Synthesis and biological activity of novel thiazolidin-4-ones with a carbohydrate moiety

Article abstract of DOI:10.1016/j.carres.2008.09.004

Some novel 2-aryl-3-[5-deoxy-1,2-O-isopropylidene-α-d-xylofuranose-5-C-yl] thiazolidin-4-ones were synthesized by the three-component condensation of an amino sugar 1, an aromatic aldehyde 2, and mercaptoacetic acid 3 in the presence of DCC and DMAP at room temperature. Two diastereoisomers 4 and 5 were afforded as the main products in totally isolated yields of 25.4-70%. The reaction was carried out with almost no observed stereoselectivity except in the case of 2c, which showed a moderate stereoselectivity. The structures of the new compounds were determined by NMR spectroscopy and mass spectrometry (MS), and the configuration of the newly generated chiral carbon (C-2) in the thiazolidin-4-one ring was tentatively assigned based on the X-ray crystallographic structure of 5d and the comparison of their corresponding NMR signals. The antitumor (human cervical cancer cells) activity and the inhibition against the glycosidases (α-glucosidase, β-glucosidase, α-amylase) have been evaluated for the new compounds, some of which exhibited antitumor activity.

Full text of DOI:10.1016/j.carres.2008.09.004

Carbohydrate Research 343 (2008) 3015–3020
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis and biological activity of novel thiazolidin-4-ones with
a carbohydrate moiety
a
a,b
Hua Chen a,b, Lingling Jiao a, Zaihong Guo a, Xiaoliu Li a,b, , Cuilan Ba , Jinchao Zhang
*
a Department of Chemistry, Laboratory of Chemical Biology, Ministry of Education, Hebei University, Baoding, Hebei 071002, China
b Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Hebei University, Baoding, Hebei 071002, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 June 2008
Received in revised form 1 September 2008
Accepted 3 September 2008
Available online 9 September 2008
Some novel 2-aryl-3-[5-deoxy-1,2-O-isopropylidene-
a
-
D
-xylofuranose-5-C-yl] thiazolidin-4-ones were
synthesized by the three-component condensation of an amino sugar 1, an aromatic aldehyde 2, and
mercaptoacetic acid 3 in the presence of DCC and DMAP at room temperature. Two diastereoisomers 4
and 5 were afforded as the main products in totally isolated yields of 25.4–70%. The reaction was carried
out with almost no observed stereoselectivity except in the case of 2c, which showed a moderate stere-
oselectivity. The structures of the new compounds were determined by NMR spectroscopy and mass
spectrometry (MS), and the configuration of the newly generated chiral carbon (C-2) in the thiazoli-
din-4-one ring was tentatively assigned based on the X-ray crystallographic structure of 5d and the com-
parison of their corresponding NMR signals. The antitumor (human cervical cancer cells) activity and the
Keywords:
Thiazolidin-4-one
Carbohydrate
X-ray
inhibition against the glycosidases (
a
-glucosidase, b-glucosidase,
a
-amylase) have been evaluated for the
Antitumor
new compounds, some of which exhibited antitumor activity.
Glycosidase inhibition
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
lidinone derivatives for investigating their biological activities and
developing structure–activity relationships.
Thiazolidinones are of considerable importance as pharmaco-
phoric groups due to their known biological activities that include
bactericidal, pesticidal, anticonvulsant, antiinflammatory, antithy-
roidal activities, among others.1,2 For instance, some 2,3-diaryl-
1,3-thiazolidin-4-ones have been reported to show strong and
selective anti-HIV activities.3–8 Therefore, studies of the synthesis
and pharmacology of thiazolidinone derivatives have attracted
more interest in recent years.9 However, such compounds are gen-
erally connected with lipophilic groups as the substituents, and to
the best of our knowledge, only a few reports on the synthesis and
pharmacology of the thiazolidinones containing hydrophilic
groups such as amino acids10 and sugar moieties11,12 have been
published. We turned our interest to the synthesis of such thiazo-
Generally, thiazolidin-4-one derivatives can be synthesized by
the three-component condensation of a primary amine, an alde-
hyde, and mercaptoacetic acid as shown in Figure 1.2 The reaction
is usually performed in refluxing toluene for 2–48 hours, but the
yields are generally not satisfactory.3,8,12 The applications of some
new synthetic methods, such as microwave-assisted synthesis,13,14
and reagents, such as Hünig’s base,10 ionic liquids,15 and KSF clay,16
have been recently explored for improving the synthesis of the
thiazolidin-4-one derivatives. We also reported a simple and con-
venient microwave-assisted synthesis of 2-aryl-3-naphthyl-1,3-
thiazolidin-4-ones.17 Herein, we would like to disclose a more
convenient method for synthesizing novel thiazolidin-4-one deriv-
atives bearing a sugar moiety at room temperature with a short
R2
R1
S
H
R2
O
R1
N
-H2O
I
-H2O
III
N
HSCH2COOH
R1CH
OH
NR2
R1CHO R2NH
+
2
S
II
O
Figure 1. A general thiazolidin-4-one synthesis.
* Corresponding author. Tel./fax: +86 312 5971116.
E-mail address: lixl@hbu.cn (X. Li).
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.09.004

3016
H. Chen et al. / Carbohydrate Research 343 (2008) 3015–3020
5'
Ar
Ar
2
S
1'
2'
O
'
O
O
3'
4
O
O
N
H2N
O
N
2
3
S
a
R
+ Ar CHO
+
HSCH COOH
S
+
2
1
O
O
O
4
O
O
HO
5
HO
4a−g
HO
2a−g
3
1
5a−g
CH3
Cl
Cl
Cl
O
N
N
Cl
Ar:
N
e
N
H
O
g
a
d
f
b
c
Scheme 1. Reagents and conditions: (a) MeOH, DMAP, DCC, rt, 1 h.
Table 2
reaction time. The antitumor and glycosidase inhibitory activities
of the new compounds were examined.
The effect of temperature on the synthesis of thiazolidin-4-ones 4d and 5d
Entry
Temperature (°C)
Total yield (%)
2. Results and discussion
1
2
3
4
rt
40
50
Reflux
59.2
54.2
46.6
48.6
2.1. The synthesis of thiazolidin-4-ones bearing a sugar moiety
The requisite 5-amino-5-deoxy-1,2-O-isopropylidene-a-D-xylo-
furanose (1) was prepared according to the literature procedure.18
The one-pot, three-component synthesis was performed (Scheme
1) as follows: First, the condensation of amino sugar 1 and the aro-
matic aldehyde 2 was carried out in dry methanol at room temper-
ature with stirring for 15–30 min until the starting materials
disappeared on TLC. Then to the reaction mixture 2 equivalents
in overall yields of 25.4–70% and the results are listed in (Table 1).
It was found that the reaction proceeded with almost no stereose-
lectivity, and only in the case of 2-chlorobenzaldehyde (2c), a mod-
erate stereoselectivity (4c:5c = 3.73) was observed (Table 1, entry
3).
The reaction was remarkably influenced by the reaction tem-
perature as shown in Table 2. Taking the piperonal derivatives 4d
and 5d as examples, when the reaction temperature was increased
from room temperature to 50 °C, the total yield decreased from
59.2% to 46.6%. But in a refluxing methanol solution, the reaction
yield increased slightly to 48.6%. Moreover, when the reaction
was performed at 100 °C in a sealed tube, a small amount of the
products were obtained, probably because of the decomposition
of the newly generated products.
of mercaptoacetic acid
3 were added, followed by DMAP
(0.2 equivalents) and DCC (2 equivalents) with stirring for
20 min. Finally, the mixture was stirred for another 20 min to com-
plete the reaction. It should be mentioned that the reaction yield
has not been observed to improve by prolonging the reaction time.
After workup and purification by silica gel column chromatogra-
phy, the diastereoisomeric products 4 (the less polar component)
and 5 (the more polar component) were obtained, respectively,
Table 1
2.2. The structure of the compounds 4 and 5
The synthesis of thiazolidin-4-ones 4 and 5
Yielda (%)
The structures of the products 4 and 5 were determined by the
analyses of their spectral data including 1H NMR, 13C NMR, and MS.
The structure of 5d was determined by X-ray crystallography
(Fig. 2). From the perspective view of 5d, the configuration of C-2
is confirmed as R. Accordingly, its diastereomer 4d should be of
the S configuration. Furthermore, each diastereoisomers of 4 and
5 exhibited similar NMR signals in H-2 and C-2 as shown in Table
3, that is, H-2 of the less polar 4 was in more downfield than that of
the more polar 5. In contrast, C-2 of 4 appeared more upfield in
comparison to that of 5. According to the X-ray structure of 5d
Entry
Ar
Total
4
5
4:5
1
2
3
4
5
6
7
a
b
c
d
e
f
70.0
41.4
62.9
59.5
59.1
64.5
25.4
39.4
18.4
49.6
30.3
28.7
31.0
14.6
30.6
23.0
13.3
29.2
30.4
33.5
10.8
1.29
0.8
3.73
1.03
0.94
1.08
1.35
g
a
Isolated yield.
Figure 2. Perspective view of compound 13d.

H. Chen et al. / Carbohydrate Research 343 (2008) 3015–3020
3017
determined on an SGWÒ-1 automatic polarimeter. 1H NMR, 13C
NMR spectra were measured on a RT-NMR Bruker AVANCE 400
NMR spectrometer using tetramethylsilane (Me4Si) as the internal
standard. High-resolution mass spectra (HRMS) were carried out
on a FTICR-MS (Ionspec 7.0T) mass spectrometer in the electro-
spray-ionization (ESI) mode. X-ray crystallographic measurements
were made on a Bruker SMART CCD diffractometer. The optical
densities for examining the activities of glycosidase inhibition
and antitumor were measured on a TU-1901 UV–vis spectropho-
tometer and a Bio-Rad Model 3550 microplate spectrophotometer,
respectively. Thin-layer chromatography (TLC) was performed on
precoated plates (Qingdao GF254) with detection by UV light or
with phosphomolybdic acid in EtOH–H2O followed by heating.
Column chromatography was performed using SiO2 (Qingdao
300–400 mesh).
Table 3
chemicals shifts of H-2 (dH-2) and C-2 (dC-2
)
Ar
dH-2 (ppm)
dC-2 (ppm)
4(S)
5(R)
4(S)
5(R)
a
b
c
d
e
f
5.67
5.88
6.12
5.61
5.91
5.68
6.09
5.60
5.77
6.01
5.56
5.90
5.61
5.99
64.13
59.73
61.33
64.90
60.77
63.22
59.09
66.71
61.41
66.70
67.44
60.78
65.57
61.54
g
Table 4
The cytotoxicity of the compounds 4 and 5 against human cervical cancer cells
Compounds
Inhibition % (in vitro at 100
17.6
lM)
3.2. General procedure for the synthesis of thiazolidin-4-ones
4a
4b
4c
4d
4e
4f
4g
5a
5b
5c
5d
5e
5f
a
—
31.8
28.0
—
The partially protected amino sugar 1 (0.189 g, 1 mmol) was
dissolved in 3 mL anhyd MeOH. The aromatic aldehyde 2 (1 mmol)
was then added to the solution, and the mixture was stirred in
room temperature for 15–30 min. Mercaptoacetic acid 3 (0.14 ml,
2 mmol) was then added. After continued stirring for 20 min at
rt, DMAP (0.2 mmol, 24.4 mg) and DCC (2 mmol, 412 mg) were
added. After a further 20 min of stirring, DCU was removed by fil-
tration, and the mixture was neutralized with solid KCO3. The sol-
vent was evaporated under reduced pressure to get a crude
product that was purified using flash column chromatography
(4:1:1 CH2Cl2–Et2O–cyclohexane) to get two diastereomers, 4
and 5.
—
20.5
—
20.2
11.4
15.7
—
—
5g
9.9
a
No inhibition.
and the consistencies of their spectral data (Table 3) and their
polarities, the configurations of C-2 in 4 and 5 could be tentatively
assigned as S and R, respectively.
3.2.1. (2S)-2-(4-Chlorophenyl)-3-[5-deoxy-1,2-O-
isopropylidene-
a
-D
-xylofuranose-5-C-yl]thiazolidin-4-one (4a)
ꢀ95.8; (c 2.0, CHCl3); dH
White solid; mp 154–156 °C; [
a
]
D
(400 MHz, CDCl3): 1.32 (3H, s, CH3); 1.52 (3H, s, CH3); 5.87 (1H,
d, J = 3.5 Hz, H-10); 4.59 (1H, d, J = 3.6 Hz, H-20); 4.31 (1H, d,
J = 2.8 Hz, H-30); 4.13–4.15 (1H, m, H-40); 2.91 (1H, dd,
J1 = 14.4 Hz, J2 = 4.0 Hz, H-50); 3.83–3.90 (2H, m, H-50, H-5); 3.73
(1H, d, J = 16.0 Hz, H-5); 5.67 (1H, s, H-2); 7.21–7.40 (4H, m, Ar–
H); 4.15 (1H, s, OH). dC (100 MHz, CDCl3): 26.31, 27.18, 32.83,
40.72, 64.13 (C-2), 74.40, 77.84, 85.23, 105.13, 112.03, 128.63,
130.01, 135.89, 137.67, 173.41. HRESIMS: calcd for C17H20ClNO5S-
Na ([M+Na]+), 408.0643, found: 408.0649.
2.3. Biological activities
Glycosidase inhibition and antitumor activities were prelimi-
narily evaluated with all the compounds 4 and 5. The cytotoxicity
of the compounds against Hela cell lines (human cervical cancer
cells) was examined by the modified Mosmann’s protocol,19 and
the results are shown in Table 4. Some compounds, such as 4c,
4d, 4g, and 5b, showed weak cytotoxicity at 100
dase inhibitory activities were measured on hydrolytic reactions
of -amylase, -glucosidase, and b-glucosidase by comparison
lM. The glycosi-
a
a
3.2.2. (2R)-2-(4-Chlorophenyl)-3-[5-deoxy-1,2-O-
with acarbose, respectively, but none of the compounds had any
inhibitory activity.
isopropylidene-
a
-
D
-xylofuranose-5-C-yl]thiazolidin-4-one (5a)
ꢀ17.7 (c 1.0, CHCl3); dH
White solid; mp 147–149 °C; [
a]
D
In conclusion, we have synthesized a series of novel thiazolidin-
4-one derivatives bearing sugar moieties by the one-pot, three-
component condensation of an amino sugar, an aromatic aldehyde,
and mercaptoacetic acid at room temperature, providing a conve-
nient method for constructing such thiazolidin-4-one derivatives
under very mild conditions. The configurations of the diastereo-
mers were determined by NMR spectroscopy and X-ray crystallo-
graphic structural analyses. The preliminary biological evaluation
of compounds 4 and 5 showed weak antitumor activities, but no
inhibition of glycosidases. Further syntheses and biological studies
of new thiazolidin-4-ones containing sugar moieties are underway
in this laboratory.
(400 MHz, CDCl3): 1.19 (3H, s, CH3); 1.24 (3H, s, CH3); 5.77 (1H,
d, J = 3.6 Hz, H-10); 4.47 (1H, d, J = 3.6 Hz, H-20); 4.68 (1H, d,
J = 2.2 Hz, H-30); 3.77–3.93 (4H, m, OH, H-50, H-5); 3.16–3.23 (2H,
m, H-40, H-50); 5.60 (1H, s, H-2); 7.26–7.39 (4H, m, Ar–H). dC
(100 MHz, CDCl3): 26.68, 26.94, 33.47, 43.20, 66.71 (C-2), 74.02,
77.72, 84.93, 105.00, 112.12, 128.63, 130.01, 135.89, 137.67,
173.84. HRESIMS: calcd for C17H20ClNO5SNa ([M+Na]+), 408.0643,
found: 408.0651.
3.2.3. (2S)-2-(2,6-Dichlorophenyl)-3-[5-deoxy-1,2-O-
isopropylidene-
a
-
D
-xylofuranose-5-C-yl]thiazolidin-4-one (4b)
ꢀ49.1 (c 1.0, CHCl3); dH
White solid; mp 59–61 °C; [
a]
D
(400 MHz, CDCl3): 1.32 (3H, s, CH3); 1.51 (3H, s, CH3); 6.73 (1H,
d, J = 2.4 Hz, H-10); 4.49 (1H, d, J = 2.6 Hz, H-20); 4.60 (1H, d,
J = 3.4 Hz, H-30); 4.21 (1H, m, H-40); 2.78 (1H, dd, J1 = 14.2 Hz,
J2 = 4.00 Hz, H-50); 3.86–3.92 (2 H, m, H-50, H-5); 3.79 (1H, d,
J = 15.6 Hz, H-5); 5.88 (1H, d, J = 3.4 Hz, H-2); 7.24–7.39 (3H, m,
Ar–H); 4.08 (1H, s, OH). dC (100 MHz, CDCl3): 26.55, 27.32; 34.36,
40.50, 59.73 (C-2), 74.14, 77.73, 85.10, 105.27, 112.26; 128.63,
3. Experimental
3.1. General methods
Melting points were measured on an SGWÒ X-4 micro melting
point apparatus and are uncorrected. Optical rotations were

3018
H. Chen et al. / Carbohydrate Research 343 (2008) 3015–3020
130.01, 135.89, 136.48, 173.95. HRESIMS: calcd for C17H19Cl2NO5S-
Na ([M+Na]+), 442.0254, found: 442.0258.
149.50, 173.79. HRESIMS: calcd for
396.1110, found: 396.1114.
C
18H21NO7S ([M+H]+),
3.2.4. (2R)-2-(2,6-Dichlorophenyl)-3-[5-deoxy-1,2-O-
3.2.9. (2S)-2-(1-Ethyl-1H-imidazol-2-yl)-3-[5-deoxy-1,2-O-
isopropylidene- -xylofuranose-5-C-yl]thiazolidin-4-one (4e)
White solid; mp 69–71 °C; +63.8 (c 1.0, CHCl3); dH
isopropylidene-
a
-D
-xylofuranose-5-C-yl]thiazolidin-4-one (5b)
ꢀ30.8 (c 2.0, CHCl3); dH
a-D
White solid; mp 127–129 °C; [
a]
[a]
D
D
(400 MHz, CDCl3): 1.15 (3H, s, CH3); 1.24 (3H, s, CH3); 6.75 (1H,
d, J = 2.6 Hz, H-10); 4.82 (1H, d, J = 2.6 Hz, H-20); 4.51 (1H, d,
J = 3.4 Hz, H-30); 3.37–3.40 (m, 1H, H-40); 3.24 (1H, dd,
J1 = 14.4 Hz, J2 = 4.0 Hz, H-50); 3.80–3.97 (3H, m, H-50, H-5); 5.78
(1H, d, J = 3.4 Hz, H-2); 7.23–7.40 (3H, m, Ar–H); 4.08 (1H, s, OH).
dC (100 MHz, CDCl3): 26.65, 27.15, 34.89, 43.57, 61.41 (C-2),
74.65, 77.75, 85.17, 104.83, 111.91, 129.69, 131.15, 131.29,
132.66, 136.31, 136.44, 174.34. HRESIMS: calcd for C17H19Cl2NO5S-
Na ([M+Na]+), 442.0254, found: 442.0252.
(400 MHz, CDCl3); 1.27 (3H, s, CH3); 1.36 (3H, s, CH3); 5.82 (1H,
d, J = 3.6 Hz, H-10); 4.53 (1H, d, J = 3.5 Hz, H-20); 4.14 (1H, s,
H-30); 3.49–3.52 (1H, m, H-50); 3.61–3.73 (3H, m, H-40, H-50,
H-5); 3.88–3.92 (1H, dd, J1 = 15.8 Hz, J2 = 1.4 Hz, H-5); 5.91 (1H,
d, J = 1.4 Hz, H-2); 6.95 (1H, s, Ar–H); 7.02 (1H, s, Ar–H); 3.97–
4.07 (2H, m, N–CH2); 1.47 (3H, t, J = 7.2 Hz, N–CH2–CH3). dC
(100 MHz, CDCl3): 16.46, 26.62, 27.15, 32.84, 41.59, 42.77, 60.77
(C-2), 74.48, 77.73, 85.41, 104.86, 112.00, 121.41, 129.16, 143.18,
173.14; HRESIMS: calcd for C16H24N3O5S ([M+H]+), 370.1430,
found: 370.1428.
3.2.5. (2S)-2-(2-Chlorophenyl)-3-[5-deoxy-1,2-O-
isopropylidene-
a
-
D
-xylofuranose-5-C-yl]thiazolidin-4-one (4c)
ꢀ129.3 (c 1.0, CHCl3); dH
3.2.10. (2R)-2-(1-Ethyl-1H-imidazol-2-yl)-3-[5-deoxy-1,2-O-
White solid; mp 185–187 °C; [
a]
isopropylidene-
White solid; mp 76–78 °C; [a]
D
a
-
D
-xylofuranose-5-C-yl]thiazolidin-4-one (5e)
D
(400 MHz, CCl3); 1.32 (3H, s, CH3); 1.53 (3H, s, CH3); 5.88 (1H, d,
J = 3.5 Hz, H-10); 4.61 (1H, d, J = 3.4 Hz, H-20); 4.49 (1H, d,
J = 2.2 Hz, H-30); 4.20–4.21 (1H, m, H-40); 2.98 (1H, dd, J1 = 14.3
Hz, J2 = 3.60 Hz, H-50); 3.93–4.0 (1H, q, J = 14.3 Hz, H-50); 3.67
(1H, d, J = 15.9 Hz, H-5); 3.78 (1H, d, J = 15.9, H-5); 6.12 (1H, s, H-
2); 7.13–7.45 (4H, m, Ar–H); 4.09 (1H, s, OH). dC (100 MHz, CDCl3):
26.41, 27.24, 32.29, 41.08, 61.33 (C-2), 74.23, 77.93, 85.21, 105.17,
112.14, 129.69, 131.15, 131.29, 136.31, 136.44, 174.35. HRESIMS:
calcd for C17H20ClNO5S ([M]+), 385.0751, found: 385.0747.
ꢀ164.9 (c 1.0, CHCl3); dH
(400 MHz, CDCl3); 1.30 (3H, s, CH3); 1.50 (3H, s, CH3); 5.76 (1H,
d, J = 3.5 Hz, H-10); 4.54 (1H, d, J = 3.5 Hz, H-20); 4.11 (1H, d,
J = 2.1 Hz, H-30); 4.15–4.22 (1H, m, H-40); 3.18 (1H, dd,
J1 = 14.6 Hz, J2 = 4.60 Hz, H-50); 3.90–3.98 (3H, m, H-50, N–CH2);
3.62 (1H, d, J = 15.6 Hz, H-5); 3.84 (1H, d, J = 15.6 Hz, H-5); 5.91
(1H, d, J = 1.4 Hz, H-2); 6.95 (1H, s, Ar-H); 7.01 (1H, s, Ar–H);
1.46 (3H, t, J = 7.2 Hz, N–CH2–CH3). dC (100 MHz, CDCl3): 16.41,
26.39, 27.20, 32.32, 41.30, 42.46, 60.78 (C-2), 74.83, 78.57, 85.54,
105.17, 111.98, 121.08, 128.93, 143.63, 173.37. HRESIMS: calcd
for C16H24N3O5S ([M+H]+), 370.1430, found: 370.1434.
3.2.6. (2R)-2-(2-Chlorophenyl)-3-[5-deoxy-1,2-O-
isopropylidene-
a
-
D
-xylofuranose-5-C-yl]thiazolidin-4-one (5c)
+16.2 (c 2.07, CHCl3); dH (400
White solid; mp 52–54 °C; [
a]
3.2.11. (2S)-2-(Pyridin-4-yl)-3-[5-deoxy-1,2-O-isopropylidene-
D
MHz, CDCl3); 1.17 (3H, s, CH3); 1.23 (3H, s, CH3); 5.78 (1H, d,
J = 3.4 Hz, H-10); 4.49 (1H, d, J = 3.4 Hz, H-20); 4.66 (1H, s, H-30);
4.11–4.14 (1H, m, H-40); 3.68–3.83 (2H, m, H-50, H-5); 3.89 (1H,
d, J = 16.0 Hz, H-5); 3.34 (1H, d, J = 12.3 Hz, H-5’); 6.01 (1H, s, H-
2); 7.26–7.42 (4H, m, Ar-H); 3.99 (1H, s, OH). dC (100 MHz, CDCl3):
26.64, 27.08, 34.34, 43.44, 66.70 (C-2), 74.40, 77.65, 85.13, 104.93,
111.98, 128.00, 131.07, 133.82, 174.36. HRESIMS: calcd for
C17H20ClNO5SNa ([M+Na] +), 408.0649, found: 408.0654.
a
-
D
-xylofuranose-5-C-yl]thiazolidin-4-one (4f)
White solid; mp 71–73 °C; [ ꢀ106.7 (c 1.0, CHCl3); dH
a]
D
(400 MHz, CDCl3); 1.32 (3H, s, CH3); 1.53 (3H, s, CH3); 5.88 (1H,
d, J = 3.5 Hz, H-10); 4.59 (1H, d, J = 3.5 Hz, H-20); 4.09–4.58 (2H,
m, H-30, H-40); 2.90 (1H, dd, J1 = 14.6 Hz, J2 = 4.4 Hz, H-50); 3.73
(1H, d, J = 15.9 Hz, H-5); 3.86 (1H, dd, J1 = 15.9 Hz, J2 = 1.7 Hz,
H-5); 3.96 (1H, q, J = 14.6 Hz, H-50); 5.68 (1H, d, J = 1.5 Hz, H-2);
7.17–8.66 (4H, m, Py–H); 3.99 (1H, s, OH). dC (100 MHz, CDCl3):
26.31, 27.16; 32.58, 41.34, 63.22 (C-2), 74.60, 78.22, 85.28,
105.16, 112.10, 121.43, 148.52, 151.31, 173.44. HRESIMS: calcd
for C16H20N2O5SNa ([M+Na]+), 375.0985, found: 375.0979.
3.2.7. (2S)-2-(Benzo[d][1,3]dioxol-5-yl)-3-[5-deoxy-1,2-O-
isopropylidene-
a
-
D
-xylofuranose-5-C-yl]thiazolidin-4-one (4d)
+98.7 (c 1.0, CHCl3); dH
White solid; mp 70–72 °C;
[a]
D
(400 MHz, CDCl3); 1.32 (3H, s, CH3); 1.52 (3H, s, CH3); 5.86 (1H,
d, J = 3.5 Hz, H-10); 4.60 (1H, d, J = 3.4 Hz, H-20); 4.50 (1H, d,
J = 2.5 Hz, H-30); 4.11–4.13 (1H, m, H-40); 2.98 (1 H, dd,
J1 = 14.2 Hz, J2 = 3.60 Hz, H-50); 3.83–3.87 (1 H, m, H-50); 3.72 (1H,
d, J = 16.0 Hz, H-5); 3.81 (1H, d, J = 14.2 Hz, H-5); 5.61 (1H, s,
H-2); 6.74–6.80 (3H, m, Ar–H); 4.03 (1H, s, OH); 6.00 (2H, s,
O–CH2–O). dC (100 MHz, CDCl3): 26.33, 27.21, 32.93, 40.40, 64.90
(C-2), 74.27, 77.72, 85.20, 102.03, 105.14, 107.02, 108.82, 112.00;
121.66, 132.52, 149.21, 173.39. HRESIMS: calcd for C18H22NO7S
([M+H]+), 396.1110, found: 396.1106.
3.2.12. (2R)-2-(Pyridin-4-yl)-3-[5-deoxy-1,2-O-isopropylidene-
a-
D
-xylofuranose-5-C-yl]thiazolidin-4-one (5f)
White solid; mp 129–131 °C; [ +14.2 (c 1.0, CHCl3); dH
a]
D
(400 MHz, CDCl3); 1.20 (3H, s, CH3); 1.23 (3H, s, CH3); 5.78 (1H,
d, J = 3.52 Hz, H-10); 4.57 (2H, d, J = 3.5 Hz, H-20); 4.49 (1H, d,
J = 3.5 Hz, H-30); 3.45–3.49 (1H, m, H-40); 3.36 (1H, dd,
J1 = 14.2 Hz, J2 = 3.8 Hz, H-50); 3.71–3.75 (1H, m, H-50); 3.78 (1H,
d, J = 16.0 Hz, H-5); 3.89–3.93 (1H, dd, J1 = 16.0 Hz, J2 = 1.8 Hz,
H-5); 5.61 (1 H, d, J = 1.4 Hz, H-2); 7.31(2 H, d, J = 4.8 Hz, Py–H),
8.66 (2H, d, J = 4.4 Hz, Py–H); 3.96 (1H, d, J = 1.4 Hz, OH). dC
(100 MHz, CDCl3): 26.58, 27.09, 33.16, 43.22, 65.57 (C-2), 74.32,
77.74, 85.04, 104.93, 112.15; 122.49, 148.59, 151.19, 174.07. HRE-
SIMS: calcd for C16H20N2O5SNa ([M+Na]+), 375.0985, found:
375.0990.
3.2.8. (2R)-2-(Benzo[d][1,3]dioxol-5-yl)-3-[5-deoxy-1,2-O-
isopropylidene-
a
-
D
-xylofuranose-5-C-yl]thiazolidin-4-one (5d)
ꢀ8.0 (c 1.0, CHCl3); dH
White solid; mp 138–140 °C; [
a
]
D
(400 MHz, CDCl3); 1.24 (3H, s, CH3); 1.25 (3H, s, CH3); 5.78 (1H,
d, J = 3.5 Hz, H-10); 4.50 (1H, d, J = 3.4 Hz, H-20); 4.81 (1H, s,
H-30); 3.37 (1H, m, H-40); 3.18 (1H, dd, J1 = 14.0 Hz, J2 = 4.0 Hz,
H-50); 3.82–3.89 (2H, m, H-50, H-5); 3.77 (1H, t, J = 16.2 Hz, H-5);
5.56 (1H, s, H-2); 6.78–6.94 (3H, m, Ar–H); 3.91 (1H, s, OH);
5.95–5.99 (2H, d, J = 15.7 Hz, O–CH2–O). dC (100 MHz, CDCl3):
26.72, 26.94; 33.53, 42.97, 67.44 (C-2), 74.02, 77.90, 85.03,
102.05, 105.03, 108.26, 108.75, 111.96; 122.77, 132.42, 148.92,
3.2.13. (2S)-2-(1H-Indole-3-yl)-3-[5-deoxy-1,2-O-
isopropylidene-a-D-xylofuranose-5-C-yl]thiazolidin-4-one (4g)
White solid; mp 99–101 °C;
[
a
]
ꢀ65.3 (c 1.0, CHCl3);
D
dH(400 MHz, CDCl3); 1.32 (3H, s, CH3); 1.53 (3H, s, CH3); 5.84
(1H, d, J = 3.5 Hz, H-10); 4.60 (1H, d, J = 3.49 Hz, H-20); 4.70 (1H,
d, J = 2.6 Hz, H-30); 4.15 (1H, m, H-40); 3.09 (1H, dd, J1 = 14.2 Hz,
J2 = 3.6 Hz, H-50); 3.78–3.81 (1H, m, H-50); 3.85 (1H, d, J = 17.7 Hz,

H. Chen et al. / Carbohydrate Research 343 (2008) 3015–3020
3019
H-5); 3.89–3.94 (1H, d, J = 17.8 Hz, H-5); 6.10 (1H, s, H-2); 7.14–
7.51 (5H, m, Ar–H); 8.28 (1H, s, NH); 3.94 (1H, s, OH). dC
(100 MHz, CDCl3): 26.32, 27.22, 33.48, 40.01, 59.09 (C-2), 74.22,
77.73, 85.19, 102.05, 105.12, 111.93, 112.29, 112.85, 119.49,
121.22, 123.77, 124.78, 124.98, 137.53, 149.50, 173.33. HRESIMS:
calcd for C19H23N2O5S ([M+H]+), 391.1321, found: 391.1328.
trophotometer at 540 nm using distilled deionized water as a blank
control.
The a-glucosidase assay was performed using PNPG (1 mg/mL)
as substrates in phosphate buffer, pH 6.8, at 37 °C. The enzyme
solution (0.1 mL, 10 mg of solid enzyme in 10 mL of pH 6.8 phos-
phate buffer), 0.1 mL of inhibitor (1 mg/mL), 1.9 mL of buffer, and
0.05 mL glutathione (reduced, 1 mg/mL) were incubated for
10 min, and then 0.15 mL of substrate was added. The reaction
was quenched with 10 mL of sodium carbonate (0.1 mol/L) after
10 min, and the solution was finally diluted to 20 mL after cooling
down. Absorbance readings were taken on a TU-1901 UV–vis spec-
trophotometer at 400 nm using distilled deionized water as a blank
control.
3.2.14. (2R)-2-(1H-Indole-3-yl)-3-[5-deoxy-1,2-O-
isopropylidene-
a
-
D
-xylofuranose-5-C-yl]thiazolidin-4-one (5g)
+24.7 (c 1.0, CHCl3); dH (400
White solid; mp 227–229 °C; [
a
]
D
MHz, CDCl3); 0.69 (3H, s, CH3); 1.21 (3H, s, CH3); 5.71 (1H, d,
J = 3.5 Hz, H-10); 4.42 (1H, d, J = 3.5 Hz, H-20); 5.08 (1H, d, J = 2.0
Hz, H-30); 3.19–3.24 (2H, m, H-40, H-50); 3.82–3.97 (4H, m, H-50,
H-5, OH); 5.99 (1H, s, H-2); 7.17–7.68 (5H, m, Ar–H); 8.46 (1H, s,
NH). dC (100 MHz, CDCl3): 26.62, 33.87, 42.78, 61.54 (C-2), 74.10,
77.93, 85.06, 104.85, 111.89; 112.40, 120.11, 121.19, 123.75,
125.18, 125.59, 137.58, 173.87. HRESIMS: calcd for C19H23N2O5S
([M+H]+), 391.1321, found: 391.1326.
3.4.2. Antitumor activity
The cytotoxicity of the compounds against Hela cell lines
(human cervical cancer cells) was examined by the modified
Mosmann’s protocol as follows: Briefly, cells (104 cells per well)
were plated in 96-well culture plates and cultured overnight at
37 °C in a 5% CO2 humidified incubator. Compounds were added
3.3. Single-crystal X-ray crystallographic analysis of 5d20
to the wells at final concentrations of 1, 10, and 100 lmol/L. Con-
A single crystal of compound 5d was obtained by recrystalliza-
tion from the solution of CH2Cl2 and mounted on a Bruker SMART
CCD diffractometer for analysis. The intensity data were collected
trol wells were prepared by addition of DMEM. Wells containing
DMEM without cells were used as blanks. The plates were incu-
bated at 37 °C in a 5% CO2 incubator for 48 h. Upon completion
with graphite-monochromated MoK
a
radiation (k = 0.71073 Å)
single-crystal of
of the incubation, stock MTT dye solution (10
added to each well. After 4 h of incubation, the supernatant was re-
moved and DMSO (100 L) was added to dissolve the MTT. The
optical density of each well was measured on a microplate spectro-
photometer at a wavelength of 570 nm. The inhibition rate was
calculated according to the formula: (ODcontrol ꢀ ODtreated)/
ODcontrol ꢁ 100%. The results are listed in Table 4.
lL, 5 mg/mL) was
using the h/2 scan technique from
x
a
0.20 mm ꢁ 0.18 mm ꢁ 0.16 mm, and a semi-empirical absorption
correction was applied for all complexes. The crystal system was
monoclinic, and the space group was P2(1). The structures were
solved by direct methods and refined by full-matrix least-squares
on F2. The absolute structure parameter was 0.92(9). All non-
hydrogen atoms were refined anisotropically. The crystallographic
structure is shown in Figure 2.
l
Supplementary data
Complete crystallographic data for the structural analysis have
been deposited with the Cambridge Crystallographic Data Centre,
CCDC No. 694699. Copies of this information may be obtained free
of charge from the Director, Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: +44 1223
336033, e-mail: deposit@ccdc.cam.ac.uk or via: www.ccdc.
cam.ac.uk).
3.4. Biological activity assays
3.4.1. Inhibition of glycosidases
The inhibitory activity of the synthesized compounds against
a
-amylase,
cosidase (yeast) and b-glucosidase (almonds) were obtained from
Fluka; -amylase (Bacillaceae, 4000 U/mg) from Sanland-chen
International Inc, Xiamen, China. Two substrates, p-nitrophenyl
-salicin, were purchased from
a-glucosidase and b-glucosidase: The enzymes a-glu-
a
Acknowledgments
a-glucopyranoside (PNPG) and (ꢀ)-
D
Sigma Chemical Co. All other commercial reagents were used as
Financial support from the National Natural Science Foundation
of China (NSFC) (20472015, 20672027), the Natural Science Foun-
dation of Hebei (2005000106, 2008000588), the Research Founda-
tion from the Ministry of Education of China (206013), and the
Postdoctoral Foundation of China is gratefully acknowledged.
received. Each enzyme assay was measured as follows.
The
a-amylase assay was performed using 1% starch as sub-
strate in phosphate buffer, pH 6.0, at 50 °C. The enzyme solution
(0.1 mL, 5 mg of solid enzyme in 50 mL of pH 6.0 phosphate buf-
fer), 0.1 mL of inhibitor (1 mg/mL) and 1 mL of buffer were incu-
bated for 10 min, and then 1 mL of substrate was added. After
10 min, 2 mL of 3,5-dinitrosalicylic acid was added, and then the
reaction was heated in boiling water for 5 min. The solution was
finally diluted to 20 mL after cooling down. Absorbance readings
were taken on a TU-1901 UV–vis spectrophotometer at 540 nm
using distilled deionized water as a blank control and acarbose
as a positive control.
References
1. Brown, C. F. Chem. Rev. 1961, 61, 463–520.
2. Singh, S. P.; Parmar, S. S.; Raman, K.; Stenberg, V. I. Chem. Rev. 1981, 81, 175–
203.
3. Rawal, R. K.; Tripathi, R.; Katti, S. B.; Pannecouque, C.; De Clercq, E. Bioorg. Med.
Chem. 2007, 15, 3134–3142.
4. Rawal, R. K.; Tripathi, R.; Katti, S. B.; Pannecouque, C.; De Clercq, E. Bioorg. Med.
Chem. 2007, 15, 1725–1731.
5. Rawal, R. K.; Prabhakar, Y. S.; Rawal, R. K.; De Clercq, E. Bioorg. Med. Chem. 2005,
13, 6771–6776.
6. Rao, A.; Balzarini, J.; Carbone, A.; Chimirri, A.; De Clercq, E.; Monforte, A. M.;
Monforte, P.; Pannecouque, C.; Zappalà, M. Antiviral Res. 2004, 63, 79–84.
7. Barreca, M. L.; Chimirri, A.; De Clercq, E.; De Luca, L.; Monforte, A. M.; Monforte,
P.; Rao, A.; Zappala, M. Il Farmaco 2003, 58, 259–263.
8. Barreca, M. L.; Balzarini, J.; Chimirri, A.; De Clercq, E.; De Luca, L.; Höltje, H. D.;
Höltje, M.; Monforte, A. M.; Monforte, P.; Pannecouque, C.; Rao, A.; Zappalà, M.
J. Med. Chem. 2002, 45, 5410–5413.
9. Verma, A.; Saraf, S. K. Eur. J. Med. Chem. 2008, 43, 897–905.
10. Gududuru, V.; Nguyen, V.; Dalton, J. T.; Miller, D. D. Synlett 2004, 2357–2358.
The b-glucosidase assay was performed using (ꢀ)-
D-salicin
(2 mg/mL) as substrate in phosphate buffer, pH 4.8, at 35 °C. The
enzyme solution (0.1 mL, 10 mg of solid enzyme in 10 mL of pH
4.8 acetate buffer), 0.1 mL of inhibitor (1 mg/mL), and 0.9 mL of
buffer were incubated for 10 min, and then 0.8 mL of substrate
was added. After 10 min, 2 mL of 3,5-dinitrosalicylic acid was
added, and then the reaction mixture was heated in boiling water
for 5 min. The solution was finally diluted to 20 mL after cooling
down. Absorbance readings were taken on a TU-1901 UV–vis spec-

3020
H. Chen et al. / Carbohydrate Research 343 (2008) 3015–3020
11. Al-Thebeiti, M. S. J. Carbohydr. Chem. 1999, 6, 667–674.
12. Rauter, A. P.; Padilha, M.; Figueiredo, J. A.; Ismael, M. I.; Justino, J.; Ferreira, H.;
Ferreira, M. J.; Rajendran, C.; Wilkins, R.; Vaz, P. D.; Calhorda, M. J. J. Carbohydr.
Chem. 2005, 24, 275–296.
13. Rao, A.; Chimirri, A.; Ferro, S.; Monforte, A. M.; Monforte, P.; Zappalà, M. Arkivoc
2004, V, 147–155.
15. Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron 2003, 59, 6121–6130.
16. Dandia, A.; Singh, R.; Khaturia, S.; Me-rienne, C.; Morgantc, G.; Loupyd, A.
Bioorg. Med. Chem. 2006, 14, 2409–2417.
17. Chen, H.; Bai, J.; Zhao, L.; Yuan, X. G.; Li, X. L.; Cao, K. Q. Chin. J. Org. Chem. 2008,
28, 1092–1096.
18. Li, X. L.; Zhang, P. Z.; Tian, J.; Duan, K. F.; Chen, H. Chin. J. Org. Chem. 2007, 27,
1013–1017.
19. Mosmann, T. J. Immunol. Methods 1983, 65, 55–63.
14. Sriram, D.; Yogeeswari, P.; Kumar, TG A. J. Pharm. Pharm. Sci. 2005, 8 3, 426–
429.