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Inorganica Chimica Acta 328 (2002) 61 68

Curcuminoids as potential new iron-chelating agents:

spectroscopic, polarographic and potentiometric study on their
Fe(III) complexing ability
Marco Borsari, Erika Ferrari, Romano Grandi, Monica Saladini *
Department of Chemistry, Uni6ersity of Modena and Reggio Emilia, Via Campi 183, 41100 Modena, Italy
Received 9 April 2001; accepted 12 September 2001

Abstract
The pKa values of curcumin and diacetylcurcumin are, here doubtless, determined by means of spectroscopic and potentiometric
measurements, and the enolic proton is the more acidic one. The interaction of Fe3 + with curcumin and diacetylcurcumin, in
water/methanol 1:1 solution, leads to the formation of the complex species [FeH2CU(OH)2] and [FeDCU(OH)2] (H2CU and
DCU= curcumin or diacetylcurcumin monoanion, respectively) which prevails near pH 7. At more basic condition the prevailing
species are [FeH2CU(OH)3] and [FeDCU(OH)3], which prevent metal hydroxide precipitation. 1H NMR data state that the
dissociated b-diketo moiety of the ligands is involved in metal chelation. The pKa value of the deprotonation reaction is strongly
anticipated by the metal ion, as shown by UV spectral data. The stability constants, evaluated from potentiometric data, are near
to that of desferrioxamine, which is, by now, the only iron-chelating agent for clinical use. 2002 Elsevier Science B.V. All rights
reserved.
Keywords: Iron complexes; Curcumin complexes; Chelate-ligand complexes

1. Introduction
Curcumin, a yellow spice and pigment from Curcuma
longa L. (Zingiberaceae), is by far known for its antioxidant [14], antiinflammatory [4,5] and anticancer
[3,4,6,7] activities. Curcumin has proved not to have
toxic, genotoxic or teratogenic properties [8 10], so this
safe phytonutrient has been widely implied in preclinical and clinical studies [4]. Curcumin and its derivatives
have shown the ability of being free-radical scavenger,
interacting with oxidative cascade, quenching oxygen
and chelating and disarming oxidative properties of
metal ions [11 13]. Biological activity of curcumin has
been attributed to the hydroxyl group substituted on
the benzene rings and also to the diketonic structure
[14]. The b-diketo moiety of curcumin undergoes a
keto enol tautomerism. Crystal studies [15 17] have
shown that the symmetric structure of curcumin leads
* Corresponding author. Tel.: + 39-059-205 5040; fax: +39-059373 543.
E-mail address: saladini@unimo.it (M. Saladini).

to a statistically even distribution of the enol proton

between the two oxygen atoms. The strong chelating
ability of diketones has been widely investigated towards a great number of metal ions; therefore, curcumin could be of great importance in the chelating
treatment of metal intoxication and overload. Among
all metals, iron earns a relevant position due to its
indispensability in life, since it takes part in processes
such as oxygen transport and electron transfer and
DNA synthesis. Iron regulation undergoes complex
mechanisms that tend to limit external exchange and
make efficient the reutilisation from internal sources.
Anyway, iron overload may occur as a result of hyperabsorption by diet and blood transfusions, such as in
treatment of anaemia. Desferrioxamine, the only ironchelating agent for clinical use, has to be administrated
by parental injection, because of its low gastrointestinal
absorption. In this context, we focused our attention on
curcumin and its derivative diacetylcurcumin as new
potential chelating agents. In this study we have elucidated the active chelating site of these ligands and their
complexing ability towards iron(III).

0020-1693/02/$ - see front matter 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 0 - 1 6 9 3 ( 0 1 ) 0 0 6 8 7 - 9

M. Borsari et al. / Inorganica Chimica Acta 328 (2002) 6168

62

2. Experimental

2.1. Materials
Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6heptadiene-3,5-dione] (H3CU) and diacetylcurcumin

[1,7-bis(4-acetyl-3-methoxyphenyl)-1,6-heptadiene-3,5dione] (HDCU) were synthesised as in Refs. [18,19].

FeCl3 salt was preferred to Fe(NO3)3 one in the preparation of the stock solution because of its greater
stability towards hydrolysis process. Standardisation of
FeCl3 stock solution was performed by means of Spectroflame D ICP plasma spectrometer, samples contained
1% of HNO3 (BDH-Aristar).

2.2. Spectroscopy
1

Scheme 1.

Fig. 1. pH (in methanol) dependence of chemical shifts of H1trans and

H2trans protons of curcumin in CD3OD: () H1trans and () H2trans.

H NMR spectra were obtained in a Bruker Avance

AMX-400 spectrometer at 400.13 MHz with a broad
band 5 mm probe (inverse detection). Acquisition
parameters were as follows: spectral bandwidth; 17
ppm, pulse width; 7.6 ms (90 pulse), pulse delay; 1 s,
number of scans; 216512. Ligands spectra were run in
deuterated DMSO and CD3OD millimolar solutions.
For CD3OD solution the combined electrode was standardised with CH3OH buffers (pH 5.79 and 7.53), pD
values were then corrected to 0.4 unit according to the
relationship: pD= pH +0.4. [20]. All the pH values
reported are referred to methanolic scale. All spectra
were collected at 259 0.1 C and referenced to TMS.
Solution of Ga(III) was prepared by dissolving 2.5 mg
of Ga(NO3)39H2O in 0.1 ml of CD3OD. Equimolar
solutions of curcumin and diacetylcurcumin in the same
solvent were prepared. Constant additions (10 ml each
time) of Ga(III) solution were performed using a micropipette, the system was maintained under stirring
and spectra were registered after few minutes of
addition.
Complete NMR data and assignment for curcumin
and diacetylcurcumin, taking into account the previous
studies [19,21,22], the materials are available from the
author on request.
Spectrophotometric titrations were performed using a
PerkinElmer Lambda 20 spectrophotometer at 259
0.1 C in the 200600 nm spectral range, employing 1
cm quartz cell; 2.510 5 M ligand solutions were
investigated both in methanolic and methanolic/
aqueous (1:1 v/v) media; pH values were adjusted by
adding small amounts of concentrated NaOH and
HNO3. Standardisation of combined electrode in
CH3OH was performed as described in Section 3.2,
while in methanolic/aqueous (1:1 v/v) solutions two
appropriate buffers (pH 5.57 and 8.02), as explained in
Ref. [20], were employed. The reported pH values are
referred to the suitable solvent scale. Solutions of binary
systems M/L 1:1 were analysed under the same condition of concentration, solvent media and pH range.

2.3. Potentiometry
Fig. 2. pH (in methanol) dependence of aromatic proton Ha of
curcumin in CD3OD.

Potentiometric measurements were performed in

methanolic/aqueous (1:1 v/v) solutions at 2590.1 C

M. Borsari et al. / Inorganica Chimica Acta 328 (2002) 6168

63

Fig. 3. 1H NMR spectra of curcumin after progressive addition of gallium(III) in CD3OD solution. Ga(III)/curcumin ratio increases from
downwards to up page.

using fully automated Orion 960 Autochemistry system

and following the general procedures previously reported [23], with millivolt reading by stability of the
electrode (stability criterion 0.2 mV min 1). A constant
ionic strength 0.1 M (solid NaNO3) and nitrogen atmosphere were maintained in all experiments. The stability
constants (iprs ), which are defined by Eqs. (1) and (2),
where M is the metal, L is the ligand in the deprotonated form and H is the proton, were refined by
least-squares calculation using computer program SUPERQUAD [24], taking into account the presence of
[Fe(OH)]2 + , [Fe(OH)2]+ and [Fe(OH)3] species [25].
Owing to the extremely diluted conditions of the solutions, it seems reasonable to neglect the mixed aqueous
and hydroxo [FeCln ]3 n species, which were previously
found in concentrated solutions [26]. In addition, the
stability constants of these species [25] are very small,
compared to those of our complexes, as a consequence
they may be disregarded.
pM +rL+ sHUMp Lr Hs
iprs =[Mp Lr Hs ]/[M] (L) [H]
p

[Fe3 + ] was 210 4 and 10 4 M in presence of H3CU

and HDCU, respectively. Aqueous NaOH was used as
titrant, its concentration ranged from 2 10 2 to 5
10 3 M. At least ten measurements were performed for
each system with 40 data points in each titration in the
pH range 310.

2.4. Cyclic 6oltammetry

All data were collected through a PAR 273A potentiostat/galvanostat, working at different scan rates,
ranging from 0.02 to 0.5 V s 1. Ionic strength was kept
constant in all systems (0.05 M in NaNO3), maintaining

(1)
s

(2)

Protonation constants of ligands were determined by

the titration of, at least, four 5 10 4 M solutions, for
both H3CU and HDCU in methanolic/aqueous (1:1
v/v) solutions. The ligandmetal systems were investigated in the 1:1 molar ratio while the low solubility of
the ligands prevented the study in presence of ligand
excess (i.e. 2:1, 3:1 molar ratios).
Because of the different solubilities of complex and
due to the specific ligand employed, concentration of

Fig. 4. Spectrophotometric titration of curcumin with NaOH in

aqueous/methanolic (50:50 v/v) solution.

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M. Borsari et al. / Inorganica Chimica Acta 328 (2002) 6168

3. Results and discussion

3.1. Cyclic 6oltammetry

Fig. 5. Plotting of absorbance of curcumin vs. pH (in water/

methanol) at u= 423 nm.

Fig. 6. pH dependence of absorbance for Fe3 + /curcumin () and

Fe3 + /diacetylcurcumin () 1:1 molar ratio systems, respectively, at
430 and 416 nm in aqueous/methanolic 1:1 v/v solution.

argon atmosphere at 2590.1 C. The working microelectrode was constituted by a carbon glass surface
of 2 mm diameter. A saturated calomel electrode (SCE)
was used as the reference and a platinum sheet as a
counter electrode. All measurements were collected in
aqueous/methanolic (1:1 v/v) solutions, the concentration of ligands was kept 2 10 4 M in all the experiments. Same conditions were maintained also for
voltammetric titrations of the ligands and M/L 1:1
systems; the pH values were recorded using a Jenway
3045 ion analyser equipped with an Ingold U402 pH
combination electrode. Adjustment of pH values was
performed by adding small amounts of concentrated
NaOH.

Voltammetric measurements performed on a 1:1 water/methanol solution of FeCl3 show a reduction peak
(1), with an Epc value of 0.184 V versus SCE, while a
less-defined anodic counterpart (2) appears at 0.442 V
versus SCE. A third peak (3), at a more cathodic
potential ( 1.239 V vs. SCE), shows a current value,
which is twice that of peak (1). The dependence of ipc
(1) and (3) on Fe(III) concentration and 6 1/2 (6=scan
rate) shows diffusion controlled processes, but the number of electrons involved is one for peak (1) and two for
peak (3), respectively. The data indicate that peaks (1)
and (2) correspond to the quasi-reversible redox equilibrium Fe(III)/Fe(II) and peak (3) to the irreversible
reduction of Fe(II) to Fe(0) [27]. The presence of an
equimolar amount of H3CU, at pHB4.5 does not
affect the cyclic voltammetry curves observed for
Fe(III). At pH\ 4.5, on increasing pH, the cathodic
peak (1) shifts towards more negative potentials (Epc =
0.303 V at pH 6.75; Epc = 0.342 V at pH 8.04),
while the anodic peak (2) became poorly defined and
almost vanishes. In the presence of an equimolar
amount of HDCU, the CV signals differ from those of
Fe(III) even at pH 3.8 and remain constant until pH
4.5. At higher pH, at increasing pH, the Epc values shift
cathodically (Epc = 0.320 V at pH 7.26; Epc =
0.375 V at pH 8.07), as observed for the Fe(III)CU
system. The cyclic voltammetry measurements at pHB
4.5 and 3.8 for H3CU and HDCU, respectively, agree
with the presence of Fe(III) only. At higher pH, the
shift of the Epc value suggests the progressive formation
of Fe(III) complexes, which give poorly reversible electrochemical reduction. The pH dependent Epc shifts
suggest the presence of at least two species in a pH-dependent equilibrium.

3.2. 1H NMR spectroscopy

Curcumin and diacetylcurcumin give very similar
spectral patterns, actually the only relevant difference
between these two molecules is the presence, in the
second one, of acetyl groups that protect hydroxylic
functions. The ketoenol tautomerism of b-diketones,
under slow chemical exchange conditions, can be detected by NMR spectroscopy. Under slightly alkaline
pH, curcumin and its derivatives are present in the
enolic tautomer with proton exchange within the enol
structure, as a consequence the chemical shift of H1/H7
(H1trans ) are equivalent and so are the ones of H2/H6
(H2trans ) (Scheme 1).
DMSO spectra show a broad peak at 16.4 ppm, this
great shift of the enolic hydrogen proton (H), at very
low field, is due to the combined effect of the strong

M. Borsari et al. / Inorganica Chimica Acta 328 (2002) 6168

65

Table 1
Logarithm of protonation constants of the ligands and complexes formation constants (water/methanol 1:1 v/v solution)
Curcumin (H3CU)
[HCU]2
[H2CU]
[H3CU]
[FeH2CU]2+
[FeH2CU(OH)2]

[FeH2CU(OH)3]

log i011
log K3
log i012
log K2
log i013
log K1
log i112
log i112log i012
log i110
log i110log i012
log K a
log i111
log i111log i012

Diacetylcurcumin (HDCU)
10.69(2)
10.69(2)
19.99(1)
9.30(3)
28.53(2)
8.54(3)
29.13(6)
9.14(8)
22.06(4)
2.07(6)
29.1(1)
12.51(6)
7.48(7)

[HDCU]

log i011

8.75(4)

[FeDCU]2+

log i110

11.44(7)

[FeDCU(OH)2]

log i112
log K a

3.06(4)
30.1(1)

[FeDCU(OH)3]-

log i113

5.00(5)

a
log K is referred to the equilibria: Fe3++H2CU+2OH X [FeH2CU(OH)2] for curcumin and Fe3++DCU+2OH X [FeDCU(OH)2]
for diacetylcurcumin [pKw (water/methanol 1:1) 13.52].

intramolecular hydrogen bond and of the conjugation

through p system. By progressive addition of NaOH,
this peak disappears, while the He signal does not show
any variation.
Even though curcumin is a quite stable molecule in
CD3OD solution, spectra show, after few days, the
decrease in integrated area of He proton signal, until it
disappears; this behaviour suggests an exchange process
of the He proton with the deuterated solvent. The
presence of acid or base makes the process faster and
the signal disappears in few hours, suggesting a great
mobility of this proton. Recent photolic data attributed
the antioxidant action of curcumin to this H-atom
transfer ability [28].
1
H NMR titration in CD3OD-d4 helps the assignment of pKa values of curcumin.
On increasing pD values, all proton signals are
shifted suggesting deprotonation processes. From the
pH dependence of the H2trans chemical shift (Fig. 1) is
detected a pKa value of 12.5 (methanol scale), which
can be associated to the enolic deprotonation. On the
other hand, from the pH dependence of the chemical
shift of aromatic protons (Fig. 2), a second pKa value
of 13.6 is found, and it is attributed to the dissociation
of phenolic groups.
The behaviour of H1trans l is slightly different as it is
influenced by both deprotonation reactions, giving an
intermediate pKa value around 13 (Fig. 1). Diacetylcurcumin shows a similar behaviour, except for aromatic
protons, whose peaks do not shift because phenolic
groups are protected. Plotting l for H1trans and H2trans
versus pH, a pKa value of 13 is found.
NMR data are also useful in identifying the binding
site in metalchelate complexes; for this purpose we
substituted the paramagnetic Fe(III) with diamagnetic
Ga(III), as suggested in many recent works [2931],
and we followed the changes in curcumin and diacetyl-

curcumin 1H NMR spectra, induced by progressive

addition of Ga(NO3)3 solution in CD3OD. As shown in
Fig. 3, two new doublets are observed, respectively, at
l= 7.92 and 6.92 with the same coupling constant JHH
of 15.6 Hz. These signals correspond to H1trans and
H2trans protons of the complexed form of curcumin (or
dieacetylcurcumin) with Ga(III). These resonances are
downfield shifted according to the deshielding effect
due to the replacement of H with Ga(III) in the enolic
structure. No particular changes are, however, observed
for aromatic protons, while He proton is minimally
downfield shifted and the exchange with the deuterated
solvent is still present.

Fig. 7. Species distribution curves for binary systems Fe(III)/curcumin () and Fe(III)/diacetylcurcumin ( ) in 1:1 molar ratio.
[Fe3 + ]= 2 10 4 M. (1) [FeH2CU]2 + ; (2) [Fe(OH)]2 + ; (3)
[Fe(OH)2]+; (4) [FeH2CU(OH)2]; (5) [FeH2CU(OH)3]; (6)
[Fe(OH)]2 + ; (7) [Fe(OH)2]+; (8) [FeDCU]2 + ; (9) [FeDCU(OH)2];
(10) [FeDCU(OH)3].

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M. Borsari et al. / Inorganica Chimica Acta 328 (2002) 6168

Table 2
Logarithms of equilibrium constants of some Fe(III) complexes with chelating agents. Literature data are taken from Ref. [34]

The electronic effect of gallium is extended along the

carbon chain, and it is more relevant for H2trans (Dl =
0.16 ppm) than H1trans (Dl =0.10 ppm) according
to the resonance structure that makes C1 a carbocation.
By adding Ga(III) to the ligand solution, the integrated area of both H1trans and H2trans of the complexed
form increases, while a diminishing in the area of
uncomplexed H1trans and H2trans protons is registered,
until they disappear when M/L (1:1) is reached. The
replacement of H with Ga(III), does not require any
alkali addition, but it is observed at acidic pH (45),
indicating a great metal inducing deprotonation of the
enolic structure.
The system Ga(III)diacetylcurcumin parallels well
with the behaviour of Ga(III) curcumin.
NMR data undoubtedly confirm that the binding site
is represented by b-diketonic structure in the enolic
tautomer.

3.3. UV spectroscopy
The electronic spectra of curcumin in methanolic
solution show a band maximum at 420 nm, whose
intensity lowers on increasing pH with the formation of
an isobestic point at 460 nm. From the plot of absorbance versus pH, a pKa value of 12.1(2) (methanol
scale) is found, in agreement with the NMR data.
Diacetylcurcumin behaves similarly, and the pKa value
obtained from spectrophotometric titration is 12.9(2).
The same trend for the two ligands enforces the attribution of this pKa value to the dissociation of the enolic
proton.
Spectrophotometric titration of both ligands in
methanolic/aqueous (1:1 v/v) mixed solution (Fig. 4)
matches the one in methanolic media, although the pKa
values are lowered about 3 units.
The absorbance versus pH for curcumin is plotted in
Fig. 5, and the observed pKa value is 8.7(2). This value

M. Borsari et al. / Inorganica Chimica Acta 328 (2002) 6168

is close to that previously found by Dietze et al. (8.89)

[32], even though it was attributed to the dissociation of
a phenolic proton; while photochemical studies [28]
found a pKa of 8.55(5), related to the dissociation of the
enolic group.
The addition of Fe3 + to the methanolic/water solution of the ligands leads to a decrease in the intensity of
the band maximum at 420 nm and a new absorption,
which is due to a ligand to metal charge-transfer
(LMCT) band [33], appears near 500 nm [13], similar to
what previously found for analogous ligands. The
LMCT intensity is proportional to the number of ligands and a progressive lowering of umax is usually
observed while increasing the number of coordinated
ligands. In our case the LMCT intensity rises until L/M
1:1 molar ratio, while no changes in umax are observed.
Further increase of L/M ratio the spectra do not
change any more, suggesting a metal coordination by
only one ligand molecule. The lack of 1:2 and 1:3
complexes is probably due to the great steric hindrance
of curcuminoids.
Spectrophotometric titration of Fe3 + /curcumin (1:1)
system (Fig. 6) shows two equivalent points: the first
one at pH 5 is attributed to the metal induced deprotonation of enolic proton, while the second one at pH
10.5 is probably due to the phenolic groups dissociation, that, in the ligand alone, was masked by the enolic
one.
In the Fe3 + /diacetylcurcumin system the metal promoting deprotonation leads to a single PE at pH 4.2.

67

neutral [FeL(OH)2] one (L =H2CU or DCU).

The stability constants of the species [FeH2CU(OH)2]
(log K= 29.1(1)) is greater than the one found for
[Fe(acac)3] (25.3 [25]), which is a tris-chelate complex
with the same coordination moiety of our ligands.
A comparison of stability constants of chelate complexes used as sequestering agents towards Fe(III) overload is reported in Table 2.
The stability of our complexes is greater than that of
EDTA complex and, in general, of aminopolycarboxylate complexes, due to the fact that the carboxylate ion
has a relatively low degree of hardness; as a consequence the ferric hydroxide precipitates around pH
89.
The iron(III) affinity for cathecol and cathecol-containing ligands seems very high, but the value of log K
is not a good measure of the stability of 1:3 complex,
because these ligands have very high pKa, so the hydrogen ion competition is effective at physiological pH.
Pyridinones possess more than a single negative
charge upon one proton dissociation, although less
than the two negative charges characteristic of cathecol;
therefore, these ligands have a definite advantage over
cathecols when they come to equilibrium in physiological solutions.
The exadentate desferrioxamina, which is the only
iron-chelating agent currently in widespread clinical
use, shows a log K similar to those of our complexes, so
we may propose curcuminoid ligands as alternative in
clinical treatment of iron overload, also in view of the
absence of toxic effects even at high dosage.

3.4. Potentiometry
The potentiometric titration of curcumin in methanolic/aqueous media allowed to calculate three protonation constants (Table 1); the pKa value (8.5) associated
with the first deprotonation equilibrium is near to that
found via UV spectroscopic data in the same solvent
system.
The potentiometric titration of diacetylcurcumin, in
the same solvent, shows only one dissociation equilibrium with a pKa of 8.75 in agreement to what was
previously found.
The Fe3 + /curcumin or diacetylcurcumin systems in
1:1 molar ratio originate at one equivalent point in
accordance to the reaction:
mNaOH =mL + 3mFe3 +

(3)

where m is the number of moles. The complex species

found are reported in Table 1.
Diacetylcurcumin forms more stable complexes than
curcumin, possibly due to its greater basicity. The great
ability of Fe3 + to coordinate hydroxylic groups allows
the formation of mixed hydroxo complexes, and, as
shown in the species distribution curves (Fig. 7), the
prevailing species, at acidic and slightly basic pH, is the

Acknowledgements
We are grateful to the Centro Interdipartimentale
Grandi Strumenti (CIGS) of the University of Modena
and Reggio Emilia which supplied the NMR spectrometer, we are also thankful to the Ministero dellUniversita` e della Ricerca Scientifica e Tecnologica of Italy for
financial support.

References
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]

Sreejayan, M.N.A. Rao, J. Pharm. Pharmacol. 46 (1994) 1013.

Sreejayan, M.N.A. Rao, Int. J. Pharm. 100 (1993) 93.
M.K. Unnikrishnan, M.N.A. Rao, Pharmazie 50 (1995) 490.
H.P.T. Ammon, M.A. Wahl, Planta Med. 57 (1991) 1.
R.J. Anto, G. Kuttan, K.V.D. Babu, K.N. Rajasekharan, R.
Kuttan, Pharm. Pharmacol. Commun. 4 (1998) 103.
R.J. Anto, G. Kuttan, K.V.D. Babu, K.N. Rajasekharan, R.
Kuttan, Int. J. Pharm. 131 (1996) 1.
H.H. Tnnesen, H. De Vries, J. Karlsen, G.B. van Henegouwen,
J. Pharm. Sci. 76 (1987) 371.
B. Wahlstrom, G. Blennow, Acta Pharmacol. Toxicol. 43 (1978)
86.
Vijayalaxmi, Mutat. Res. 79 (1980) 125.

68
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]

[22]

M. Borsari et al. / Inorganica Chimica Acta 328 (2002) 6168

S.K. Abraham, P.C. Kesavan, Mutat. Res. 136 (1984) 85.
H.H. Tnnesen, Int. J. Pharm. 50 (1989) 91.
E. Kunchandy, M.N.A. Rao, Int. J. Pharm. 58 (1990) 237.
H.H. Tnnesen, J.V. Greenhill, Int. J. Pharm. 87 (1992) 79.
M.T. Huang, T. Lysz, T. Ferraro, T. Abidl, J.D. Laskin, A.H.
Conney, Cancer Res. 51 (1991) 813.
H.H. Tnnesen, J. Karlsen, A. Mostad, Acta Chem. Scand., B
36 (1982) 475.
H.H. Tnnesen, J. Karlsen, A. Mostad, U. Pedersen, P.B. Rasmussen, S.O. Lawesson, Acta Chem. Scand., B 37 (1983) 179.
J. Karlsen, A. Mostad, H.H. Tnnesen, Acta Chem. Scand., B
42 (1988) 23.
H.J.J. Pabon, Recl. Trav. Chim. Pays-Bas 83 (1964) 379.
P.J. Roughley, D.A. Whiting, J. Chem. Soc., Perkin Trans.
(1973) 2379.
D.D. Perrin, B. Dempsey, Buffers for pH and Metal Ion Control, Chapman and Hall, London, 1979.
A.N. Nurfina, M.S. Reksohadiprodjo, H. Timmerman, U.A.
Jenie, D. Sugiyanto, H. van der Goot, Eur. J. Med. Chem. 32
(1997) 321.
A. Mazumder, N. Neamati, S. Sunder, J. Schulz, H. Pertz, E.
Eich, Y. Pommier, J. Med. Chem. 40 (1997) 3057.

[23] M. Borsari, L. Menabue, M. Saladini, Polyhedron 18 (1999)

1983.
[24] P. Gans, A. Sabatini, A. Vacca, J. Chem. Soc., Dalton Trans.
(1985) 1185.
[25] NIST Standard Reference Database 46, Critical Selected Stability Constants Version 5.
[26] G. Giubileo, M. Magini, G. Licheri, G. Paschina, G. Piccaluga,
G. Pinna, Inorg. Chem. 22 (1983) 1001.
[27] K.E. Heusler, in: A.J. Bard (Ed.), Encyclopedia of Electrochemistry of the Elements, Marcel Dekker, New York, 1982, p. 230.
[28] S.V. Jovanovic, S. Steenken, C.W. Boone, M.G. Simic, J. Am.
Chem. Soc. 121 (1999) 9677.
[29] R.A. Atkinson, A.L.M.S. El Din, B. Kieffer, J.F. Lefevre, M.A.
Abdallah, Biochemistry 37 (1998) 15965.
[30] Y. Hara, L. Shen, A. Tsubouchi, M. Akiyama, K. Umemoto,
Inorg. Chem. 39 (2000) 5074.
[31] S. Kazanis, T.C. Pochapsky, J. Biomol. NMR 9 (1997) 337.
[32] F. Dietze, A.F. Arrieta, U. Zimmer, Pharmazie 52 (1997) 302.
[33] R.L. Lintvedt, L.K. Kernitsky, Inorg. Chem. 9 (1970) 491.
[34] R. Bergeron, G.M. Brittenham, Development of Iron Chelators
for Clinical Use, CRC Press, Boca Raton, FL, 1994.