A new salicylic acid-derivatized kojic acid vanadyl complex: Synthesis, characterization and anti-diabetic therapeutic potential

Article abstract of DOI:10.1016/j.jinorgbio.2011.05.008

The molecular mechanisms of vanadium toxicity suggest that incorporation of antioxidant groups in the structure of vanadium complexes could be a preferable strategy in designing novel hypoglycemic vanadium complexes with proper efficacy and safety. By con

Full text of DOI:10.1016/j.jinorgbio.2011.05.008

Journal of Inorganic Biochemistry 105 (2011) 1081–1085
Contents lists available at ScienceDirect
Journal of Inorganic Biochemistry
journal homepage: www.elsevier.com/locate/jinorgbio
A new salicylic acid-derivatized kojic acid vanadyl complex: Synthesis,
characterization and anti-diabetic therapeutic potential
⁎
Yongbiao Wei, Chengyue Zhang, Pan Zhao, Xiaoda Yang , Kui Wang
State Key Laboratories of Natural and Biomimetic Drugs and Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center,
Beijing 100191, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The molecular mechanisms of vanadium toxicity suggest that incorporation of antioxidant groups in the
structure of vanadium complexes could be a preferable strategy in designing novel hypoglycemic vanadium
complexes with proper efficacy and safety. By conjugating a pyrone skeleton to provide a coordination group
and antioxidative motifs, we synthesized a novel complex of bis ((5-hydroxy-4-oxo-4 H-pyran-2-yl) methyl
2-hydroxy- benzoatato) oxovanadium (IV) (BSOV). Evaluation of the anti-diabetic effects of BSOV using
streptozotocin (STZ)-induced diabetic rats with bis (maltolato) oxovanadium (BMOV) as a positive control
showed that BSOV effectively lowered blood glucose level, ameliorated damages of hepatic and renal function
in diabetic rats and improved lipid metabolism. The signs of potential alteration of renal function caused by
BSOV and BMOV were observed and are discussed. Overall, the experimental results suggest BSOV as a potent
hypoglycemic agent and further studies using this strategy for anti-diabetic agents.
Received 15 October 2010
Received in revised form 13 May 2011
Accepted 18 May 2011
Available online xxxx
Keywords:
Vanadium
BSOV
Diabetes
Antioxidants
ADMET
© 2011 Elsevier Inc. All rights reserved.
1. Introduction
prevent observable vanadium toxicity without compromising its anti-
diabetic potential [19].
Vanadium compounds have shown substantial promise as hypogly-
cemic agents for the pharmacotherapy of diabetes [1,2] and cancer
chemoprevention agents [3,4]. Potential metal toxicity and poor
pharmacokinetic behavior have limited the development of vanadium
drugs. To overcome these problems, a number of vanadium compounds
with organic ligands have been synthesized and evaluated for their
insulin mimetic activity, e.g., bis(ethylmaltolato)oxovanadium(IV)
(BEOV) by Orvig et al. [5,6], bis(allixinato)- oxovanadium(IV) and bis
(picolinato)oxovanadium(IV) by Sakurai et al. [7–10] and vanadium(III,
IV,V)-dipicolinate by Crans et al. [11,12]. Recently, BEOV was in the
phaseIIclinical trial, however, a potentialsideeffect, i.e., kidney changes,
prevented further applications [13].
Previously, great efforts have been put in elucidating the
mechanisms of vanadium toxicity [14–16]. Although the toxicity of
vanadium compounds involves many aspects, e.g., damage of cell
tight junction, cell apoptosis, and immunosuppression, vanadium-
induced reactive oxygen species (ROS) and mitochondrial damages
have been suggested to be the major adverse reaction mechanisms
especially for normal cells [17]. Treatment with antioxidants has
significantly reduced vanadium toxicity both in vitro and in vivo [18].
Co-administration of vanadate in an herbal decoction was shown to
Based on the molecular mechanism of vanadium toxicity, incorpo-
ration of antioxidant groups in the structure of vanadium complexes
could be a preferable strategy in designing novel anti-diabetic
vanadium complexes. Previously, direct coordination of vanadyl ions
with natural antioxidants produced novel complexes such as bis
(quercetinato)oxovanadium(IV) (BQOV) [20,21] and bis[curcumino]
oxovanadium (BCOV) [22]. BQOV was shown to improve carbohydrate
metabolism and to reduce overall oxidative stress [20,21]; BCOV was
shown to improve the cardiovascular complications associated with
diabetes [22].
To develop anti-diabetic vanadium agents with desirable efficacy
and safety, we designed a novel type of ligands containing a pyrone
skeleton as coordination motif and an antioxidative group derived
from natural antioxidants. In the present work, we report the
synthesis and evaluation of bis((5-hydroxy-4-oxo-4 H-pyran-2-yl)
methyl 2-hydroxybenzo- atato) oxovanadium, BSOV. The hypoglyce-
mic effects were tested on streptozotocin-induced diabetic rats. The
salicylate group is expected to provide a balanced lipo/hydrophilicity
of the complex and a property of antioxidative activity.
2. Experimental
2.1. Chemicals and instrumentation
Vanadyl sulfate (VOSO4·xH2O, x=3 to 5) was purchased from
Aldrich, streptozotocin (STZ) from Sigma and L-Ascorbic acid from
Beijing Chemical Reagent Company (Beijing, China). All other
⁎
Corresponding author: Fax: +86 10 62015584.
E-mail address: xyang@bjmu.edu.cn (X. Yang).
0162-0134/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.jinorgbio.2011.05.008

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Y. Wei et al. / Journal of Inorganic Biochemistry 105 (2011) 1081–1085
chemicals and solvents were reagent grade and used without further
purification unless otherwise specified. The positive control, bis
(maltolato)oxovanadium (BMOV), was prepared and purified accord-
ing to the published method [23].
The synthesized ligands and their complexes were characterized
by infrared (IR) spectroscopy, mass spectrometry, elemental analysis,
and NMR spectroscopy. Where appropriate, 1H NMR was use for
further characterization. Infrared spectra were recorded as KBr disks
in the range 4000–400 cm−1 on a Nexus-470 FTIR spectrophotometer
(Nicolet Instruments, USA). Mass spectra (positive ion mode) were
obtained with a QSTAR (Applied Biosystems, USA) quadrupole time-
of-flight (TOF) hybrid mass spectrometer.
Rhodamine B, 1.0 mM FeSO4, 5 mM of cetyl trimethyl ammonium
bromide (CTAB), and 20 mM acetic acid (pH 2.8). After addition of
2.0 mM (final concentration) of H2O2, the reactions were left for
10 min at room temperature. Then absorbance As at 550 nm was
measured. The antioxidant recovery capacity R was calculated as:
R = ðAs−AbÞ= ðA0−AbÞ
Where A0 is the control (cantioxidant =0) and Ab is the reagent blank.
Then the data was further fitted to the following equation:
2.2. Synthesis
1
R
1
K
1
Rmax
=
+
:
cantioxidant k·Rmax
The synthesis route is illustrated in Scheme 1:
2-(chloromethyl)-5-hydroxy-4 H-pyran-4-one (Chlorokojic, 2).
Compound 2 was prepared according to a previously reported method
[24].
Then Rmax and k/K were obtained using an Origin 7.0 program. HRSC
index was calculated by setting the k/K value of ascorbic acid as 1.0.
(5-hydroxy-4-oxo-4 H-pyran-2-yl)methyl 2-hydroxybenzoate (3).
Compound 3 was prepared using a modified literature procedure [25].
Briefly, sodium salicylate (1 g, 6.3 mmol) and chlorokojic acid (0.9 g,
5.6 mmol) were dissolved into 80 ml of N,N- dimethylformamide. The
resulting solution was heated with stirring for 2 h in an oil bath at
110 °C. After cooled to room temperature, the solution was poured
into water. The product (1.3 g, 80%) was obtained by filtration
2.4. Animal treatments
Male Sprague–Dawley rats, weighing about 220–240 g, were
obtained from Experimental Animal Center of Peking University,
and maintained on a light/dark cycle. All animals were allowed free
access to standard, solid rat chow and water. Temperature and
relative humidity were maintained at 24 °C and 50%, respectively. Rats
were acclimatized for 7 days prior to induction of diabetes. All care
and handling of animals were performed with the approval of
Institutional Authority for Laboratory Animal Care.
Diabetes was induced by a single intravenous injection of freshly
prepared STZ (55 mg/kg body weight) in 0.1 mol/L citrate buffer (pH
4.5) [27]. The control rats were injected with an equal volume of
vehicle. Rats were supplied with 5% glucose solution for 48 h after STZ
injection in order to prevent hypoglycemia. Seven days after the
streptozotocin administration, blood was collected from the tail vein
and serum samples were analyzed for blood glucose. Animals showing
fasting (12 h) blood glucose higher than 13.3 mmol/L were consid-
ered to be diabetic and used for the study. All drug candidates were
administered as suspensions in 0.5% methyl-cellulose (MC) by oral
gavage in a volume of 5.0 ml/kg body weight at a dose of 0.4 mmol/kg
body weight for 4 weeks. The control groups received an equivalent
volume of 0.5% methyl-cellulose alone.
A total of 56 rats (32 diabetic rats and 24 control rats) were
randomly divided into seven groups: Group I, Control rats (n=8);
Group II, Ligand-treated non-diabetic rats (n=8); Group III, BSOV-
treated non-diabetic rats (n=8); Group IV, Diabetic rats (n=8);
Group V, Ligand-treated diabetic rats (n=8); Group VI, BSOV-treated
diabetic rats (n=8); and Group VII, BMOV-treated diabetic rats
(n=8). The BMOV-treated group was considered as the positive
control group.
Throughout the experimental period, the body weight and
drinking water intake were monitored daily. In the meantime, the
food consumption was recorded. Blood samples were obtained from
the tail vein of the rats and blood glucose levels were determined with
an Accu-Chek blood glucose monitor (Roche Diagnostics GmbH,
Mannheim, Germany).
and purified by the recrystallization from methanol. IR (cm−1
,
KBr disk) data: 3268 cm−1(νO−H); 3500–3000 cm−1(νC−H); 1686,
1651 cm−1(salicylic acid νC=O);1619, 1594, 1484 cm−1(pyroneνC=O
,
ring νC=C); 1H NMR (DMSO-d6, 400 Hz, s=singlet, m=multiplet)
data: δ 5.22 (s, 2 H), 6.85 (s, 1 H), 6.94–7.83 (m, 4 H), 8.13 (s, 1 H), 9.26
(s, 1 H), 10.31 (s, 1 H); m/z 263.05 (calc. 263.21) [M+1]+
.
Bis ((5-hydroxy-4-oxo-4 H-pyran-2-yl)methyl 2-hydroxyben-
zoatato) oxovanadium (BSOV). (5-Hydroxy-4-oxo-4 H-pyran-2-yl)
methyl 2-hydroxybenzoate (2.7 g, 10.3 mmol) and sodium hydrox-
ide (0.4 g, 10.0 mmol) were dissolved into 100 ml water and 1.9 g of
vanadyl sulfate was added. The resulting mixture was heated with
stirring for 12 h in an oil bath at 90 °C. After the mixture was cooled to
room temperature, the precipitate was filtered. The yield of the complex
was 65% on the basis of the ligand. The prepared complex was
characterized by elemental analysis and IR absorption, and Mass
spectrometry. IR (cm−1, KBr disk) data: 3500–300 cm−1(νO−H, νC−H);
1679 cm−1(salicylic acid νC=O); 1610, 1565, 1512, 1473 cm−1(pyrone
ν
C=O, ring νC=C); 984 cm−1(νV=O). ESI-MS data: m/z 590.01 (calc.
590.35) [M+1]+. Anal. Calcd. for C26H18O13V:C, 52.99; H, 3.08. Found: C
52.77, H 3.12.
2.3. In vitro tests of antioxidant activity
The antioxidant activity of vanadium complexes and free ligand
were tested by hydroxyl radical scavenging capacity (HRSC) as
previously described [26]. Briefly, antioxidants at various concentra-
tions were added to Fenton reaction media containing 0.010 mM
2.5. Glucose tolerance tests (OGTT)
After the administration of BMOV or BSOV for 4 weeks, OGTT was
carried out. The rats were fasted for 12 h, and glucose (200 mg/mL)
was given by oral gavage at a dose of 2 g/kg body weight. Blood
samples were obtained from the tail vein at 0, 30, 60, 120 and 180 min
after glucose loading, respectively. Blood glucose levels were
measured with an Accu-Chek blood glucose monitor.
Scheme. 1. The pathway for synthesis of BSOV.

Y. Wei et al. / Journal of Inorganic Biochemistry 105 (2011) 1081–1085
1083
2.6. Serum biochemical parameters test
The rats were deprived of food overnight, and blood samples were
collected for determination of biochemical parameters. Biochemical
parameters in serum, including total cholesterol (TCHO), triglycerides
(TG), alanine amino transferase (GPT), aspartate amino transferase
(GOT), creatinine (CRE), blood urea nitrogen (BUN), and albumin
(ALB) were determined using assay kits from Randox (Antrim, UK) on
an OLYMPUS AU400 chemistry analyzer (Olympus, Tokyo, Japan).
2.7. Statistical analysis
All data are presented as means SD. The statistical analysis was
performed by one-way analysis of variance (ANOVA) followed by
Dunnett's multiple comparison tests using a SPSS 13.0 software.
Statistical significance was accepted at the level of pb0.05.
Fig. 1. Changes in blood glucose levels upon vanadium treatment. Control rats (■),
Ligand-treated normal rats (▲), BSOV-treated normal rats (△), Diabetic rats (●),
Ligand-treated diabetic rats (▼), BSOV-treated diabetic rats (▽), BMOV-treated
3. Results
⁎
diabetic rats ( ). Values are expressed as means SD. pb0.01 vs. diabetic rats.
◆
3.1. In vitro antioxidative activity
The antioxidant activity of BSOV, BMOV and ligand were tested as
hydroxyl radical scavenging capacity (HRSC), Table 1. The salicylic
acid-derivatized ligand gave better HRSC index than the parental
compounds. Interestingly, both vanadyl complexes, especially BSOV,
exhibited excellent antioxidant activity.
3.4. Serum biochemical parameters test
The levels of TCHO, TG, GPT, GOT, BUN ALB, and CRE in serum have
been summarized in Table 2. Compared to the control rats, results can
be summarized as: (i) treatment with vanadium complexes amelio-
rated most of hyperglycemia-elevated serum biochemical parameters,
i.e., BUN, TG, TCHO, GOT, and CRE. The effects of treatment with BSOV
were similar to those of BMOV; (ii) significant decrease of TCHO and
TG levels to even lower than those in normal control rats; (iii) no
significant improvements of ALB levels of diabetic rats; (iv) with
diabetic rats, the free ligand reduced the serum parameters similar to
the complexes; and (v) both BSOV and free ligand did not significantly
affect the serum parameters of normal rats.
3.2. Blood glucose level
Fig. 1 illustrates the changes of fasting blood glucose level in
control and diabetic rats treated with BSOV and BMOV each at a dose
of 0.4 mmol/kg body weight/day. Compared with the blood glucose
level of STZ-diabetic rats, the blood glucose level of diabetic rats
treated with BSOV and BMOV reverted back close to normal levels;
while the salicylic acid-derivatized ligand did not show any
hypoglycemic effects.
3.5. Physiological parameters
3.3. Glucose tolerance test
The changes of body weights of control and diabetic rats are
shown in Fig. 3. The none diabetic rats (control rats, ligand-treated,
and BSOV-treated groups) steadily gained weight until the end of
the study. While the diabetic rats (diabetic control and vanadium-
treated groups) remain their body weight. At the end of the experiment,
To evaluate the improvement in the glucose tolerance ability in
diabetic rats, an OGTT was performed after the 4 weeks treatment
(Fig. 2). After oral administration of glucose, the blood glucose
concentration in diabetic rats reached a maximal concentration in 1 h
and returned to the baseline in the next 2 h. Although both BSOV and
BMOV-treated diabetic rats still showed significant fluctuation in
blood glucose level, the peak values were much lower than that of the
diabetic rats (pb0.01) and returned close to the normal blood glucose
level at 2–3 h after glucose administration, indicating comparable
extent of improvement in glucose tolerance in the two vanadium
compound-treated rats. The ligand treatment did not affect glucose
tolerance with significance in diabetic or none diabetic rats.
Table 1
Hydroxyl radical scavenging capacity of vanadium compounds and the references.
Compounds
Fitting results
HRSC
index
Rmax
k/K
r2
L-ascorbic acid
Salicylic acid
Kojic acid
Salicylic-derivatized ligand
BSOV
1.32
1.12
1.36
0.95
0.73
1.23
0.31
0.72
2.01
2.53
14.34
2.45
0.9673
0.9677
0.9606
0.8284
0.9399
0.9293
1.0
2.3
6.5
8.1
46.3
7.9
Fig. 2. Oral glucose tolerance test curves. Control rats (■), Ligand-treated normal rats
(▲), BSOV-treated normal rats (△), Diabetic rats (●), Ligand-treated diabetic rats (▼),
BSOV-treated diabetic rats (▽), BMOV-treated diabetic rats ( ). Values are expressed
◆
BMOV
⁎
as means SD. pb0.01 vs. diabetic rats.

1084
Y. Wei et al. / Journal of Inorganic Biochemistry 105 (2011) 1081–1085
Table 2
Effects of BSOV on serum biochemical parameters in STZ-induced diabetic rats.
BUN (mM)
ALB (g/L)
TG (mM)
TCHO (mM)
GPT (U/L)
GOT (U/L)
CRE (mg/dL)
⁎
⁎
⁎
⁎
⁎
⁎
⁎
⁎
⁎
⁎
⁎
⁎
⁎
Control
7.09 0.60
6.02 1.20
7.14 1.40
30.91 1.87
31.63 0.78
30.66 1.04
0.63 0.19
0.55 0.13
0.74 0.27
1.66 0.32
1.38 0.24
1.56 0.19
45
9
95 18
103 23
116 82
0.64 0.07
0.71 0.06
0.67 0.09
⁎
⁎
⁎
⁎
Normal+Ligand
Normal+BSOV
Diabetic
Diabetic+Ligand
Diabetic+BSOV
Diabetic+BMOV
52 10
57 13
⁎
⁎
⁎
32.53 6.81#
26.16 1.06#
27.47 0.94#
28.28 2.21#
27.48 1.56#
0.94 0.39#
0.51 0.48
2.26 0.29#
245 57#
206 51#
209 45#
216 27#
711 95#
0.77 0.06#
0.57 0.12
,#
,#
,#
,#
,#
,#
⁎
⁎
⁎
⁎
⁎
23.98 3.98
22.79 7.39
23.00 5.89
1.03 0.48
0.82 0.16
0.78 0.25
218 106
255 115
,#
,#
⁎
⁎
⁎
⁎
0.48 0.13
0.46 0.29
0.58 0.06
0.61 0.03
,#
⁎
⁎
⁎
⁎
294 91
Values are expressed as mean SD for ten rats in each group.
#
pb0.05 or less vs. control rats (Dunnett's test).
⁎
pb0.05 or less vs. diabetic rats (Dunnett's test).
the body weights of both vanadium- and ligand-treated groups were
close to their control groups.
profound alterations in the concentration and composition of lipids
[29]. BSOV treatment was found to significantly reduce the elevated
serum TG and TCHO concentrations (Table 2), suggesting enhance-
ment of lipid metabolism. Overall, BSOV treatment improved hyper-
glycemia state in a similar extent to those of BMOV.
The daily food and water intake of diabetic rats were significantly
higher than that of normal control rats (Fig. 4). Both BMOV and BSOV
treatment significantly lowered food and water consumption 2 days
after drug administration and remained constant throughout the
experiment. During the experimental period, no signs of GI stress
were observed for BMOV, BSOV and salicylic acid-derivatized ligand.
However, there were signs indicating potential toxicity of both
BSOV and BMOV: the body weight of vanadium compound-treated
diabetic rats did not grow as the normal rats, and the level of ALB
was not improved. The reasons may be complex: (i) a malabsorption
caused by vanadium complexes. However, since GI stress signs were
not observed, further evidence needed to support this statement;
(ii) the toxicity of the dissociated ligands. However, as shown in
Table 2, the free ligand did not exhibit any significant toxicological
effects on normal rats. The recovery of the altered organ function
in the diabetic rats was probably due to the antioxidant activity;
and (iii) the unexpected excretion of serum albumin (ALB) due to
change of renal function. Previously, it was suggested that vanadium
compounds can cause damage of cell tight junction [30] and the
alteration of the tight junction of the podocytes in glomerulus was an
important reason for urine protein elevation in diabetes [31–33].
4. Discussion
The insulin-mimetic effect of vanadium compounds has been
widely documented in diabetes animal models [7,27,28]. In this study,
BSOV was designed to combine kojato and salicylic acid to provide a
balanced lipo/hydrophilicity of the complex and a property of
antioxidative activity. In testing the anti-diabetic effects of BSOV,
BMOV, a well-known vanadium complex, was used as the positive
control.
As shown in Figs. 1–4, BSOV was observed to (i) effectively lower
blood glucose level to close to the normal in 4 weeks treatment
(Fig. 1), (ii) significantly ameliorate the impaired glucose tolerance
in STZ-diabetic rats (Fig. 2), and (iii) remarkably decrease food and
water intake in group diabetic rats (Fig. 4). Compared to the positive
control, the experimental results indicate that BSOV was as potent a
hyperglycemic agent as the previously investigated BMOV.
In addition to the hypoglycemic effects, BSOV treatment amelio-
rated damages of hepatic and renal function in diabetic rats as
revealed by decrease of GPT, GOT, and BUN levels (Table 2). It has
been well documented that STZ-induced hyperglycemia causes
Fig. 3. Changes of body weight during vanadium treatment. Control rats (■), Ligand-
treated normal rats (▲), BSOV-treated normal rats (△), Diabetic rats (●), Ligand-
treated diabetic rats (▼), BSOV-treated diabetic rats (▽), BMOV-treated diabetic rats
Fig. 4. Food (A) and water (B) intake of control and experiment groups of rats. Values
are given as mean SD. #Pb0.05 or less vs. control rats; pb0.05 or less vs. diabetic rats.
⁎
(
◆
). Values are expressed as means SD.

Y. Wei et al. / Journal of Inorganic Biochemistry 105 (2011) 1081–1085
1085
Therefore, the vanadium toxicity on cell tight junction may increase
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Abbreviations
ALB
albumin
BCOV
BEOV
BMOV
BQOV
BSOV
bis[curcumino]oxovanadium
bis(ethylmaltolato)oxovanadium(IV)
bis(maltolato)oxovanadium
bis(quercetinato)oxovanadium(IV)
bis((5-hydroxy-4-oxo-4 H-pyran-2-yl)
methyl2-hydroxybenzoatato)oxovanadium(IV)
blood urea nitrogen
BUN
CRE
GOT
creatinine
glutamine-oxaloacetic transaminase/aspartate
aminotransferase
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