Arch Pharm Res Vol 31, No 5, 555-561, 2008
DOI 10.1007/s12272-001-1192-7
555
http://apr.psk.or.kr
A Convenient Preparation of a Disaccharide Motif and its Role
in the Cytotoxicity of the Triterpenoid Saponin, α-Hederin
Seong-Cheol Bang, Hyun-Hee Seo, Hye-Rim Shin, Ki-Cheul Lee, Le Tuan Anh Hoang, and Sang-Hun Jung
College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea
(Received May 24, 2007)
The sugar structures of triterpenoid saponins, such as
D
-hederin, are intimately associated
with their antitumor activities and other biological activities. The
D
-
L
-rhamnopyranosyl-(1o2)-
D
-
L
-arabinopyranoside group of
D
-hederin alters the cytotoxicity of its aglycon, hederagenin.
This study explored the role of this saccharide unit in the cytotoxic effect of
D
-hederin and the
possibility of its use as a carrier moiety in prodrugs of anticancer agents. A new convenient
and practical procedure for the preparation of 4-methoxybenzoyl-2,3,4-tri-O-benzoyl-
D
-
L
-rham-
nopyranosyl-(1o2)-3,4-O-dibenzoyl-
E
-
L
-arabinopyranoside (2) from 4-methoxybenzoyl-
E
-
L
-
arabinopyranoside was accomplished using four steps with an overall yield of 63%. The use of
BF
3
-OEt
2
as a catalyst in the glycosylation step in this procedure had a large advantage over
the TMSOTf catalyst used in the usual method. Moreover, the key intermediate obtained in this
procedure, 4-methoxybenzoyl-2,3,4-tri-O-benzoyl-
D
-
L
-rhamnopyranosyl-(1o2)-
D
-
L
-arabinopyr-
anoside (7), was selectively transformed to 4-methoxybenzoyl-2,3,4-tri-O-benzoyl-
D
-
L
-rham-
nopyranosyl-(1o2)-4-O-acetyl-
D
-
L
-arabinopyranoside (9) and 4-methoxybenzoyl-2,3,4-tri-O-
benzoyl-
D
-
L
-rhamnopyranosyl-(1o2)-3-O-benzoyl-
E
-
L
-arabinopyranoside (10). These deriva-
tives did not show any cytotoxicity against human cancer cell lines. Thus the 3-O-
D
-
L
-rham-
nopyranosyl-(1o2)-
D
-
L
-arabinopyranoside could be used as a nontoxic carrier moiety to
enhance the activity of anticancer drugs.
Key words: Triterpenoid saponins, Disaccharide moiety,
D
-Hederin
INTRODUCTION
Saponins are widely distributed in many plants and are
intimately involved in our daily lives (Hostettmann and
Marston, 1995). They are well known to be active cons-
tituents in many medicinal plants such as ginseng, noto-
ginseng, licorice, horse chestnut, red clover, senegae, and
primula (Shaojiang et al., 1999). Many studies revealed
that saponins have excellent physiological and pharma-
cological activities (Arao et al., 1997; Nakamura et al.,
1996). Among them,
D
-hederin (hederagenin 3-O-
D
-
L
-
rhamnopyranosyl-(1o2)-
D
-
L
-arabinopyranoside, also
known as kalopanaxsaponin A or sapinoside A) has been
proposed to be the basic saponin structure providing
saponins’ biological activities such as their antitumor (Park
et al., 2001), anti-inflammatory (Li et al., 2003; Kim et al.,
2002), antigenotoxic (Mba et al. 1999), antihepatotoxic
(Jeong et al., 1998), antihepatic microsomal cytochrome
P450 (Shi et al., 1996), and metallothionein-inducing
activities (Iszard et al., 1995). We recently reported our
preliminary investigation into the structure activity relation-
ship of
D
-hederin (Bang et al., 2005a, 2005b). It seems
that the first sugar (arabinose) linked to the hydroxyl
group on C-3 of aglycone (hederagenin) has a negative
role in the cytotoxic activity of hederagenin, whereas the
second sugar (rhamnose) on C-2' of the first sugar
compensates for the decline of activity of the first sugar
and enhances its activity by up to approximately five-fold
(Fig. 1). Moreover, it is very interesting that a number of
antitumoral saponins with a (1o2) glycoside linkage
between the first and second sugars have been found in
nature (Kizu et al., 1995; Quetin-Leclercq et al., 1992;
Bhandari et al., 1987; Choi and Woo, 1987). Judging from
these results and evidence, the sugar moiety O-
D
-
L
-rham-
nopyranosyl-(1o2)-
D
-
L
-arabinopyranoside is very important
for saponins’ biological activity and its introduction at an
optimal site of anticancer agents would be expected to
enhance their anticancer activity as well as their solubility
in water. Indeed, glucose as a conjugate has been investi-
gated as a useful drug targeting tool due to the increased
Correspondence to: Sang-Hun Jung, College of Pharmacy, Chun-
gnam National University, Daejeon 305-764, Korea
Tel: 82-42-821-7314, Fax: 82-42-821-3686
E-mail: jungshh@cnu.ac.kr