Evaluation of polyhydroxybenzophenones as α-glucosidase inhibitors

Article abstract of DOI:10.1002/ardp.201000147

This experiment was designed to synthesize 18 kinds of polyhydroxybenzophenones by using Friedel-Crafts reaction, and to measure the inhibitory activity on α-glucosidase with p-nitrophenyl-β-D- galactopyranoside (PNPG) as a substrate. Here, acarbose (IC₅₀a= a1674.75aaμmolaL^-1) was used as the reference inhibitor. The results demonstrated that most of the target compounds had remarkable inhibitory activities on α-glucosidase. Among all these compounds, 2,4,4′,6-butahydroxydiphenylketone (11) was found to be the most potent α-glucosidase inhibitor with an IC₅₀ value of 10.62aaμmolaL^-1. In addition, we found these compounds were competitive inhibitors through the kinetic analysis. The results suggested that such compounds might be utilized for the development of new candidates for diabetes treatment. A series of polyhydroxybenzophenones was synthesized and evaluated as α-glucosidase inhibitors. Compound 11 was found to be the most potent inhibitor. Copyright

Full text of DOI:10.1002/ardp.201000147

Arch. Pharm. Chem. Life Sci. 2011, 2, 71–77
71
Full Paper
Evaluation of Polyhydroxybenzophenones as a-Glucosidase
Inhibitors
Xuesen Hu, Yang Xiao, Jianlong Wu, and Lin Ma
School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, P.R. China
This experiment was designed to synthesize 18 kinds of polyhydroxybenzophenones by using Friedel-
Crafts reaction, and to measure the inhibitory activity on a-glucosidase with p-nitrophenyl-b-D-
galactopyranoside (PNPG) as a substrate. Here, acarbose (IC50 ¼ 1674.75 mmol Lꢀ1) was used as the
reference inhibitor. The results demonstrated that most of the target compounds had remarkable
inhibitory activities on a-glucosidase. Among all these compounds, 2,4,40,6-butahydroxydiphenylketone
(11) was found to be the most potent a-glucosidase inhibitor with an IC50 value of 10.62 mmol Lꢀ1
.
In addition, we found these compounds were competitive inhibitors through the kinetic analysis.
The results suggested that such compounds might be utilized for the development of new candidates
for diabetes treatment.
Keywords: a-Glucosidase / Inhibitor / Polyhydroxybenzophenone
Received: May 20, 2010; Revised: August 5, 2010; Accepted: August 20, 2010
DOI 10.1002/ardp.201000147
Introduction
To date, few a-glucosidase inhibitors, such as acarbose,
voglibose from microorganisms, and miglitol are of clinical
value and widely applicable [16]. The needs for new diverse
therapeutic agents necessitate the creation of new classes of
inhibitors [17–24]. Nowadays, synthesis of stronger a-gluco-
sidase inhibitors has attracted more and more researchers’
attention [25, 26].
In the last decades, intense academic interest has been caused
by 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. It is also involved in a
variety of diseases such as diabetes mellitus, viral attach-
ment, and cancer formation [1–5]. Among them, diabetes
mellitus (Type 1 and 2), a condition in which a person has
a high blood sugar (glucose) level, has been recognized as
a serious global health problem due to the changes in
people’s lifestyle and dietary habits [6]. Presently, one of
the most effective therapeutic approaches for Type 2
diabetes mellitus is a-glucosidase inhibitors, which inhibit
intestinal a-glucosidases to delay the digestion and absorp-
tion of carbohydrates [7–14]. a-Glucosidases are responsible
for the catalytic cleavage of a glycosidic bond in the digestive
process of carbohydrates with specificity depending on
the number of monosaccharides, the position of cleavage
site, and the configuration of the hydroxyl groups in the
substrate [15].
In the last decades, polyhydroxybenzophenones have
been widely utilized for the production and development
of plastic, resin, coating materials, synthetic rubber, light-
sensitive materials, and cosmetic materials. However, its
other properties such as antioxidant activity, tyrosinase
inhibitory activity, and a-glucosidase inhibitory activity
have not been reported yet.
Recently, exifone (10) was found to exhibit inhibitory
effect on tyrosinase [27, 28], and the structures of this
series of compounds are similar to flavonoids which
have significant inhibitory activity on both tyrosinase
and a-glucosidase [29, 30]. So, we speculated that poly-
hydroxybenzophenones might exhibit potent a-glucosidase
inhibitory activity. Therefore, our team synthesized a
series of polyhydroxybenzophenones and evaluated
their inhibitory activity of a-glucosidase with PNPG
as substrate. To the best of our knowledge, this is the first
time to report the inhibitory effects on a-glucosidase of
polyhydroxybenzophenones.
Correspondence: Lin Ma, School of Chemistry and Chemical
Engineering, Sun Yat-sen University, 135 Xin Gang Xi Road, Guangzhou
510275, P.R. China
E-mail: cesmal@mail.sysu.edu.cn
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X. Hu et al.
Arch. Pharm. Chem. Life Sci. 2011, 2, 71–77
O
R5
R1
R5
R1
R6
R6
R7
R2
R3
R2
R3
COOH
ZnCl2, POCl3
R7
R4
R4
R8
R8
Scheme 1. Synthetic route of polyhydroxybenzophenones 1–18.
Results and discussion
some modification. The obtained IC50 values of all com-
pounds investigated were summarized in Table 1 and
Figs. 1 and 2. All compounds that had been tested exhibited
more potent a-glucosidase inhibitory activities than
Synthetic Chemistry
The synthetic routes of compound 1–18 were outline in
Scheme 1, and the chemical structures of polyhydroxyben-
zophenones 1–18 were given in Table 1. The chemical struc-
tures of all the synthesized compounds were characterized by
1H-NMR, 13C-NMR spectra, and IR.
acarbose (IC50 ¼ 1674.75 mmol Lꢀ1), especially 11 (IC50
¼
10.62 mmol Lꢀ1
)
which demonstrated excellent in-vivo
activity, see Table 1.
Of all polyhydroxybenzophenones 1–18, the trihydroxy-
substituted diphenylketones 2, 12, and 13 display none or
very weak inhibitory effects on a-glucosidase. In contrast,
tetrahydroxy-, pentahydroxy-, and hexahydroxy-substituted
Effects on a-Glucosidase Inhibitory Activity
a-Glucosidase inhibition activity were evaluated by using
methods similar to those described in the literature [31] with
diphenylketones exhibited
a
significant increase in
Table 1. Chemical structure of polyhydroxybenzophenones 1–18 and inhibitory effects on a-glucosidase of polyhydroxybenzophenones
and acarbose as reference inhibitor.
O
R5
R1
R6
R7
R2
R3
R4
R8
Compound
R1
R2
R3
R4
R5
R6
R7
R8
IC50 (mmol Lꢀ1
)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
H
OH
H
H
H
H
H
H
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
H
H
H
H
H
H
H
H
H
H
OH
H
H
H
H
OH
H
H
–
H
H
H
OH
H
H
H
OH
H
H
OH
H
OH
H
OH
H
H
H
H
OCH3
H
OCH3
OH
H
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
H
OH
H
H
H
H
H
H
H
H
OH
H
H
H
OH
H
H
H
OH
H
H
H
H
–
NTꢁ
78.13
92.83
49.72
86.11
90.00
ꢂ100
77.03
31.10
33.24
10.62
ꢂ100
NT
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
OH
OH
OH
OH
–
H
OH
OH
OH
OH
H
H
H
H
OH
H
H
OCH3
OH
H
OH
H
OH
H
H
34.33
83.39
NT
NT
NT
17
18
Acarbose
OH
OH
–
H
H
–
H
–
H
–
–
1674.75
* NT: Not Tested.
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Arch. Pharm. Chem. Life Sci. 2011, 2, 71–77
Evaluation of Polyhydroxybenzophenones
73
bearing two hydroxyl substituent at position R1 and R5 dis-
play potent inhibitory activity.
In addition, compounds substituted by
a hydroxyl
group on position R1, R2, and R3 exhibited more potent
a-glucosidase inhibition potencies than unsubstituted com-
pounds with similar structure, such as compounds 9
(IC50 ¼ 31.10 mmol Lꢀ1) and 7 (IC50 ꢂ 100 mmol Lꢀ1).
Kinetic Assay
As the compounds with potent inhibitory activities to a-
glucosidase have similar structures to each other, we
concluded that they could exhibit the same inhibition
type to a-glucosidase. Therefore, 2,20,4,40-butahydroxy-
diphenylketone (4), 2,3,4,40-butahydroxy-30-methoxydiphe-
nylketone (9), 2,3,4,30,40,50-hexahydroxydiphenylketone
(10), and 3,4,40,5-butahydroxydiphenylketone (14) had
been chosen to investigate the kinetic behavior of a-gluco-
sidase during the oxidation of PNPG. The result
demonstrated that the mechanism of a-glucosidase
inhibition of the compounds 4, 9, 10, and 14 is competitive
because an increase of their concentrations resulted
in similar lines with a common intercept on the 1/V
axis but with different slopes (Figs. 3–6) and Ki values
(Table 2).
Figure 1. The inhibition of polyhydroxybenzophenones (2, 4, 6, 14)
for a-glucosidase.
By identifying the mechanism of a-glucosidase inhibition
of compounds, we supposed that the synthesized com-
pounds have a similar structure to PNPG. To make this idea
convinced, all structures were compared with the
Figure 2. The inhibition of polyhydroxybenzophenones (3, 8, 9, 11,
15) for a-glucosidase.
inhibitory activity on a-glucosidase along with growing
number of hydroxyl groups. This finding seems to be a
tendency.
Interestingly, most of the compounds which display potent
a-glucosidase inhibitory activities are substituted by
hydroxyl group on the positions R1 and R2. Hence, the result
suggests that the introduction of hydroxyl group on
positions R1 and R2 strengthen the a-glucosidase inhibitory
activity. Compared to compounds 6 and 14, compounds 8
Figure 3. Lineweaver-Burk plots for inhibition of 2,20,4,40-buta-
hydroxydiphenylketone on a-glucosidase for the catalysis of
PNPG at 308C, pH 7.0. Concentrations of 2,20,4,40-butahydroxydi-
phenylketone for curves 1 and 2 were 0 and 40 mmol LS1
,
(IC50 ¼ 77.03 mmol Lꢀ1
)
and 11 (IC50 ¼ 10.62 mmol Lꢀ1
)
respectively.
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74
X. Hu et al.
Arch. Pharm. Chem. Life Sci. 2011, 2, 71–77
Figure 4. Lineweaver-Burk plots for inhibition of 2,3,4,40-butahy-
droxy-30-methoxy-diphenylketone on a-glucosidase for the catalysis
of PNPG at 308C, pH 7.0. Concentrations of 2,3,4,40-butahydroxy-
Figure 6. Lineweaver-Burk plots for inhibition of 3,4,40,5-butahy-
droxydiphenylketone on a-glucosidase for the catalysis of PNPG
at 308C, pH 7.0. Concentrations of 3,4,40,5-butahydroxydiphenyl-
ketone for curves 1 and 2 were 0 and 50 mmol LS1, respectively.
30-methoxy-diphenylketone for curves
1 and 2 were 0 and
50 mmol LS1, respectively.
substrate’s structure. The results indicated that the best
inhibitor 11 got the proximal framework of PNPG. By collat-
ing 11 with PNPG, Ii is evident that positions R1, R3, R4,
and R7 of 11 substituted by hydroxyl group are similar with
position O-1, C-5, C-3, and C-50 of PNPG substituted by
hydroxyl group and nitro group. As shown in Fig. 7, a
replacement of R4 by hydrogen for 4, or of R7 for 15 led
to a drop in the activity [4 (IC50 ¼ 49.72 mM) and 15
(IC50 ¼ 83.39 mM)]. Furthermore, if R1 and R4 are replaced
by hydrogen as in 2, or R4 and R7 in 13, the compounds exhibit
a significant drop in the activity [2 (IC50 ¼ 78.133 mM) and
13 (NT)]. Hence, these results suggested that the positions
R1, R3, R4, and R7 substituted by hydroxyl group are essential
to the activity, which make compounds’ structure close to
substrates’. This rationale is supported by the activity of
compounds 1 (NT) and 18 (NT). From the results, it is fair
to conclude that polyhydroxybenzophenone are substrate
analogs.
From the above point of view, polyhydroxybenzophenone
with the substituted positions R1, R3, R4, and R7 by a hydroxyl
group presents equivalent inhibition activity, because this
kind of compound can enter into active center of a-glucosi-
dase like the substrate PNPG.
Table 2. IC50 and Ki values for selected inhibitors of a-glucosidase.
Compound
IC50 (mmol LS1
)
Ki (mmol LS1
)
Figure 5. Lineweaver-Burk plots for inhibition of 2,3,4,30,40,50-
hexahydroxydiphenylketone on a-glucosidase for the catalysis
of PNPG at 308C, pH 7.0. Concentrations of 2,3,4,30,40,50-hexa-
4
9
10
14
49.72
31.10
33.24
34.33
29.83
18.95
20.13
22.42
hydroxy-diphenylketone for curves
80 mmol LS1, respectively.
1 and 2 were 0 and
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Arch. Pharm. Chem. Life Sci. 2011, 2, 71–77
Evaluation of Polyhydroxybenzophenones
75
O
1
O
1'
O
R5
R8
R1
7
3'
6'
2'
R6
R2
R3
4'
5'
OH
2
6
7'
4
O
R7
R4
OH
OH
3
N
O
5
OH
substrate PNPG
compounds
OH
O
O
O
OH
O
OH
OCH3
OH
HO
HO
OH
HO
HO
OH
HO
HO
OH
OH
1
NT
2
78.13µM
3
92.83µM
4 49.72µM
OH
O
OH
OH
O
OH
OH
O
OH
O
HO
HO
OH
OH
HO
HO
OCH3
OH
OH
8
77.03µM
6
90.00µM
7
≥100µM
5
86.11µM
OH
O
OH
O
OH
O
OH
OH
O
HO
HO
OH
OH
HO
HO
OCH3
OH
OH
HO
OH
OH
HO
OH
9
31.10µM
10 33.24µM
11 10.62µM
12 ≥100µM
O
OH
O
OH
OH
O
OH
O
OH
OH
OH
HO
HO
HO
HO
HO
OH
HO
OH
14 34.33µM
15 83.39µM
16
NT
13 NT
OH
O
OH
O
HO
HO
18 NT
17
NT
Figure 7. Structures of the substrate (PNPG) and the compounds 1–18 and inhibitory effects (IC50) on a-glucosidase of compounds 1–18.
Conclusions
activity to a-glucosidase. In addition, the inhibition kinetics
analyzed by Linewear-Burk plots revealed that such com-
pounds were competitive inhibitors. The results suggested
that such compounds might be utilized for the development
of new candidates for treatment of diabetes mellitus.
In conclusion, in the present investigation, a series of poly-
hydroxybenzophenones was synthesized and evaluated as a-
glucosidase inhibitors. The results demonstrated that most of
the target compounds showed remarkable inhibitory activi-
ties to a-glucosidase. In fact, all tested compounds exhibited
much more potent a-glucosidase activity compared with
acarbose. This research indicates that both the number
and position of hydroxyl groups in diphenylketone seem
to play a critical role in exerting the inhibitory effect on
Experimental
Materials
The resorcinol, pyrogallol, salicylic acid, m-hydroxybenzoic acid,
p-hydroxybenzoic acid, and 2,4-dihydroxybenzoic acid were
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76
X. Hu et al.
Arch. Pharm. Chem. Life Sci. 2011, 2, 71–77
purchased from Sanchang Chemical Co. (ShangHai, China). a-
Glucosidase and 4-nitrophenyl-b-D-glucopyranoside (PNPG) were
purchased from Sigma Chemical Co. All commercially available
reagents and solvents were used without further purification.
Kinetic Assay of a-Glucosidase Inhibition
Various concentrations of PNPG (0.1 to 1.2 mM) as the substrate,
10 mL of a-glucosidase, and 10 mM potassium phosphate buffer
(pH 7.0) were added to a test tube in a total volume assay mixture
of 1000 mL. The initial rate of the reaction mixture was deter-
mined by the increase of absorbance at 400 nm per min (DOD400
min). The Michaelis constant (Ki) and the maximal velocity (Vmax
of the a-glucosidase activity were determined by the Lineweaver–
Burk plot.
/
)
Synthesis
To the mixture of appropriate phenol (50 mmol) and polyhy-
droxybenzoic acid (55.6 mmol), anhydrous zinc chloride (27.2 g),
and phosphorus oxychloride (25 mL) were added. The reaction
mixture was refluxed for 2.5 h in the water bath of 708C with
stirring. Then the mixture was added to appropriate ice and
cooled to 48C for 24 h. The precipitate solid was filtered, washed
with 3% sodium bicarbonate twice, and purified by recrystalli-
zation from boiling water to afford compounds 1–18 (Fig. 1). The
synthetic route of compounds 1–18 is given in Scheme 1.
NMR spectra were recorded on a Varian INOVA 300 MB NMR
spectrometer in DMSO-d6 and tetramethylsilane was used as an
internal standard. IR spectra were obtained on a Bruker
EQUINOX55 Fourier transformation infrared spectrometer.
This work was supported by the Undergraduate Research Programmes of
Sun Yat-sen University, China (2009-73).
The authors have declared no conflict of interest.
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