Synthesis, crystal structures and insulin-like activity of three new oxidovanadium(V) complexes with aroylhydrazone ligand

Article abstract of DOI:10.1016/j.jinorgbio.2019.03.020

Three new oxidovanadium(V) complexes were designed, synthesized and characterized by C, H, N elemental analysis, single crystal X-ray diffraction，UV/Vis and IR spectra. Complex 1: [VOL¹X] (H₂L¹ = (E)-N′-(2-hydroxybenzylidene)-3-methbenzohydrazide, HX = ethylmaltol = 2-ethyl-3-hydroxy-4-pyrone), Complex 2: [VOL²(CH₃O)(CH₃OH)], (H₂L² = C₁₆H₁₆N₂O₄ = (E)-N′-(2-hydroxybenzylidene)-3,5-dimethoxybenzohydrazide, CH₃OH = methanol), Complex 3: [VOL³X] (H₂L³ = (E)-N′-(3-ethoxy-2-hydroxybenzylidene)-3,5-dimethoxybenzohydrazide). The insulin-like activity of the three complexes was tested. Both normal and streptozotocin (STZ)-diabetic mice were administered intragastrically for two weeks. It was found that the complexes at doses of 10.0 and 5.0 mg V·kg^?1 can significantly decrease the blood glucose level in STZ-diabetic mice, and the blood glucose level in the treated normal mice was not altered. The lesions of kidney and liver caused by diabetes have varying degrees of improvement.

Full text of DOI:10.1016/j.jinorgbio.2019.03.020

JournalofInorganicBiochemistry196(2019)110680
Contents lists available at ScienceDirect
Journal of Inorganic Biochemistry
journal homepage: www.elsevier.com/locate/jinorgbio
Synthesis, crystal structures and insulin-like activity of three new
oxidovanadium(V) complexes with aroylhydrazone ligand
Quan-Cheng Zhoua,1, Tian-Rui Wangb,1, Hui Lia, Lei Chenb, Jia-Jin Xinb, Shen Guob,
⁎
⁎
Gui-Hua Shenga, , Zhong-Lu Youc,
a School of Agricultural Engineering and Food Science, Shandong University of Technology, ZiBo 255049, PR China
b School of Life Sciences, Shandong University of Technology, ZiBo 255049, PR China
c Department of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Three new oxidovanadium(V) complexes were designed, synthesized and characterized by C, H, N elemental
analysis, single crystal X-ray diffraction，UV/Vis and IR spectra. Complex 1: [VOL1X] (H2L1 = (E)-N′-(2-hy-
droxybenzylidene)-3-methbenzohydrazide, HX = ethylmaltol = 2-ethyl-3-hydroxy-4-pyrone), Complex 2:
[VOL2(CH3O)(CH3OH)], (H2L2 = C16H16N2O4 = (E)-N′-(2-hydroxybenzylidene)-3,5-dimethoxybenzohydrazide,
CH3OH = methanol), Complex 3: [VOL3X] (H2L3 = (E)-N′-(3-ethoxy-2-hydroxybenzylidene)-3,5-dimethox-
ybenzohydrazide). The insulin-like activity of the three complexes was tested. Both normal and streptozotocin
(STZ)-diabetic mice were administered intragastrically for two weeks. It was found that the complexes at doses
of 10.0 and 5.0 mg V·kg−1 can significantly decrease the blood glucose level in STZ-diabetic mice, and the blood
glucose level in the treated normal mice was not altered. The lesions of kidney and liver caused by diabetes have
varying degrees of improvement.
Oxidovanadium complex
Aroylhydrazones
Crystal structure
Insulin-like activity
Hypoglycaemic
1. Introduction
complexes have been prepared and studied on their insulin-like activity
to both normal and streptozotocin (STZ)-diabetic mice.
Since 1980s, inorganic vanadium salts and vanadium complexes
with various ligands have been reported to possess potent pharmaco-
logical effects of insulin-like activity [1–4]. Studies indicated that va-
nadium compounds improve not only hyperglycemia in human subjects
and animal models of type I diabetes but also glucose homeostasis in
type II diabetes [5,6]. However, the inorganic vanadium salts are
considered as less active and more toxic. In order to reduce the side
effects of inorganic vanadium salts, vanadium complexes have received
particular attention and demonstrated to be effective [7–9]. Schiff bases
play important role in the development of coordination chemistry re-
lated to their biological properties. Several vanadium complexes de-
rived from Schiff bases have shown to normalize blood glucose level
with high efficiency and low toxicity, even at low concentrations
[10,11]. Schiff bases with hydrazone type are particular interesting due
to their biological properties [12–16]. In addition, vanadium complexes
with maltol ligands such as bis(maltolato)oxovanadium(IV) (BMOV)
and bis(ethylmaltolato)oxovanadium(IV) (BEOV) have been proved to
possess effective insulin enhancing activity [17–19]. In order to explore
novel material with effective insulin-like activity, Three oxidovanadium
2. Experimental
2.1. Materials and measurements
Starting materials, reagents and solvents were purchased from
commercial suppliers with AR grade, and used without purification.
The aroylhydrazones were prepared according to the literature method
[16]. Elemental analyses were performed on a Perkin-Elmer 240C ele-
mental analyzer. IR spectra were recorded on a Jasco FT/IR-4000
spectrometer as KBr pellets in the 4000–400 cm−1 region.
2.2. Synthesis of the complexes
2.2.1. Complex 1
Hydrazinium hydroxide (0.012 mol) were added to a ethanol solu-
tion (30 mL) of 3-methoxybenzoate (0.01 mol). After 10 h refluxing and
stirring, the 3-methoxybenzohydrazide were obtained by reducing
pressure distillation, filtering and recrystallizing. Mixing the 3-
⁎ Corresponding authors.
E-mail addresses: sgh76@126.com (G.-H. Sheng), youzhonglu@lnnu.edu.cn (Z.-L. You).
1 This author contributed equally to this work and should be considered co-first authors.
https://doi.org/10.1016/j.jinorgbio.2019.03.020
Received 10 October 2018; Received in revised form 21 March 2019; Accepted 27 March 2019
Availableonline29March2019
0162-0134/©2019ElsevierInc.Allrightsreserved.

Q.-C. Zhou, et al.
JournalofInorganicBiochemistry196(2019)110680
Scheme 1. Synthesis of complex 1.
methoxybenzohydrazide (1.0 mmol) and salicylaldehyde (1.0 mmol)
into the methanolic solution (20 mL) with stirring. After 30 min, the
ethyl maltol (1.0 mmol) and vanadyl acetylacetonate [VO(acac)2]
(1.0 mmol) were added to the solution with stirring and brown solution
were obtained (Schemes 1). The solution were left for 7 days at room
temperature, brown block shaped single crystals of the complex, which
are suitable for the structure determination, were got at the bottom of
the vessel because of the slow evaporation of the solvent. Yields: 63%.
Anal. Calc. for C22H19N2O6V (MW = 458.33): C, 57.60; H, 4.15; N,
6.11%.
2.2.3. Complex 3
Hydrazinium hydroxide (0.012 mol) were added to a ethanol solu-
tion (30 mL) of 3,5-dimethoxybenzoate (0.01 mol). After 10 h refluxing
and stirring, the 3,5-dimethoxybenzohydrazide were obtained by re-
ducing pressure distillation, filtering and recrystallizing. Mixing the
3,5-dimethoxybenzohydrazide (1.0 mmol) and 3-ethoxysalicylaldehyde
(1.0 mmol) into the methanolic solution (20 mL) with stirring. After
30 min, the ethyl maltol (1.0 mmol) and VO(acac)2 (1.0 mmol) were
added to the solution with stirring and brown solution were obtained
(Schemes 3). The solution were left for 7 days at room temperature,
brown block shaped single crystals of the complex, which are suitable
for the structure determination, were got at the bottom of the vessel
because of the slow evaporation of the solvent. Yields: 56%.
Anal. Calc. for C25H25N2O9V (MW = 548.41): C, 54.70; H, 4.56; N,
5.11%.
Found: C, 57.57; H, 4.15; N, 6.13%.
IR data (cm-1): 3433(w), 1603(s), 1549(s), 1520(m), 1469(w),
1444(m), 1373(w), 1337(s), 1278(m), 1258(s), 1223(w), 1192(m),
972(s), 908(w), 837(m), 812(w), 763(m), 728(m), 650(m), 632(w),
588(w), 525(w), 478(w).
1H NMR (300 MHz, DMSO) δ 9.18 (s, 1H,CH=N), 8.46 (d, 1H, ArH),
7.81 (d, 1H, ArH), 7.68–7.55 (m, 3H, ArH), 7.35 (t, 2H, ArH), 7.05 (t,
1H, ArH), 6.88 (d, 1H, ArH), 6.67 (d, 1H, ArH), 2.99 (q, 2H, CH2CH3),
2.34 (s, 3H, CH3), 1.30 (s, 3H, CH3).
Found: C, 54.72; H, 4.55; N, 5.10%.
IR data (cm−1): 3393(w), 1603(s), 1560(m), 1499(s), 1465(w),
1445(s), 1341(m), 1269(s), 1226(m), 1192(m), 1112(w), 1083(w),
1018(w), 976(s), 942(w), 899(w), 858(w), 831(w), 764(m), 738(m),
649(m), 618(w), 602(w), 535(w), 475(w).
1H NMR (300 MHz, DMSO) δ 9.21 (s, 1H,CH=N), 8.48 (d, 1H, ArH),
7.41 (d, 1H, ArH), 7.27 (t, 1H, ArH), 7.00 (m, 3H, ArH), 6.67 (m, 2H,
ArH), 4.07 (q, 2H, OCH2CH3), 3.80 (s, 6H, OCH3), 3.02 (q, 2H,
CH2CH3), 1.34–1.26 (m, 6H, CH3).
2.2.2. Complex 2
Hydrazinium hydroxide (0.012 mol) were added to a ethanol solu-
tion (30 mL) of 3,5-dimethoxybenzoate (0.01 mol). After 10 h refluxing
and stirring, the 3,5-dimethoxybenzohydrazide were obtained by re-
ducing pressure distillation, filtering and recrystallizing. Mixing the
2.3. X-ray crystallography
3,5-dimethoxybenzohydrazide
(1.0 mmol)
and
salicylaldehyde
(1.0 mmol) into the methanolic solution (20 mL) with stirring. After
30 min, the VO(acac)2 (1.0 mmol) were added to the solution with
stirring and brown solution were obtained (Schemes 2). The solution
were left for 7 days at room temperature, brown block shaped single
crystals of the complex, which are suitable for the structure determi-
nation, were got at the bottom of the vessel because of the slow eva-
poration of the solvent. Yields: 57%.
Diffraction intensities were collected at 298(2) K for complexes 1
and 3, 273(2) K for complex 2 using a Bruker SMART 1000 CCD area-
detector diffractometer with Mo-Kα radiation (λ = 0.71073 Å). The
collected data were reduced with SAINT [20], and multi-scan absorp-
tion correction was performed using SADABS [21]. Structures of the
complexes were solved by direct methods and refined against F2 by full-
matrix least-squares method using SHELXTL [22] and SHELXL-2017
[23]. All of the non‑hydrogen atoms were refined anisotropically. All
hydrogen atoms were placed in calculated positions and constrained to
ride on their parent atoms. Crystallographic data for the complexes are
summarized in Table 1. Selected bond lengths and angles are given in
Table 2.
Anal. Calc. for C18H21N2O7V (MW = 428.31): C, 50.43; H, 4.90; N,
6.53%.
Found: C, 50.44; H, 4.87; N, 6.50%.
IR data (cm−1): 3420(w), 1602(s), 1552(s), 1522(m), 1471(w),
1455(w), 1425(w), 1396(w), 1379(m), 1344(m), 1277(m), 1205(m),
1153(s), 1061(m), 1001(w), 975(m), 912(w), 884(m), 822(m), 780(m),
668(w), 640(w), 623(w), 585(w), 456(w).
2.4. Glucose-lowering assay
1H NMR (300 MHz, DMSO) δ 9.06 (s, 1H,CH=N), 7.79 (d, 1H, ArH),
7.58–7.50 (m, 2H, ArH), 7.17 (s, 2H, ArH), 7.09 (t, 1H, ArH), 6.68 (s,
1H, ArH), 5.28 (s, 1H, OH), 3.82 (s, 6H, OCH3), 3.73 (s, 3H, CH3), 3.17
(s, 3H, CH3).
The animal study was carried out according to the guidelines of
Animals Ethics Committee. Male Kunming mice, weighing about
25–30 g, were obtained from Experimental Animal Center, Shandong
Xinhua Pharmaceutical Co., Ltd. of China, and maintained on a light/
2

Q.-C. Zhou, et al.
JournalofInorganicBiochemistry196(2019)110680
Scheme 2. Synthesis of complex 2.
Scheme 3. Synthesis of complex 3.
Table 1
Crystal data for the complexes.
Parameter
1
2
3
Empirical formula
Formula weight
T (K)
C22 H19 N2 O6
458.33
V
C18 H21 N2 O7
428.31
V
C25 H25 N2 O9
548.41
V
298
273
298
Crystal system
Space group
a (Å)
Monoclinic
C2/c
Triclinic
P-1
Monoclinic
P21/n
29.241(3)
8.2507(9)
18.899(2)
112.178(3)
4222.2(8)
8
8.3863(14)
11.5351(19)
11.6142(17)
107.706(5)
945.6(3)
2
9.0130(5)
13.1683(8)
20.8106(12)
92.588(1)
2467.4(2)
4
b (Å)
c (Å)
β (°)
V (Å3)
Z
μ (mm−1
)
0.511
0.568
0.460
Dcalc (Mg m−3
F(000)
)
1.442
1.504
1.476
1888
444
1136
θ (°)
2.2–25.4
3841
2.2–25.4
4259
1.8–25.5
4574
Independent reflections
Data/restraints/parameters
Goodness-of-fit (GOF) on F2
Final R indices
3841/0/281
1.071
4259/1/260
1.036
4570/0/338
1.030
0.0524/0.1253
0.0764/0.1338
−0.27, 0.76
0.0416/0.1067
0.0567/0.1165
−0.23, 0.74
0.0325/0.0867
0.0400/0.0922
−0.320, 0.330
R indices (all data)
Largest difference peak and hole (e Å−3
)
3

Q.-C. Zhou, et al.
JournalofInorganicBiochemistry196(2019)110680
Table 2
Selected distances(Å) and angles(°) for the complexes.
1
V1-O1
1.842(3)
V1-O2
1.941(2)
V1-O3
2.247(3)
V1-O4
1.856(2)
V1-O6
1.583(2)
V1-N1
2.086(3)
O1-V1-O2
O1-V1-O4
O1-V1-N1
O2-V1-O4
O2-V1-N1
O3-V1-O6
O4-V1-O6
O6-V1-N1
152.71(11)
103.76(11)
83.46(12)
92.45(10)
75.10(11)
175.96(12)
98.17(11)
96.95(12)
O1-V1-O3
O1-V1-O6
O2-V1-O3
O2-V1-O6
O3-V1-O4
O3-V1-N1
O4-V1-N1
81.34(10)
100.54(13)
80.81(10)
98.67(12)
77.87(9)
86.80(10)
161.70(10)
2
V1-O1
1.8418(16)
1.7681(18)
2.1205(17)
103.96(7)
83.95(7)
V1-O2
1.9457(17)
1.5840(19)
151.78(7)
100.71(9)
91.06(7)
V1-O6
V1-O7
V1-N1
O1-V1-O2
O1-V1-O7
O2-V1-O6
O2-V1-N1
O6-V1-N1
O1-V1-O6
O1-V1-N1
O2-V1-O7
O6-V1-O7
O7-V1-N1
98.80(9)
74.14(6)
103.35(9)
95.15(8)
157.95(8)
3
Fig. 1. Molecular structure of 1, showing the atom-numbering scheme.
Displacement ellipsoids are drawn at the 30% probability level and H atoms are
shown as small spheres of arbitrary radii.
V1-O1
1.8414(13)
1.8650(13)
1.5895(13)
153.03(6)
83.97(6)
V1-O2
1.9302(14)
2.3034(14)
2.0875(15)
103.23(6)
99.11(7)
V1-O6
V1-O7
V1-O9
V1-N1
O1-V1-O2
O1-V1-O7
O1-V1-N1
O2-V1-O7
O2-V1-N1
O6-V1-O9
O7-V1-O9
O9-V1-N1
O1-V1-O6
O1-V1-O9
O2-V1-O6
O2-V1-O9
O6-V1-O7
O6-V1-N1
O7-V1-N1
83.85(6)
92.79(6)
78.66(5)
99.65(6)
74.67(6)
76.85(5)
98.96(6)
160.87(6)
86.39(6)
175.33(6)
97.39(6)
dark cycle. All animals were allowed free access to food and water.
Temperature and relative humidity were maintained at 24 °C and 50%.
Mice were acclimatized for seven 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 in-
duced by a single intra-peritoneal injection of freshly prepared strep-
tozotocin (100 mg/kg body weight) in 0.1 M citrate buffer. The control
mice were injected with an equal volume of citrate buffer. After seven
days, blood was collected from the tail vein and serum samples were
analyzed for blood glucose. Animals showing fasting (12 h) blood glu-
cose higher than 11.1 mM were considered to be diabetic and used for
the study.
Fig. 2. Molecular structure of 2, showing the atom-numbering scheme.
Displacement ellipsoids are drawn at the 30% probability level and H atoms are
shown as small spheres of arbitrary radii.
The experimental animals were randomly divided into 11 groups
with six mice each according to the blood glucose. Group 1, normal
control group: normal mice treated with 0.5% carboxymethyl cellulose
(CMC). Group 2–4, treated normal group: normal mice treated with
10 mg V·kg−1 vanadium complexes. Group 5, diabetic control group:
Streptozotocin diabetic mice treated with 0.5% CMC. Group 6–11,
treated diabetic group: STZ-diabetic mice treated with vanadium
complexes at dose of 10 and 5 mg V kg−1. The complexes were ad-
ministered as suspensions in 0.5% CMC. The substances were ad-
ministered intragastrically once a day at the volume of 10 mL·kg−1 for
two week.
3. Results and discussion
Three new oxidovanadium(V) complexes with complex 1: [VOL1X]
(H2L1 = C15H14N2O2 = (E)-N′-(2-hydroxybenzylidene)-3-methbenzohy-
drazide, HX = C7H10O3 = ethylmaltol = 2-ethyl-3-hydroxy-4-pyrone),
Complex 2: [VOL2(CH3O)(CH3OH)], (H2L2 = C16H16N2O4 = (E)-
N′-(2-hydroxybenzylidene)-3,5-dimethoxybenzohydrazide, CH3OH =
methanol), Complex 3: [VOL3X] (H2L3 = C18H20N2O5 = (E)-N′-(3-
ethoxy-2-hydroxybenzylidene)-3,5-dimethoxybenzohydrazide) It should
be pointed out that the vanadium in the starting materials is in V(IV)
oxidation state, but it appears to be V(V) in the complexes, indicating
that it was oxidized by air during the reaction procedures. From the X-
ray analysis, it can be seen that the five negative charges come from the
hydrazone ligand (−2), the oxo group (−2), and the secondary ligands
(−1), viz. ethylmaltolate for 1 and 3, and methoxide for 2. Crystals of the
complexes are stable in open air at room temperature. Elemental
Throughout the experimental period of 3 weeks, the body weight
and blood glucose level were monitored weekly, blood samples were
obtained from the tail vein of the mice and blood glucose levels were
determined with an Accu-Chek blood glucose monitor (Roche
Diagnostics GmbH, Mannheim, Germany.
4

Q.-C. Zhou, et al.
JournalofInorganicBiochemistry196(2019)110680
effect at doses of 10.0 and 5.0 mg V·kg−1, can significantly decrease the
blood glucose level of STZ-diabetic mice, but the blood glucose level in
the treated normal mice (10.0 mg V·kg−1 ig for two weeks) was not
altered as compared with the untreated normal mice (P > 0.05). After
one-week administration with the complex 1 or two-week administra-
tion with the complex 3 (10.0 mg V·kg−1), the blood glucose level of
treated diabetic group was decreased compared with the diabetic con-
trol group (P < 0.05). Compared with complex 2, complex 1 and
complex 3 had a quicker effect of glucose-lowering, but when the
treatment was stopped, the blood glucose level had a slight increase.
Complex 2 have a slower effect but its durability is better. One week
after the administration (10.0 mg V·kg−1) was stopped, complex 1 and
2 still exhibit excellent insulin-like activity, P < 0.05 vs STZ-diabetic
group, P > 0.05 vs normal group, that means the blood glucose of the
treated groups have return to normal blood-glucose levels. During the
experiment, no mice died, the complex did not exhibited toxicity to the
mice at dose of 10.0 mg V·kg−1
.
Fig. 3. Molecular structure of 3, showing the atom-numbering scheme.
Displacement ellipsoids are drawn at the 30% probability level and H atoms are
shown as small spheres of arbitrary radii.
Effects of the vanadium complexes on body weight was shown in
Table 4, the untreated normal mice gained weight over the three weeks,
the body weight reach 39.7 g after 3 weeks, the body weight of STZ-
diabetic group dropped from 27.8 g to 23.5 g during the 3 weeks. The
treated group complex 1 (10 and 5 10.0 mg V·kg−1), complex 2
(10.0 mg V·kg−1) and complex 3 (10 mg V·kg−1) gained weight, the
increase was smaller than the untreated normal group, the body weight
was 30.3–33.2 g after 3 weeks. It can be seen that the complex have
positive effect on gaining body weight.
analyses are in good agreement with the chemical formulae proposed for
the compounds.
3.1. Structure description of the complexes
Figs. 1–3 give perspective view of complex 1–3, respectively, to-
gether with the atomic labeling system. All of the V atoms in the
complexes are in octahedral coordination.
3.3. Biochemical indexes and organs
Complex 1 coordinate with two O atoms and one N atom from the
(E)-N′-(2-hydroxybenzylidene)-3-methbenzohydrazide ligand, two O
atoms from ethylmaltol ligand, and one O atom from the oxo group.
Complex 2 coordinate with two O atoms and one N atom from the (E)-
N′-(2-hydroxybenzylidene)-3,5-dimethoxybenzohydrazide ligand, two
O atoms from two methanol moleculars, and one O atom from the oxo
group. Complex 3 coordinate with two O atoms and one N atom from
Liver is an important organ for sugar metabolism in human body,
and diabetes can cause liver damage. The ratio of glutamic-oxaloacetic
transa minase (GOT) to glutamic pyruvic transaminase (GPT) increases
when liver was damaged. The blood biochemical index value were
measured (Table 5). We can find that the ratio of the model group GOT/
GPT is 60.4/116.9. After the treatment, the ratio of GOT/GPT in each
group has decreased in varying degrees, proving that the degree of liver
damage is decreased. The three complexes have a certain degree of
protection to the liver, and can reduce the liver damage caused by
diabetes.
the
(E)-N′-(3-ethoxy-2-hydroxybenzylidene)-3,5-dimethoxybenzohy-
drazide ligand, two O atoms from ethylmaltol ligand, and one O atom
from the oxo group.
Total cholesterol and triglycerides are important indicators to blood
health. With the increase of total cholesterol and triglyceride levels, the
probability of form thrombosis will rise. According to the data in
Table 5, the three complexes can effectively reduce triglyceride content
but have no obvious effect on total cholesterol content.
3.2. Effects of complex on blood glucose and body weight
The complexes were administered intragastrically to both treated
normal and treated STZ-diabetic group for two weeks. The results
(Table 3) showed that all the complexes had blood glucose-lowering
Impaired renal function is another complication of diabetes. When
Table 3
Effects of the vanadium complexes on blood glucose levels in both normal and diabetic mices.
Group
Dose
Blood glucose (mM)
(mgV·kg−1
)
0 week
1st week
2nd week
3rd week
Normal mices
Normal mices A10
Normal mices B10
Normal mices C10
STZ mices
CMC
10
10
10
CMC
10
5
6.6
6.8
0.7
6.9
6.5
1.1
6.4
7.1
0.5
7.0
6.9
0.6
0.9
1.7
0.7
3.4a
0.3
1.3
0.5
6.4
1.0
6.4
0.3
6.8
1.7
6.4
6.0
1.1
5.9
0.6
6.3
1.4
6.1
12.3
0.7a
12.6
7.90
7.40
10.68
16.60
9.15
10.86
0.9a
14.1
6.83
6.67
8.58
14.15
7.25
9.20
1.7a
14.7
STZ mices A10
STZ mices A5
STZ mices B10
STZ mices B5
12.60
12.27
11.60
16.95
13.03
13.83
1.37a
1.00a
0.51a
3.75a,b
0.94a
1.68a
0.45b
0.30b
1.21a
2.29a,b
0.58a
1.3a
0.62b
0.93b
2.04
1.95a
0.53b
1.67a
7.40
8.37
0.42b
1.20
10
5
7.23
2.19b
3.85a
0.45
11.88
8.50
STZ mices C10
STZ mices C5
10
5
10.63
1.85a
Data were expressed as mean
standard deviations for six mices in each group.
A = complex 1, B = complex 2, C = complex 3.
a
P < 0.05 vs. normal mices.
b
P < 0.05 vs. STZ-diabetic mices (Dunnett's test).
5

Q.-C. Zhou, et al.
JournalofInorganicBiochemistry196(2019)110680
Table 4
Effects of the vanadium complexes on body weight.
Group
Dose
Body weight (g)
0 week
(mgV·kg−1
)
1st week
2nd week
3rd week
Normal mices
STZ mices
CMC
CMC
10
5
26.4 + 1.5
27.8 + 2.0
25.4 + 1.9
26.2 + 1.8
27.3 + 2.0
26.2 + 1.4
25.6 + 1.9
26.8 + 1.8
31.4 + 1.2
26.5 + 1.7
25.1 + 2.2
25.9 + 2.2
27 + 1.2
35.4 + 1.2
25.5 + 2.2
28.5 + 2.1
27.4 + 1.6
28.6 + 1.9
25.0 + 1.5
28.2 + 2.5
27.1 + 1.1
39.7 + 1.3
23.5 + 1.3
33.2 + 1.8
31.3 + 1.4
31.2 + 1.3
25.4 + 1.0
30.3 + 1.2
26.2 + 1.2
STZ mices A10
STZ mices A5
STZ mices B10
STZ mices B5
STZ mices C10
STZ mices C5
10
5
25.5 + 1.2
25.1 + 2.1
25.6 + 1.8
10
5
Table 5
weight and liver weight/body weight is the lowest in the normal group
and the highest in the model group, and the ratio of complex groups
have varying degrees of decrease after the treatment compared to the
model group. It is concluded that the three vanadium complexes play
an important role in maintaining normal kidney weight/body weight
and liver weight/body weight ratio in mice, and the complexes have
protective effects on the lesions of kidney and liver caused by diabetes.
The photographs of mice kidneys and livers were taken. For kidneys
(Fig. 4), there is no obvious difference between the normal group, the
complex group and the model group in appearance. The liver (Fig. 5) of
the normal group is healthy. In the model group, there are many big
transparent vesicles on the surface of liver. With the deterioration of the
situation, it may cause the unknown liver disease. After treatment, the
liver of complex groups shows a relatively healthy state with only a few
small white granular matter on the surface. The photographs provided
the evidence of protective effects of complexes on the lesions liver
caused by diabetes.
Blood biochemical index value.
Index
Abbreviation Unit Value
A10
B10
C10
Model
Glutamic-pyruvic
transaminase
GPT/ALT
GOT/AST
U/L 83.30 143.50 150.10 116.90
Glutamic-oxaloacetic
transaminase
U/L 21.20
34.00
46.00
60.40
Triglyceride
TG
mM
mM
mM
1.56
2.32
7.04
1.57
3.07
7.75
2.03
2.97
2.35
2.48
Total cholesterol
Blood urea nitrogen
TCHO
BUN
12.04
15.51
A = complex 1, B = complex 2, C = complex 3.
Table 6
Liver, kidney and body weight of each group.
Group
Liver (mg)
Kidney (mg)
Body weight (g)
The liver biopsy was carried out (Fig. 6). The gap between the liver
cells of the normal mice was obvious, and the color was brighter than
model group. The liver cell gap of model group was not obvious, and
the color was slightly dark red. These two kinds of situation were not
obvious for complex groups. However, the subtle changes in the gap
and color of liver cells do not confirm whether the liver cells are dis-
eased or not.
A10
A5
2100.3
2403.2
1913.4
2660.6
2486.1
2526.6
1749.1
2847.3
683.7
600.2
614.6
697.8
615.6
665.6
578.8
699.8
33.2
31.3
31.2
25.4
30.3
26.2
39.7
23.5
B10
B5
C10
C5
Normal
Model
4. Conclusion
A = complex 1, B = complex 2, C = complex 3.
The present study reports synthesis, crystal structures and insulin-
like activity of three new oxidovanadium(V) complexes. The complexes
have fine insulin-like activity on streptozotocin diabetic mice. Complex
1 and complex 3 had a quicker effect of glucose-lowering, complex 2
have a slower effect but its durability is better. One week after the
administration (10.0 mg V·kg−1) was stopped, complex 1 and 2 still
exhibit excellent insulin-like activity, the blood glucose of the treated
groups have return to normal blood-glucose levels. The complexes have
the renal function is impaired, the glomerular filtration rate will de-
crease, thus increasing the blood urea nitrogen content. It is known
from the Table 5 that all the three complexes can reduce the blood urea
nitrogen content in the blood of diabetic mice to varying degrees, and
prove that the complexes have certain protective effect on kidney da-
mage caused by diabetes in mice.
From the data in Table 6, it is found that the kidney weight/body
Fig. 4. Mice kidney.
a: The kidney of normal group, b: The kidney of complex group, c: The kidney of model group.
6

Q.-C. Zhou, et al.
JournalofInorganicBiochemistry196(2019)110680
Fig. 5. Mice liver.
a: The liver of normal group, b: The liver of complex group, c: The liver of model group.
Fig. 6. Mice liver biopsy (400×).
a: The liver biopsy of normal group, b: The liver biopsy of complex group, c: The liver biopsy of model group.
protective effects on the lesions of kidney and liver caused by diabetes.
Various mechanisms of action have been implicated in the anti-
diabetic effects of V.
Conflicts of interest
There is no interest conflict in this paper.
The most widely accepted mode of action for V compounds thus far
is attributed to the inhibition of protein tyrosine phosphatases, some V
compounds are reversible inhibitors, whereas others are irreversible by
modifying the protein through redox processes [24]. Vanadium com-
pounds exert antidiabetic effects both on glucose and lipidmetabolism,
they can attenuate basal lipolysis in adipocytes, AKT pathway activa-
tion contributes to the antilipolytic effect of vanadium compounds [25].
Some vanadium compound show antitumor activity through triggering
a decrease of in situ AKT1 expression in cell [26].
Appendix A. Supplementary data
CCDC 1854600, 1,500,374 and 1,854,603 contains the supple-
mentary crystallographic data for complexes 1–3. These data can be
obtained free of charge from The Director, CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: (+44) 1223–336,033; e-mail: deposit@
ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk). Supplementary data to
this article can be found online at doi: https://doi.org/10.1016/j.
jinorgbio.2019.03.020.
Abbreviations
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