Bioorganic & Medicinal Chemistry Letters 19 (2009) 2796–2800
Bioorganic & Medicinal Chemistry Letters
Synthesis and cytotoxicities of icogenin analogues with disaccharide residues
Haixing Wang , Fuqin Su b, , Liang Zhou , Xiaoguang Chen , Pingsheng Lei
a,
a
b
a,*
a
Key Laboratory of Bioactivity Substance and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Materia Medica,
Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 10050, PR China
Department of Pharmacology, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 10050, PR China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
For further structure–activity relationships (SAR) research of furostan saponin, two icogenin analogues:
Received 2 February 2009
Revised 6 March 2009
Accepted 23 March 2009
Available online 26 March 2009
(
25R)-22-O-methyl-furost-5-en-3b,26-diol-3-O-
a
-
L
-rhamnopyranosyl-(1 ? 2)-b-
D
-glucopyranoside 1
-glucopyrano-
and (25R)-22-O-methyl-furost-5-en-3b,26-diol-3-O-
a
-
L
-rhamnopyranosyl-(1 ? 2)-a-D
side 2, with valuable disaccharide moieties, were synthesized from diosgenin through eight steps.
Both of the analogues behaved the similar cytotoxic activities with icogenin, towards nine types of
human tumor cells herein.
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Furostan saponin
Icogenin analogue
Diosgenin
Cytotoxicity
Cytotoxic activity
As a common and significative feature, the cytotoxicity of furostan
saponin has been given particular attention by researchers in
position was synthesized following the modified method of
4
,5
Hou as shown in Scheme 2. In the presence of trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf), glucosyl pentaacetate 5 was
treated with ethanethiol to give two epimers: 6 and 7 (6:7 = 1:1).
The latter was deacetylated, then treated with benzaldehyde
dimethylacetal and p-toluenesulfonic acid monohydrate (p-
1
,2
3
recent years. Icogenin, namely (25R)-22-O-methyl-furost-5-en-
b,26-diol-3-O- -rhamnopyranosyl-(1 ? 2)-[b- -gluco-pyanosyl-
1 ? 3)]-b- -glucopyranoside, a typical furostan saponin isolated
from Dracaena draco, showed potent cytotoxic activity on the growth
of HL-60, the IC50 was 2.6 ± 0.9 M at 72 h, owing to the induction of
-epimer were first
3
a-L
D
(
D
l
TsOHꢀH
2
O) in DMF to afford 8. Under the condition of tert-buty-
apoptosis in HL-60 cells. In 2006, icogenin and its
a
ldimethylsiyl chloride (TBDMSiCl), imidazole and catalytic amount
of 4-dimethylamino pyridine (DMAP), the TBDMS group masked
product 9 was formed. Using Triethylsilyl trifluoromethanesulfo-
synthesized by Hou in our lab.4 Icogenin consists of a biggish trisac-
charide moiety and a furostan sapogenin (Fig. 1). In order to decipher
the structure–activity relationships and mechanism of action of
,5
1
0
nate (TESOTf) as a promoter, the remaining 2-OH of 9 coupled
1
1
furostan saponin, we employed the simplified disaccharide [
Rhap-(1-2)-b- -Glcp], which commonly existed in the oligosaccha-
rides’ skeletons of icogenin and many natural saponins,
a-L-
with rhamnopyranosyl trichloroacetimidate 10, the expected
product 11 was obtained. Treated with acetic acid-water (4:1, v/
v) at 80 °C, the benzylidene group and TBDMS group were removed
in one pot, followed with acetylation, 11 was transformed into
thioglycoside 3 in 70% yield.
D
6
–8
and
9
contributed to the cytotoxic activity of saponin molecule, replacing
the trisaccharidemoietyof icogenintodesigntwoicogeninanalogues
(
1 and 2, Fig. 1). Herein, a facile and efficient way for the synthesis of
The sapogenin 4 was prepared from disogenin (Scheme 3) by the
approach of Chen. Diosgenin was protected with TBDMSiCl at 3-OH
provided 12 in a satisfactory 98% yield. Oxyfunctionalization of C-16
2
these two analogues and their cytotoxicities against human tumor
cells were reported.
Inspired by the report about the synthesis of methyl protodio-
scin2 by Chen, we designed a concise and efficient approach in
Scheme 1 for the synthesis of icogenin analogues. The analogues
were attempted to construct with 3 and 4. To get both 1,2-trans
and 1,2-cis products in the reaction of glycosylation, the thioglyco-
side 3 having a non-neighbouring group-active substituent at C-2
3
and 5,6 double bond with oxone in the presence of NaHCO afford
two isomer: 13 and 14 (13:14 = 1:1), which were readily distin-
1
guished by their H NMR spectra. In isomer 13, the signal of 3-proton
appeared at 3.63 ppm, while it was shifted downfield to 3.85 ppm in
14, because of the affection of 5,6-epoxy ring. As both isomers could
be used in the next step, treatment of 13 and 14 with Zn/KI in Ac O/
2
HOAc gave 16,22-dione 15 successfully. Removal of the 3-TBDMS
group of 15 provided the sapogenin 4 at last.
In Scheme 4, glycosylation of the 3-OH in sapogenin 4 with thio-
glycoside 3 under the promotion of N-iodosuccinimide (NIS) and
*
Authors contributed equally to this work.
0
960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.092