 R=H
HOOC
O
OH
O
O
O
COOR
COOH
OH
HO
HOOC
328 R=Glc
329 R=H
HO
OHO CO
330
AcO
OAc
O CO
331
O
O O CO
332
HO
COOH
334
pg_0023
SUN
et al. ¡X Structure-activity relationships of oleanane- and ursane-type triterpenoids
361
Membrane-disrupting activity may cause hemolysis
and other various biological activities. Fifteen triterpenoid
saponins were classified into four types based on their
chemistries and membrane-disrupting activities (Hu et al.,
1996).
I: 356-359. Are glycosylated at two sites (C-3 and
C-28), and the carboxylic group of the glucuronic acid
residue connecting to C-3 was esterified by an alkyl group.
Their actions are so strong that they can cause catastrophic
rupture when sufficiently accumulated.
II: 360-363. Are glycosylated at a single site (C-3).
They bind to the liposomal membrane more strongly than
type I, but not enough to cause membrane disruption.
III: 290, 286 and 324. Are glycosylated at two
sites (C-3 and C-28), and the carboxylic group of the
glucuronic acid was free. Although these saponins bind
to the membrane as efficiently as type I, their disruptive
ability was much weaker.
IV: 283, 333 and 322. Are glycosylated at a single
site (C-3) with two carboxylic groups. Their membrane
disrupting activity could only be shown in the presence of
cholesterol.
335 R
1
=H, R
2
=
B
-D-galp-(1
m
4)-
B
-D-glc-(1
m
338 R
1
=CH
3
, R
2
=
B
-D-galp-(1
m
4)-
B
-D-glc-(1
m
351 R
1
=H, R
2
=
B
-D-glc-(1
m
2)-
B
-D-glc-(1
m
352 R
1
=H, R
2
=
B
-D-glc-(1
m
3)-
B
-D-glc-(1
m
353 R
1
=H, R
2
=
A
-D-glc-(1
m
4)-
B
-D-glc-(1
m
354 R
1
=H, R
2
=
B
-D-glc-(1
m
4)-
B
-D-glc-(1
m
355 R
1
=H, R
2
=
B
-D-glc-(1
m
6)-
B
-D-glc-(1
m
R
2
O
COOR
1
H
O
336 R
1
=H, R
2
=
B
-D-galp-(1
m
4)-
B
-D-glc-(1
m
339 R
1
=CH
3
, R
2
=
B
-D-galp-(1
m
4)-
B
-D-glc-(1
m
R
2
O
COOR
1
H
O
337 R
1
=H, R
2
=
B
-D-galp-(1
m
4)-
B
-D-glc-(1
m
R
2
O
COOR
1
H
340 R
1
=CH
3
, R
2
=
B
-D-galp-(1
m
4)-
B
-D-glc-(1
m
341 R
1
=H, R
2
=
B
-D-galp-(1
m
4)-
B
-D-glc-(1
m
342 R
1
=H, R
2
=
B
-D-galp-(1
m
3)-
B
-D-glc-(1
m
344 R
1
=H, R
2
=
B
-D-galp-(1
m
2)-
B
-D-glc-(1
m
343 R
1
=H, R
2
=
A
-D-galp-(1
m
2)-
A
-D-glc-(1
m
345 R
1
=H, R
2
=
A
-D-galp-(1
m
6)-
B
-D-glc-(1
m
346 R
1
=H, R
2
=
B
-D-galp-(1
m
6)-
B
-D-glc-(1
m
R
2
O
COOR
1
H
347 R
1
=H, R
2
=
B
-D-glc-(1
m
2)-
B
-D-glc-(1
m
6)-
B
-D-glc-(1
m
348 R
1
=H, R
2
=
B
-D-glc-(1
m
3)-
B
-D-glc-(1
m
6)-
B
-D-glc-(1
m
349 R
1
=H, R
2
=
A
-D-glc-(1
m
4)-
B
-D-glc-(1
m
6)-
B
-D-glc-(1
m
350 R
1
=H, R
2
=
B
-D-glc-(1
m
2)-
B
-D-glc-(1
m
6)-
B
-D-glc-(1
m
O
OH
HO
HO OH
galp=
O
OR
1
H
O
COOR
4
COOR
3
OH
OR
2
R
1
R
2
R
3
R
4
H H Bu Glu
356
H H Me Glu
357
H Ara Me Glu
358
Gal H Me Glu
359
H H Me H
360
H Ara Me H
361
Gal H Me H
363
Gal H Bu H
362
pg_0024
362
Botanical Studies, Vol. 47, 2006
MiSCeLLaNeOUS
Oleanane- and ursane-type triterpenoids have many
other activities besides the above nine activities, but they
have been researched and reported less. The following
activities, which have structure-activity relationships, are
introduced briefly all together.
Spasmolytic activity
Eucalyptanoic acid (364) and its acetyl (365) an d
acetylmethyl (366) derivatives, as well as O A and OA
acetyl (197) and acetylmethyl (282) derivatives, were
tested for spasmolytic activity (Table 15). Among them,
the presence of the 28-COOMe and C-9(11) double bond
enhanced the activity, while the acetoxy group at C-3
decreased it (Begum et al., 2002).
antipruritic activity
OA 3-O-monodesmosides (283-285, 288, 289, and
367-370) were examined for the antipruritic effects
using a compound 48/80-induced pruritic model in mice
(Table 16). OA 3-O-monodesmosides showed antipruritic
effects, while O A and its 3, 28-O-bisdesmosides did not.
Moreover, the 3-O-glucuronides showed more potent
activity than the corresponding 3-O-glucosides (Kubo et
al., 1997; Matsuda et al., 1998a).
anti-thrombotic activity
OA showed inhibitory effects on blood platelet
aggregation. It not only inhibited blood platelet
aggregation induced by adenosine 5¡¦-diphosphate
(ADP) and collagen in old mice, but also increased
electrophoretic mobility at therapeutical dosage (75-300
mg/kg) (Liu and Wang, 1993). Compounds 371, 372,
UA and OA were isolated from Chaenomeles sinensis,
and tested for the inhibitory activity of tissue factor (TF),
which could accelerate the blood clotting. Among these
compounds, only 371 and its aglycone 371a inhibited TF
activity, and IC
50
values were 0.036 and 0.028 mM/unit,
respectively. However, 372, UA, OA and the dimethyl
ester derivative 371b o f 371a showed no inhibitory
activity. These results indicated that the presence of two
free carboxyl groups of 371a played an important role
in exerting the inhibitory activity on TF (Lee and Han,
2003).
R
2
O
COOR
1
364 R
1
=R
2
=H
365 R
1
=H, R
2
=CH
3
CO
366 R
1
=CH
3
, R
2
=CH
3
CO
Table 15. Effect on Spontaneous conreactions and K
+
-
inducedcontractions.
Effect (% inhibition)
Spontaneous
conreactions
K
+
-induced
contractions
364
58.2
31.1
365
No effect
No effect
366
95.3
85.9
OA
No effect
No effect
197
No effect
No effect
282
67.7
35.5
O
H
R
1
OH
OR
2
OR
3
O
COOH
367 R
1
=CH
2
OH, R
2
=R
3
=H
368 R
1
=CH
2
OH, R
2
=Xyl, R
3
=H
369 R
1
=COOH, R
2
=Ara, R
3
=H
370 R
1
=COOH, R
2
=Glc, R
3
=Glc
Table 16. Effects on compound 48/80-induced scratch behavior
in mice.
Dose (mmol/kg) Inhibition (%)
OA
0.05
13.7
0.2
9.9
283
0.05
-0.9
0.2
52.4
284
0.05
2.2
0.2
65.8
288
0.05
16.0
0.2
2.0
367
0.05
-4.5
0.2
17.0
368
0.05
28.5
0.2
48.9
289
0.05
-16.8
0.2
64.0
369
0.065
4.2
0.13
58.9
370
0.05
43.6
0.10
43.6
285
0.05
-1.1
0.11
9.4
Positive control was diphenhydramine hydrochloride, which
inhibitions were 26.4 and 84.7 at dosage 0.05 and 0.2 mmol/
kg, respectively.
pg_0025
SUN
et al. ¡X Structure-activity relationships of oleanane- and ursane-type triterpenoids
363
inhibitory activity of ethanol absorption
Excessive consumption of ethanol is known to
profoundly affect nearly every organ in the body. OA
3-O-monodesmosides (321, 373, 375 and 376) were
found to show potent inhibitory activity on ethanol
absorption, while 3, 28-O-bisdesmosides (323, 374,
377 and 378) lacked the inhibitory activity (Table 17).
Some OA 3-O-monodesmosides were found to show
potent inhibitory activity on ethanol absorption, while
3, 28-O-bisdesmosides lacked the inhibitory activity
(Yoshikawa et al., 1993 and 1996c).
effects on nonmalignant prostate cell
proliferation
Eight synthesized A-ring cleaved oleanane and ursane
analogues (379-386) were assessed for their ability to
inhibit cell proliferation in NRP.152 (nonmalignant)
prostate cells (Table 18). It was found that each pair
of ursane and oleanane derivatives exhibited similar
activities, and A-ring cleaved compounds were more
active. In A ring cleaved series, both conversions of
nitriles corresponding aldehydes and reduction of the
nitriles to the amines resulted in increased activity (Finlay
et al., 1997).
HO
HOOC
COO-Glc
HO
371
HO
CH
3
OOC
COOCH
3
HO
371b
HO
HOOC
COOH
HO
HO
372
HO
HOOC
COOH
HO
371a
O
H
COOH
OR
3
OR
2
OR
1
O
COOR
4
R
1
R
2
R
3
R
4
Gal Gal H H
Gal Gal H Glc
H Glc H H
H Glc Ara(f) H
H Glc H Glc
H Glc Ara(f) Glc
373
374
375
376
377
378
Table 17. Inhibitory activity of 321, 323, 373-378 on ethanol
absorption.
Dose
(mg/kg p.o.)
Ethanol absorption in blood (mg/ml)
1 h
2 h
3 h
321
25
0.11
0.13 0.02
50
0.01
0.04 0.01
100
0
0
0
373
25
0.56
0.19 0.01
50
0.50
0.19 0.02
100
0.25
0.18 0.02
341 100
0.57
0.24 0.04
374 100
0.57
0.23 0.04
375
25
0.26
0.20 0.03
50
0.03
0.04 0.02
100
0.03
0.02 0.01
376
25
0.42
0.21 0.03
50
0.34
0.18 0.01
100
0.08
0.09
0
377 100
0.58
0.21
0
378 100
0.56
0.23 0.04
Table 18. Inhi bit ory ac ti vit y o n NRP 15 2 pro s ta te ce ll
proliferation.
Compound IC
50
(£gM) Compound IC
50
(£gM)
386
0.3
OA
>5.0
385
0.7
UA
>5.0
383
1.5 OA-3-oxo
>5.0
384
2.4 UA-3-oxo
>5.0
379
3.8
381
>5.0
380
>5.0
382
>5.0
pg_0026
364
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COOH
NC
379 380
COOH
HO
O
381
COOH
HO
O
COOH
H
O
COOH
H
O
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COOH
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COOH
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