Synthesis of xanthone derivatives with extended π-systems as α-glucosidase inhibitors: Insight into the probable binding mode

Article abstract of DOI:10.1016/j.bmc.2007.02.030

A series of novel xanthone derivatives with extended π-systems, that is, benzoxanthones 2-4, and their structurally perturbed analogs 5-9 have been designed and synthesized as α-glucosidase inhibitors. Their inhibitory activities toward yeast's α-glucosidase were evaluated with the aim to enrich the structure-activity relationship. The results indicated that benzoxanthones 2-4 were capable of inhibiting in vitro yeast's α-glucosidase 17- to 28-fold more strongly than xanthone derivative 1 that has smaller conjugated π-system. Benzoxanthone 8, bearing angularly fused aromatic rings, and reduced benzoxanthone 5 showed decreased activities, strongly suggesting that linearly conjugated π-systems play a crucial role in the inhibition process. O-Methylation of 3-OH of benzoxanthone 2 and nitration at C4 position led to a large decrease in the activity. This indicates that 3-OH of benzoxanthone was crucial to the inhibitory activity, primarily as an H-bonding donor. The present results suggest that π-π stacking effect and H-bonding make substantial contributions to elicit the inhibitory activities of this general class of inhibitors.

Full text of DOI:10.1016/j.bmc.2007.02.030

Bioorganic & Medicinal Chemistry 15 (2007) 2810–2814
Synthesis of xanthone derivatives with extended p-systems as
a-glucosidase inhibitors: Insight into the probable binding mode
*
Yan Liu, Lin Ma, Wen-Hua Chen, Bo Wang and Zun-Le Xu
School of Chemistry & Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China
Received 12 January 2007; revised 13 February 2007; accepted 14 February 2007
Available online 16 February 2007
Abstract—A series of novel xanthone derivatives with extended p-systems, that is, benzoxanthones 2–4, and their structurally
perturbed analogs 5–9 have been designed and synthesized as a-glucosidase inhibitors. Their inhibitory activities toward yeast’s
a-glucosidase were evaluated with the aim to enrich the structure–activity relationship. The results indicated that benzoxanthones
2–4 were capable of inhibiting in vitro yeast’s a-glucosidase 17- to 28-fold more strongly than xanthone derivative 1 that has smaller
conjugated p-system. Benzoxanthone 8, bearing angularly fused aromatic rings, and reduced benzoxanthone 5 showed decreased
activities, strongly suggesting that linearly conjugated p-systems play a crucial role in the inhibition process. O-Methylation of
3
-OH of benzoxanthone 2 and nitration at C4 position led to a large decrease in the activity. This indicates that 3-OH of
benzoxanthone was crucial to the inhibitory activity, primarily as an H-bonding donor. The present results suggest that p–p stacking
effect and H-bonding make substantial contributions to elicit the inhibitory activities of this general class of inhibitors.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
into the interaction with a-glucosidase whose crystal
structure remains presently unclear.
During the last few decades, there has been widespread
interest in a-glucosidase (EC 3.2.1.20) because of its
important role not only in carbohydrate digestion, but
also in the processing of glucoproteins and glycolipids.
The enzyme is also involved in a variety of metabolic
disorder and other diseases such as diabetes, viral
In these aspects, increasing attention has been paid to
xanthones that are widely present as a class of secondary
metabolites in some higher plants, fungi, and lichen fam-
ilies. These naturally occurring compounds and their
synthetic analogs have demonstrated multiple pharma-
9
–11
1
–5
12,13
attachment, and cancer formation.
The biological
cological properties, such as antioxidant,
15
anti-
inflammatory, and antimalarial activities, inhibition
1
4
and practical importance ensures the use of a-glucosi-
dase inhibitors as a vital tool to understand the mecha-
nisms of action of a-glucosidase and as therapeutic
agents for some degenerative diseases. Therefore, con-
siderable endeavors have been made to develop inhibi-
tors that can probe the structure and function of
a-glucosidase. To date, many a-glucosidase inhibi-
1
6–18
of a variety of tumor cell lines’ growth,
and modu-
20–22
lation of PKC isoforms. Recent studies by others
and us have indicated that xanthone derivatives (e.g.,
compound 1, Chart 1) are capable of inhibiting a-gluco-
sidase with moderate to good activities. This preliminary
work has highlighted the high potentials of xanthones as
1
9
2
3
6
–8
tors have been reported, such as acarbose and vogli-
bose from microorganisms, and 1-deoxynojirimycin
isolated from plants, however, they are largely confined
to glycosidic derivatives. The needs for new diverse ther-
apeutic agents necessitate the creation of new classes of
inhibitors. These inhibitors may provide more insight
O
OH
O
12
OH
1
0
11
C
1
R2 9
2
D
B
A
4
O
1
OH
8
O
3 OH
7
6
5
R1
2
3
: R1 = R2 = H
: R1 = H, R2 = OH
Keywords: Benzoxanthones; Synthesis; a-Glucosidase; Inhibitory
activity.
4: R = OH, R = H
1
2
*
Corresponding author. Tel.: +86 20 84113083; fax: +86 20
4112245; e-mail: ceswb@mail.sysu.edu.cn
8
Chart 1.
0
968-0896/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.02.030

Y. Liu et al. / Bioorg. Med. Chem. 15 (2007) 2810–2814
2811
a promising building motif for the development of a new
class of potent a-glucosidase inhibitors.
hydroxylxanthones 2 and 8 by lithium aluminum hy-
2
5,26
27,28
dride.
group of 2 with methyl iodide in acetone at room temper-
Selective O-methylation
of the 3-hydroxyl
6
,28
However, little is known about the action mode of xan-
thones with a-glucosidases. In previous study we have
shown that two or more phenolic hydroxyl groups are
ature afforded 6 in 83%. Nitration
70% HNO in acetic acid gave compound 7. All these xan-
of compound 2 with
3
thone derivatives were characterized by NMR, mass, IR,
and elemental analyses (see Section 4).
2
3
fundamental for the inhibitory activity, however their
roles are not clear. In addition, our attempt to enhance
the activity by modifying the phenolic hydroxyl group
with diverse substituents proved unsuccessful. This
observation, together with the structural features inherent
in xanthones, makes us aware that the conjugated
p-systems in xanthones may contribute significantly to
the inhibitory activity. With this thought in mind, we
describe herein the synthesis of xanthone derivatives
with extended p-systems, that is, benzoxanthones 2–4,
and a comparative study of their a-glucosidase inhibi-
tory activities with those of structurally perturbed
analogs 5–9 (Chart 1 and Scheme 1). The primary aim
of this work was to gain some insight into the effect of
each structural factor in benzoxanthones on the inhibi-
tory activity as well as into the probable binding mode
of these compounds toward a-glucosidase.
2.2. a-Glucosidase inhibitory activity
The inhibitory activities of xanthone derivatives 2–9 to-
ward yeast’s a-glucosidase were evaluated by using
methods similar to those described in the literature.
29–31
The obtained IC50 values, together with those of com-
pound 1 and 1-deoxynojirimycin 10, for comparison
are shown in Table 1.
Under our assay condition, compound 1, bearing
three fused aromatic rings, showed very weak inhibi-
tory activity. However, benzoxanthones 2–4 bearing
four fused aromatic rings exhibited greatly enhanced
inhibitory activities. For example, compound 2 having
one more conjugated aromatic ring was at least
17-fold more active in inhibiting a-glucosidase than
compound 1. More significantly, benzoxanthones 2–4
were much more active than 1-deoxynojirimycin 10,
a classical a-glucosidase inhibitor. These results clearly
indicate that benzoxanthones 2–4 are quite potent
a-glucosidase inhibitors and the weak inhibitory activ-
ity of xanthones can be largely amplified by inserting
one aromatic ring to extend the p-conjugated systems.
In addition, benzoxanthone 8 bearing angularly fused
aromatic rings was less favorable to the activity than
compound 2 bearing linearly fused aromatic rings.
Thus, it appears that yeast’s a-glucosidase has
apparent preference for linearly angular aromatic
structures.
2
. Results and discussion
2
.1. Chemistry
The synthetic route that was used to synthesize xanthone
derivatives 2–9 is shown in Scheme 1. Compounds 2–4
and 8 were synthesized in 31–79% yields from the conden-
sation of hydroxybenzoic acid or hydroxy-2-naphthoic
acid with phloroglucinol or b-naphthol in the presence
of anhydrous zinc chloride and phosphoryl chloride.
Compounds 5 and 9 were obtained in 29% and 17% yields,
respectively, from the reduction of their corresponding
2
4,25
OH
b
O
O
OH
R2
CO H
2
5
6
7
OH
a
O
O
OH
OH
R1
R2
2
c
+
OH
OH
O
O
OCH3
OH
R1
2
3
4
: R = R = H
1 2
OH
: R = H, R = OH
HO
OH
1
1
2
: R = OH, R = H
d
2
O
NO2
O
OH
OH
OH
OH
COOH
OH
b
a
+
O
OH
O
OH
HO
8
9
Scheme 1. Synthetic route for xanthone derivatives 2–9. Reagents and conditions: (a) ZnCl
CO /acetone, 0.5 h; (d) 70% HNO
, AcOH, 60–70 °C, 1 h.
2
, POCl
3
4 3
, 70–80 °C; (b) LiAlH , THF, rt; (c) CH I,
K
2
3
3

2812
Y. Liu et al. / Bioorg. Med. Chem. 15 (2007) 2810–2814
Table 1. a-Glucosidase inhibitory activities of compounds 1–10 (IC50
lM)
,
and fully characterized by NMR, IR, MS, and elemental
analyses. The results indicate that bezoxanthones exhib-
ited quite high inhibitory activities, and thus are exploit-
able as potent a-glucosidase inhibitors. Structural
variation on benzoxanthones has provided some insight
into their potencies that may be as a result of coopera-
tive p-stacking and H-bonding interactions with a-glu-
cosidase. Further efforts aiming at clarifying the
mechanisms underlying the a-glucosidase inhibitory
activities of xanthones are continuing in our laborato-
ries, which will be reported in due course.
a
Compound
IC50
1
2
3
4
5
6
7
8
9
160.8
9.3
5.8
8.0
27.8
31.3
20.1
39.9
34.9
26.4
1
0
4
. Experimental
a
Determined against yeast’s a-glucosidase in 50 mM phosphate buffer
pH 6.8) containing 5% v/v DMSO at 37 °C. The experiments were
(
NMR spectra were recorded on a Varian INOVA 300
MB NMR spectrometer in either CDCl or d -acetone
or d -DMSO and tetramethylsilane was used as an inter-
performed in triplicate and repeated at least three times, and the mean
values were adopted.
3
6
6
nal standard. Mass spectra were measured on a DSQ
low resolution mass spectrometer or on a Shimadzu
LCMS-2010A liquid chromatography mass spectrome-
ter. IR spectra were obtained on a Bruker EQUINOX55
Fourier transformation infrared spectrometer. Elemen-
tal analyses were carried out on an Elementar Vario
EL series elemental analyzer. Melting points were deter-
mined on a WRS-1B digital melting point apparatus and
are uncorrected. UV spectra were recorded on a
Shimadzu UV-3150 scanning spectrophotometer.
To further clarify the role of p-system in the inhibitory
activity, we reduced the carbonyl unit in benzoxanthones
3
2
5
and 8 to sp hybridized methylene to afford compounds
and 9, respectively. The reduction partially destroys the
conjugated p-system, and in principle should weaken the
ability of forming p-stacking interaction. As expected,
compound 5 showed a decrease in the potency by three
times. However, the reason why compound 9 showed
3
2
comparable activities with 8 is not presently clear.
Compound 1 was prepared according to the reported
2
3
The aforementioned results strongly suggest that the
extended p-conjugated systems in 2–4 make substantial
contributions to the remarkably enhanced inhibitory
activities, most probably through p-stacking interaction
method.
1-Deoxynojirimycin, p-nitrophenyl (PNP)
glycoside, and a-glucosidase (from baker’s yeast) used
in this study were purchased from Sigma (St. Louis,
MO, USA). All other reagents were of analytical quality
and used upon received.
3
3
with yeast’s a-glucosidase.
To the best of our
knowledge, this represents the first example that has
demonstrated the crucial role of p-stacking effect in
a-glucosidase inhibition. This result is in agreement with
previous reports that p-stacking effect plays a significant
4.1. Synthesis of compounds 2–4 and 8
General procedures: To a mixture of hydroxybenzoic
acid or hydroxy-2-naphthoic acid (0.01 mol), phloroglu-
cinol or b-naphthol (0.01 mol), and freshly fused zinc
chloride (5 g), phosphoryl chloride (30–50 mL) was
added. The reaction mixture was stirred at 70 °C for
3
4–37
role in biological activities,
and may be rationalized
by taking into account the fact that there usually exist
many aromatic amino acid residues in an enzyme that
enables the formation of stable p-stacking interaction.
1
.5–4 h, poured into crushed ice, and allowed to stand
It is noteworthy that compounds 2–4 showed compara-
ble inhibitory activities, and thus the additional 9-OH
overnight. The solid was collected by filtration, washed
with saturated aqueous sodium bicarbonate and water,
and dried. The crude products were purified by flash col-
umn chromatography to afford 2–4 and 8 as yellow
solids.
(
in 3) or 7-OH (in 4) was not crucial to the activity, how-
ever this is not the case for 3-OH. As shown in our data,
O-methylation of 3-OH led to a large decrease in the
activity. This indicates that 3-OH in compound 2 was
crucial, primarily as an H-bonding donor to interact
with a-glucosidase since hydroxyl group is an H-bond-
ing donor/acceptor, while methoxy group can only act
as an H-bonding acceptor. This was further supported
by the decreased activity observed with compound 7 in
which 3-OH as an H-bonding donor forms strong intra-
molecular H-bond with nitro group at C4 position.
4.1.1. 1,3-Dihydroxy-12H-benzo[b]xanthen-12-one (2).
Yield 79% from 3-hydroxy-2-naphthoic acid and phlor-
2
4
1
oglucinol. Mp 283–285 °C (278–279 °C ); H NMR
(300 MHz, d -acetone) d: 12.97 (s, 1H), 9.91 (s, 1H),
6
8.86 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.06 (d,
J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.74–7.68 (m, 1H), 7.62–
7.56 (m, 1H), 6.46 (d, J = 2.4 Hz, 1H), 6.28 (d,
J = 2.4 Hz, 1H).
3
. Conclusions
4.1.2. 1,3,9-Trihydroxy-12H-benzo[b]xanthen-12-one (3).
Yield 42% from 3,7-dihydroxy-2-naphthoic acid and
phloroglucinol. Mp >300 °C; IR (KBr): 3458, 3267,
2925, 1647, 1611, 1520, 1469, 1402, 1313, 1267, 1167,
In summary, a series of novel benzoxanthones and their
structurally perturbed analogs have been synthesized

Y. Liu et al. / Bioorg. Med. Chem. 15 (2007) 2810–2814
2813
À1
1
078, 832, 750, 710 cm ; H NMR (300 MHz, d -ace-
À
1
([MÀH] ); Anal. Calcd for C H O : C, 77.26; H,
6
17 12
3
tone) d: 13.03 (s, 1H), 9.89 (s, 1H), 8.98 (s, 1H), 8.62
s, 1H), 7.96 (d, J = 9.0 Hz, 1H), 7.92 (s, 1H), 7.47 (d,
J = 2.7 Hz, 1H), 7.38 (dd, J = 9.0, 2.7 Hz, 1H), 6.44 (d,
J = 2.7 Hz, 1H), 6.26 (d, J = 2.7 Hz, 1H); ESI-MS m/z:
293 ([MÀH] ); Anal. Calcd for C H O : C, 69.39;
H, 3.43. Found: C, 69.45; H, 3.51.
4.58. Found: C, 77.53; H, 4.39.
(
4.3. 1-Hydroxy-3-methoxy-12H-benzo[b]xanthen-12-one
(6)
À
1
7
10
5
To a solution of xanthone 2 (139 mg, 0.5 mmol) in dry
acetone (30 mL) and potassium carbonate (276 mg,
2.0 mmol) was added 10-fold excess iodomethane. The
mixture was stirred at room temperature for 0.5 h. The
excess iodomethane and acetone were removed under re-
duced pressure. Then the reaction mixture was parti-
tioned between dilute hydrochloric acid (50 mL, 5%)
4.1.3. 1,3,7-Trihydroxy-12H-benzo[b]xanthen-12-one (4).
Yield 35% from 3,5-dihydroxy-2-naphthoic acid and
phloroglucinol. Mp >300 °C; IR (KBr): 3400, 2927,
1
1
636, 1607, 1501, 1475, 1427, 1301, 1280, 1164, 1079,
H NMR
À1
1
034, 1007, 810, 740, 630, 600 cm
;
(
300 MHz, d -acetone) d: 12.98 (s, 1H), 9.91 (br, 1H),
and CHCl . The crude product obtained after removal
3
6
9
.40 (br, 1H), 8.77 (s, 1H), 8.19 (s, 1H) 7.69 (d,
of the solvent was purified by flash column chromatog-
raphy (petroleum ether/CH Cl , 3:1) to afford 6
J = 8.1 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.09 (d,
J = 8.1 Hz, 1H), 6.46 (d, J = 2.7 Hz, 1H), 6.26 (d,
2
2
(121 mg, 83%) as a yellow solid. Mp 208–210 °C; IR
(KBr): 3427, 2940, 1652, 1589, 1510, 1454, 1348, 1160,
À
J = 2.7 Hz, 1H); ESI-MS m/z: 293 ([MÀH] ); Anal.
À1
1
Calcd for C H O : C 69.39, H 3.43. Found: C,
1
1029, 824, 756 cm ; H NMR (300 MHz, CDCl ) d:
7
10
5
3
6
9.10; H, 3.67.
12.89 (s, 1H), 8.79 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H),
7.87 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.63–7.58 (m,
3
8
4.1.4. 9,11-Dihydroxy-12H-benzo[a]xanthen-12-one (8).
Yield 31% from 2,4,6-trihydroxybenzoic acid and
b-naphthol. H NMR (300 MHz, d -acetone) d: 13.42
1H), 7.51–7.46 (m, 1H), 6.42 (d, J = 2.1 Hz, 1H), 6.32
(d, J = 2.1 Hz, 1H), 3.91 (s, 3H); EI-MS m/z (%): 292
([M] 100); Anal. Calcd for C H O : C, 73.97; H,
1
+
6
18 12
4
(
(
(
s, 1H), 9.95 (d, J = 9.0 Hz, 1H), 9.78 (br, 1H), 8.34
d, J = 9.0 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.82–7.76
m, 1H), 7.68–7.63 (m, 1H), 7.61 (d, J = 9.0 Hz, 1H),
4.14. Found: C, 73.91; H, 4.09.
4.4. 1,3-Dihydroxy-4-nitro-12H-benzo[b]xanthen-12-one
(7)
6
.51 (d, J = 2.1 Hz, 1H), 6.33 (d, J = 2.1 Hz, 1H);
À
ESI-MS m/z: 277 ([MÀH] ).
Nitric acid (70%, 0.5 mL) in acetic acid (5 mL) was
slowly added to a solution of compound 2 (2 mmol)
in acetic acid (20 mL). The mixture was stirred at
60 °C for 1 h and then poured into ice-cooled water
(200 mL). The formed precipitates were filtered,
washed with water, and recrystallized from ethanol
to give 7 (342 mg, 53%) as a yellow solid. Mp 272–
274 °C; IR (KBr): 3420, 3044, 2923, 2853, 1641,
1593, 1497, 1421, 1351, 1307, 1184, 876, 744,
4
.2. Synthesis of compounds 5 and 9
General procedures: To a dry flask flushed with nitrogen
and equipped with a reflux condenser was added LiAlH4
(
50–100 mg, excess) in anhydrous THF (30 mL). The
benzoxanthone analogs (1.0 mmol) in THF (5 mL) were
added dropwise at room temperature, and the mixture
was then refluxed for 6–10 h. Excess LiAlH was de-
stroyed by the addition of ethyl acetate. The reaction
mixture was poured into ice-water and then extracted
with ethyl acetate. The crude products obtained after re-
moval of the solvent were purified by flash column chro-
matography to afford 5 and 9 as yellow solids.
4
À1
624 cm ; H NMR (300 MHz, d -DMSO) d: 13.07
6
1
(s, 1H), 8.86 (s, 1H), 8.25 (d, J = 8.1 Hz, 1H), 8.13 (s,
1H), 8.07 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 8.1 Hz,
1H), 7.59 (t, J = 8.1 Hz, 1H), 6.31 (s, 1H); EI-MS
+
m/z (%): 323 ([M] 100); Anal. Calcd for C H NO :
6
1
7
9
C, 63.16; H, 2.81; N, 4.33. Found: C, 63.25; H, 2.90;
N, 4.49.
4
2
3
1
.2.1. 1,3-Dihydroxy-12H-benzo[b]xanthene (5). Yield
9% from compound 2. Mp 236 °C (dec); IR (KBr):
426, 3055, 1628, 1509, 1459, 1272, 1241, 1164, 1043,
4.5. Enzyme assays
À1
1
003, 859, 810, 735, 622 cm ; H NMR (300 MHz,
d6-acetone) d: 8.60 (s, 1H), 8.26 (s, 1H), 7.82–7.77 (m,
H), 7.43 (s, 1H), 7.41–7.32 (m, 2H), 6.20 (d,
J = 2.1 Hz, 1H), 6.13 (d, J = 2.1 Hz, 1H), 4.06 (s, 2H);
The inhibitory activities of all the xanthone derivatives
were measured by using the methods similar to those
3
2
9–31
described previously.
Typically, a-glucosidase
À
ESI-MS m/z: 263 ([MÀH] ); Anal. Calcd for
activity was assayed in 50 mM phosphate buffer (pH
6.8) containing 5% v/v dimethylsulfoxide and the
PNP glycoside was used as a substrate. The inhibitors
were pre-incubated with the enzyme at 37 °C for 0.5 h.
The substrate was then added and the enzymatic reac-
tion 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 triplicate with five different concentrations around
the IC50 values that were roughly estimated in the first
round of experiments, and the mean values were
adopted.
C H O : C, 77.26; H, 4.58. Found: C, 77.11; H, 4.33.
1
7
12
3
4
1
3
1
.2.2. 9,11-Dihydroxy-12H-benzo[a]xanthene (9). Yield
7% from compound 8. Mp 205–207 °C; IR (KBr):
433, 3050, 1625, 1519, 1450, 1262, 1241, 1163, 1048,
À1
1
008, 854, 811, 737, 626 cm ; H NMR (300 MHz,
d6-acetone) d: 9.91 (d, J = 8.7 Hz, 1H), 9.18 (s, 1H),
.58 (s,1H), 8.31 (d, J = 8.7 Hz, 1H), 8.16 (d,
J = 8.7 Hz, 1H), 7.81–7.74 (m, 1H), 7.65–7.60 (m, 1H),
.60 (d, J = 8.7 Hz, 1H), 6.21 (d, J = 2.1 Hz, 1H), 6.13
d, J = 2.1 Hz, 1H), 4.25 (s, 2H); ESI-MS m/z: 263
8
7
(

2814
Y. Liu et al. / Bioorg. Med. Chem. 15 (2007) 2810–2814
22. Sanugul, K.; Akao, T.; Li, Y.; Kakiuchi, N.; Nakamura,
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