Characterization and insulin-mimetic potential of oxidovanadium(IV) complexes derived from monoesters and -carboxylates of 2,5-dipicolinic acid

Article abstract of DOI:10.1002/ejic.200600130

The monomethyl ester 2MeOdipicH (1) of 2,5-dipicolinic acid, characterized as its magnesium salt [Mg(H₂O)₆]-(2MeOdipic)₂, was converted, via the diesters 2MeO-5ROdipic and the copper complexes [Cu(5ROdipic)₂], t

Full text of DOI:10.1002/ejic.200600130

FULL PAPER
DOI: 10.1002/ejic.200600130
Characterization and Insulin-Mimetic Potential of Oxidovanadium(IV)
Complexes Derived from Monoesters and -carboxylates of 2,5-Dipicolinic Acid
Jessica Gätjens,*[a][‡] Beate Meier[b] Yusuke Adachi,[c] Hiromu Sakurai,[c] and
Dieter Rehder[a]
Keywords: Vanadium / N,O Ligands / Picolinates / Insulin mimesis
The monomethyl ester 2MeOdipicH (1) of 2,5-dipicolinic
acid, characterized as its magnesium salt [Mg(H2O)6]-
(2MeOdipic)2, was converted, via the diesters 2MeO-
5ROdipic and the copper complexes [Cu(5ROdipic)2], to the
ligands 5ROdipicH (R = iPr 2a, (S)-2-Bu 2b). The proligands
[Mg(H2O)6](2MeOdipic)2·4H2O, 2b, 3a and 4a·0.5H2O were
characterized by single-crystal X-ray diffraction analysis. Se-
lected type 4 and 5 complexes were submitted to in vitro tests
(fibroblasts, SV 3T3 mice fibroblasts) for their uptake kinetics
and insulin-mimetic behavior. The compounds were compar-
able to insulin in their ability to stimulate cellular glucose
uptake and metabolism. In vitro tests with rat adipocytes
showed that the complexes also mimic the ability of insulin
to inhibit lipolysis.
2MeO-5ROdipic (with R = diisopropyl-
inositol-orthoformate 2d) and 2MeO-5RЈNHdipic (where RЈ
represents the ethyl-protected -amino acid residues Gly 3a,
D-galactose 2c, myo-
L
Ala 3b, Val 3c and Phe 3d) were obtained from 2-MeO-
5Cldipic and the amino acid ethyl esters. Reaction of 2 and
3 with VOSO4 afforded the complexes [VO(H2O)(5ROdipic)2] (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
(4a–d) and [VO(H2O)(5RЈNHdipic)2], 5a–d, respectively.
Germany, 2006)
of 2,5-dipicolinate, is clearly more effective than the corre-
sponding ethyl ester both in the ability to trigger cellular
glucose uptake (and metabolism) and to inhibit lipolysis.[8]
These differences in impact correlate with the net amount
of vanadium taken up by the cells, possibly indicative for a
balanced hydro/lipophilicity being a key factor in efficacy.
An apparent advantage of vanadium complexes in the
treatment of diabetes mellitus type 1 (lacking insulin pro-
duction) and type 2 (tolerance/resistance against insulin) is
their application per os, and the possibility to design the
compounds so as to provide minimal toxicity and optimal
efficiency along with stability against redox- and hydrolytic
break-down. The compound has to survive the acidic con-
ditions pertinent to the stomach (pH typically around 2), as
well as the slightly alkaline conditions in the small intestines
(pH7–8) and the blood stream (pH7.35). It has to resist
to a certain extent competing ligands such as the plasma
constituents citrate, phosphate and transferrin in order to
preserve the information implanted by the specific proper-
ties of the ligands used in the synthesis of the potential
drug. The complex should be easily absorbed in the gastro-
intestinal tract, transported by the blood stream at least
partly intact, and traffic across the cell membrane. Oxidova-
nadium complexes carrying monoesters of 2,5-dipicolinic
acid as ligands have been shown to fulfil several of these
conditions.[8] Picolinates are natural metabolites; toxicity by
degradation of the complexes thus will be minimized. In
order to improve the trans-membrane transport, a fine-tun-
ing of the hydro/lipophilicity by choosing the “correct” sub-
Introduction
During the last two decades, in vitro and in vivo studies
have demonstrated the potential of many vanadium
compounds as insulin-mimetic (or insulin-enhancing)
agents.[1–3] Among those which have been shown to be ef-
fective are bis(maltolato)oxidovanadium complexes,[4a]
which successfully passed clinical tests phase I,[4b] [VO-
(pic)2] which normalizes serum glucose and fatty acid levels
in rats with streptozotozin-induced diabetes type 1,[5] and
[VO2(H2O)(2,6-dipic)]–, which had beneficial effects in cats
suffering from diabetes type 2.[6] Picolinato complexes of
vanadium appear to be generally effective,[7] the extent,
however, to which they actually mimic the involvement of
insulin in the glucose and lipid metabolisms is subject to
variations in the coordination periphery. We have recently
shown that the methyl ester derivative [VO(H2O)-
(5MeOdipic)2], where 5MeOdipic is the monomethyl ester
[a] Institute of Inorganic and Applied Chemistry, University of
Hamburg,
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
E-Mail: jgaetjens@yahoo.de
dieter.rehder@chemie.uni-hamburg.de
[b] bcm-research,
Entrischenbrunn 12, 85307 Entrischenbrunn, Germany
[c] Department of Analytical and Bioinorganic Chemistry, Kyoto
Pharmaceutical University,
Kyoto, 607-8414, Japan
[‡] Present address: Department of Chemistry, University of
Michigan,
930 N. University Ave., Ann Arbor, MI 48109, USA,
Fax: +1-734-936-7628
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Scheme 1.
stituents in the ligand periphery is one option. A second were converted via the copper complexes [Cu(5ROdipic)2]
option is to attach groups to the periphery for which mem- into the acids 5ROdipicH, 2a–b. For the structure of the
brane receptors exist and which can thus be recognized by anion of 1, 1H–1, see below.
the cell. Following these concepts, we have extended earlier
Single crystals of 2b were grown from aqueous acetone
investigations on picolinates to galactose and inositol deriv- solution. 2b crystallizes in the monoclinic space group P21.
atives on the one hand, and carboxamides derived from Bond lengths and angles are in the expected range (Table 1).
amino acids on the other hand. Scheme 1 gives an overview The molecular structure and a picture showing the hydro-
of the types of compounds discussed in the present work. gen-bonding network are displayed in Figure 1. The mole-
Along with the vanadium complexes and their in vitro insu- cules are linked through OH···N hydrogen bonds, compar-
lin-mimetic properties, structural features of ligands and li- able to the features exhibited by other members of this fam-
gand precursors will be described.
ily of dipicolinic acid derivatives.[8]
The proligands 2c–d were synthesized in analogy to the
ligands 2a–b, with the modification that equimolar amounts
of acyl chloride and alcohol were reacted. The deprotection
step via the copper complexes was omitted. The cleavage of
the methyl ester group occurred in situ under the conditions
chosen for the synthesis of the vanadium complexes and
concomitantly with the coordination of the carboxylate
function to vanadium.
For the syntheses of the amino acid derivatives 3a–d, cf.
Scheme 2, a solution of the acyl chloride in dichlorometh-
ane was treated with a solution containing the amino acid
ethyl ester hydrochloride and triethylamine in CH2Cl2,
Results and Discussion
Synthesis, Characterization and Structure Determination
The syntheses of the ligands 2a–b followed the route de-
picted in Scheme 2. 6-(Methoxycarbonyl)pyridine-3-car-
boxylic acid (1) was converted into the corresponding acyl
chloride by reaction with thionyl chloride. Addition of a
solution of the acid chloride in toluene to a solution of the
alcohol ROH (R = iPr, (S)-sBu, in 1.4 fold excess) in pyri-
dine yielded the mixed diesters 2MeO-5ROdipic, which
Scheme 2.
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Table 1. Selected bond lengths [Å] and angles [°] for [Mg(H2O)6](1H–1)2·4H2O, 2b and 3a.
[Mg(H2O)6](1H–1)2·4H2O
2b
3a
C1–O1
C2–O1
C2–O2
C2–C3
C6–C8
C8–O3
C8–O4
C1–O1–C2
O1–C2–O2
O3–C8–O4
1.4516(13)
C1–C2
C1–O1
C1–O2
C5–C7
C7–O3
C7–O4
C8–O4
O1–C1–O2
O3–C7–O4
1.499(4)
1.323(4)
1.197(4)
1.492(4)
1.198(4)
1.340(4)
1.479(4)
125.5(3)
124.91(10)
C1–O1
C2–O1
C2–C3
C6–C8
C8–N2
C8–O3
C9–N2
1.458(2)
1.328(2)
1.504(3)
1.503(2)
1.337(2)
1.227(2)
1.442(2)
1.3251(14)
1.2080(13)
1.4960(14)
1.5083(13)
1.2716(13)
1.2390(13)
116.05(9)
O1–C2–O2
O3–C8–N2
124.31(18)
122.13(17)
124.91(10)
125.91(10)
which led to the formation of the desired products in good
yields. The compounds were characterized by the standard
spectroscopic and spectrometric methods. In the case of the
glycine ethyl ester derivative 3a, colorless single crystals
were grown from dichloromethane/hexane at room tem-
perature. 3a crystallizes in the monoclinic space group P21/
c. The molecular structure is shown in Figure 2. Bond
lengths and angles are in the expected range (Table 1).
The magnesium salt of 1, [Mg(H2O)6](1H–1)2·4H2O, was
isolated in low yields as a by-product of the synthesis of the
amino acid derivatives and characterized by IR and 1H
NMR spectroscopy. The magnesium apparently stemmed
from MgSO4 employed as a drying agent for the solvents.
Single crystals grew from a methanolic solution by slow
evaporation of the solvent. The compound crystallizes in
the monoclinic space group P21/c with two independent
molecules in the asymmetric unit. The magnesium cation is
octahedrally coordinated by six water ligands. The molecu-
lar structure is depicted in Figure 3, bonding parameters
are contained in Table 2. There are hydrogen bonds between
the waters of crystallization O8 and O9 (2.74 Å), O8 and
the pyridine-N (2.83 Å), and O9 and water coordinated to
Mg2+ (2.79 Å).
Following a procedure described previously,[8] the vana-
dium(IV) complexes 4a–b were isolated from the reaction of
vanadyl sulfate and the acids 2a–b as green microcrystalline
powders. Green single crystals of compound 4a·0.5H2O
were obtained from a hot aqueous solution on slow cooling.
Figure 1. Top: XSHELL plot of 2b (50% probability level). Bot-
tom: Hydrogen bonding network for 2b (Mercury, vers. 1.1).
Figure 2. XSHELL plot of 3a (50% probability level).
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Figure 3. XSHELL plot of [Mg(H2O)6](1H–1)2·4H2O (50% probability level). Only one of the anions 1H–1 and two of the waters of
crystallization are shown.
Table 2. Crystal data and structure refinement for (1H–1)2, 2b, 3a, 4a.
[Mg(H2O)6](2-MeOdipic)2
2b
3a
4a·0.5H2O
Emperical formula
M [gmol–1]
Crystal system
Space group
Cell dimensions
a [Å]
b [Å]
c [Å]
α [°]
β [°]
C16H32MgN2O18
564.75
monoclinic
P2(1)/c
C11H13NO4
223.23
monoclinic
P2(1)
C12H14N2O5
266.25
monoclinic
P2(1)/c
C20H23N2O10.5
510.35
V
triclinic
¯
P1
13.7795(7)
7.5126(4)
13.8657(8)
90
117.2500(10)
90
1276.07(12)/2
1.470
0.156
4.4079(15)
9.434(3)
13.354(4)
90
91.478(6)
90
555.1(3)/2
1.335
0.102
13.0421(17)
6.8948(9)
15.465(2)
90
112.338(2)
90
1286.3(3)/4
1.375
0.108
10.9185(5)
13.4119(5)
17.6792(8)
69.6350(10)
78.2570(10)
77.8200(10)
2348.42(17)/4
1.440
γ [°]
V [Å3]/Z
ρ(calcd.) [g cm–3]
µ [mm–1]
0.481
F(000)
596
236
560
996
Crystal size [mm]
θ range [°]
Index ranges
0.41×0.34×0.10
2.94–32.50
–20ϽhϽ20,
–11ϽkϽ11,
–20ϽlϽ20
33675
0.55×0.26×0.07
2.64–27.49
–5ϽhϽ5,
–12ϽkϽ12,
–16ϽlϽ16
6338
0.65×0.10×0.07
1.69–27.49
–16ϽhϽ16,
–8ϽkϽ8,
–19ϽlϽ19
14783
0.50×0.250×0.10
2.14–29.00
–14ϽhϽ14,
–18ϽkϽ18,
–24ϽlϽ24
57316
Reflections collected
Independent reflections (Rint
Restraints/parameters
GooF on F2
)
4587 (0.0457)
15/200
1.004
0.0414/0.0985
0.0582/0.1050
0.555/–0.259
1328 (0.0746)
1/148
0.928
0.0473/0.0871
0.0694/0.0932
0.225/–0.184
2916 (0.0460)
0/175
1.055
0.0464/0.0942
0.0765/0.1200
0.518/–0.430
12361 (0.0478)
13/661
0.969
0.0470/0.1208
0.0748/0.1348
1.099/–0.521
Final R (I Ͼ 2σI0), R1/wR2
R indices (all data), R1/wR2
Largest diff. peak and hole [e·Å–3]
¯
The compound crystallizes in the monoclinic space group P1 with two independent molecules and one water of
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Figure 4. XSHELL plot of 4a (50% probability level). Only one of the two independent molecules, containing one of the iPr substituents
in a disordered state, is shown. Water of crystallization omitted. Selected bonding parameters: V1–O1 1.5989(14), V1–O2 2.0175(14), V1–
O3 1.1290(15), V1–O7 1.9890(15), V1–N1 2.1503(17), V1–N2 2.1072(16) Å; O1–V1–O3 164.55(7), O2–V1–N2 164.62(7), O7–V1–N1
161.62(6)°.
crystallization, disordered over two positions, in the asym- formazan blue is determined photometrically and correlates
metric unit. Two ligands coordinate in the expected biden- with the ability of either insulin or the vanadium compound
tate manner to form, together with an aqua ligand (O2) in to stimulate cellular glucose uptake and metabolism by the
the equatorial plane and an oxo ligand (O1) in the apical cells. The cells were grown to sub-confluency, and incubated
position, a distorted octahedron, Figure 4. The oxygen O3 in insulin-free medium for 24 h in order to minimize effects
of one of the carboxylato groups occupies the axial position other than those imparted by the vanadium compound.
trans to the oxo ligand, leading to the rather long V1–O3 This procedure was followed by 3 h incubation with the me-
distance 2.1290(15) Å due to the trans influence of the dou- dium supplemented with the vanadium compound. This
bly bonded oxygen. The isopropyl group of one of the li- modified MTT test has previously been verified using -
gands is disordered over two positions (1:1) in one of the [C6–3H]glucose.[16] In order to determine the time depend-
two independent molecules. The bonding parameters for ent effect, a sample was taken every 15–30 minutes. Com-
the coordinated ligand anion are the same within the error pounds included in this study are 4c, 5a, 5c, 5d, VOSO4,
limits as in the free ligand 2a (Table 1). The water of and [VO(5MeOdipic)2], the insulin-mimetic activity of
crystallization is in hydrogen-bonding contact with the car- which has been established earlier, and which proved most
boxylate oxygens O4 (2.79 Å) and O3 (2.83 Å).
effective among the alkyl derivatives [VO(5ROdipic)2].[8]
For the synthesis of the vanadium(IV) complexes 4c–d The amino acid derivative with alanine, 5b, displayed a be-
and 5a–d, an aqueous solution of vanadylsulfate was mixed havior similar to the glycine derivative 5a.
with a solution of the proligand and sodium acetate in
THF/water and heated to reflux for 6 h. Under these condi-
tions, the deprotection of the 2-position of the ligand pre-
cursor and the subsequent formation of the desired vana-
dium complex took place. The resulting dark green solution
was evaporated to dryness. Recrystallization from THF
yielded complexes 4c–d and 5a–d as green solids. All analy-
ses confirmed the coordination of two ligand molecules to
the metal center plus a solvent molecule, commonly water;
cf. Scheme 1 and 4a in Figure 4.
Figure 5 shows the absorbance for different concentra-
tions of the vanadium compounds relative to a control
group (without vanadium or insulin), and cells incubated
with insulin instead of the vanadium compound. The data
after 60 minutes incubation time are shown. During this
time, about 90% of the overall effect is observed (see be-
low). Except for the glycine derivative 5a, all compounds
exhibit insulin-mimetic properties in the concentration
range (1 µ Յ c Յ 200 µ) tested. The most promising re-
sults are those for the phenylalanine derivative 5d, showing
comparable stimulation of glucose uptake and metabolism
as insulin. Particularly noteworthy is the fact that even at
rather low concentrations (c Ͻ 10 µ) the vanadium com-
plexes are still active (Figure 5).
Insulin-Mimetic Tests
The biological tests with regard to glucose uptake and
metabolism were carried out with a modified (see below)
The time-dependent effect of compounds 4c and 5a, [VO-
MTT reduction assay using Simian virus transformed mice (5MeOdipic)2] and [VO(pic)2] is shown in Figure 6. At an
fibroblasts as described earlier.[16] In this assay, yellow solu- intermediate vanadium concentration of c = 40 µ the
ble MTT is reduced to insoluble formazan blue by re- maximum level of activity is reached after an incubation
duction equivalents generated by the metabolism of glucose time of approximately 90 minutes. Similar results have been
by the mitochondrial respiratory chain. The amount of found for other concentrations and other complexes. The
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Figure 5. Glucose uptake stimulated by the vanadium picolinates 4c, 5a, 5c and 5d after 60 min. The absorbance, shown relative to a
control group, reflects the efficacy of the compounds. The diagram also shows the data for [VO(5MeOdipic)2], VOSO4, and a group of
cells where insulin was added instead of vanadium.
time dependence in activity for the compounds apparently
Testing of compounds 4c and 5a–c with respect to their
is not as significant as one might expect when considering ability to inhibit lipolysis in rat adipocytes required the
the differences in the ligand spheres. Further, Figure 6 presence of 1 m ascorbic acid as a reducing agent. In the
clearly shows that the galactose derivative 4c exhibits, at absence of ascorbic acid, aerial oxidation (51V NMR evi-
this specific concentration, an insulin-mimetic activity com- dence) in the Krebs–Ringer buffer to species of low activity
parable to the well established efficiency of [VO(pic)2][5] and occurred. Figure 8 shows the effects on the release of free
[VO(5MeOdipic)2].[8] The time dependent insulin-mimetic fatty acids (FFA) by [VIVO(pic)2], the four vanadium(IV)
effect of 4c at different concentrations reveals that the maxi- complexes 4c and 5a–c, and the two dioxidovanadium(V)
mum level of activity at high concentrations (c = 400 µ complexes K[VO2(pic)2] and K[VO2(2,5dipic)2]. All of the
and 200 µ) is already reached after an incubation time of compounds show an inhibitory effect with respect to the
approx. 45 minutes, cf. Figure 7. In this respect, 4c is control C (epinephrine [= adrenalin], which works as an
unique, since all of the other compounds considered in this effective antagonist to insulin), an effect which increases as
study displayed the highest activity after 60 to 90 minutes, concentration is increased from 0.1 to 1 m. The results
even at high concentrations (not shown). Furthermore, the obtained with insulin (B in Figure 8) are not quite reached.
effect promoted by 4c at c = 400 µ and 200 µ is signifi- There is no sizeable difference in efficiency between the neu-
cantly higher than the activity of insulin itself.
tral oxidovanadium(IV) and the anionic dioxidovanadi-
Figure 6. Glucose uptake stimulated by 4c and 5a (c = 40 µ) presented as a function of time. This diagram also includes the results for
[VO(pic)2], [VO(5MeOdipic)2] and insulin. Data are not corrected for background.
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Figure 7. Glucose uptake stimulated by the galactosyl derivative 4c as a function of time over a wide concentration range. Data are not
corrected for background.
Figure 8. Inhibitory effects of vanadium complexes on FFA-release from rat adipocytes treated with epinephrine. Data are expressed as
the means SDs for three experiments. B: adipocytes treated with insulin. C: adipocytes pre-incubated with saline for 30 min before
treatment with 10 µ epinephrine for 3 h.
um(V) compounds, nor between the different picolinate de- plexes. Here, we have employed amino acids, galactose and
rivatives. The ligands themselves did not show any appreci- inositol residues, along with alkyl derivatives for compari-
able activity (data not shown).
son. Selected compounds were subjected to in vitro studies
of their ability to stimulate glucose uptake and oxidative
degradation by modified fibroblasts on the one hand, and
to inhibit lipolysis by adipocytes on the other hand. Except
for the glycine and -alanine derivatives, all compounds
were effective insulin-mimetics in the glucose uptake experi-
ments in the concentration range 200 to 1 µ. The galactose
containing complex initiated an earlier saturation of glucose
uptake in the time-dependent studies than other com-
pounds, which can be interpreted in terms of a faster uptake
of the galactosyl complex by the cells. All of the complexes
also showed insulin-mimetic activity in the inhibition of li-
Conclusions
In extension of earlier work,[8] we have introduced here
a new concept for the design of potentially insulin-mimetic
vanadium(IV) compounds. The framework represented by
pyridine-2,5-dicarboxylic acid was extended by introducing,
into the 5-position, organic molecules into the ligand sphere
for which membrane receptors exist and/or which modify
the hydro/lipophilicity of the dipicolinatovanadium com-
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ferent concentrations were added to the cells and incubated for up
to 3 h at 37 °C in a 5% CO2 atmosphere. The cells were separated
from the medium and the reaction was stopped by addition of 0.1 
HCl in 2-propanol. The insoluble dye was extracted by HCl/2-pro-
panol, and the amount of formazan blue formed by reduction of
MTT was measured at 570 nm in a multi-well reader (SLT 340
ATC). All measurements were carried out in triplicate; standard
deviations for the absorbances typically amount to 4 2%.
polysis, in particular at relatively high concentrations of
1 m.
Experimental Section
General and Chemicals: All preparations of vanadium complexes in
the oxidation state +IV were carried out under nitrogen atmo-
sphere, using Schlenk techniques. For further handling of the com-
plexes, Schlenk techniques were dispensable. Chemicals were ob-
tained from Merck, Aldrich and Fluka and used without further
purification unless stated otherwise. Solvents were dried and puri-
fied by standard procedures. Tetrahydrofuran (THF) was dried and
deoxygenated by refluxing for at least three hours over LiAlH4 and
distilled in an N2 stream. Triethylamine was distilled (88–90 °C)
and stored over molecular sieves (4 Å). Dichloromethane was re-
fluxed for 24 h over calcium hydride. Toluene was refluxed for 24 h
over sodium and then distilled in an N2 stream. Pyridine (H2O
Յ 0.005%) was stored over molecular sieve. Deionized water was
degassed before use. Products were dried at room temperature un-
der vacuum and stored under N2. The following compounds were
prepared according to published procedures: 6-(methoxycarbonyl)-
pyridine-3-carboxylic acid (1),[9] methyl 5-(chlorocarbonyl)pyri-
dine-2-carboxylate,[10] myo-inositol-orthoformate,[11,12] 1,2:3,4-di-
O-isopropylidene-α--galactose,[13] [VO(pic)2],[14]K[VO2(pic)2],[14]
K[VO2(2,5dipic)].[15]
Tests for the inhibition of free fatty acid (FFA) release were per-
formed on epidymal fat pads, excised from male Wistar rats (7
weeks) anesthetized with diethyl ether. The pads were cut into ap-
propriately sized pieces and were incubated with collagenase in
KRB buffer (Krebs–Ringer hydrogen carbonate buffer; 120 m
NaCl, 1.27 m CaCl2, 1.2 m MgSO4, 4.75 m KCl, 1.2 m
KH2PO4, and 24 m NaHCO3; pH7.4) containing 2% BSA at
37 °C with gentle shaking at 100 cycle/min for 1 h. At the end of
the incubation period, the prepared cells were filtered through steri-
lized cotton gauze and washed three times with the KRB buffer.
The cells were incubated at 37 °C for 30 min with the vanadium
complexes, dissolved in DMSO, at various concentrations (0.1–
1.0 m), including 1 m ascorbic acid to prevent their oxidations
in KRB buffer containing 2% DMSO. A 10 µ solution of epi-
nephrine was then added to the reaction mixtures, and the resulting
solutions were incubated at 37 °C for 3 h. The mixtures were centri-
fuged at 3000 rpm for 10 min at 4 °C. On the outer solution of the
cells, the FFA level was determined with a FFA kit (NEFA C test;
Wako, Osaka, Japan).
Analyses and Methods: Elemental analyses were carried out in the
Analytical Laboratory of the Chemistry Department, University of
Hamburg. Infrared spectra were recorded as KBr pellets on a Per-
kin–Elmer 1720 FT–IR spectrometer. NMR spectra were obtained
either on a Varian Gemini 200 BB or a Bruker Avance 400 spec-
trometer at room temperature in 5 mm tubes. Chemical shifts δ are
All animal experiments in the present study were approved by the
Experimental Animal Research Committee of Kyoto Pharmaceuti-
cal University (KPU), and were performed according to the Guide-
line for Animal Experimentation of the KPU.
Synthesis and Characterization
reported in ppm (parts per million) relative to TMS for 1H and 13
C
For the NMR assignments, the numbering of the ring-H and -C
atoms follows the usual one. C1 and C7 refer to the carboxylic
carbons in the ring positions 2 and 5, respectively.
NMR spectra. Coupling constants (J) are quoted in Hertz. Mass
spectrometry was carried out at the Institute of Organic Chemistry,
University of Hamburg, with the usual spectrometer settings on a
Varian MAT 311A (70 eV, EI) or a VG Analytical 70–250 S (FAB).
EPR spectra of 4a–d and 5a–d were scanned at ca. 9.6 GHz (X-
band) on a Bruker ESP-300 E spectrometer at room temperature
and 100 K. Parameter adaptations by simulation were achieved by
using the Bruker software SimFonia. X-ray structure analyses were
carried out at 153(2) K using Mo-Kα irradiation (λ = 0.71073 Å,
graphite monochromator) on a Smart Apex CCD diffractometer.
Hydrogen atoms were usually found, and otherwise calculated into
idealized positions and included in the last cycles of refinement.
Absorption corrections were carried out by SADABS. Structure
solution and refinement were carried out using the SHELXTL-
Plus software package (G. M. Sheldrick, Version 5.1, Bruker AXS,
1998). For crystal data and structure refinement see Table 2.
[Mg(H2O)6](1H–1)2: This compound was obtained in low yields as
a by-product during the syntheses of the amino acid derivatives 3a–
d (see below). Single crystals were grown by slow evaporation of a
methanolic solution. IR (KBr) ν = 3114, 3075 (ar. C–H); 2955,
˜
2924, 2851 (C–H); 1730 (sh), 1708 (C=O); 1636, 1605, 1561 (C=C),
(C=N); 1479, 1439, 1391, 1324 (C–H); 1287, 1258 (C=C), (C=N);
1158, 1122, 1072, 1030, 1005 (C–O–C); 818 (ar. C–H), ν(C–CO2);
746 (ar. C–H) cm–1. 1H NMR (400 MHz, CD3OD/TMS): δ = 9.19
(m, 1 H, H-2), 8.47–8.45 (m, 1 H, H-4), 8.18–8.16 (m, 1 H, H-5),
3.98 (s, 3 H, H-1) ppm.
General Procedure for the Syntheses of the Ligands 2a–b: To a solu-
tion of methyl 5-(chlorocarbonyl)pyridine-2-carboxylate (1.5 g,
7.56 mmol) in toluene (5 mL) was added dropwise and with cooling
a 1.4 fold excess of the alcohol in pyridine (15 mL). After the ad-
dition of a catalytic amount of 4-(dimethylamino)pyridine, the re-
sulting dark solution was stirred overnight at room temperature.
The solvent was evaporated and the residue dissolved in water. The
aqueous solution was extracted with dichloromethane (5×30 mL).
The organic layer was dried with Na2SO4 and the solvent evapo-
rated. Purification was carried out using column chromatography
on silica gel, elutant ethyl acetate/n-hexane, 1:1, to give a light yel-
low solid (yield 59–65%) which was treated with an equimolar
amount of Cu(NO3)2·3H2O, followed by treatment with hydrogen
sulfide as has been described earlier[8] to produce the ligands as
white solids in yields of 50–85%.
CCDC-22102, -285853, -225187, and -257605 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Insulin-Mimetic Tests: Tests for the glucose uptake activity were
based on the MTT (MTT = 3-(4,5-dimethylthiazol-2-yl)-2,5-di-
phenyl-2H-tetrazolium bromide) reduction assay.[16] The cells were
cultured in glucose-rich DMEM medium (Dulbecco’s modification
of Eagle’s medium) supplemented with 10% fetal calf serum at
37 °C/5% CO2 to subconfluency. Afterwards, the cells were passed
to an insulin-free, DMEM high glucose medium for 24 h. For the
MTT tests, DMEM (without phenol red) supplemented with MTT
(Sigma; 0.5 g/L) and solutions of the vanadium complexes in dif-
5-(Isopropyloxycarbonyl)-2-pyridinecarboxylic Acid (2a): Yield 44%
(0.69 g). C10H11NO4 (209.20): calcd. C 57.41, H 5.30, N 6.70; found
3582
www.eurjic.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2006, 3575–3585

Insulin-Mimetic Potential of Oxidovanadium(IV) Complexes
C 57.34, H 5.31, N 6.67. IR (KBr) ν = 3053 (ar. C–H); 2980, 2875, 2MeO-5-Inodipic (2d): Yield 69% (0.73 g). C15H15N1.3O9 (357.48):
FULL PAPER
˜
2767 (C–H); 1718 (C=O); 1600, 1583, 1498 (C=C), (C=N); 1471,
calcd. C 50.39, H 4.23, N 5.09; found C 51.90, H 4.35, N 5.18. IR
(KBr) ν = 3399, 3326 (O–H), 3013 (ar. C–H); 2952, 2924, 2852 (C–
1459, 1377 (C–H), (O–H); 1301, 1269 (C=C), (C=N); 1108, 1036
˜
1
(C–O–C); 750 (ar. C–H) cm–1. H NMR (200 MHz, [D6]DMSO): H); 1729, 1717 (C=O); 1627, 1597, 1580, 1478 (C=C), (C=N); 1440,
4
5
δ = 9.12 (dd, J6,4 = 2.17 Hz, J6,3 = 0.82 Hz, 1 H, H-6), 8.40 (dd,
1385 (C–H); 1275, 1162, 1139, 1060, 1007, 993, 960 (C–O), (C–N),
4J4,6 = 2.17 Hz, 3J4,3 = 8.10 Hz, 1 H, H-4), 8.13 (dd, 5J3,6 = 0.82 Hz,
(C–O–C); 748 (ar. C–H) cm–1. 1H NMR (200 MHz, CD3OD/
3J3,4 = 8.10 Hz, 1 H, H-3), 5.16 (h, J = 6.23 Hz, 1 H, CH(CH3)2), TMS): δ = 9.21–9.20 (m, 1 H, H-7), 8.28–8.22 (m, 1 H, H-5), 7.98–
3
1.32 (d, J = 6.23 Hz, 6 H, CH(CH3)2) ppm. 13C NMR (50 MHz,
7.88 (m, 1 H, H-4), 5.41 (d, 4J = 1.28 Hz, 1 H, H-7Ј), 4.44–4.40
3
[D6]DMSO): δ = 166.17 (C-1), 164.21 (C-7), 152.32 (C-2), 150.39 (m, 2 H, H-1Ј, H-4Ј), 4.18–4.06 (m, 4 H, H-2Ј, H-3Ј, H-5Ј, H-6Ј),
(C-6), 138.82 (C-4), 128.98 (C-5), 125.24 (C-3), 69.95 (CH(CH3)2),
4.01 (s, 3 H, H-1) ppm. 13C NMR (100 MHz, CD3OD/TMS): δ =
22.21 (CH(CH3)2) ppm. MS (70 eV, EI): m/z (%): 209 (5) (M+·), 166.9, 165.9 (C-8, C-2), 151.5 (C-7), 147.9 (C-3), 140.3 (C-5), 131.3
168 (42) (M – C3H5), 165 (34) (M – CO2), 150 (100) (M – C3H7O), (C-6), 126.1 (C-4), 103.9 (C-7Ј), 76.0 (C-2Ј, C-6Ј), 70.6 (C-4Ј), 69.1
123 (41) (M – C4H6O2), 43 (21) (C2H4N+).
(C-3Ј, C-5Ј), 61.1 (C-1Ј), 53.5 (C-1) ppm. MS (70 eV, EI): m/z (%):
+
352 (3) (M+·-H), 236 (10) (M – C7H3NO), 182 (44) (C8H8NO4
)
5-[(S)-sec-Butyloxycarbonyl]-2-pyridinecarboxylic Acid (2b): Yield
50% (0.84 g). C10H11NO4 (223.23): calcd. C 59.19, H 5.87, N 6.27;
164 (100) (C8H6NO3+), 137 (26) (C7H7NO2+), 106 (20)
(C6H4NO+), 73 (41) (C3H5O2+), 44 (41) (CO2+).
found C 58.88, H 5.91, N 6.31. IR (KBr) ν = 3047 (ar. C–H); 2976,
˜
2935, 2878, 2768 (C–H); 1715 (C=O); 1599, 1581 (C=C), (C=N);
1457, 1419, 1372 (C–H), (O–H); 1297, 1267 (C=C), (C=N); 1119,
1109, 1035 (C–O–C); 749 (ar. C–H) cm–1. 1H NMR (200 MHz,
[D6]DMSO): δ = 9.17 (br. m, 1 H, H-6), 8.46 (m, 1 H, H-4), 8.19
General Procedure for Compounds (2MeO-5RЈNHdipic) 3a–d: To a
solution of the -amino acid ethyl ester hydrochloride (5.0 mmol)
in dichloromethane (10 mL) was added triethylamine (1.52 mL,
1.11 g, 11.0 mmol). The resulting mixture was stirred for 5 minutes
(sometimes formation of a white precipitate was observed). Then a
solution of methyl 5-(chlorocarbonyl)pyridine-2-carboxylate (1.0 g,
5.0 mmol) in dichloromethane (10 mL) was added drop wise with
cooling (5–10 °C). The resulting yellow solution was stirred for 12 h
at room temperature. The solvent was removed by evaporation and
the residue was dissolved in ethylacetate. The solution was filtered,
and the precipitate washed with a small amount of ethylacetate.
The filtrate was concentrated. Purification was carried out using
column chromatography on silica gel; elutant ethyl acetate/n-hex-
ane, 1:1. The products were isolated as slightly yellow oils, which
solidified upon cooling. Yields were 36 to 66%. Single crystals of
compound 3a were obtained by slow diffusion of n-hexane into a
saturated solution of the compound in dichloromethane.
3
(br. m, 1 H, H-3), 5.06 (tq, J = 6.2 Hz, 1 H, CH(CH3)CH2CH3),
1.78–1.64 (m, 2 H, CH(CH3)CH2CH3), 1.33 (d, 3J = 6.23 Hz, 3 H,
CH(CH3)CH2CH3), 0.94 (t, 3J
= 7.4 Hz, 3 H, CH(CH3)-
CH2CH3) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 165.87 (C-
1), 163.84 (C-7), 151.9 (C-2), 148.88 (C-6), 138.24 (C-4), 128.26 (C-
5), 124.75 (C-3), 73.63 (CH(CH3)CH2CH3), 28.26 (CH(CH3)-
CH2CH3),
19.21
(CH(CH3)CH2CH3),
9.53
(CH(CH3)-
CH2CH3) ppm. MS (70 eV, EI): m/z (%): 223 (1) (M+·), 168 (60)
(M – C4H7), 150 (100) (M – C4H9O), 122 (25) (M – C5H9O2).
Preparation of the Galactose/Inositol Derivatives 2c, 2d: To a solu-
tion of methyl 5-(chlorocarbonyl)pyridine-2-carboxylate (600 mg,
3.0 mmol) in toluene (10 mL) in an ice bath was added a solution
of the corresponding alcohol (3.0 mmol) in pyridine (15 mL). After
addition of a catalytic amount of 4-(dimethylamino)pyridine, the
resulting solution was stirred for 12 h at room temperature. The
solvent was evaporated and the residue extracted with toluene
(10 mL), followed by dichloromethane (10 mL). The galactose de-
rivative was dissolved in 1-butanol and the organic phase washed
with water and a diluted solution of Na2CO3. The organic layer
was dried with MgSO4 and the solvent was evaporated to yield a
yellow oil. The inositol derivative was dissolved in water and the
aqueous phase was extracted with ethyl acetate. The organic layer
was dried with MgSO4 and the solvent was evaporated to yield a
light yellow solid.
2MeO-5GlyNHdipic (3a): Yield 36% (0.50 g). C12H14N2O5
(266.25): calcd. C 54.13, H 5.30, N 10.52; found C 54.15, H 5.57,
N 9.71. IR (KBr): ν = 3355 (N–H); 3063 (ar. C–H); 2977, 2961 (C–
˜
H); 1753, 1727, 1664 (C=O); 1595, 1531, 1480 (C=C), (C=N), (N–
H); 1440, 1383 (C–H); 1311, 1253, 1200, 1169, 1128, 1024 (C–O),
(C–N), (C–O–C); 753 (ar. C–H) cm–1. 1H NMR (400 MHz, CDCl3/
TMS): δ = 9.14–9.13 (m, 1 H, H-7), 8.33–8.30 (m, 1 H, H-5), 8.21–
8.19 (m, 1 H, H-4), 7.36 (br. t, 1 H, NH), 4.28–4.23 (m, 4 H, H-9,
H-11), 4.03 (s, 3 H, H-1), 1.31 (t, 3J12,11 = 7.1 Hz, 3 H, H-12) ppm.
13C NMR (100 MHz, CDCl3/TMS): δ = 169.74 (C-8), 164.96 (C-
2), 164.90 (C-10), 149.81 (C-3), 148.36 (C-7), 136.63 (C-5), 132.22
(C-6), 124.77 (C-4), 61.78 (C-11), 53.18 (C-1), 41.90 (C-9), 14.13
(C-12) ppm. MS (70 eV, EI): m/z (%): 266 (6) (M+·), 208 (33) (M –
C3H6O), 193 (13) (M – C3H5O2), 164 (100) (M – C5H10O2), 40 (16)
(C3H4+).
2MeO-5GalOdipic
(2c):
Yield
89%
(0.98 g).
C20H25NO9·2H2O·0.5(C4H10O) (496.51): calcd. C 53.22, H 6.90, N
2.82; found C 53.56, H 6.52, N 2.66. IR (KBr) ν = 3112, 2989 (ar.
˜
C–H); 2933, 2851 (C–H); 1728, 1716 (sh) (C=O); 1627, 1597, 1580,
1479 (C=C), (C=N); 1439, 1384 (C–H); 1311, 1275, 1255, 1213,
1168, 1139, 1071, 1003 (C–O), (C–N), (C–O–C); 748 (ar. C–H) 2MeO-5AlaNHdipic (3b): Yield 66% (0.92 g). C13H16N2O5
1
cm–1. H NMR (400 MHz, CD3OD/TMS): δ = 9.22–9.15 (m, 1 H, (280.28): calcd. C 55.71, H 5.75, N 9.99; found C 55.74, H 5.52, N
H-7), 8.56–8.53 (m, 1 H, H-5), 8.27–8.22 (m, 1 H, H-4), 5.52–5.50
9.74. IR (KBr) ν = 3296 (N–H); 3067 (ar. C–H); 2985, 2951, 2854
˜
(m, 1 H, H-1Ј), 4.64–4.61 (m, 1 H, H-5Ј), 4.36–4.28 (m, 2 H, H-2Ј, (C–H); 1744, 1718, 1645 (C=O); 1595, 1540 (C=C), (C=N), (N–
H-3Ј), 4.02 (s, 3 H, H-1), 3.89–3.85 (m, 1 H, H-4Ј), 3.69–3.66 (m, H); 1455, 1442, 1381 (C–H); 1311, 1291, 1246, 1214, 1177, 1136,
2 H, H-6Ј), 1.53, 1.41, 1.34, 1.33 (s, 12 H, H-9Ј, H-10Ј, H-11Ј, H- 1020 (C–O), (C–N), (C–O–C); 744 (ar. C–H) cm–1. 1H NMR
12Ј) ppm. 13C NMR (100 MHz, CD3OD/TMS): δ = 165.9, 165.4
(400 MHz, CDCl3/TMS): δ = 9.13–9.12 (m, 1 H, H-7), 8.28–8.21
3
(C-8, C-2), 151.8 (C-3), 151.3 (C-7), 140.0 (C-5), 130.3 (C-6), 126.1
(m, 2 H, H-4, H-5), 6.94 (br. d, 1 H, NH), 4.82–4.75 (dq, J9,NH =
(C-4), 110.8, 109.7 (C-7Ј, C-8Ј), 97.7 (C-1Ј), 72.4 (C-2Ј), 72.2 (C- 7.1 Hz, 3J9,10 = 7.14 Hz, 1 H, H-9), 4.27 (q, J12,13 = 7.14 Hz, 2 H,
3
3
3Ј), 71.9 (C-4Ј), 67.5 (C-5Ј), 66.0 (C-6Ј), 53.5 (C-1), 26.3, 26.2, 25.1,
24.6 (C-9Ј, C-10Ј, C-11Ј, C-12Ј) ppm. MS (70 eV, EI): m/z (%): 408
H-12), 4.04 (s, 3 H, H-1), 1.56 (d, J10,9 = 7.14 Hz, 3 H, H-10),
3
1.33 (t, J13,12 = 7.14 Hz, 3 H, H-13) ppm. 13C NMR (50 MHz,
(100) (M – CH3), 183 (27) (C8H9NO4+), 164 (50) (C8H6NO3+), 115 CDCl3/TMS): δ = 172.90 (C-8), 164.86 (C-2), 164.25 (C-11), 149.74
(26) (C6H11O2+), 100 (45) (C5H8O2+), 85 (24) (C5H9O+), 81 (57) (C-3), 148.41 (C-7), 136.43 (C-5), 132.27 (C-6), 124.81 (C-4), 61.82
(C5H5O+), 59 (29) (C2H3O2+), 43 (53) (C3H7+).
(C-12), 53.16 (C-1), 48.83 (C-9), 18.09 (C-10), 14.12 (C-13) ppm.
Eur. J. Inorg. Chem. 2006, 3575–3585
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
3583

J. Gätjens, B. Meier, Yu. Adachi, H. Sakurai, D. Rehder
FULL PAPER
MS (70 eV, EI): m/z (%): 280 (33) (M+·), 235 (13) (M – C2H5O),
208 (34) (M – C3H4O2), 207 (100) (M – C3H5O2), 165 (33) (M –
C6H11O2), 164 (76) (M – C6H12O2), 136 (21) (M – C6H10NO3), 106
(20) (M – C7H12NO4), 78 (25) (C5H4N+).
= 93·10–4 cm–1; (100 K, ethanol): gЌ = 1.985, AЌ = 60·10–4 cm–1,
gII = 1.945, AII = 167·10–4 cm–1.
[VO(5-sBuOdipic)2] (4b): Yield 65% (190 mg). C22H24N2O9V·THF
(583.49): calcd. C 53.52, H 5.53, N 4.80; found C 52.70, H 5.47, N
4.98. IR (KBr) ν = 3116, 3080 (ar C–H); 2974, 2931, 2880, 2854
˜
2MeO-5ValNHdipic (3c): Yield 66% (1.01 g). C15H20N2O5
(308.33): calcd. C 58.43, H 6.54, N 9.09; found C 58.43, H 6.25, N
–
(C–H); 1727 (C=O); 1687 νas(CO2 ); 1643, 1627, 1606, 1578 (C=C),
–
(C=N); 1485, 1457, 1419, 1357 (C–H), νs(CO2 ); 1283 (C=C),
8.94. IR (KBr) ν = 3307 (N–H); 3103 (ar. C–H); 2971, 2932, 2872
˜
(C=N); 1130, 1108, 1046 (C–O–C); 977 (V=O); 851 (ar. C–H), (C–
CO2); 748 (ar. C–H) cm–1. MS (FAB): m/z = 512 (M–THF]. EPR
(100 K, ethanol): gЌ = 1.983, AЌ = 60·10–4 cm–1, gII = 1.945, AII
= 165·10–4 cm–1.
(C–H); 1746, 1713, 1645 (C=O); 1597, 1569, 1523 (C=C), (C=N),
(N–H); 1472, 1437, 1393, 1373 (C–H); 1313, 1301, 1248, 1190,
1
1160, 1139, 1021 (C–O), (C–N), (C–O–C); 698 (ar. C–H) cm–1. H
NMR (400 MHz, CDCl3/TMS): δ = 9.14–9.13 (m, 1 H, H-7), 8.29–
8.19 (m, 2 H, H-4, H-5), 6.74 (br. d, 1 H, NH), 4.81–4.78 (dd,
[VO(5-GalOdipic)2]
(4c):
Yield
84%
(530 mg).
3
3J9,NH = 8.44 Hz, J9,10 = 4.70 Hz, 1 H, H-9), 4.38–4.14 (m, 2 H,
C38H44N2O19V·4THF·0.75Na2SO4 (1260.64): calcd. C 51.45, H
3
3
H-13), 4.04 (s, 3 H, H-1), 2.32 (dq, J10,9 = 4.70 Hz, J10,11/11Ј
=
6.08, N 2.22; found C 51.01, H 5.93, N 2.13. IR (KBr) ν = 3114,
˜
3
–
6.91 Hz, 1 H, H-10), 1.33 (t, J14,13 = 7.14 Hz, 3 H, H-14), 1.03,
3081 (ar C–H); 2988, 2936 (C–H); 1731 (C=O); 1681 νas(CO2 );
1.01 (d, d, J11/11Ј,10 = 6.91 Hz, 6 H, H-11, H-11Ј) ppm. 13C NMR
3
1642, 1608, 1578 (C=C), (C=N); 1457, 1437, 1415, 1383 (C–H),
–
(100 MHz, CDCl3/TMS): δ = 175.56 (C-8), 164.92 (C-2), 164.64
(C-12), 149.99 (C-3), 148.41 (C-7), 136.20 (C-5), 132.53 (C-6),
124.87 (C-4), 61.69 (C-9), 57.74 (C-13), 53.20 (C-1), 31.38 (C-10),
19.01, 18.00 (C-11, C-11Ј), 14.30 (C-14) ppm. MS (70 eV, EI): m/z
(%): 308 (5) (M+·), 235 (85) (M – C3H5O2), 181 (32) (M –
C7H11O2), 164 (100) (M – C6H10NO3), 78 (12) (C5H4N+).
νs(CO2 ); 1282, 1256, 1283, 1212 (C=C), (C=N); 1168, 1113, 1070,
1002 (O–CH); 973 (V=O); 898, 863 (ar. C–H), (C–CO2); 747 (ar.
C–H) cm–1. MS (FAB): m/z = 884 (M+1). EPR (293 K, THF): g0
= 1.975, A0 = 95·10–4 cm–1; (100 K, ethanol): gЌ = 1.983, AЌ
60·10–4 cm–1, gII = 1.945, AII = 165·10–4 cm–1.
=
[VO(5-InoOdipic)2]
(4d):
Yield
85%
(331 mg).
C28H24N2O19V·2H2O (779.47): calcd. C 43.15, H 3.62, N 3.59;
2MeO-5PheNHdipic (3d): Yield 54% (0.96 g). C19H20N2O5
(356.37): calcd. C 64.04, H 5.66, N 7.86; found C 63.88, H 5.66, N
found C 43.06, H 4.17, N 3.65. IR (KBr) ν = 3075 (ar C–H); 2929,
˜
–
2851 (C–H); 1724 (C=O); 1664 (sh) νas(CO2 ); 1635, 1577 (C=C),
7.74. IR (KBr) ν = 3321 (N–H); 3137, 3068, 3029 (ar. C–H); 2980,
˜
–
(C=N); 1488, 1397, 1348 (C–H), νs(CO2 ); 1287 (C=C), (C=N);
2946, 2870 (C–H); 1734, 1647 (C=O); 1595, 1568, 1526, 1498
(C=C), (C=N), (N–H); 1455, 1439, 1375 (C–H); 1309, 1285, 1194,
1161, 1117, 1099, 1022 (C–O), (C–N), (C–O–C); 748, 700 (ar. C–
1162, 1124, 1090, 1048, 1006 (O–CH); 985 (V=O); 752 (ar. C–H)
cm–1. MS (FAB): m/z = 778 (M–1]. EPR (293 K, THF): g0 = 1.97,
A0 = 100·10–4 cm–1; (100 K, water): gЌ = 1.983, AЌ = 60·10–4 cm–1,
gII = 1.945, AII = 165·10–4 cm–1.
1
H) cm–1. H NMR (400 MHz, CDCl3/TMS): δ = 9.00–8.99 (m, 1
H, H-7), 8.21–8.16 (m, 2 H, H-4, H-5), 7.32–7.24 (m, 3 H, H-13,
H-14, H-15), 7.15–7.12 (m, 2 H, H-12, H-16), 6.67 (br. d, 1 H,
[VO(5-GlyOEtdipic)2]
(5a):
Yield
73%
(241 mg).
3
3
NH), 5.09–5.04 (dt, J9,NH = 7.49 Hz, J9,10 = 5.93 Hz, 1 H, H-9),
C22H22N4O11V·THF·H2O (659.50): calcd. C 47.35, H 4.89, N 8.50;
4.25 (q, 3J18,19 = 7.16 Hz, 2 H, H-18), 4.03 (s, 3 H, H-1), 3.34–3.23
found C 47.30, H 4.59, N 9.11. IR (KBr) ν = 3067 (ar C–H); 2981,
˜
(m, 2 H, H-10), 1.31 (t, J19,18 = 7.16 Hz, 3 H, H-19) ppm. 13C
3
2953, 2873 (C–H); 1745 (C=O); 1670 νas(CO2–); 1597, 1542 (C=C),
–
NMR (100 MHz, CDCl3/TMS): δ = 171.27 (C-8), 164.87 (C-2),
164.15 (C-17), 150.01 (C-3), 148.14 (C-7), 136.26 (C-5), 135.49 (C-
11), 132.34 (C-6), 129.28 (C-12, C-16), 128.74 (C-13, C-15), 127.40
(C-14), 124.91 (C-4), 61.96 (C-18), 53.66 (C-9), 53.21 (C-1), 37.70
(C-10), 14.15 (C-19) ppm. MS (70 eV, EI): m/z (%): 356 (6) (M+·),
283 (14) (M – C3H5O2), 176 (97) (M – C11H16O2), 164 (100) (M –
C11H14NO2), 148 (11) (M – C12H16O3), 131 (18) (M – C12H19NO3),
91 (19) (C7H7+), 78 (12) (C5H4N+).
(C=N); 1437, 1417, 1377, 1353 (C–H), νs(CO2 ); 1311, 1248, 1207
(C=C), (C=N); 1119, 1029 (O–CH); 975 (V=O); 873, 829 (ar. C–
H), (C–CO2); 749 (ar. C–H) cm–1. MS (FAB): m/z = 570 (M), 592
[M+Na]. EPR (100 K, ethanol): gЌ = 1.99, AЌ = 60·10–4 cm–1, gII
= 1.95, AII = 170·10–4 cm–1.
[VO(5-AlaOEtdipic)2]
(5b):
Yield
65%
(235 mg).
C24H26N4O11V·THF·H2O·0.25Na2SO4 (723.06): calcd. C 46.51, H
5.02, N 7.75; found C 46.15, H 4.45, N 7.99. IR (KBr) ν = 3070
˜
–
(ar C–H); 2986, 2936, 2854 (C–H); 1738 (C=O); 1665 νas(CO2 );
Preparation of the Vanadium(IV) Compounds 4a–d and 5a–d. 4a–
b: A solution of the ligand (1.0 mmol) and sodium acetate·3H2O
(136 mg, 1.0 mmol) in water (10 mL) and THF (1 mL) was mixed
with a solution of VOSO4·5H2O (127 mg, 0.5 mmol) in water
(2 mL) at 50 °C to yield light green solids. 4c–d, 5a–d: To a solution
of the proligand (1.0 mmol) and sodium acetate·3H2O (136 mg,
1.0 mmol) in water (3 mL) and THF (6 mL) was added a solution
of vanadyl sulfate·5H2O (127 mg, 0.5 mmol) in water (3 mL). The
resulting green slurry was kept at reflux for ca. 6 h to yield a clear
green solution. The solvent was evaporated, the residue was dis-
solved in THF and filtered. Evaporation to dryness yielded green
solids.
1605, 1575, 1541 (C=C), (C=N); 1484, 1452, 1418, 1370, 1343 (C–
–
H), νs(CO2 ); 1284, 1212, 1179 (C=C), (C=N); 1123, 1047 (O–CH);
977 (V=O); 851 (ar. C–H), (C–CO2); 749 (ar. C–H) cm–1. MS
(FAB): m/z = 598 (M), 620 [M+Na]. EPR (100 K, ethanol): gЌ
=
1.985, AЌ = 60·10–4 cm–1, gII = 1.950, AII = 163·10–4 cm–1.
[VO(5-ValOEtdipic)2]
(5c):
Yield
69%
(228 mg).
C22H22N4O11V·THF·H2O (659.50): calcd. C 47.35, H 4.89, N 8.50;
found C 47.30, H 4.59, N 9.11. IR (KBr) ν = 3065 (ar C–H); 2967,
˜
–
2937, 2876 (C–H); 1739 (C=O); 1651 νas(CO2 ); 1570, 1538 (C=C),
–
(C=N); 1438, 1419, 1393, 1373 (C–H), νs(CO2 ); 1312, 1249, 1197
(C=C), (C=N); 1157, 1021 (O–CH); 975 (V=O); 862, 823 (ar. C–
H), (C–CO2); 744, 697 (ar. C–H) cm–1. MS (FAB): m/z = 654
[VO(5-iPrOdipic)2] (4a): Yield 74% (185 mg). C20H20N2O9V·H2O
(501.34): calcd. C 47.91, H 4.42, N 5.59; found C 47.56, H 4.45, N
(M+1], 676 [M+Na]. EPR (100 K, ethanol): gЌ = 1.981, AЌ
60·10–4 cm–1, gII = 1.945, AII = 166·10–4 cm–1.
=
5.08. IR (KBr) ν = 3114, 3058 (ar C–H); 2983, 2873 (C–H); 1730
˜
–
(C=O); 1687, 1652 νas(CO2 ); 1609 (C=C), (C=N); 1484, 1397,
[VO(5-PheOEtdipic)2]
(5d):
Yield
50%
(203 mg).
–
1353 (C–H), νs(CO2 ); 1289 (C=C), (C=N); 1108, 1051 (C–O–C); C36H34N4O11V·0.5THF·1.5H2O (812.71): calcd. C 56.16, H 5.08,
967 (V=O); 848 (ar. C–H), (C–CO2); 750 (ar. C–H) cm–1. MS N 6.89; found C 56.35, H 5.19, N 6.78. IR (KBr) ν = 3061, 3030
˜
(FAB): m/z = 484 (M–H2O]. EPR (293 K, ethanol): g0 = 1.975, A0
(ar C–H); 2980, 2952, 2929, 2868 (CH); 1739 (C=O); 1665
3584
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2006, 3575–3585

Insulin-Mimetic Potential of Oxidovanadium(IV) Complexes
FULL PAPER
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–
νas(CO2 ); 1602, 1536, 1497 (C=C), (C=N); 1455, 1438, 1374 (C–
–
H), νs(CO2 ); 1309, 1247, 1197, 1157 (C=C), (C=N); 1122, 1025
(O–CH); 966 (V=O); 855 (ar. C–H), (C–CO2); 745, 700 (ar. C–H)
cm–1. MS (FAB): m/z = 750 (M+1]. EPR (100 K, ethanol): gЌ
1.983, AЌ = 60·10–4 cm–1, gII = 1.945, AII = 165·10–4 cm–1.
=
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Received: February 15, 2006
Published Online: May 30, 2006
231, 23–35.
Eur. J. Inorg. Chem. 2006, 3575–3585
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
3585