Chemical synthesis and in vitro antitumor activity of quinizarin glycoside analogs

Article abstract of DOI:10.1080/00397910802279852

A series of new glycoside derivatives of quinizarin were synthesized and characterized by NMR and IR spectrometry, and in vitro antitumor activity of some of these derivatives was evaluated against the mouse leukaemia P388 and the human leukaemia HL-60 cell lines by the standard MTT assay. They were proven to possess moderate antitumor activity. Copyright Taylor & Francis Group, LLC.

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Chemical Synthesis and In
Vitro Antitumor Activity of
Quinizarin Glycoside Analogs
a
a
a
a
Xiaofei Sun , Li Ji , Sumei Ren , Shengbiao Wan
a
&
a
Tao Jiang
School of Medicine and Pharmacy, Key Laboratory
of Marine Drugs, Ministry of Education , Ocean
University of China , Qingdao, China
Published online: 31 Oct 2008.
To cite this article: Xiaofei Sun , Li Ji , Sumei Ren , Shengbiao Wan & Tao Jiang (2008)
Chemical Synthesis and In Vitro Antitumor Activity of Quinizarin Glycoside Analogs,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:23, 4116-4124, DOI: 10.1080/00397910802279852
To link to this article: http://dx.doi.org/10.1080/00397910802279852
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Synthetic Communications , 38: 4116–4124, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802279852
Chemical Synthesis and In Vitro Antitumor
Activity of Quinizarin Glycoside Analogs
Xiaofei Sun, Li Ji, Sumei Ren, Shengbiao Wan, and Tao Jiang
School of Medicine and Pharmacy, Key Laboratory of Marine Drugs,
Ministry of Education, Ocean University of China, Qingdao, China
Abstract: A series of new glycoside derivatives of quinizarin were synthesized and
characterized by NMR and IR spectrometry, and in vitro antitumor activity of
some of these derivatives was evaluated against the mouse leukaemia P388 and
the human leukaemia HL-60 cell lines by the standard MTT assay. They were
proven to possess moderate antitumor activity.
Keywords: Antitumor activity, chemical synthesis, glycoside derivatives,
quinizarin
INTRODUCTION
Anthraquinones are widely distributed in nature. They can be found not
only in higher plants, but also in animals, microorganisms, and fungi.
Anthraquinones show a variety of activities, such as antiviral, antitumor,
[
1–5]
antifungal, antioxidant, and antibacterial activities.
none drugs have received attention in treating diseases. Mitoxantrone
2) and daunorubicin (3), two different kinds of anthraquinones, have
been in clinical use more than 30 years for chemotherapy of various
The anthraqui-
(
[6]
tumors (Fig. 1). Their inhibition of topoisomerase II, which eventually
leads to DNA double-strand breaks in the tumor cells and possibly cell
death, has been established as the key mechanism of action for the
Received March 4, 2008.
Address correspondence to Tao Jiang, School of Medicine and Pharmacy, Key
Laboratory of Marine Drugs, Ministry of Education, Ocean University of China,
Qingdao 266003, China. E-mail: jiangtao@ouc.edu.cn
4
116

Quinizarin Glycoside Analogs
4117
Figure 1. Structures of quinizarin (1), mitoxantrone (2), and daunorubicin (3).
antitumor and cytotoxic effects. At the same time, the function of these
two drugs as noncovalent DNA binders is generally believed to be
essential for their activities. Most DNA binding compounds share two
common structural features to contribute to their activity: the presence
of planar polycyclic aromatic systems and the occurrence of one or
two side chains containing polymethyleneamine or sugar fragments in a
[7–9]
strictly defined orientation to the chromophore.
The polyhydroxylated anthraquinone quinizarin (1, 1,4-dihydroxy-
9
antioxidant, antitumor, antimutagenic, and antibacterial activities.
,10-anthraquinone, Fig. 1), a natural product of anthraquinones, exhibits
[
4,10,11]
However, quinizarin itself has lower DNA binding affinity and lower or
less insignificant cytotoxicity against cancer cells. Addition of side chains
such as polymethyleneamine, sugar, or heterocycles to quinizarin chromo-
phore can substantially increase DNA binding affinity and antitumor
activity. Moreover, chains of varying length, polarity, rigidity, charge
[
12–14]
and steric bulk may confer different DNA binding affinities.
This work aims to synthesize a group of new quinizarin glycoside
derivatives with improved DNA binding affinity and antitumor activity
by attaching various saccharide side chains to quinizarin.
RESULTS AND DISCUSSION
The chemical synthesis of target compounds is shown in Scheme 1.
[
15,16]
According to the literatures,
able D-pyranose, glycosyl bromide donors b1–b3 were obtained in excel-
starting with the commercially avail-
ꢀ
lent yield at the temperature of less than 20 C. Using the phase- transfer
[
17]
catalysis method, quinizarin 1 was coupled with the glycosyl bromide
donors successfully. Because the two hydroxyls of quinizarin 1 are in
the same chemical condition, there is no selectivity in the glycosidation
reaction. By controlling the proportion of quinizarin 1 and the glucosyl

4118
X. Sun et al.
Scheme 1. a1, d1, R ¼ OH, R ¼ H, R ¼ CH OH; a2, d2, R ¼ H, R ¼ OH,
1
2
3
2
1
2
R
R
3
3
¼ CH
2
2
OH; a3, d3, R
OAc; b2, c2, c5, R
1
¼ OH, R
2
¼ H, R
3
¼ H; b1, c1, c4, R
1
¼ OAc, R ¼ H,
2
¼ CH
1
¼ H, R
2
¼ OAc, R
3
¼ CH
2
OAc; and b3, c3,
R ¼ OAc, R ¼ H, R ¼ H.
1
2
3
donors (1:1 and 1:2), compounds c1–c3 and c4–c5 were prepared in good
yields. Deprotection of compounds c1–c3 using newly prepared sodium
methoxide in methanol gave compounds d1–d3, which were easily puri-
[18]
fied by washing with methanol.
Taking compound c1 as representative, the new b-glycosidic linkage
was established by the H-1 coupling constant (J ¼ 7.7 Hz) and the chemi-
cal shift (5.56 ppm) of glycopyranoside, which was consistent with the
assignment that the H-1 coupling constant of b-glycosidic linkage was
[
19]
about 8 Hz and the chemical shift was 4.3–5.5 ppm.
The in vitro tumor-inhibitory effect of compounds c1, c2, c4, and c5
was evaluated by the standard 3-(4,5-dimethylthiazo-2-yl)-2,5-phenylte-
trazolium bromide (MTT) assay against the mouse leukaemia P388 and
the human leukaemia HL-60 cell lines’ growth. Compared to the
inhibitory rate of compounds c1, c2, c4 and c5 (Table 1), the selected four

Quinizarin Glycoside Analogs
4119
Table 1. Inhibitory effect of compounds c1, c2, c4, and c5 on the mouse leukae-
mia P388 and the human leukaemia HL-60 cell lines (MTT)
Inhibitory rate (%)
Cell line
P388
Concentration (mol=L)
c1
c2
c4
c5
ꢁ4
ꢁ5
ꢁ6
ꢁ7
ꢁ8
10
100
55.9
9.0
11.0
4.8
73.6
92.8
18.3
16.2
12.7
8.7
96.9
95.2
0
0
0
10
10
10
10
0
0
0
0
ꢁ4
ꢁ5
ꢁ6
ꢁ7
ꢁ8
HL-60
10
100
93.7
86.2
0
0
0
55.0
23.0
15.8
22.4
20.3
92.7
90.9
40.6
14.2
15.0
10
10
10
10
91.9
46.6
18.4
22.6
compounds show higher inhibitory activity on the human leukaemia HL-
0 cell line’s growth than on the mouse leukaemia P388 cell line. The anti-
6
tumor activity of quinizarin acetyl–protected glycopyranoside (c1, c4) is
better than that of quinizarin acetyl–protected galactoside (c2, c5), but
they are all proven to possess moderate antitumor activity.
In summary, the quinizarin glycoside derivatives c1–c5 have been
synthesized through the phase-transfer catalysis method, and compounds
d1–d3 were obtained in excellent yield by deprotection of c1–c3. All the
target compounds are synthesized for the first time by a chemical method
and characterized by NMR and IR spectrometry. Compounds c1, c2, c4,
and c5 are proven to possess moderate antitumor activity, which was
evaluated against the mouse leukaemia P388 and the human leukaemia
HL-60 cell lines by the standard MTT assay.
EXPERIMENTAL
All reactions were monitored by thin-layer chromatography (TLC), on
aluminium sheets (silica gel 60-F254, E. Merck). Compounds were
visualized by UV light. Melting points were measured on a WRX-1S
melting-point apparatus and were uncorrected. IR spectra were
recorded using KBr pellets for solid samples on a Nicolet Nexus 470
FT-IR. NMR spectra were recorded on a Jeol JNM-ECP spectrometer
1
13
at 600 MHz for H NMR and 125 MHz for C NMR with TMS as
the internal standard. Chemical shifts are expressed in d (ppm) and

4120
X. Sun et al.
coupling constants (J) in hertz. Column chromatography was carried
out using silica gel (200–300 mesh). Silica-gel chromatography solvents
were of analytical grade. All reaction solvents were dried prior to use
according to standard procedures. All primary reagents were commer-
cially available.
[15,16]
According to the literature,
obtained in excellent yield.
glycosyl bromide donors b1–b3 were
2
der; yield 83.8%; mp: 85–87 C (lit. 88–89 C).
,3,4,6-Tetra-O-acetyl-a-D-glucopyranosyl bromide (b1): white pow-
ꢀ
[20]
ꢀ
2
,3,4,6-Tetra-O-acetyl-a-D-galactopyranosyl bromide (b2): white pow-
ꢀ
[21]
ꢀ
der; yield 81.2%; mp: 83–85 C (lit. 84–85 C).
,3,4-Tri-O-acetyl-a-D-xylopyranosyl bromide (b3): white powder;
2
yield 80.0%; mp: 96–98 C (lit.
ꢀ
[16]
ꢀ
97–98 C).
1-Hydroxy-4-[(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)oxy]-9,10-
anthracenedione (c1)
To a suspension of quinizarin 1 (1.2 g, 5 mmol) in water (15 mL), K CO
2
3
(2.07 g, 1.5 mmol) was added with stirring. Then a solution of tetrabutyl
ammonium bromide (0.33 g, 1 mmol) in chloroform (5 mL) and water
ꢀ
(5 mL) was added, and the temperature rosen to 40 C. A solution of com-
pound b1 (2.05 g, 5 mmol) in chloroform (10 mL) was added dropwise,
ꢀ
and the reaction mixture was stirred at 40 C overnight. The reaction mix-
ture was diluted with chloroform (20 mL); then the organic layer was sepa-
rated and the water layer washed with chloroform (3 ꢂ 30 mL). The
organic layer was combined and washed with small portions of water three
times. Then the organic layer was neutralized with saturated NaHCO3
liquorand brine. The organic layer was dried with MgSO overnight.
4
The solvent was removed under reduced pressure using a rotary evapora-
tor. After purification by column chromatography over silica gel (petro-
leum ether–EtOAc ¼ 1:1), compound c1 was obtained as yellow powder;
ꢀ
1
yield 1.60 g, 56.1%; mp 167–168 C; H NMR (CDCl , 600 MHz) d
3
(
7
ppm): 12.87 (s, 1H), 8.21 (d, J ¼ 7.3 Hz, 1H), 8.12 (d, J ¼ 7.0 Hz, 1H),
.95 (m, 2H), 7.68 (d, J ¼ 9.5 Hz, 1H), 7.47 (d, J ¼ 9.2 Hz, 1H), 5.56 (d,
J ¼ 7.7 Hz, 1H), 5.41 (t, J ¼ 9.5 Hz, 1H), 5.19 (m, 1H), 5.06 (t, J ¼ 9.5 Hz,
Hz, 1H), 4.25 (m, 2H), 4.13 (d, J ¼ 9.8 Hz, 1H), 2.07 (s, 3H), 2.04 (s, 3H),
1
3
2
1
1
7
.02 (s, 3H), 1.99 (s, 3H); C NMR (CDCl , 151 MHz) d (ppm): 188.47,
3
80.35, 170.03, 169.62, 169.35, 169.06, 158.01, 149.78, 135.27, 134.34,
33.91, 131.80, 129.22, 126.71, 126.14, 125.64, 120.80, 115.61, 98.70,
1.98, 70.94, 70.39, 67.95, 61.61, 20.61, 20.51, 20.42, 20.33; IR (KBr,
ꢁ1
cm ): 3427, 1751, 1364, 1233, 1065, 911.
Compounds c2–c3 were prepared with similar procedures.

Quinizarin Glycoside Analogs
4121
1
9
-Hydroxy-4-[(2,3,4,6-tetra-O-acetyl-b-D-galactopyranosyl)oxy]-
,10-anthracenedione (c2)
ꢀ
1
Yellow powder; yield 1.42 g, 49.8%; mp 106–110 C; H NMR (CDCl ,
3
6
8
00 MHz) d (ppm): 13.08 (s, 1H), 8.29 (dd, J ¼ 1.5 Hz and 7.3 Hz, 1H),
.23 (m, 1H), 7.83 (m, 2H), 7.64 (d, J ¼ 9.2 Hz, 1H), 7.44 (d, J ¼ 9.5 Hz,
Hz, 1H), 5.66 (dd, J ¼ 7.7 Hz and 10.3 Hz, 1H), 5.47 (d, J ¼ 3.3 Hz,
1
4
2
1
H), 5.16 (dd, J ¼ 3.3 Hz and 10.3 Hz, 1H), 5.05 (d, J ¼ 7.7 Hz, 1H),
.36 (m, 1H), 4.25 (m, 1H), 4.01 (m, 1H), 2.25 (s, 3H), 2.20 (s, 3H),
ꢁ
1
.05 (s, 3H), 2.03 (s, 3H); IR (KBr, cm ): 3441, 1751, 1371, 1238,
069, 951.
1
-Hydroxy-4-[(2,3,4-tri-O-acetyl-b-D-xylopyranosyl)oxy]-
9
,10-anthracenedione (c3)
ꢀ
1
Yellow powder; yield 1.25 g, 50.2%; mp 163–165 C; H NMR (CDCl ,
3
6
8
1
00 MHz) d (ppm): 13.06 (s, 1H), 8.29 (dd, J ¼ 1.5 Hz and 7.7 Hz, 1H),
.22 (dd, J ¼ 1.5 Hz and 7.7 Hz, 1H), 7.82 (m, 2H), 7.56 (d, J ¼ 9.5 Hz,
H), 7.28 (d, J ¼ 9.5 Hz, 1H), 5.36 (dd, J ¼ 5.5 Hz and 7.3 Hz, 1H), 5.27
(
t, J ¼ 7.3 Hz, 1H), 5.23 (d, J ¼ 5.5 Hz, 1H), 5.05 (m, 1H), 4.34 (dd,
J ¼ 4.0 Hz and 12.1 Hz, 1H), 3.58 (dd, J ¼ 6.6 Hz and 12.1 Hz, 1H),
ꢁ1
2
.21 (s, 3H), 2.18 (s, 3H), 2.10 (s, 3H); IR (KBr, cm ): 3626, 1756,
371, 1228, 1043, 953.
1
1
9
,4-Di-[(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)oxy]-
,10-anthracenedione (c4)
To a suspension of quinizarin 1 (1.2 g, 5 mmol) in water (15 mL), K CO3
2
(
ammonium bromide (0.66 g, 2 mmol) in chloroform (5 mL) and water
4.14 g, 3 mmol) was added with stirring. Then a solution of tetrabutyl
ꢀ
(
pound b1 (4.10 g, 10 mmol) in chloroform (20 mL) was added dropwise,
5 mL) was added, and the temperature rosen to 40 C. A solution of com-
ꢀ
and the reaction mixture was stirred at 40 C overnight. The product
c4 was obtained as orange powder according to the purification of
ꢀ
1
compound c1; yield 1.94 g, 43.1%; mp 220–222 C; H NMR (CDCl ,
3
6
00 MHz) d (ppm): 8.00 (dd, J ¼ 3.3 Hz and 5.5 Hz, 1H), 7.85 (dd,
J ¼ 3.3 Hz and 5.5 Hz, 1H), 7.64 (s, 1H), 5.61 (d, J ¼ 7.7 Hz, 1H), 5.42
t, J ¼ 9.5 Hz, 1H), 5.19 (t, J ¼ 9.1 Hz, 1H), 5.07 (t, J ¼ 9.5 Hz, 1H),
.25 (m, 2H), 4.14 (d, J ¼ 10.3 Hz, 1H), 2.08 (s, 3H), 2.04 (s, 3H), 2.02
(
4
1
3
(
s, 3H), 2.00 (s, 3H); C NMR (CDCl , 151 MHz) d (ppm): 181.33,
3
1
70.02, 169.62, 169.33, 169.03, 151.55, 133.82, 133.59, 125.90, 125.16,

4122
X. Sun et al.
1
IR (KBr, cm ): 1754, 1371, 1236, 1041, 917.
23.73, 98.56, 71.96, 70.95, 70.30, 67.92, 61.55, 20.59, 20.48, 20.41, 20.33;
ꢁ
1
Compounds c5 were prepared with the similar procedures.
1
,4-Di-[(2,3,4,6-tetra-O-acetyl-b-D-galactopyranosyl)oxy]-
9
,10-anthracenedione (c5)
ꢀ
1
Orange powder; yield 1.80 g, 40.0%; mp 214–217 C; H NMR (CDCl ,
3
6
7
1
00 MHz) d (ppm): 8.12 (dd, J ¼ 3.3 Hz and 5.5 Hz, 1H), 7.74 (m, 1H),
.55 (s, 1H), 5.69 (dd, J¼ 8.0 Hz and 10.6 Hz, 1H), 5.49 (d, J ¼ 3.3 Hz,
H), 5.16 (dd, J ¼ 3.3 Hz and 10.6 Hz, 1H), 5.09 (d, J ¼ 8.0 Hz, 1H), 4.28
(
dd, J ¼ 6.6 Hz and 11.4Hz, 1H), 4.17 (m, 1H), 4.05 (t, J ¼ 6.6 Hz, 1H),
13
2
1
1
2
.22 (s, 3H), 2.20 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H); C NMR (CDCl ,
3
51 MHz) d (ppm): 181.91, 170.31, 170.23, 170.19, 169.94, 152.42, 133.82,
33.58, 127.12, 126.43, 125.15, 101.02, 71.15, 70.67, 68.09, 66.81, 61.14,
ꢁ
1
1.08, 20.71, 20.65, 20.62; IR (KBr, cm ): 1753, 1371, 1236, 1041, 910.
1
-Hydroxy-4-(b-D-glucopyranosyloxy)-9,10-anthracenedione (d1)
Compound c1 (0.5 g, 0.9 mmol) was dissolved in dry methanol (30 mL)
ꢀ
and methylene chloride (20 mL). The solution was cooled to 0 C, and
newly prepared NaOMe in methanol (0.2 M, 0.8 mL) was added. The
mixture was stirred overnight at room temperature. The resulting preci-
pitate was collected and washed with methanol to obtain compound d1
ꢀ
1
as orange powder; yield 0.36 g, 99.2%; mp 178–180 C; H NMR (CDCl ,
3
6
00 MHz) d (ppm): 12.87 (s, 1H), 8.23 (d, J ¼ 7.3 Hz, 1H), 8.17 (d,
J ¼ 7.7 Hz, 1H), 7.97 (m, 2H), 7.78 (d, J ¼ 9.5 Hz, 1H), 7.43 (d, J ¼ 9.5 Hz,
Hz, 1H), 5.15 (s, 1H), 5.14 (s, 1H), 5.10 (d, J ¼ 5.5 Hz, 1H), 5.02 (d,
J ¼ 7.7 Hz, 1H), 4.65 (t, J ¼ 5.5 Hz, 1H), 3.73 (m, 1H), 3.51 (m, 1H),
ꢁ
1
3
1
.42 (m, 2H), 3.33 (m, 1H), 3.22 (m, 1H); IR (KBr, cm ): 3423, 1747,
360, 1239, 1068, 904.
Compounds d2–d3 were prepared with similar procedures.
1
-Hydroxy-4-(b-D-galactopyranosyloxy)-9,10-anthracenedione (d2)
ꢀ
1
Orange powder; yield 0.35 g, 96.8%; mp 151–152 C; H NMR (CDCl ,
3
600 MHz) d (ppm): 12.88 (s, 1H), 8.23 (dd, J ¼ 1.1 Hz and 7.3 Hz, 1H),
8.17 (dd, J ¼ 0.8 Hz and 7.3 Hz, 1H), 7.96 (m, 2H), 7.78 (d, J ¼ 9.5 Hz,
1H), 7.43 (d, J ¼ 9.5 Hz, 1H), 5.15 (s, 1H), 5.14 (d, J ¼ 1.1 Hz, 1H),
5.09 (d, J ¼ 5.5 Hz, 1H), 5.01 (d, J ¼ 7.7 Hz, 1H), 4.64 (t, J ¼ 5.8 Hz,

Quinizarin Glycoside Analogs
4123
1H), 3.72 (m, 1H), 3.52 (m, 1H), 3.42 (m, 2H), 3.32 (m, 1H), 3.23 (m, 1H);
IR (KBr, cm ): 3380, 1730, 1358, 1231, 1051, 904.
ꢁ1
1
-Hydroxy-4-(b-D-xylopyranosyloxy)-9,10-anthracenedione (d3)
ꢀ
1
Orange powder; yield 0.33 g, 98.1%; mp 67–69 C; H NMR (CDCl ,
3
6
8
1
00 MHz) d (ppm): 12.89 (s, 1H), 8.30 (dd, J ¼ 1.5 Hz and 7.7 Hz, 1H),
.23 (dd, J ¼ 1.5 Hz and 7.7 Hz, 1H), 8.00 (m, 2H), 7.76 (d, J ¼ 9.5 Hz,
H), 7.44 (d, J ¼ 9.5 Hz, 1H), 5.23 (m, 2H), 4.71 (s, 1H), 4.48 (d,
J ¼ 6.2 Hz, 1H), 3.82 (m, 1H), 3.64 (m, 1H), 3.52 (m, 1H), 3.24 (m,
ꢁ1
1
H), 3.11 (m, 1H); IR (KBr, cm ): 3380, 1728, 1359, 1241, 1072, 905.
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