Synthesis and pharmacological activities of xanthone derivatives as α-glucosidase inhibitors

Article abstract of DOI:10.1016/j.bmc.2006.04.014

Considerable interest has been attracted in xanthone and its derivatives because of their large variety of pharmacological activities. In this project, a series of hydroxylxanthones and their acetoxy and alkoxy derivatives were synthesized and evaluated a

Full text of DOI:10.1016/j.bmc.2006.04.014

Bioorganic & Medicinal Chemistry 14 (2006) 5683–5690
Synthesis and pharmacological activities of xanthone
derivatives as a-glucosidase inhibitors
Yan Liu, Lan Zou, Lin Ma, Wen-Hua Chen, Bo Wang* and Zun-Le Xu
School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, PR China
Received 13 March 2006; revised 6 April 2006; accepted 7 April 2006
Available online 2 May 2006
Abstract—Considerable interest has been attracted in xanthone and its derivatives because of their large variety of pharmacological
activities. In this project, a series of hydroxylxanthones and their acetoxy and alkoxy derivatives were synthesized and evaluated as
a-glucosidase inhibitors, aimed at clarifying the structure–activity correlation. The results indicated that these xanthone derivatives
were capable of inhibiting in vitro a-glucosidase with moderate to good activities. Among them, polyhydroxylxanthones exhibited
the highest activities and thus may be exploitable as a lead compound for the development of potent a-glucosidase inhibitors.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
8
5
1
4
O
It is well known that a-glucosidase (EC.3.2.1.20) cata-
lyzes the final step of carbohydrate digestion in biologi-
cal systems. This biological importance of a-glucosidase
prompts various efforts to develop new agents capable
of efficiently inhibiting a-glucosidase. These agents,
namely a-glucosidase inhibitors, have wide application,
for example, in elucidating the action mechanism of a-
glucosidase at molecular levels and in developing che-
motherapeutic agents for clinic use in the treatment of
carbohydrate mediated diseases such as diabetes, cancer,
HIV, hepatitis, and certain forms of hyperlipoprotein-
emia and obesity.1–5 Therefore in the past two decades,
there has been increasing interest in the development of
inhibitors that can probe the structure and function of
a-glucosidase. To date, many new and effective a-gluco-
sidase inhibitors have been reported, such as acarbose
and voglibose from microorganisms and 1-deoxynojiri-
mycin isolated from plants.6,7 Recently, flavones
(Fig. 1) and their related derivatives, thanks to their
strong inhibitory activities, have attracted considerable
attentions as a new class of a-glucosidase inhibitors.6,8,9
These flavone-based compounds feature two fused aro-
matic rings and a conjugated phenyl substituent. Studies
on hydroxyflavones and other polyphenols have shown
2
7
6
3
O
O
O
flavone
isoflavone
xanthone (1)
Figure 1. Structures of flavone, isoflavone, and xanthone.
that phenolic hydroxyl groups play a determinant role
in their a-glucosidase inhibitory activities.10,11
Our concern in this field is to design and synthesize nov-
el a-glucosidase inhibitors, by using xanthones as build-
ing motifs. Xanthones (1, Fig. 1), readily isolated from
some medicinal plants, have been reported to exhibit
several important biological activities, such as anti-tu-
mor,12,13 anti-inflammatory,14 anti-thrombotic,15 and
eukaryote kinase effects.16 Recent studies have indicated
that some xanthone derivatives, such as mangiferin, a
xanthone C-glycoside, serve as potent a-glucosidase
inhibitors,17–19 however, few systematic studies of the
interaction of xanthones and their derivatives with a-
glucosidase have been reported. Consequently, their
structure–activity relationships remain to be established.
As shown in Figure 1, xanthones having three linear
fused aromatic rings may be viewed as flavone deriva-
tives in which the phenyl group is fused with the two
fused aromatic rings. This structural ‘similarity’, togeth-
er with the aforementioned studies on hydroxyflavones
Keywords: Xanthone analogues; Synthesis; a-Glucosidase; Inhibitory
activity.
*
Corresponding author. Tel.: +86 20 84113083; fax: +86 20
84112245; e-mail: ceswb@mail.sysu.edu.cn
0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.04.014

5684
Y. Liu et al. / Bioorg. Med. Chem. 14 (2006) 5683–5690
R5
O
O
R1
O
R4
R3
COOH
NaOAc
PPA
(HO)n
(HO)n
+
(CH3CO)2O, 60˚C
78~88%
MW or
R2
O
OH
HO
(OH)m
(OH)m
10: R1=R2=OAc, R3=R4=R5=H
11: R1=OAc, R2=R3=R4=R5=H
12: R1=R3=OAc, R2=R4=R5=H
13: R1=R2=R4=OAc, R3=R5=H
14: R1=R2=R3=R5=OAc, R4=H
2
9
m=1, 2
n=0, 1, 2
O
OH
O
OH
R2SO4 / RBr / RCl
K2CO3
Acetone or DMF
47~83%
O
OR
O
OH
3
15-27
O
O
OH
OH
10% NaOH
51%
O
O
O
O
OCH2CH(OH)CH2OH
23
28
OH
O
OH
O
RCl, K2CO3
DMF, 80˚C
49~65%
O
OR
O
6
OH
29-31
Scheme 1. Synthetic route for xanthone derivatives 2–31.
and other polyphenols, makes us aware that hydroxyx-
anthones and their appropriately modified derivatives
may serve as new a-glucosidase inhibitors. With this
rational in mind, we describe herein the synthesis and
a-glucosidase inhibitory activities of a series of hydrox-
yxanthones 2–9 and their acetoxy and alkoxy derivatives
10–31 (Scheme 1 and Table 1), aiming at clarifying the
structure–activity correlation involved in the inhibition
process of a-glucosidase.
28 in 51% yield. All these xanthone derivatives were
characterized by NMR, mass, IR, and elemental analy-
ses (see Section 4) and are summarized in Table 1.
2.2. a-Glucosidase inhibitory activity
The a-glucosidase inhibitory activities of xanthone
derivatives 2–31 were evaluated by using methods simi-
lar to those described in the literatures.8,26–28 The ob-
tained IC50 values, together with that of parent
xanthone (1) for comparison, are shown in Table 1.
2. Results and discussion
2.1. Chemistry
Several interesting structure–activity relationships can
be extracted from the analyses of the IC50 values of
hydroxylxanthones 2–9. The first observation is that
all the hydroxylxanthones exhibit much higher
inhibitory activities than the parent xanthone. The par-
ent xanthone 1 was inactive under our assay condi-
tions. However hydroxyl derivatives 2–9 showed up
to 21-fold higher inhibitory activities. This result is in
agreement with the fact that hydroxyl xanthones al-
ways possess a variety of biological activities,12–14,29
and suggests that modification of xanthones with
hydroxyl groups is an efficient approach to increase
their inhibitory activities. Second, inhibitory activities
show significant dependence on the number of hydrox-
yl groups. For example, compound 8 bearing three
hydroxyl groups has 12-fold stronger activity than
compound 2 bearing one hydroxyl group. The data
listed in Table 1 indicate that inhibitory activities in-
crease in the order of tetrahydroxyl (i.e., compound
9) ꢀ trihydroxyl (i.e., compounds 6–8) > bishydroxyl (i.e.,
compounds 3–5) > monohydroxyl (i.e., compound 2)
The synthetic route of hydroxylxanthones 2–9 and their
acetoxy and alkoxy derivatives 10–31 is shown in
Scheme 1. Compounds 2–9 were synthesized in 4–35%
yield from the condensation of salicylic acid or hydroxyl
salicylic acid with polyhydric phenols in the presence of
polyphosphoric acid (PPA) as a condensing agent.20 It
should be noted that microwave irradiation can efficient-
ly accelerate these reactions in slightly improved yields.
Acetoxyxanthones 10–14 were obtained in good to high
yields (78–88%) from the acetylation of their corre-
sponding hydroxylxanthones by acetic anhydride in
the presence of freshly fused sodium acetate.21,22
According to the protocols described in the litera-
tures,22–24 alkylation of 3 with dimethyl sulfate and alkyl
halides in acetone or DMF afforded 15–27 in moderate
to good yields (47–83%).25 Similar procedures smoothly
produced compounds 29–31. Hydrolyzation of 23 in
10% aqueous NaOH afforded ring-opened compound

Y. Liu et al. / Bioorg. Med. Chem. 14 (2006) 5683–5690
5685
Table 1. Structures of compounds 1–31 and their a-glucosidase inhibitory activities (IC50, lM)a
R5
O
R1
R4
R3
O
R2
Compound
R1
R2
R3
R4
R5
IC50
>200
177.4
Compound
R1
R3–5
R2
IC50
130.1
1
2
3
4
5
H
H
H
H
H
H
H
H
H
17
18
19
20
21
OH
OH
OH
OH
OH
H
H
H
H
H
OC4H9
OH
OH
OH
OH
H
H
H
OC5H11
OC7H15
OC8H17
OC10H21
120.9
113.8
123.7
115.6
OH
H
H
H
160.8
91.5
131.4
H
OH
OH
H
H
6
7
8
OH
OH
OH
OH
OH
OH
H
H
OH
H
81.8
41.5
14.7
22
23
24
OH
OH
OH
H
H
H
98.2
66.6
53.0
CH2O
CH2O
O
OH
H
H
O
OH
H
CH2O
9
OH
OH
OH
H
H
H
OH
H
17.1
31.9
25
26
OH
OH
H
H
115.4
61.8
N
CH2O
N C3H6O
Cl
10
OAc
OAc
N
11
12
13
OAc
OAc
OAc
H
H
H
H
H
H
>200
27
28
OH
OH
R1
H
OCH2CH2OH
OCH2CH(OH)CH2OH
R3
>200
>200
IC50
H
OAc
OAc
H
H
OAc
138.9
46.5
H
R2,4–5
Compound
O
14
OAc
OAc
OAc
H
OAc
49.7
29
OH
H
63.5
CH2O
15
16
OH
OH
OCH3
H
H
H
H
H
H
172.9
110.8
30
31
OH
OH
H
H
132.7
>200
N
CH2O
OC2H5
OCH2CH2OH
a Determined against yeast a-glucosidase in 50 mM phosphate buffer (pH 6.8) at 37 °C. A classical a-glucosidase inhibitor, 1-deoxynojirimycin,5 was
adopted as a positive control with an IC50 value of 26.4 lM. The experiments were performed in triplicate and repeated at least three times, and the
mean values were taken.
derivatives, suggesting that the presence of more pheno-
lic hydroxyl groups gives favorable effect on a-glucosi-
dase and that three and more hydroxyl groups are
necessary to achieve significant inhibitory activities.
Compounds 8 and 9 became slightly more active than
1-deoxynojirimycin. Third, the position of hydroxyl
groups has obvious effect on the inhibitory activities of
trihydroxyxanthones. Hydroxyl group at C7 (i.e., com-
pound 8) was more favorable to the activity than that
at C6 (i.e., compound 7), which in turn was more
favorable than that at C8 (i.e., compound 6). However,
bishydroxylxanthones 3–5 show comparable activities.
was not crucial for the improvement of the inhibitory
activities of xanthones.
Since acetylation of compound 3 led to an obvious
increase in the activity, it will be interesting to investi-
gate the effect of other groups as side chain. To achieve
this goal, a series of various alkoxy groups were intro-
duced to the C3-position of 3 to afford compounds
15–28 (Table 1). These substituents included straight al-
kyl, hydroxyalkyl, and heterocyclic groups, which are
frequently used in drug design. It can be seen that the
introduction of straight alkoxy chains, that is, com-
pounds 16–21 resulted in a slight increase in the activi-
ties, but compound 15 having a methoxy group was
an exception. However, compounds 15–21 exhibited
comparable IC50 values, suggesting that the introduc-
tion of straight alkoxy groups at C3 was not essential
for the increase of inhibitory activities. That compounds
27 and 28 bearing hydroxyl groups at the side chains
showed extremely weak inhibitory activities, suggesting
that hydroxyl groups on the parent xanthone backbones
were more potent in the improvement of inhibitory
It is reported that acetylation of phenolic compounds
has some impact on their biological activities.30,31 To
test this possibility, we prepared acetoxyxanthones 10–
14 from their corresponding hydroxylxanthones and
evaluated their inhibitory activities. It can be seen that
compound 10 exhibits at least 5-fold higher activity than
3, however, compounds 11–14 show much lower activi-
ties than their corresponding hydroxylxanthones. This
result indicated that the introduction of acetoxy groups

5686
Y. Liu et al. / Bioorg. Med. Chem. 14 (2006) 5683–5690
activities than those at the side chain (vide supra). Addi-
tionally, the derivatives having heterocyclic groups and
benzyl group at the C3 position, that is, compounds
22–26 showed enhanced inhibitory activities. It is note-
worthy that the compound 23 having oxirane ring was
more active than its ring-opened form 28. For compar-
ison, the introduction of heterocyclic group and hydro-
xy-containing side chain onto C6 position was carried
out, leading to compounds 29–31. Their IC50 values
were comparable to those of 23, 25, and 27, respectively,
which revealed that the attaching of similar side chains
has comparable influence on the activities (vide supra).
ed at 80–140 °C in an oil bath for 4 h. The reaction
mixture was cooled and poured over crushed ice and
then the resulting mixture was extracted with ethyl ace-
tate (15 mL). The extract was washed with saturated
NaHCO3 (30 mL), dried over Na2SO4, and evaporated
under reduce pressure to give 2–9 as yellow solids.
4.1.1. 1-Hydroxyxanthone (2).20,32 Yield 29% from sali-
cylic acid and resorcinol. H NMR (500 MHz, CDCl3)
1
d: 12.64 (s, 1H), 8.28 (dd, J = 8.0, 2.0 Hz, 1H), 7.76–
7.73 (m, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.47 (d,
J = 8.0 Hz, 1H), 7.41–7.38 (m, 1H), 6.93 (d,
J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H).
3. Conclusions
4.1.2. 1,3-Dihydroxyxanthone (3).20,32 Yield 35% from
salicylic acid and phloroglucinol. H NMR (500 MHz,
1
A series of hydroxylxanthones and their acetoxy and
alkoxy derivatives have been successfully synthesized
in moderate to high yields. The results revealed that
these xanthone derivatives were capable of inhibiting
a-glucosidase with moderate to good activities, indicat-
ing that structural modification of xanthones is a practi-
cal approach to increase their inhibitory activities.
Among all the derivatives, polyhydroxylxanthones show
the highest activities, and thus may be exploitable as
potentially potent a-glucosidase inhibitors. Further
efforts aiming at developing potent a-glucosidase inhib-
itors based on appropriately modified polyhydroxylx-
anthones are continuing in our laboratories, which will
be reported in due course.
d6-acetone) d: 12.92 (s, 1H), 9.89 (br, 1H), 8.22–8.20 (m,
1H), 7.87–7.83 (m, 1H), 7.56–7.53 (m, 1H), 7.49–7.45
(m, 1H), 6.45 (d, J = 2.5 Hz, 1H), 6.28 (d, J = 2.5 Hz, 1H).
4.1.3. 1,8-Dihydroxyxanthone (4)33 and 1,6-dihydroxyx-
anthone (5).34 Yield 4% and 19%, respectively, simulta-
neously obtained from 2,6-dihydroxybenzoic acid and
resorcinol. Compound 4 has 1H NMR (300 MHz,
d6-acetone) d: 11.74 (s, 2H), 7.78 (t, J = 8.4 Hz, 2H),
7.05 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 8.1 Hz, 2H). Com-
1
pound 5 has H NMR (300 MHz, d6-acetone) d: 12.86
(s, 1H), 9.89 (br, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.66 (t,
J = 8.1, 8.4 Hz, 1H), 7.01 (dd, J = 2.7, 9.0 Hz, 1H),
6.96 (d, J = 9.0 Hz, 1H), 6.93 (d, J = 2.7 Hz, 1H), 6.76
(d, J = 8.1 Hz, 1H).
4. Experimental
4.1.4. 1,3,8-Trihydroxyxanthone (6).22 Yield 31% from
2,6-dihydroxybenzoic acid and phloroglucinol. 1H
NMR (300 MHz, d6-acetone) d: 11.86 (s, 1H), 11.83 (s,
1H), 9.93 (br, 1H), 7.68 (t, J = 8.4 Hz, 1H), 6.94 (dd,
J = 8.4, 1.5 Hz, 1H), 6.77 (dd, J = 8.4, 1.5 Hz, 1H),
6.44 (d, J = 1.8 Hz, 1H), 6.29 (d, J = 1.8 Hz, 1H).
NMR spectra were recorded on a Varian INOVA 500
MB or Mercury – Plus 300 NMR spectrometer in either
CDCl3 or CD3COCD3 and tetramethylsilane was used
as an internal standard. Mass spectra were measured
on a Bruker REFLEX III ionization time-of-flight mass
spectrometer or on a Shimadzu LCMS-2010A liquid
chromatograph mass spectrometer. IR spectra were ob-
tained on a Bruker EQUINOX55 Fourier transforma-
tion infrared spectrometer. Elemental analyses were
carried out on an Elementar Vario EL series elemental
analyzer. Melting points were determined on a WRS-
1B digital melting point apparatus and are uncorrected.
UV spectra were recorded on a Shimadzu UV-3150
scanning spectrophotometer.
4.1.5. 1,3,6-Trihydroxyxanthone (7).34 Yield 25% from
2,4-dihydroxybenzoic acid and phloroglucinol. 1H
NMR (300 MHz, d6-acetone) d: 13.09 (s, 1H), 9.74 (br,
2H), 8.05 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.1 Hz,
1H), 6.87 (d, J = 2.1 Hz, 1H), 6.39 (d, J = 2.1 Hz, 1H),
6.24 (d, J = 2.1 Hz, 1H).
4.1.6. 1,3,7-Trihydroxyxanthone (8).34 Yield 21% from
2,5-dihydroxybenzoic acid and phloroglucinol. 1H
NMR (300 MHz, d6-acetone) d: 12.96 (s, 1H), 9.64 (br,
1H), 8.93 (br, 1H), 7.57 (d, J = 2.7 Hz, 1H), 7.44 (d,
J = 8.7 Hz, 1H), 7.35 (dd, J = 8.7, 2.7 Hz, 1H), 6.41 (d,
J = 2.7 Hz, 1H), 6.26 (d, J = 2.7 Hz, 1H).
p-Nitrophenyl (PNP) glycoside and a-glucosidase (from
Baker’s yeast) used in this study were purchased from
Sigma (St. Louis, MO, USA). Xanthone (1) was pur-
chased from Sigma–Aldrich (Sintra, Portugal). All other
reagents were of analytical quality and used upon re-
ceived. Microwave reactions were carried out in a
CEM Discover 300W focused microwave reactor.
4.1.7. 1,3,6,8-Tetrahydroxyxanthone (9).35 Yield 17% as
a white solid from 2,4,6-trihydroxybenzoic acid and
phloroglucinol. 1H NMR (300 MHz, d6-acetone) d:
11.96 (s, 2H), 9.89 (br, 2H), 6.38 (d, J = 2.4 Hz, 2H),
6.25(d, J = 2.4 Hz, 2H).
4.1. Synthesis of hydroxylxanthones 2–9
General procedures: a mixture of salicylic acid or poly-
hydric salicylic acid (0.5 mmol), polyhydric phenols
(0.5 mmol), and polyphosphoric acid (3–5 mL) was irra-
diated at 80–140 °C in a sealed tube for 2–5 min or heat-
4.2. Synthesis of acetoxyxanthones 10–14
General procedures: to a solution of hydroxylxanthone
(0.2 mmol) in acetic anhydride (5–8 mL) was added

Y. Liu et al. / Bioorg. Med. Chem. 14 (2006) 5683–5690
5687
freshly fused sodium acetate (0.25–0.9 mmol). The mix-
ture was stirred at 60 °C for 3–5 h. Solvent was evapo-
rated under reduced pressure. The residue was
partitioned between water (30 mL) and CHCl3
(15 mL). The organic layer was separated. Flash column
chromatography on a silica gel column (petroleum
ether/acetone, 8:1) afforded 10–14 as white solids.
609 cmÀ1 1H NMR (500 MHz, CDCl3) d: 12.86 (s,
;
1H), 8.21 (dd, J = 8.0, 1.0 Hz, 1H), 7.88–7.84 (m, 1H),
7.55 (dd, J = 8.0, 0.5 Hz, 1H), 7.49–7.46 (m, 1H), 6.54
(d, J = 2.5 Hz, 1H), 6.34 (d, J = 2.5 Hz, 1H), 4.18 (t,
J = 6.5 Hz, 2H), 1.84–1.78 (m, 2H), 1.57–1.49 (m, 2H),
1.00 (t, J = 6.5 Hz, 3H); FAB-MS m/z: 285 ([M+H]+);
Anal. Calcd for C17H16O4: C, 71.82; H, 5.67. Found:
C, 72.03; H, 5.69.
4.2.1. 1,3-Diacetoxyxanthone (10).32 Yield 88% from 3.
1H NMR (300 MHz, CDCl3) d: 8.23 (dd, J = 8.1,
1.8 Hz, 1H), 7.73–7.66 (m, 1H), 7.43 (d, J = 8.7 Hz,
1H), 7.39–7.33 (m, 1H) 7.26 (d, J = 2.4 Hz, 1H), 6.83
(d, J = 2.4 Hz, 1H), 2.49 (s, 3H), 2.36 (s, 3H).
4.3.4. 1-Hydroxy-3-pentyloxyxanthone (18). Yield 71%.
Mp 113–116 °C; IR (KBr): 3450, 3090, 3062, 2952,
2862, 1940, 1832, 1669, 1604, 1567, 1468, 1296, 1175,
1
1075, 821, 758 cmÀ1; H NMR (300 MHz, CDCl3) d:
12.83 (s, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.70 (t,
J = 7.8 Hz, 1H), 7.43–7.34 (m, 2H), 6.42 (s, 1H), 6.34
(s, 1H), 4.05 (t, J = 7.2 Hz, 2H), 1.88–1.79 (m, 2H),
1.50–1.27 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H); ESI-MS m/
z: 299 ([M+H]+); Anal. Calcd for C18H18O4: C, 72.47;
H, 6.08. Found: C, 72.58; H, 6.28.
1
4.2.2. 1-Acetoxyxanthone (11).32 Yield 82% from 2. H
NMR (300 MHz, CDCl3) d: 8.22 (dd, J = 8.1, 1.8 Hz,
1H), 7.72–7.64 (m, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.39
(dd, J = 8.1, 0.9 Hz, 1H), 7.36–7.30 (m, 1H), 6.98 (dd,
J = 8.1, 0.9 Hz, 1H), 2.49 (s, 3H).
4.2.3. 1,6-Diacetoxyxanthone (12).36 Yield 85% from 5.
1H NMR (300 MHz, CDCl3) d: 8.24 (d, J = 8.7 Hz, 1H),
7.67 (t, J = 8.1 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.25 (d,
J = 2.1 Hz, 1H), 7.08 (dd, J = 8.7, 2.1 Hz, 1H), 6.78 (d,
J = 8.1 Hz, 1H), 2.48 (s, 3H), 2.35 (s, 3H).
4.3.5. 1-Hydroxy-3-heptyloxyxanthone (19). Yield 79%.
Mp 111–113 °C; IR (KBr): 3450, 3090, 3062, 2966,
2855, 1939, 1831, 1667, 1604, 1567, 1467, 1208, 1075,
1
821, 757 cmÀ1; H NMR (300 MHz, CDCl3) d: 12.82
(s, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.70 (t, J = 7.8 Hz,
1H), 7.42–7.35 (m, 2H), 6.42 (s, 1H), 6.34 (s, 1H), 4.05
(t, J = 6.6 Hz, 2H), 1.89–1.79 (m, 2H), 1.52–1.27 (m,
8H), 0.92 (t, J = 6.6 Hz, 3H); ESI-MS m/z: 327
[M+H]+; Anal. Calcd for C20H22O4: C, 73.60; H, 6.79.
Found: C, 73.88; H, 6.98.
4.2.4. 1,3,7-Triacetoxyxanthone (13).37 Yield 78% from
8. 1H NMR (300 MHz, CDCl3) d: 7.92 (dd, J = 2.1,
0.9 Hz, 1H), 7.48–7.44 (m, 2H), 7.27 (d, J = 2.4 Hz,
1H), 6.48 (d, J = 2.4 Hz, 1H), 2.48 (s, 3H), 2.36 (s,
3H), 2.34 (s, 3H).
4.3.6. 1-Hydroxy-3-octyloxyxanthone (20).41 Yield 83%
1H NMR (300 MHz, CDCl3) d: 12.83 (s, 1H), 8.24
(dd, J = 7.8, 1.2 Hz, 1H), 7.73–7.67 (m, 1H), 7.43–7.34
(m, 2H), 6.42 (d, J = 1.8 Hz, 1H), 6.34 (d, J = 1.8 Hz,
1H), 4.05 (t, J = 6.9 Hz, 2H), 1.88–1.79 (m, 2H), 1.56–
1.26 (m, 10H), 0.91 (t, J = 6.6 Hz, 3H).
4.2.5. 1,3,6,8-Tetraacetoxyxanthone (14).38 Yield 80%
from 9. 1H NMR (300 MHz, CDCl3) d: 7.20 (d,
J = 2.1, 2H), 6.80 (d, J = 2.1 Hz, 2H), 2.43 (s, 6H),
2.35 (s, 6H).
4.3. Synthesis of alkoxyxanthones 15–22
4.3.7. 1-Hydroxy-3-decyloxyxanthone (21). Yield 69%.
Mp 124–126 °C; IR (KBr): 3422, 3063, 2922, 2854,
1937, 1829, 1660, 1604, 1568, 1469, 1327,1292, 1167,
To a solution of 3 (0.2 mmol) and dimethyl sulfate or
haloalkane (0.3 mmol) in acetone (6–8 mL) was added
K2CO3 (0.25 mmol). The mixture was refluxed under
stirring for 2–4 h. After cooling, the mixture was filtered
and the organic filtrate was concentrated. The crude
product was purified by chromatography on a silica-
gel column to afford 15–22 as yellow solids.
1
1078, 821, 793, 671 cmÀ1; H NMR (300 MHz, CDCl3)
d: 12.83 (s, 1H), 8.24 (d, J = 8.1 Hz, 1H), 7.70 (t,
J = 8.1 Hz, 1H), 7.44–7.34 (m, 2H), 6.42 (s, 1H), 6.35
(s, 1H), 4.05 (t, J = 6.6 Hz, 2H), 1.86–1.77 (m, 2H),
1.58–1.29 (m, 14H), 0.90 (t, J = 6.3 Hz, 3H); FAB-MS
m/z: 369 ([M+H]+); Anal. Calcd for C23H28O4: C,
74.97; H, 7.66. Found: C, 74.75; H, 7.81.
4.3.1. 1-Hydroxy-3-methoxyxanthone (15).39 Yield 65%.
1H NMR (500 MHz, d4-methanol) d: 8.20 (dd, J = 8.0,
1.0 Hz, 1H), 7.82–7.77 (m, 1H), 7.51 (dd, J = 8.0,
0.5 Hz, 1H), 7.42–7.41 (m, 1H), 6.54 (d, J = 2.5 Hz,
1H), 6.34 (d, J = 2.5 Hz, 1H), 3.91 (s, 3H).
4.3.8. 1-Hydroxy-3-benzyloxyxanthone (22). Yield 83%.
1H NMR (500 MHz, CDCl3) d: 12.85 (s, 1H), 8.26
(dd, J = 8.0, 1.5 Hz, 1H), 7.78–7.69 (m, 1H), 7.46–7.34
(m, 7H), 6.51 (d, J = 2.5 Hz, 1H), 6.44 (d, J = 2.5 Hz,
1H), 5.16 (s, 2H).
4.3.2. 1-Hydroxy-3-ethoxyxanthone (16).40 Yield 83%.
1H NMR (500 MHz, CDCl3) d: 12.85 (s, 1H), 8.25
(dd, J = 8.0, 1.0 Hz, 1H), 7.73–7.69 (m, 1H), 7.43 (dd,
J = 8.0, 0.5 Hz, 1H), 7.39–7.35 (m, 1H), 6.42 (d,
J = 2.5 Hz, 1H), 6.34 (d, J = 2.5 Hz, 1H), 4.13 (q,
J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H).
4.4. Synthesis of alkoxyxanthones 23–26 and 29–31
To a solution of 3 or 5 (0.2 mmol) and haloalkane
(0.3 mmol) in DMF (6–8 mL) was added K2CO3
(0.25 mmol). The mixture was stirred at 60–80 °C for
4–8 h. Solvent was evaporated under reduced pressure.
The residue was treated with 1 N HCl (30 mL) and
extracted with ethyl acetate (15 mL). The organic layer
4.3.3. 1-Hydroxy-3-butoxyxanthone (17). Yield 78%. Mp
118–120 °C; IR (KBr): 3423, 3071, 2927, 2871, 1940,
1833, 1660, 1609, 1466, 1297, 1162, 1079, 823, 758,

5688
Y. Liu et al. / Bioorg. Med. Chem. 14 (2006) 5683–5690
was washed with water (30 mL) and concentrated. Puri-
fication by chromatography on a silica-gel column
(petroleum ether/EtOAc, 12:1) afforded 23–27 and 29–
31 as yellow solids.
2H), 6.58 (d, J = 2.4 Hz, 1H), 6.38 (d, J = 2.4 Hz, 1H),
4.34 (t, J = 5.4 Hz, 2H), 3.95 (t, J = 5.4 Hz, 2 H); ESI-
MS m/z: 273 ([M+H]+); Anal. Calcd for C15H12O5: C,
66.17; H, 4.44. Found: C, 66.35; H, 4.42.
4.4.1. 1-Hydroxy-3-(2-oxiranylmethoxy)xanthone (23).42
Yield 51% from 3 and 2-(chloromethyl)oxirane. 1H
NMR (500 MHz, CDCl3) d: 12.86 (s, 1H), 8.26 (dd,
J = 8.0, 1.5 Hz, 1H), 7.74–7.70 (m, 1H), 7.44 (d,
J = 8.0 Hz, 1H), 7.40–7.36 (m, 1H), 6.47 (d,
J = 2.0 Hz, 1H), 6.37 (d, J = 2.0 Hz, 1H), 4.34 (dd,
J = 11.0, 3.0 Hz, 1H), 4.03 (q, J = 5.5 Hz, 1H), 3.41–
3.37 (m, 1H), 2.94 (dd, J = 4.5, 4.0 Hz, 1H), 2.78 (q,
J = 2.5 Hz, 1H).
4.4.6.
1-Hydroxy-3-(2,3-dihydroxypropoxy)xanthone
(28). A mixture of 23 (28.4 mg, 0.1 mmol) and 10%
NaOH (10 mL) was heated on an oil bath until the solid
was dissolved. The mixture was acidified with 1 N
hydrochloric acid and extracted with ethyl acetate.
Evaporation of the solvent and flash column chroma-
tography (petroleum ether/EtOAc, 6:1) yielded 28
(15.4 mg, 51%) as a yellow solid. Mp 161–162 °C; IR
(KBr): 3342, 3065, 2926, 1660, 1568, 1466, 1324, 1172,
1034, 822, 755, 671 cmÀ1; H NMR (500 MHz, d6-ace-
1
4.4.2. 1-Hydroxy-3-((tetrahydrofuran-2-yl)methoxy)xan-
thone (24). Yield 48% from 3 and 2-(chloromethyl)-tet-
rahydrofuran. Mp 158–160 °C; IR (KBr): 3426, 3070,
2949, 2879, 1658, 1567, 1464, 1365, 1296, 1220,
tone) d: 12.88 (s, 1H), 8.23–8.21 (m, 1H), 7.89–7.85
(m, 1H), 7.58–7.56 (m, 1H), 7.51–7.47 (m, 1H), 6.60
(d, J = 2.5 Hz, 1H), 6.38 (d, J = 2.5 Hz, 1H), 4.28 (dd,
J = 10.0, 4.0 Hz, 1H), 4.24 (d, J = 5.5 Hz, 1H), 4.07–
4.02 (m, 1H), 3.86 (t, J = 4.0 Hz, 2H); FAB-MS m/z:
303 ([M+H]+); Anal. Calcd for C16H14O6: C, 63.57; H,
4.67. Found: C, 63.85; H, 4.57.
1161,1080, 926, 824, 759, 606 cmÀ1
;
1H NMR
(300 MHz, CDCl3) d: 12.83 (s, 1H), 8.23 (dd, J = 7.5,
1.8 Hz, 1H), 7.73–7.66 (m, 1H), 7.43–7.33 (m, 2H),
6.45 (d, J = 2.4 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H),
4.35–4.27 (m, 1H), 4.16–4.06 (m, 2H), 3.97–3.92 (m,
1H), 3.89–3.82 (m, 1H), 2.21–2.06 (m, 1H), 2.01–1.93
(m, 2H), 1.84–1.75 (m, 1H); ESI-MS m/z: 313
([M+H]+); Anal. Calcd for C18H16O5: C, 69.22; H,
5.16. Found: C, 69.21; H, 5.16.
4.4.7.
1-Hydroxy-6-(oxiran-2-ylmethoxy)xanthone
(29)42. Yield 55% from 6 and 2-(chloromethyl)oxirane.
1H NMR (300 MHz, CDCl3) d: 12.75 (s, 1H), 8.13 (d,
J = 8.7 Hz, 1H), 7.52 (t, J = 8.7 Hz, 1H), 6.93 (dd,
J = 8.7, 2.1 Hz, 1H), 6.88–6.84 (m, 2H), 6.76 (d,
J = 7.8 Hz, 1H), 4.33 (dd, J = 11.0, 3.0 Hz, 1H), 4.13
(q, J = 5.5 Hz, 1H), 3.45–3.36 (m, 1H), 2.96 (dd,
J = 4.5, 4.0 Hz, 1H), 2.76 (q, J = 2.5 Hz, 1H).
4.4.3.
1-Hydroxy-3-(2-(1-piperidinyl)ethoxy)xanthone
(25). Yield 68% from 3 and 1-(2-chloroethyl)piperidine.
Mp 114–116 °C; IR (KBr): 3450, 3092, 3064, 2930, 2834,
2790, 1964, 1821, 1659, 1605, 1466, 1317, 1172,1075,
4.4.8.
1-Hydroxy-6-(2-(1-piperidinyl)ethoxy)xanthone
829, 759 cmÀ1
;
1H NMR (500 MHz, d4-methanol) d:
(30). Yield 64% from 6 and 1-(2-chloroethyl)piperidine.
Mp 110–112 °C; IR (KBr): 3391, 3074, 2966, 2850, 2790,
1916, 1647, 1608, 1574, 1448, 1379, 1262, 1231, 1105,
8.21 (dd, J = 8.0, 2.0 Hz, 1H), 7.82–7.78 (m, 1H), 7.52
(d, J = 8.0 Hz, 1H), 7.45–7.41 (m, 1H), 6.57 (d,
J = 2.5 Hz, 1H), 6.38 (d, J = 2.5 Hz, 1H), 4.27 (t,
J = 5.5 Hz, 2H), 2.88 (t, J = 5.5 Hz, 2H), 2.64 (br, 4H),
1.70–1.64 (m, 4H), 1.53–1.50 (m, 2H); FAB-MS m/z:
340 ([M+H]+); Anal. Calcd for C20H21NO4: C, 70.78;
H, 6.24; N, 4.13. Found: C, 70.67; H, 6.38; N 4.05.
1
1053, 800, 763, 677 cmÀ1; H NMR (300 MHz, CDCl3)
d: 12.75 (s, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.52 (t,
J = 8.7 Hz, 1H), 6.93 (dd, J = 8.7, 2.1 Hz, 1H), 6.88–
6.84 (m, 2H), 6.76 (d, J = 7.8 Hz, 1H), 4.22 (t,
J = 6.0 Hz, 2H), 2.84 (t, J = 6.0 Hz, 2H), 2.54 (t,
J = 5.4 Hz, 4H), 1.67–1.59 (m, 4H), 1.50–1.45 (m, 2H);
FAB-MS m/z: 340 ([M+H]+); Anal. Calcd for
C20H21NO4Æ0. 25H2O: C, 69.85; H, 6.30; N, 4.07.
Found: C, 70.10; H, 6.34; N, 3.89.
4.4.4.
1-Hydroxy-3-(3-(4-(3-chlorophenyl)piperazin-1-
yl)propoxy)xanthone (26). Yield 50% from 3 and 1-(3-
chlorophenyl)-4-(3-chloropropyl)piperazine. Mp 258–
260 °C; IR (KBr): 3120, 3065, 2947, 2824, 2758, 1664,
1601, 1568, 1467, 1324, 1291, 1163, 1081, 950, 782,
4.4.9. 1-Hydroxy-6-(2-hydroxyethoxy)xanthone (31).
Yield 49% from 6 and 2-chloroethanol. Mp 140–
142 °C; IR (KBr): 3350, 3071, 2941, 2874, 1728, 1603,
1
760, 676 cmÀ1; H NMR (300 MHz, CDCl3) d: 12.83
(s, 1H), 8.25 (dd, J = 8.1, 1.5 Hz, 1H), 7.74–7.67 (m,
1H), 7.44–7.34 (m, 2H), 7.16 (t, J = 8.1 Hz, 1H), 6.88
(t, J = 2.4 Hz, 1H), 6.83–6.77 (m, 2H), 6.46 (d,
J = 2.4 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 4.17 (t,
J = 6.3 Hz, 2H), 3.25 (t, J = 5.7 Hz, 4H), 2.70–2.59 (m,
6H), 2.12–2.03 (m, 2H); FAB-MS m/z: 465 ([M+H]+);
Anal. Calcd for C26H25ClNO5: C, 67.17; H, 5.42; N,
6.03. Found: C, 66.94; H, 5.70; N, 5.88.
1450, 1378, 1230, 1048, 884, 802, 679, 614 cmÀ1 1H
;
NMR (300 MHz, d6-acetone) d: 12.82 (s, 1H), 8.15 (d,
J = 8.7 Hz, 1H), 7.68 (t, J = 8.7 Hz, 1H), 7.13–7.07 (m,
2H), 6.98 (d, J = 7.2 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H),
4.32 (t, J = 5.4 Hz, 2H), 3.97 (t, J = 5.4 Hz, 2H); ESI-
MS m/z: 273 ([M+H]+); Anal. Calcd for C15H12O5: C,
66.17; H, 4.44. Found: C, 66.01; H, 4.53.
4.4.5. 1-Hydroxy-3-(2-hydroxyethoxy)xanthone (27).
Yield 51% from 3 and 2-chloroethanol. Mp 147–
149 °C; IR (KBr): 3350, 3071, 2941, 2874, 1728, 1603,
4.5. Enzyme assays
The inhibitory activities of all the xanthone derivatives
were measured by using the methods similar to those de-
scribed previously.8,26–28 Typically, a-glucosidase activi-
ty was assayed in 50 mM phosphate buffer (pH 6.8)
1450, 1378, 1230, 1048, 884, 802, 679, 614 cmÀ1 1H
;
NMR (300 MHz, CDCl3) d: 12.86 (s, 1H), 8.24 (dd,
J = 7.8, 1.5 Hz, 1H), 7.73–7.67 (m, 1H), 7.44–7.34 (m,

Y. Liu et al. / Bioorg. Med. Chem. 14 (2006) 5683–5690
5689
20. Desai, B. M.; Desai, P. R.; Desai, R. D. J. Indian Chem.
Soc. 1960, 37, 53–55.
21. Pillai, R. K. M.; Naiksatam, P.; Johnson, F.; Rajagopa-
lan, R.; Watts, P. C.; Cricchio, R.; Borras, S. J. Org.
Chem. 1986, 51, 717–723.
22. Fonteneau, N.; Martin, P.; Mondon, M.; Ficheux, H.;
Gesson, J. P. Tetrahedron 2001, 57, 9131–9135.
23. Sittisombut, C.; Costes, N.; Michel, S.; Koch, M.;
Tillequin, F.; Pfeiffer, B.; Renard, P.; Pierre, A.; Atassi,
G. Chem. Pharm. Bull 2001, 49, 675–679.
containing 5% v/v dimethylsulfoxide and the PNP glyco-
side was used as a substrate. The inhibitors were pre-in-
cubated with the enzyme at 37 °C for 0.5 h. The
substrate was then added and the enzymatic reaction
was carried out at 37 °C for 60 min. The reaction was
monitored spectrophotometrically by measuring the
absorbance at 400 nm. The assay was performed in trip-
licate with five different concentrations around the IC50
values that were roughly estimated in the first round of
experiments, and the mean values were taken.
24. Qin, Y.; Pang, J.-Y.; Chen, W.-H.; Cai, Z.-W.; Jiang, Z.-
Y. Bioorg. Med. Chem. 2006, 14, 25–32.
25. By the same method described for 15–22, 1-hydroxy-3-
tetradececyloxyxanthone (yield 66%) was obtained as a
yellow solid. Mp 129–131; IR (KBr): 3455, 3063, 2920,
2852, 1660, 1603, 1567, 1469, 1326, 1292, 1167, 1077, 1033,
820, 757, 671 cmÀ1; 1H NMR (300 MHz, CDCl3) d: 12.83
(s, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H),
7.44–7.34 (m, 2H), 6.42 (d, J = 1.5 Hz, 1H), 6.34 (d,
J = 1.5 Hz, 1H), 4.06 (t, J = 6.6 Hz, 2H), 1.88–1.78 (m,
2H), 1.56–1.28 (m, 22H), 0.90 (t, J = 6.9 Hz, 3H); FAB-
MS m/z: 425 [M+H]+; Anal. Calcd for C23H28O4: C, 76.38;
H, 8.55. Found: C, 76.42; H, 8.79. 1-hydroxy-3-hexadece-
cyloxyxanthone (yield 63%) was obtained as a yellow
solid. Mp 136–138 °C; IR (KBr): 4045, 3106, 2920, 2852,
1937, 1829, 1660, 1603, 1469, 1326, 1291, 1166, 1077, 1030,
792, 721, 671 cmÀ1; 1H NMR (300 MHz, CDCl3) d: 12.83
(s, 1H), 8.24 (dd, J = 7.8, 1.5 Hz, 1H), 7.73–7.67 (m, 1H),
7.44–7.34 (m, 2H), 6.42 (d, J = 2.1 Hz, 1H), 6.34 (d,
J = 2.1 Hz, 1H), 4.05 (t, J = 6.6 Hz, 2H), 1.88–1.78 (m,
2H), 1.56–1.27 (m, 26H), 0.89 (t, J = 7.2 Hz, 3H); ESI-MS
m/z: 453 [M+H]+; Anal. Calcd for C29H40O4: C, 76.95; H,
8.91. Found: C, 76.80; H, 9.08. 1-hydroxy-3-tetredececyl-
oxyxanthone (yield 71%) was obtained as a yellow solid.
Mp 141–143 °C; IR (KBr): 4040, 3109, 2920, 2852, 1937,
1829, 1665, 1603, 1471, 1326, 1290, 1166, 1077, 1033, 792,
Acknowledgments
The project was partially supported by the Innovative
Research Fund from the School of Chemistry and
Chemical Engineering, Sun Yat-sen University.
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