New vanadyl complexes with metformin derivatives as potential insulin mimetic agents

Article abstract of DOI:10.1007/s10973-012-2274-x

Three new complexes with formula [VOL₂]·xH₂O [(1) HL: N,N-dimethylbiguanide, x = 0.5; (2) HL: 1-phenylbiguanide, x = 0; (3) HL: 1-(o-tolyl)biguanide, x = 0.5] were synthesised and characterised. The IR and UV-Vis spectral data indicate that these biguanide derivatives act as bidentate chelating anionic ligands and generate VO(II) complexes with a square-pyramidal stereochemistry. The thermal analysis (TG, DTA) elucidated the composition and also the number and nature of the water molecules.

Full text of DOI:10.1007/s10973-012-2274-x

J Therm Anal Calorim (2012) 110:257–262
DOI 10.1007/s10973-012-2274-x
New vanadyl complexes with metformin derivatives as potential
insulin mimetic agents
•
•
•
Rodica Olar Andreea Dogaru Dana Marinescu
Mihaela Badea
CEEC-TAC1 Conference Special Issue
´
´
Ó Akademiai Kiado, Budapest, Hungary 2012
Abstract Three new complexes with formula [VOL2]Á
xH2O [(1) HL: N,N-dimethylbiguanide, x = 0.5; (2) HL:
1-phenylbiguanide, x = 0; (3) HL: 1-(o-tolyl)biguanide,
x = 0.5] were synthesised and characterised. The IR and
UV–Vis spectral data indicate that these biguanide deriva-
tives act as bidentate chelating anionic ligands and generate
VO(II) complexes with a square–pyramidal stereochemis-
try. The thermal analysis (TG, DTA) elucidated the com-
position and also the number and nature of the water
molecules.
One likely mechanism for the insulin-mimetic activity
of vanadium compounds relates to their potent inhibition of
PTP’s. A variety of vanadium compounds have been
shown to directly inhibit a wide range of PTP’s, including
PTP1B. A lot of paper revealed the superior insulin-
mimetic activities for vanadium complexes compared to
sodium orthovanadate [5, 7, 12, 13, 17].
Besides having chelating ability, the biguanide deriva-
tives demonstrated so far a large spectrum of biological
activities such antimicrobial [19], glucose lowering agents
[20], analgesic, antimalarial [21] as well as antimetabolite
for organisms that inhibit the metabolism of folic acid [22].
Having in view these aspects, new complexes of the
type [VOL2]ÁxH2O with biguanide derivatives [1-phenyl-
biguanide and 1-(o-tolyl)biguanide] together with the
known vanadyl complex of N,N-dimethylbiguanide were
synthesised and characterised by elemental analysis as well
as IR and UV–Vis spectroscopy. Considering the low
solubility in water of complexes, developing proper drug
delivery systems requires the thermal analysis amongst
others [23]. As result, the thermal analysis (TG and DTA)
of the complexes was performed to establish the thermal
stability of these compounds that showed also insulin-
mimetic properties. The thermal curves elucidated also the
composition and the number and nature of the water
molecules.
Keywords Biguanide derivative Á Paracyanide Á
Thermal stability Á Vanadyl(IV) complex
Introduction
A variety of vanadium chelate complexes have been shown
to have insulin-mimetic properties in animal model and cell
culture systems, thus these compounds have great potential
for the pharmacotherapy of diabetes [1–17]. The first report
of vanadium’s insulin mimetic and antidiabetic potential in
vivo was published by Poucheret et al. [18]. The study was
performed on streptozotocin (STZ) diabetic rats treated
with sodium orthovanadate. In cultured cells lines, vana-
dium compounds enhance insulin receptor activation and
downstream signalling. In animal models of diabetes,
vanadium compounds enhance insulin sensitivity resulting
in decreased levels of plasma glucose.
Experimental
R. Olar Á A. Dogaru Á D. Marinescu Á M. Badea (&)
Department of Inorganic Chemistry, Faculty of Chemistry,
University of Bucharest, 90–92 Panduri St., Sector 5,
050663 Bucharest, Romania
Materials and methods
All chemicals were purchased from Sigma-Aldrich, reagent
grade and were used without further purification.
e-mail: e_m_badea@yahoo.com
123

258
R. Olar et al.
The chemical analyses were performed on a Perkin
The obtained complexes are sparingly soluble in water,
methanol, ethanol, acetonitrile, partially soluble in
dimethylformamide and soluble in dimethylsulphoxide.
Elmer PE 2400 analyzer (for C, H, N) and a Shimadzu AA
6300 spectrometer (for V).
IR spectra were recorded in KBr pellets with a Bruker
Tensor 37 spectrometer in the range 400–4,000 cm-1
.
Results and discussion
Electronic spectra by diffuse reflectance technique, with
Spectralon as standard, were recorded in the range
200–1,000 nm, on a Jasco V 670 spectrophotometer.
The heating curves (TG and DTA) were recorded using
a Labsys 1200 SETARAM instrument, with a sample mass
of 14–15 mg over the temperature range of 30–9008C,
using a heating rate of 10 8C/min. The measurements were
carried out in synthetic air atmosphere (flow rate
16.66 mL3/min) using alumina crucibles.
Physico-chemical characterization of complexes
Based onglucose lowering activityofN,N-dimethylbiguanide
(Metformin, HDMBG), we selected two biguanide deriva-
tives [1-phenylbiguanide (HPhBG) and 1-(o-tolyl)biguanide
(o-HTBG)] as ligands to synthesize new vanadyl complexes
as potential insulin-mimetic agents. Because the known
complex of metformin with vanadyl ion [20] was not inves-
tigated regarding the thermal stability we included it in this
study.
Synthesis of complexes
The major goal of this article was to evidence the
thermal behaviour of complexes isolated from the reactions
of these biguanide derivatives with VO(SO4)Á5H2O. The
complexes have been formulated on the basis of chemical
analysis, IR and electronic spectra as follows:
All the complexes were obtained following the general
procedure: to a solution of VOSO4Á5H2O (2.5 mmol) in
distilled water (50 cm3) was slowly added, under contin-
uous stirring, a solution of biguanide derivative (5.0 mmol
dissolved in 30 cm3 of distilled water). The reaction mix-
ture was then stirred at 50 °C for 2 h until a microcrys-
talline product was formed. The sparingly soluble product
was filtered off, washed several times with ethanol and air-
dried.
VO(DMBG)2(H2O)0.5
VO(PhBG)2
(1)
(2)
(3)
Or
Or
Or
VC8H21N10O1.5
VC16H22N10
VC18H25N10O1.5
O
VO(o-TBG)2(H2O)0.5
VO(DMBG)2(H2O)0.5. Analysis found: V, 15.27; C,
28.82; H, 6.54; N, 42.27%; requires for VC8H21N10O1.5: V,
15.33; C, 28.92; H, 6.37; N, 42.16%. Reaction yield 80%.
VO(PhBG)2. Analysis found: V, 12.15; C, 45.68; H,
5.34; N, 33.37%; requires for VC16H22N10O: V, 12.09; C,
45.60; H, 5.26; N, 33.24%. Reaction yield 72%.
The IR spectra of the complexes exhibit the character-
istic patterns of ligands (Table 1).
In the IR spectra of complexes band assigned to imine
stretching mode is shifted to higher wavenumbers whilst
the band in the range 1,600–1,700 cm-1, assigned to
vibration mode m(C=N) is shifted to higher wavenumbers
comparing with ligands spectra. These features indicate the
coordination of biguanide derivatives trough N2 and N4
VO(o-TBG)2(H2O)0.5. Analysis found: V, 11.05; C,
47.48; H, 5.46; N, 30.87%; requires for VC18H25N10O1.5: V,
11.16; C, 47.37; H, 5.52; N, 30.69%. Reaction yield 90%.
Table 1 Selected absorption maxima (cm-1) for complexes
HDMBG
(1)
HPhBG
(2)
o-HTBG
(3)
Assignments
3,420m
3,340m
3,189m
3,018m
–
–
3,435m
3,329s
3,210s
Covered
3,105m
1,680s
1,537s
1,492m
1,117w
1,383m
970s
m(OH)
3,371s
3,345s
3,278s
3,025s
3,000m
1,655vs
1,520s
1,500s
1,160w
–
3,338s
3,220s
Covered
Covered
1,683s
1,535s
1,495m
1,161w
–
3,467s
3,434m
3,377s
3,110m
1,613vs
1,532vs
1,483s
1,116w
1,375s
–
mas(NH) (NH2)
ms(NH) (NH2)
m(NH)
3,296m
3,173s
–
m(CH) aromatic ring
m(C=N)
1,635s
1,689s
–
–
m(C=C)
1,488m
1,492m
–
das(CH3)
–
d(CH) aromatic ring
ds(CH3)
1,419w
1,410w
979s
–
–
–
–
975s
m(V=O)
737m
730m
750m
754m
c(CH) aromatic ring
123

New vanadyl complexes with metformin derivatives
259
40
30
20
10
0
10
0
Table 2 Electronic data for complexes (nm)
Complex
Absorption maxima (nm)
2
2
2
2B2 ? A1
2B2 ? B1
2B2 ? E
–10
–20
–30
–40
–50
–60
–70
–80
(1)
(2)
(3)
410
405
403
564
560
568
897
900
905
↑
atoms. Furthermore, in the complexes spectra appear a new
band around 975 cm-1, which is characteristic for the
stretching vibration of the V=O bond [24].
–10
–20
In the electronic spectra of complexes (Table 2) an
intense band appears at about 400 nm accompanied by two
bands with a lower intensity around 560 and 900 nm. This
pattern is characteristic for a square–pyramidal stereo-
chemistry of VO2? ion. The bands from UV–Vis range are
30
200
400
600
800
Temperature/°C
2
2
2
2
assigned to B2 ? A1 and B2 ? B1 spin allowed tran-
sitions, respectively, whilst that from NIR region is char-
Fig. 2 TG and DTA curves of VO(DMBG)2(H2O)0.5
2
2
acteristic to B2 ? E transition [25].
On the basis of above data the proposed coordination for
water [26]. The anhydrous compound is stable up to
140 °C when decomposition starts. According to TG curve,
the rapid weight loss between 140 and 290 °C corresponds
to the partial decomposition of N,N-dimethylbiguanide
anion leading to an intermediate residue containing VO2
and paracyanide (CN)2n. This behaviour seems to be a
trend in thermal decomposition of complexes bearing
biguanide derivatives [27–31]. This step is a complex one
being an overlapping of at least two processes as DTA
curve indicates. The intermediate isolated at 290 °C
exhibits an IR spectrum with a structured band centred at
1,518 cm-1 assigned to m(C=N) (Fig. 3). The other strong
bands centred at 995, 875, 623 and 518 cm-1 are assigned
to the V=O stretching (the first one) and to V–O–V
deformation modes (the last three) [32].
the complexes is as it follows (Fig. 1):
Thermal behaviour of complexes
The results concerning the thermal behaviour of the new
complexes are presented as it follows.
Thermal decomposition of VO(DMBG)2(H2O)0.5
The TG and DTA curves corresponding to the complex (1)
heated in the 30–900 °C temperature range are presented in
Fig. 2.
The thermal decomposition of VO(C27H31O14)2(H2O)8
(1) occurs in three, well-defined steps (Table 3). The first
step, endothermic one, corresponds to the loss of all water
molecules. The reaction proceeds with a maximum rate at
85 °C. The low temperature range corresponding to this
transformation indicates the presence of crystallisation
The third step, an exothermic one, corresponds to the
oxidative degradation of the remaining paracyanide. The
intermediate product, vanadium (IV) oxide shows gradual
oxidation to V2O5 in the temperature range of 405–625 °C.
The final thermal event is the V2O5 melting as DTA curve
shows at about 682 °C. The smaller value observed com-
paring with the bulk particle (690 °C) can be due to the
particles size. The powder XRD analysis of the final resi-
due obtained after cooling reveals the structure of V2O5 as
shcherbinaite modifications (ASTM 41-1426) (found/calcd.
overall mass loss: 72.7/72.6%).
CH3
H3C
N
N
NH2
N
H
N
H
N
H
N
N
NH2
N
O
V
H
N
H
N
O
V
N
H
N
H
N
H
N
H
H2N
N
CH3
H2N
H
N
H3C
(2)
(1)
Thermal decomposition of VO(PhBG)2
H
N
N
NH2
H
N
H
N
O
V
N
The TG curve of complex VO(PhBG)2 (2) is almost stable
up to 235 °C indicating the absence of any lattice or
coordinated water molecule (Fig. 4; Table 3). The first
mass loss step corresponds to the ligand side group release
(Scheme 1). This step is a complex one being an overlap of
N
H
N
H
H2N
HN
(3)
Fig. 1 The proposed coordination for complexes
123

260
R. Olar et al.
Table 3 Thermal behaviour data (in air atmosphere) for the complexes
Complex
Step
Thermal effect
Temperature interval/8C
Dmexp/%
Dmcalc/%
VO(DMBG)2(H2O)0.5 (1)
1.
Endothermic
Exothermic
Exothermic
Exothermic
Endothermic
55–105
140–290
290–405
405–625
682*
2.8
2.7
2.
56.4
16.0
?2.5
–
56.6
15.7
?2.4
–
3.
4.
5.
Residue (V2O5)
27.3
50.6
29.7
?2.0
–
27.4
50.4
29.9
?1.9
–
VO(PhBG)2 (2)
1.
Exothermic
Exothermic
Exothermic
Endothermic
235–430
430–570
570–630
685*
2.
3.
4.
Residue (V2O5)
21.7
2.3
21.6
2.0
VO(o-TBG)2(H2O)0.5 (3)
1.
Endothermic
Exothermic
Exothermic
Exothermic
Endothermic
60–100
210–440
440–495
495–638
687*
2.
65.4
14.1
?1.8
–
65.6
14.1
?1.8
–
3.
4.
5.
Residue (V2O5)
20
19.9
* Melting point
0
30
20
–20
–40
↑
10
μ
0
–60
–80
3500
3000
2500 2000
1500
1000
500
–10
Wavenumber/cm–1
Fig. 3 IR spectrum for isolated intermediate of complex (1) at
290 °C
30
200
400
600
800
Temperature/°C
at least three processes as DTA curve indicates. Similar as
for the previous discussed complex, the low thermal effect
observed for this step indicate that there is an equilibrium
between the bonds cleavage and the oxidative processes
suggesting that at least a part of the volatile product are
released without oxidation.
Fig. 4 TG and DTA curves of VO(PhBG)2
C=C vibration from the benzene ring (1,535 cm-1 in com-
plex, Fig. 5a) also sustains this assumption. The strong band
around 1,300 cm-1 was observed for other complexes with
biguanide derivatives [33] and can be associated either with
the formation of the chelate ring or with the activation of an
IR band as result of the complex symmetry decreasing upon
packing in the new network.
The proposed decomposition mechanism is sustained by
the IR spectrum of intermediate isolated at 430 °C (Fig. 5b)
which still contains the characteristic vibration bands for
primary and secondary amine groups [mas(NH2), 3410 s;
ms(NH2), 3175 s; m(NH), 3000 sh] as well as for carbon–
nitrogen bonds [m(C=N), 1659 s; m(C–M), 1123 s]; the dis-
appearance of the strong band characteristic to stretching
The second step, which is strong exothermic, corre-
sponds to oxidative degradation of the remaining ligand
leading to VO2 oxide. The last two steps are similar with
123

New vanadyl complexes with metformin derivatives
261
Thermal decomposition of VO(o-TBG)2(H2O)0.5
H
N
N
NH2
N
NH2
N
H
N
H
N
H
N
H
N
O
V
O
V
N
The analysis of TG and DTA curves allowed us to establish
the final formula of this compound (Fig. 6). Thus, the first
endothermic mass loss in the temperature range 60–100 °C
corresponds to the lattice water molecules release. The
anhydrous compound is stable over a large temperature
range (100–210 °C) and then it decomposes in a similar
way with compound (1).
N
H
N
H
N
H
N
H
H2N
H2N
H
N
Scheme 1
(a)
Conclusions
The new complexes of oxovanadium (IV) with biguanide
derivatives that belong to a class of coordination com-
pounds of current interest for their insulin-mimetic prop-
erties have been synthesised and characterised. Spectral
data indicate a square pyramidal stereochemistry for
complexes and a chelate coordination mode for biguanide
derivatives.
(b)
Thermal analysis (TG, DTA) of these complexes con-
firms the complexes composition and allows the number
and nature of the water molecules determination. It was
also evidenced that the intermediate steps correspond to the
oxidative degradation of ligands. The residue in all cases
was shcherbinaite modifications of V2O5 as indicated by
powder X-ray diffraction.
3500 3000 2500 2000 1500 1000
Wavenumber/cm–1
500
Fig. 5 IR spectra of complex (2) (a) and isolated intermediate at
430 °C (b)
These complexes seem to be more stable in the case of
aromatic side groups present in ligands.
50
0
40
References
30
1. McNeill JH, Yuen VG, Hoveyda HR, Orvig C. Bis(maltolato)-
oxovanadium(IV) is a potent insulin mimic. J Med Chem. 1992;
35:1489–91.
2. Yuen VG, Caravan P, Gelmini L, Glover N, McNeill JH, Set-
yawati IA, Zhou Y, Orvig C. Glucose-lowering properties of
vanadium compounds: comparison of coordination complexes
with maltol or kojic acid as ligands. J Inorg Biochem. 1997;68:
109–16.
3. Sakurai H, Fujii K, Watanabe H, Tamura H. Orally active and
long-term acting insulin-mimetic vanadyl complex: bis(picoli-
nato)oxovanadium(iv). Biochem Biophys Res Commun. 1995;
214:1095–101.
4. Sakurai H, Sano H, Takino T, Yasui H. An orally active antidi-
abetic vanadyl complex, bis(1-oxy-2-pyridinethiolato)oxovana-
dium(IV), with VO(S2O2) coordination mode; in vitro and in vivo
evaluations in rats. J Inorg Biochem. 2000;80:99–105.
5. Peters KG, Davis MG, Howard BW, Pokross M, Hastogi V,
Diven C, Greis KD, Eby-Wilkens E, Mayer M, Evodokimov A,
Soper S, Gebbauffe F. Mechanism of insulin sensitization by
BMOV (bis maltolato oxovanadium); unliganded vanadium (VO)
as the active component. J Inorg Biochem. 2003;96:321–30.
6. Sakurai H, Katoh A, Yoshikawa Y. Chemistry and biochemistry
of insulin-mimetic vanadium and zinc complexes. Trial for
–20
20
↑
10
–40
–60
–80
0
–10
–20
–30
30
200
400
600
800
Temperature/°C
Fig. 6 TG and DTA curves of VO(o-TBG)2(H2O)0.5
those observed for complex (1), VO2 oxidation to V2O5
followed by the melting of final product (found/calcd.
overall mass loss: 78.3/78.4%).
123

262
R. Olar et al.
treatment of diabetes mellitus. Bull Chem Soc Jpn. 2006;79:
1645–64.
7. Zhang Y, Yang XD, Wang K, Crans DC. The permeability and
cytotoxicity of insulin-mimetic vanadium (III, IV, V)-dipicolinate
complexes. J Inorg Biochem. 2006;100:80–7.
8. Rehder D. The trigonal-bipyramidal NO4 ligand set in biologi-
cally relevant vanadium compounds and their inorganic models.
J Inorg Biochem. 2008;102:1152–8.
20. Woo LC, Yuen VG, Thompson KH, McNeill JH, Orvig C.
Vanadyl-biguanide complexes as potential synergistic insulin
mimics. J Inorg Biochem. 1999;76(3–4):251–7.
21. Pignard P. Spectrophotometric determination of N,N-dimethyl-
biguanide in blood and urine. Ann Biol Clin. 1962;20:325–33.
22. Siest G, Roos F, Gabou JJ. Dosage du N–N-dimethyl biguanide
(glucophage) par le diacetyle en milieu alcalin. Bull Soc Pharm
Nancy. 1963;58:29–38.
9. Kaliva M, Gabriel C, Raptopoulou CP, Terzis A, Salifoglou A.
pH-specific synthesis, isolation, spectroscopic and structural
characterization of a new dimeric assembly of dinuclear vana-
dium(V)–citrate–peroxo species from aqueous solutions. Inorg
Chim Acta. 2008;361:2631–40.
10. Sheela A, Roopan SM, Vijayaraghavan R. New diketone based
vanadium complexes as insulin mimetics. Eur J Med Chem.
2008;43:2206–10.
23. Kanaze FI, Kokkalou E, Niopas I, Georgarakis M, Stergiou A,
Bikiaris D. Thermal analysis study of flavonoid solid dispersions
having enhanced solubility. J Therm Anal Calorim. 2006;83:
283–90.
24. Nakamoto K. Infrared and Raman spectra of inorganic and
coordination compounds. New York: Wiley; 1986.
25. Lever ABP. Inorganic electronic spectroscopy. Amsterdam:
Elsevier; 1986.
11. Nilsson J, Degerman E, Haukka M, Lisensky GC, Garribba E,
Yoshikawa Y, Sakurai H, Enyedy EA, Kiss T, Esbak H, Rehder
D, Nordlander E. Bis- and tris(pyridyl)amine-oxidovanadium
complexes: characteristics and insulin-mimetic potential. Dalton
Trans. 2009;38:7902–11.
26. Shukla S, Mishra AP. Non-isothermal degradation-based solid
state kinetics studyof copper (II) schiff base complex, at different
heating rates. J Therm Anal Calorim. 2011. doi:10.1007/s10973-
011-1616-4.
27. Olar R, Badea M, Marinescu D. Thermal study of some new
Ni(II) and Cu(II) complexes with ligands derived from N,N-
dimethylbiguanide as potential antimicrobials. J Therm Anal
Calorim. 2010;99:893–8.
28. Olar R, Badea M, Grecu MN, Marinescu D, Lazar V, Balotescu
C. Thermal behavior, spectroscopic and biological characteriza-
tion of copper(II) complexes with N,N-dimethylbiguanide.
J Therm Anal Calorim. 2008;92:239–43.
29. Olar R, Badea M, Cristurean E, Parnau C, Marinescu D. Thermal
behaviour of new N,N-dimethylbiguanide complexes having
selective and effective antibacterial activity. J Therm Anal Cal-
orim. 2006;84:53–8.
30. Olar R, Badea M, Cristurean E, Lazar V, Cernat R, Balotescu C.
Thermal behavior, spectroscopic and biological characterization
of Co(II), Zn(II), Pd(II) and Pt(II) complexes with N,N-dimeth-
ylbiguanide. J Therm Anal Calorim. 2005;80:451–5.
31. Olar R, Badea M, Marinescu D, Iorgulescu E, Stoleriu S. Ni(II)
complexes with ligands resulted in condensation of N,N-dimeth-
ylbiguanide and pentane-2,4-dione. Synthesis, thermal behaviour
and spectroscopic characterization. J Therm Anal Calorim. 2005;
80:363–7.
´
12. Parajon-Costa BS, Baran EJ. Vibrational spectra of bis(maltola-
to)oxovanadium(IV): a potent insulin mimetic agent. Spectro-
chim Acta A Mol Biomol Spectrosc. 2011;78:133–5.
13. Willsky GR, Chi L-H, Godzala M III, Kostyniak PJ, Smee JJ,
Trujillo AM, Alfano JA, Ding W, Hu Z, Crans DC. Anti-diabetic
effects of a series of vanadium dipicolinate complexes in rats
with streptozotocin-induced diabetes. Coord Chem Rev. 2011;
255:2258–69.
14. Xie M-J, Niu Y-F, Yang X-D, Liu W-P, Li L, Gao L-H, Yan S-P,
Meng Z-H. Effect of the chloro-substitution on lowering diabetic
hyperglycemia of vanadium complexes with their permeability
and citotoxicity. Eur J Med Chem. 2010;45:6077–84.
15. Wei Y, Zhang C, Zhao P, Yang X, Wang K. A new salicylic acid-
derivatized kojic acid vanadyl complex: synthesis, characteriza-
tion and anti-diabetic therapeutic potential. J Inorg Biochem.
2011;105:1081–5.
16. Passadouro M, Metelo AM, Mela˜o AS, Pedro JR, Faneca H,
Carvalho E, Margarida M, Castro CA. Study of the antidiabetic
capacity of the VO(dmpp)2 complex. J Inorg Biochem. 2010;104:
987–92.
17. Cransa DC, Trujillo AM, Pharazyna PS, Cohenc MD. How
environment affects drug activity: localization, compartmentali-
zation and reactions of a vanadium insulin-enhancing compound,
dipicolinatooxovanadium(V). Coord Chem Rev. 2011;255:
2178–92.
32. Valmalette JC, Gavarri JR. High efficiency thermochromic
VO2(R) resulting from the irreversible transformation of
VO2(B). Mater Sci Eng. 1998;B54:168–73.
33. Babykutty PV, Prabhakaran CP, Anantaraman R, Nair CGR.
Electronic and infrared spectra of biguanide complexes of 3d-
transition metals. J Inorg Nucl Chem. 1974;36:3685–8.
18. Poucheret P, Verma S, Grynpas MD, McNeill JH. Vanadium and
diabetes. Mol Cell Biochem. 1998;188:73–80.
19. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:
574–9.
123