Taking the next step toward inert Mn2+ complexes of open-chain ligands: The case of the rigid PhDTA ligand

Article abstract of DOI:10.1039/c8nj00121a

In line with our research to find inert Mn(ii) complexes as contrast agents for magnetic resonance imaging, we have studied the aromatic-ring rigidified EDTA-analogue o-phenylenediamine-N,N,N′,N′-tetraacetic acid (PhDTA). The protonation constants (KHi) o

Full text of DOI:10.1039/c8nj00121a

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Tircsó, New J. Chem., 2018, DOI: 10.1039/C8NJ00121A.
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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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Making a next step toward inert Mn2+ complexes of open-chain
ligands: the case of the rigid PhDTA‡ ligand†
Kristóf Póta,a Zoltán Garda,a Ferenc Krisztián Kálmán,a José Luis Barriada,b David Esteban-Gómez,b
Carlos Platas-Iglesias,b Imre Tóth,a Ernő Brücher,a and Gyula Tircsó*,a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
In line with our research to find inert Mn(II) complexes as contrast agents for Magnetic Resonance Imaging, we have
studied the aromatic–ring rigidified EDTA-analogue o-phenylenediamine-N,N,N’,N’-tetraacetic acid (PhDTA). The
protonation constants (KiH) of PhDTA and stability constants of complexes formed between this open-chain ligand and
several different biogenic metal ions (Ca2+, Mg2+, Zn2+, Cu2+, Mn2+) have been determined in 0.15 M NaCl at 25 °C and
compared with the values reported in the literature previously. Protonation constants are lower than those of the
corresponding cis- and trans-CDTA complexes, which might be attributed to the electron withdrawing effect of the
phenylene group. The lower total basicity of the ligand leads to lower stability constants for all the examined metal
complexes. On the contrary, we have found that the conditional stability constants of [Mn(PhDTA)]2- and [Mn(trans-
CDTA)]2- are approximately the same, as both complexes are 100% formed by pH 5 and their pM values are also
comparable. The relaxivity of [Mn(PhDTA)]2- is nearly identical (r1 = 3.72 mM-1s-1) to that determined previously for the
[Mn(trans-CDTA)]2- complex (r1 = 3.62 mM-1s-1), and its pH-dependence confirms the equilibrium model used for the fitting
of the titration data. The results of kinetic studies of the metal exchange reactions reveal that the [Mn(PhDTA)]2- complex
possesses a slightly better dissociation kinetics profile than [Mn(trans-CDTA)]2-, which has been tested in vivo recently
(including human injections). The half-life of the dissociation of the complex near to physiological pH at 25 °C is 19 hours.
By using the rate constant calculated for the dissociation (pH=7.4, cCu2+=10 ꢀM) and the half-life of excretion (1.6 hour),
the ratio of the dissociated complex is estimated to represent 8% of the injected dose. DFT studies reveal that the metal
coordination environment of [Mn(PhDTA)]2- is very similar to that of [Mn(EDTA)]2-, both containing an inner-sphere water
molecule. Cyclic voltammetry studies indicate that [Mn(PhDTA)]2- is slightly more resistant towards oxidation to the Mn3+
complex than the EDTA analogue.
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functions (e.g. chronic kidney disease) after administration of
CAs.2 Because of these toxicity problems, there is a growing
interest in the development of new, less toxic complexes
Introduction
The effectiveness of Gd3+-based contrast agents (CAs) used in
Magnetic Resonance Imaging (MRI) examinations, such as
Magnevist® or Dotarem®, is undisputable.1 However the
toxicity of the free Gd3+ ion is high (LD50 = 0.2-0.5 mmol/kg),
and has been related to the development of Nephrogenic
Systemic Fibrosis (NSF) by patients with reduced renal acute
containing biogenic metal ions which are likely better tolerated
by living organisms. Some transition metal ions, which possess
lower electron spin than Gd3+, can be used as the central core
of a potential imaging agent. Such ions are for example high
spin Mn2+ (d5),3 Fe3+ (d5),4 Co2+ (d7)5 or Ni2+ (d8).6
In the case of the Mn2+ ion, oxidation to Mn3+ caused by
oxygen may lead to a drastic decrease of the paramagnetic
effect. Thus, the redox potential of Mn2+/Mn3+ system has to
be raised above +0.8 V by means of a suitable chelating ligand
to obtain a contrast agent that is not sensitive to the oxidative
conditions. On the other hand, the complexes undergoing
oxidation in biological conditions may also be valuable for MRI
imaging as redox-activated CAs, as it was demonstrated by
Aime7 and more recently by Caravan and co-workers.8 The
thermodynamic stability and kinetic inertness of the Mn2+
complexes are generally lower compared to the Gd3+
complexes. In this respect, to develop Mn2+ complexes for
a.Department of Inorganic and Analytical Chemistry, Faculty of Science and
Technology, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
E-mail address: gyula.tircso@science.unideb.hu
b.Centro de Investigaciones Científicas Avanzadas (CICA), Departamento de
Química, Universidade da Coruña, Campus da Zapateira-Rúa da Fraga 10, A
Coruña, Spain
† Electronic Supplementary Information (ESI) available: Structures of the ligands
mentioned in the text, cyclic voltammogram of [Mn(EDTA)]2-, bond distances of the
metal coordination environment and optimised Cartesian coordinates obtained
with DFT calculations.
‡ PhDTA = o-phenylenediamine-N,N,N',N'-tetraacetic acid
This paper is dedicated to professors Carlos F. G. C. Geraldes and Lothar Helm on
the occasion of their retirement.
This journal is © The Royal Society of Chemistry 20xx
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application as CAs is a great challenge, because it requires a to the presence of an ortho-phenylenediamine unit in the
good balance between the thermodynamic stability, relaxation molecule. In the Mn2+ complexes of the cis- and trans-CDTA
and kinetic requirements, which are all crucial for in vivo MRI ligands the two N atoms of the iminodiacetate groups define
applications. There is only one commercially available N-C-C-N angles of ∼
50º,27 while the unsaturated nature of the
(although already withdrawn from the European markets) phenyl unit of PhDTA forces a planar N-C-C-N entity. As a
non-Gd3+ based contrast agent, [Mn(DPDP)]4- (Mangafodipir, result, the structure of the Mn2+ complex of PhDTA is expected
Teslascan®), which is applied in MRI examinations of liver.9 The to be somewhat different to that of [Mn(trans-CDTA)]2-, which
human body possesses mechanisms to eliminate the excess of in turn may lead to differences between the thermodynamic
Mn2+, but this works only in a limited concentration range and kinetic properties of the two complexes. We do not expect
(beyond that range it also possesses toxic effects with a drastic change in relaxivity because of the presence of a
symptoms resembling Parkinson’s disease).10
coordinated water molecule and the identical overall charge of
The properties of Mn2+ complexes formed with macrocyclic both complexes.28 The thermodynamic properties of the
ligands (mostly derivatives of 9-aneN3, 12-aneN4, and pyridine PhDTA ligand and several of its metal complexes were studied
containing macrocycles 12-PyaneN4, 15-PyaneN5 and 15- in the 1980’s and 1990’s, but because of the differences in
PyaneN3O2) synthesized and studied in the past 7-8 years terms of the applied procedures (e.g. calorimetry, extraction
predominantly by Éva Tóth and co-workers, see Figure S1) are method, etc.) and ionic strengths (1.0 M NaClO4), as well as
also far from being optimal.11-15 For instance Mn2+ complexes due to the large differences in the reported stability data (for
of macrocyclic ligands, such as NOTA and DOTA, possess high [Cu(PhDTA)]2- a difference of 10 log units can be found in the
thermodynamic stability and suitable kinetic inertness for in literature),29-33 we decided to determine these values using an
vivo applications. However, the relaxivity (relaxation ionic strength close to the physiological conditions (0.15 M
enhancement spurred by the presence of 1 mM paramagnetic NaCl). Therefore, we synthesized the PhDTA ligand and
substance) of these complexes is low because of the lack of redetermined the stability constants of the Mn2+ complex and
the inner-sphere water molecule(s). On the other hand, those with other biogenic metal ions. Furthermore, we
coordinated water molecule(s) are observed in the complexes investigated the dissociation kinetics, relaxometric and
formed with ligands of lower denticity (e.g. ONO2A, NO2A, electrochemical properties of the [Mn(PhDTA)]2 complex.
−
PC1A or PC1P). However, the decrease in the number of metal Finally, the structure of the [Mn(PhDTA)]2− complex in solution
binding sites offered by the ligand affects negatively the kinetic was studied by using DFT calculations.
inertness and the stability of the Mn2+ chelates. An acceptable
balance of physicochemical properties (stability, redox
potential, inertness and relaxivity of Mn2+ complexes) was
found for cis-DO2A16 and its derivatives,17 opening a passable
avenue to Mn2+-based MRI CAs. The Mn2+ complexes formed
with linear ligands have almost the same thermodynamic
stability as the corresponding macrocyclic ones, but their
kinetic inertness are several orders of magnitude lower.12,13
For instance, while the [Gd(DTPA)]2- complex presents a half-
life of 33 hours at pH 5, the dissociation of [Mn(DTPA)]3- is so
fast at this pH that prevents the determination of the
Scheme 1. Ligands discussed in the present work.
dissociation rate even with the stopped-flow technique (with a
dead time of 8 ms).14 At the same time, linear ligands
represent some advantages over the macrocyclic ones, for
Results and discussion
instance because their synthesis is less challenging. Moreover,
Equilibrium and Relaxometric Studies
careful ligand design can supply candidates with improved
stability,18 and relaxivity,19 owing to the planned interaction of
the complexes with biomolecules such as HSA,19-21 or even
Mn2+-based responsive probes relying on the use of
bifunctional ligands.22 Among the Mn2+ complexes studied so
far [Mn(trans-CDTA)]2- and related trans-CDTA derivatives (e.g.
PyC3A) show by far the best kinetic parameters.22-25 More
recently, these complexes were successfully tested in vivo in
mice, in dogs and surprisingly even in human studies
confirming their applicability.26
The protonation constants of the PhDTA ligand must be
determined to subsequently measure the stability constant of
the [Mn(PhDTA)]2 complex. For this purpose direct pH-
−
potentiometric titrations have been carried out. During these
studies it is essential to choose an appropriate ionic strength
because the ions used to adjust the ionic strength interact with
both the ligand and metal ion. We have chosen a 0.15 M NaCl
ionic strength to model the NaCl background present in the
body fluids. The protonation constants obtained by
potentiometry are shown in Table 1 along with the ones
determined previously using different ionic strengths30,31,33
and the corresponding values of the EDTA and cis- or trans-
CDTA chelators.27 The comparison of the constants excels that
the log KiH values of PhDTA are lower than those of CDTA
The objective of this study is to determine the stability
constants of [M(PhDTA)]2- complexes and compare them with
the stabilities of the complexes formed with the structurally-
related EDTA, cis- and trans-CDTA ligands (Scheme 1). The
PhDTA ligand has an even more rigid structure than CDTA due
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ligands, with the total basicity of PhDTA being four orders of smaller than the value of the Cu2+ complexes of EDTA
magnitude lower. In these ligands (EDTA, cis- and trans-CDTA derivatives determined under identical conditions. On the
and PhDTA) the first two protonation processes are attributed other hand the stability constant determined in our study is in
to the two amine nitrogen atoms, while the protonations excellent agreement with the value determined previously by
occurring at acidic pH correspond to the acetate groups. The M. Tanaka and co-workers,32 indicating that the stability
considerable difference between the first two protonation constants published recently for M2+ complexes by T. Zhang
constants can be ascribed to the lower basicity of anilines and co-workers33 are not really reliable.
compared to aliphatic amines, which is the result of
The pH dependence of the relaxivity of [Mn(PhDTA)]2- was
delocalization of the nitrogen atom’s lone pair onto the studied to acquire information about the relaxivity of the
aromatic unit. The 3rd and the 4th protonation constant of the complex (r1p) on one hand, and to support the equilibrium
PhDTA chelator can be assigned to the protonation of model used in the analysis of the pH-potentiometric titrations
carboboxylate pendants while 5th and 6th protonation cannot on the other hand. As shown in Figure 4, the formation of a
be measured by pH-potentiometry. This suggests that these monoprotonated complex does not cause a considerable
protons are very acidic and dissociate easily in aqueous media, change in the relaxivity (only 0.3 – 0.5 mM-1s-1 units). The
similarly to the protons of strong acids. By comparing the dissociation of the complex starts at pH < 3.5 leading to
protonation constants with the previously reported ones, we significant increase in the relaxivity because of the formation
did not found significant deviations. The small differences may of [Mn(H2O)6]2+ (characterized by a r1p value of 7.92 mM-1s-1 at
arise from the applied ionic strength and less likely from 20 MHz and 25 oC). The measured relaxivity values remain
different measurement techniques.
constant in the pH range of 5-10, and then slightly decrease
In view of the protonation constants determined here, the above pH 10. This can be interpreted by the oxidation of
stability and protonation constants of PhDTA complexes manganese upon the dissociation of a mixed hydroxo complex.
formed with biogenic metal ions are not expected to deviate The mixed hydroxo complex has not been studied because
notably from the literature data. The acquired stability atmospheric oxygen oxidizes Mn2+ under the applied
constant values are also shown in Table 1, where the data conditions. The relaxivity of the [Mn(PhDTA)]2- complex is r1p
reported previously for PhDTA, EDTA and CDTAs are provided 3.72 mM-1s-1 (between pH 5-10), which is very similar to that
for comparison. As expected from the total basicity values, the
=
stability constants of the PhDTA complexes are significantly
1.0
0.8
0.6
0.4
0.2
0.0
lower compared to the EDTA and CDTA analogues. In the cases
of Mg2+, Ca2+ and Mn2+ the stability constants drop by 3-4
orders of magnitude, but the decrease of the stability
constants of the PhDTA complexes with Zn2+ and Cu2+ exceeds
6 orders of magnitude. However, the species distribution
curves of [Mn(PhDTA)]2- and [Mn(trans-CDTA)]2- complexes
(Figure 1) indicate that complex formation begins at pH 2.0
and ends at around pH 5.0 in both systems, which means that
their apparent stability is nearly the same. This is supported by
calculating and comparing the pMn values at pH 7.4 with 10
μM ligand and 10 μM Mn2+ concentrations (8.36 for
[Mn(PhDTA)]2- and 8.68 [Mn(trans-CDTA)]2-).15 In the case of
Mg2+, Ca2+, Mn2+, Zn2+ and Cu2+ ions the formation of ML,
mono- (MHL) and diprotonated (MH2L) complex species was
established. Potentiometric studies have also been carried out
with 2:1 metal-ligand ratios with Mn2+, Zn2+ and Cu2+ to
investigate the formation of dinuclear complexes. Both Zn2+
and Cu2+ form this kind of complexes with PhDTA, including
protonated dinuclear species, though they possess low
stability. The stability constant of the [Cu(PhDTA)]2- complex
could not be determined by using solely the pH-potentiometric
[Mn(t
CDTA)]2-
Mn2+
[Mn(Ht
CDTA)]-
[Mn(H2t CDTA)]
1.5
3.0
4.5
pH
6.0
7.5
1.0
0.8
0.6
0.4
0.2
0.0
[Mn(PhDTA)]2-
Mn2+
[Mn(HPhDTA)]-
[Mn(H2PhDTA)]
data, as the Cu2+ ion is mostly in complexed form (
near pH = 1 (Figure 2). Therefore, the stability of this complex
was assessed by using combination of the UV-vis
∼85%) even
a
spectrophotometric method (applicable to very acidic samples)
and pH-potentiometry titration data obtained at higher pH.
The absorption spectra of the [Cu(PhDTA)]2 complex as a
−
1.5
3.0
4.5
pH
6.0
7.5
function of H+ ion concentration are shown in Figure 3. In line
Figure 1. Concentration distribution curves calculated for [Mn(PhDTA)]2- and
[Mn(trans-CDTA)]2- complexes (cMn2+ = cL = 0.001 M).
with the equilibrium data obtained for the other metal ions
studied, the stability constant of the [Cu(PhDTA)]2 complex is
−
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1.0
0.8
0.6
0.4
0.2
0.0
Cu2+
[Cu(PhDTA)]2-
[Cu(H2PhDTA)]
0.30
0.23
0.15
0.08
0.00
[Cu(HPhDTA)]-
-1.0
0.5
2.0
3.5
pH
5.0
6.5
8.0
500
550
600
650
Wavelength (nm)
700
750
800
Figure 2. The species distribution curve calculated for the [Cu(PhDTA)]2- complex by
using the stability constants determined via combined UV-vis and pH-potentiometric
titration data (cCu2+ = cL = 0.001 M)).
Figure 3. Absorption spectra of the [Cu(PhDTA)]2- complex ([Cu2+
]
tot = [PhDTA]tot = 4×10-
3
M) recorded at different pH: 4.96, 4.06, 3.43, 2.99, 2.59, 2.30, 2.00, 1.71, 1.51, 1,30,
1.15, 1,0 and 0.7. The lower spectra correspond to the Cu2+ ion in solution at the same
concentration and pH=1.0, 0.7, 0.3, and 0 (pH=-log[H+]).
Table 1. Protonation and stability constants of the EDTA, cis- and trans-CDTA and PhDTA ligands and their complexes formed with Ca2+, Mg2+, Mn2+, Cu2+ and Zn2+ ions (I = 0.15 M
NaCl, T = 25 °C).a
EDTAa
9.17b
5.99b
2.73b
2.01b
1.38b
21.28b
7.61
trans-CDTAa
9.36b
5.95b
3.62b
2.57b
1.49b
22.99b
9.14
cis-CDTAc
11.00
5.20
3.41
2.30
1.41
23.32
9.01
4.72
9.65
4.55
14.19
2.85
−
PhDTADd
6.41; 5.95e
4.61; 3.70e
3.53; 2.79e
3.00; –e
–
PhDTA
6.66(5)
4.85(6)
3.53(7)
3.32(6)
–
H
H
H
H
H
H+
log K1
log K2
log K3
log K4
log K5
∑ log KiH
log KML
log KMHL
log KML
log KMHL
log KMnL
log KMnHL
log KMnH2L
pMng
17.55; 12.44e
6.48f; 10.41e
2.7f
18.36
Mg2+
Ca2+
6.94(3)
3.78(6)
8.79(2)
3.38(3)
11.79(2)
2.84(2)
1.91(5)
8.38
15.21(6)h
3.35(1)
2.18(1)
2.75(2)
13.03(3)
3.56(2)
1.90(3)
2.69(7)
−
9.53
2.92
3.53
10.23
3.53
14.32b
2.90b
1.89b
8.68
19.78h
2.91
1.10
−
16.75
2.57
−
−
8.27f; 11.25e
3.0f
Mn2+
12.46b
2.95b
11.37
2.29
1.70
b
−
7.83
19.02h
3.15
2.04
−
15.92
3.23
1.50
−
7.82
18.3(1)h
3.65
−
8.16
Cu2+
log KML
15.21h; 24.84f
3.04
log KMHL
log KMH2L
log KM2L
log KML
log KMHL
log KMH2L
log KM2L
1.80
–
12.89; 17.99f
2.96
−
Zn2+
17.06
2.76
−
1.30
−
–
a
b
c
d
e
g
0.15 M NaCl, 25°C from the diploma work of Veronika Józsa, 2015, University of Debrecen, Debrecen, Hungary; Ref. 23.; Ref. 27; Ref. 32; Ref. 33; f Ref. 31;
Calculated by using cMn=cLig=0.01 mM at pH=7.4 according to Ref. 15.; h Determined by simultaneous fitting of the UV-vis and pH-potentiometic data.
Table 2. Rate and stability constants characterizing the dissociation of the [Mn(EDTA)]2-, [Mn(cis-CDTA)]2-, [Mn(trans-CDTA)]2- and [Mn(PhDTA)]2- complexes (I = 0.15 M NaCl, T = 25
°C).
EDTAa, b
5.2×104
2.3×108
45
cis-CDTAc
trans-CDTAa, b
PhDTA
(2.01±0.04)×102
(4.9±0.3)×105
0.21±0.01
27±4
k1 (M-1s-1)
k2 (M-2s-1)
k3 (M-1s-1)
KMnLCu
1.02×105
4.0×102
−
−
79
−
−
79
−
log KH
2.65d
0.076
2.85d
0.47
2.90d
12.3
2.84d
t1/2 (h)e
19.1
a Ref. 23. b For for [Mn(edta)]2- k3 = 3.0×10-1 M–1s–1, k4 = ~4.8×101 M–2s–1 and log KMnHL=3.10 while [Mn(trans-cdta)]2- k1 = 3.2×102 M–1s–1 and t1/2 = 15 h were found in
Ref. 35. c Ref. 27. d Determined by pH-potentiometry and fixed in the data fitting. e Calculated at pH = 7.4 in the presence of cCu2+=1×10-5 M.
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complex to assure pseudo-first-order conditions. Fitting the
acquired time-absorbance curves to the equation for a first
1.0
0.8
0.6
0.4
0.2
0.0
[Mn(PhDTA)]2-
Mn2+
order reaction gave the pseudo-first-order rate constant (kobs
)
7.5
6.5
5.5
4.5
3.5
for each reaction. The H+ concentration dependence of the
dissociation rates are shown in Figure 5. It is obvious that the
reaction rates show a second order dependence on proton
concentration. Furthermore, the experiments performed using
different concentrations of Cu2+ indicate that the role of the
metal ion is not negligible, i.e. the dissociation can be realized
[Mn(HPhDTA)]-
[Mn(H2PhDTA)]
through
a heterodinuclear complex. The acquired rate
constants increase with the rise of H+ concentration and
change by varying Cu2+ concentration. Accordingly, the
reaction can occur both with the attack of protons and the
exchanging metal ion. However the effect of the exchanging
metal ion on the reaction rates depend strongly on pH. While
the increase of the Cu2+ concentration leads to lower reaction
rates in the more acidic samples, at higher pH it leads to higher
reaction rates (Figure 6). The explanation for this behavior
might be that the two reaction pathways (the proton assisted
and the metal ion assisted paths) are in competition with each
other. For the dissociation of the complex in the presence of
Cu2+ the general reaction scheme shown in Scheme 2 can be
established. Taking into account the different reaction
1.5
3.0
4.5
6.0
pH
7.5
9.0 10.5
Figure 4. The speciation distribution of [Mn(PhDTA)]2- complex with the pH
dependence of its relaxivity (I = 0.15 M NaCl, T = 25 °C, 20 MHz).
KMnLCu
kCu
Mn(L)Cu
Mn2+ + Cu(L)
Mn(L)
k0
kH
KMnHL
kCHu
Mn2+ + HnL
Mn2+ + Cu(L) + H+
Mn(HL)
pathways (characterized by the rate coefficients k0, kH, kHH, kCu
,
kCuH), the protonation constants and stability constants of the
complexes (KMnHL, KMnH and KMnLCu), the pseudo-first-order
KMnH2L
Mn(H2L)
kHH
L
2
rate constant (kobs) can be expressed by eqn. 1, where
MnHL=[Mn(HL)]/([Mn(L)][H+]),
Scheme 2. Reaction mechanisms for the dissociation of the [Mn(PhDTA)]2- complex.
K
KMnH L=[Mn(H2L)]/([Mn(HL)][H+]),
2
determined previously for the [Mn(trans-CDTA)]2- complex.23,27
Thus, we conclude that the replacement of the
cyclohexanediamine unit by ortho-phenylenediamine bridge
does not affect significantly the relaxivity of the Mn2+
complexes.
KMnLCu=[Mn(L)Cu]/([Mn(L)][Cu2+]),
k2=kHH·KMnHL·KMnH2L, k3=kCu·KMnLCu and k4=kCuH·KMnHL
k1=kH·KMnHL,
35
.
k0 + k1[H+ ] + k2[H+ ]2 + k3[Cu2+ ] + k4[Cu2+ ][H+ ]
(1)
kobs
=
1+ KMnHL[H+ ] + KMnHL KMnH L[H+ ]2 + KMnLCu [Cu2+
]
2
Dissociation kinetics of the [Mn(PhDTA)]2- complex
Initial attempts to fit the experimental data to eqn. 1
evidenced that beside two proton-assisted pathways
(characterized by k1 and k2) the attack of the metal ion with
Since Mn2+ is a biogenic metal ion, its toxicity is considerably
lower than that of Gd3+. Nevertheless Mn2+ is also harmful in
large doses and causes symptoms similar to the ones
associated with Alzheimer’s disease.34 Thus, our goal is to
prepare Mn2+-based contrast agents that do not dissociate in
vivo to avoid potential toxicity issues. With an aim of gaining
information about its inertness the rates of the exchange
reactions of [Mn(PhDTA)]2- have been studied in the presence
of Cu2+. The kinetic experiments have been conducted in the
pH range of 3.6 – 5.2 with the use of Cu2+ as exchanging metal
ion. These transmetallation reactions are slow enough in the
mentioned pH range to allow for measurements with
conventional spectrophotometric methods. The studied
exchange reactions can be delineated as follows:
the formation of
a dinuclear complex also affects the
dissociation reaction. The k4 rate constant gave a negative
value during the fitting thus the path was neglected. Taking
into consideration the pathways mentioned above, the
pseudo-first order rate constants of the exchange reaction
were analyzed using the following simplified expression (eqn.
2):
k1[H+ ]+ k2 [H+ ]2 + k3[Cu2+
]
(2)
kobs
=
1+ KMnHL [H+ ] + KMnLCu [Cu2+
]
The rate and stability constants obtained by fitting the kobs
values are compared with the data acquired for the
[Mn(EDTA)]2-, [Mn(cis-CDTA)]2- and [Mn(trans-CDTA)]2-
complexes in Table2. The results show that, in the case of the
[Mn(PhDTA)]2- + Cu2+
[Cu(PhDTA)]2- + Mn2+
For the metal exchange reactions, the concentration of
Cu2+ was 10 to 40 times higher than the concentration of the
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trans-CDTA complex, the partial decoordination of the ligand
from Mn2+ and coordination to Cu2+ is a slow process, which
10.0
1.0
results in the formation of
a quite stable dinuclear
pH=3.69
intermediate (a so-called “dead-end” complex). The formation
of the dinuclear species slows down the reaction by decreasing
the contribution of the proton assisted pathway. On the
contrary, the dinuclear complex formed with PhDTA possesses
a “Janus-face” nature in affecting the rate of the reaction
depending on H+ concentration. This can be explained by a
positive contribution of the metal-assisted pathway to the
overall exchange reaction above pH 4.6 (Fig 6), while at pH
below pH 4.3 the slower metal-assisted dissociation competes
with the proton assisted pathway, thus lowering the pseudo-
first rate constants. It is obvious from the data shown in Table
2 that the rate of the proton assisted dissociation in the case
of [Mn(PhDTA)]2- is half of that of [Mn(trans-CDTA)]2-, which is
reassuring with respect of a potential application of the
complex. The half-life of dissociation of the Mn2+ complexes
have been calculated using the first order rate constants at pH
7.4 and 25 °C (cCu2+=0.01 mM). The results indicate that the
[Mn(PhDTA)]2- complex presents the highest inertness with
respect to complex dissociation among the four complexes
(t1/2,[Mn(PhDTA)]2-= 19.1 h considering seven times the depletion
and not considering the reformation of the complex, and
pH=3.99
pH=4.30
pH=4.59
pH=4.87
pH=5.04
pH=5.21
0.1
0
2
4
6
8
10
cCu2+ (x103, mol/dm3)
Figure 6. Dissociation rates (kobs) of the [Mn(PhDTA)]2- complex plotted as a function of
Cu2+ ion concentration (I = 0.15 M NaCl, T = 25 °C).
DFT calculations
DFT calculations were carried out to gain insight into the
structure of the [Mn(PhDTA)]2- complex in solution. Geometry
optimizations were performed on the [Mn(PhDTA)(H2O)]2-
·2H2O system, as the explicit inclusion of two second-sphere
water molecules involved in hydrogen-bonding interactions
with the coordinated water molecule are required for an
accurate calculations of Mn-Owater distances and scalar
hyperfine coupling constants at the 17O nucleus of the
coordinated water molecule.36 The optimized geometry (Fig 7)
calculated at the M062X/TZVP level shows a very good
agreement with the X-ray crystallographic data reported by
Tanaka et al.37 The calculated bond distances deviate from the
experimental ones by < 0.036 Å (Table S1, ESI†). A comparison
of the structure obtained for [Mn(PhDTA)(H2O)]2-·2H2O and
that calculated for [Mn(EDTA)(H2O)]2-·2H2O using the same
methodology reveals that the average Mn-N distance is
somewhat shorter in the EDTA complex (2.411 Å) than in the
PhDTA one (2.440 Å). An opposite situation is observed for the
Mn-Ocarboxylate distances, which show average values of 2.243
t1/2,[Mn(trans-CDTA)] = 12 h) while the dissociation of the
2-
[Mn(EDTA)]2- and [Mn(cis-CDTA)]2- complexes is complete
within few minutes under these conditions). Considering the
typical excretion time of low molecular weight contrast agents
(t1/2 = 1.6 h), the [Mn(PhDTA)]2- complex appears to be a good
candidate for in vivo experiments.
5.0
10x
20x
30x
40x
4.0
3.0
2.0
1.0
0.0
and
2.215
Å
for
[Mn(EDTA)(H2O)]2-·2H2O
respectively. The
and
[Mn(PhDTA)(H2O)]2-·2H2O,
shorter
Mn-Ocarboxylate distances observed for [Mn(PhDTA)(H2O)]2-·are
likely responsible for the higher kinetic inertness of this
complex with respect to the EDTA derivative, as the
proton-assisted dissociation pathway likely involves
decoordination of a protonated acetate group, while the
metal-assisted mechanism also requires decoordination of
acetate groups to form a dinuclear intermediate.
0.0
0.5
1.0
1.5
2.0
cH+ (x104 mol/dm3)
Figure 5. Dissociation rates (kobs) of the [Mn(PhDTA)]2- complex plotted as a function of
H+ ion concentration (I = 0.15 M NaCl, T = 25 °C). The colors represent different Cu2+ ion
concentration as follows: 2 mM (red), 4 mM (green), 6 mM (blue) and 8 mM (purple).
The Mn-Owater distance calculated for [Mn(PhDTA)(H2O)]2-
·(2.273 Å) is similar to that observed in the solid state (2.242
Å)37 and only slightly longer than the value calculated for
[Mn(EDTA)(H2O)]2-·2H2O (2.251 Å). The 17O hyperfine coupling
constant obtained using DFT (AO/ħ = -42.6
excellent agreement with the experimental value reported by
Hunt (AO/ħ = -38.0
106 rad s-1),28 which indicates that our
×
106 rad s-1) is in
×
calculations provide an adequate description of the spin
density distribution on the Mn-Owater bond.
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was found to differ considerably depending on the particular
functional used. For instance the B3LYP functional stabilizes
considerably the six-coordinated structures, which in the case
of the PhDTA complex is the most stable form at the
B3LYP/TZVP level. This is in line with our recent results that
showed that M062X/TZVP calculations provided energy
profiles for the water exchange reactions of [Li(H2O)4]+ and
[Be(H2O)4]2+ in good agreement with the experiment, while
B3LYP/TZVP calculations overstabilized a lower coordination
numbers.39 While an exhaustive evaluation of different
functionals is beyond the scope of the present study, the
results obtained here suggest that M062X/TZVP calculations
may be useful in predicting hydration numbers of Mn2+
complexes relevant as MRI contrast agents.
Electrochemical measurements
The redox stability of the [Mn(PhDTA)]2- complex was
investigated using cyclic voltammetry experiments in aqueous
0.15 M NaCl. The cyclic voltammograms obtained using
different scan rates are characteristic of an irreversible system.
The cyclic voltammogram recorded at a scan rate of 50 mV/s
showed an oxidation peak at Eox = +813 mV and a reduction
peak at Ered = +552 mV (ꢁE1/2 = 683 mV vs Ag/AgCl, Fig 8). The
cyclic voltammogram obtained for [Mn(EDTA)]2- using the
same conditions shows both the anodic (Eox = +769 mV) and
cathodic (Eox = +510 mV) peaks shifted to lower potentials,
which shows that PhDTA presents a lower ability to stabilize
Mn3+ compared to EDTA. This might be related to the harder
nature of the amine nitrogen atoms of EDTA compared to the
aniline donor atoms of PhDTA (according to Pearson’s HSAB
principle). This may be also related to the differences in the
geometries as evidenced for [Mn(PhDTA)]2- by X-ray
Figure 7. Top: Structure of the [Mn(PhDTA)(H2O)]2-·2H2O system obtained using DFT
calculations at the M062X/TZVP level. Bottom: Relaxed potential energy surface scans
calculated for [Mn(PhDTA)(H2O)]2-·2H2O using different functionals.
crystallography when compared with that of the [Mn(trans-
40]
as any axial distortion of the Mn(II)
CDTA)]2- complex,[37,
coordination environment should favour Mn(III) over Mn(II),
thereby leading to a decrease in potential.[41, 42] The half-cell
The experimental determination of the number of water
molecules coordinated to Mn2+ in potential MRI contrast
agents remains a difficult task. Caravan et al.38 proposed a
method relying on the analysis of the temperature
dependence of the transverse 17O NMR relaxation rates. This
potential of [Mn(EDTA)]2-
(ꢁE1/2 = 640 mV vs Ag/AgCl, Figure
S3, ESI†) is very similar to that reported by Caravan using 0.5
M KNO3 as supporting electrolyte (633 mV).8
method can only be applied to systems undergoing
changeover from a slow exchange regime at low temperature
to fast exchange regime at high temperature. As
a
a
a
consequence, the hydration number of complexes whose
transverse relaxation rates are in the fast exchange regime in
the whole accessible temperature range cannot be estimated
using this methodology. Thus, we wanted to explore whether
our DFT calculations could provide information on the number
of coordinated water molecules. For this purpose, we explored
the potential energy surface (PES) of the [Mn(EDTA)(H2O)]2-
·2H2O and [Mn(PhDTA)(H2O)]2-·2H2O systems by increasing the
Mn-Owater distance (Fig 7, see also Fig S2, ESI†). These relaxed
PES scans provided the six-coordinate [Mn(EDTA)]2-·3H2O and
[Mn(PhDTA)]2-·3H2O structures, which turned out to be less
stable than the seven-coordinate forms at the M062X/TZVP
level, in line with the experimental evidence. However, the PES
Figure 8. Cyclic voltammograms recorded using different scan rates for
[Mn(PhDTA)]2- (pH = 7.1, 0.15 NaCl, potentials reported vs Ag/AgCl).
3 mM
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The ligand PhDTA was synthesized as shown in Scheme 3 using
a slight modification of the previously published procedure.33
Conclusions
The replacement of the ethylenediamine bridging unit in EDTA
by the ortho-phenylenediamine backbone to give PhDTA
decreases the basicity of the ligand owing to the electron
withdrawing effect of the aromatic unit, yet the PhDTA
complexes formed with Ca2+, Mg2+, Mn2+, Cu2+ and Zn2+
possess very similar conditional stabilities to those of the
corresponding EDTA complexes. The kinetic studies
approached by studying the metal exchange reactions
occurring between the Cu2+ ion and the [Mn(PhDTA)]2-
complex revealed an improved inertness compared to
[Mn(trans-CDTA)]2-. The complex possesses a half-life of 19.1
hours at physiological pH and 25 °C, thus only about 8% of the
injected amount is expected to dissociate in the body. It has to
be emphasized however that at 37 oC the extent of the
dissociation will likely be slightly higher, and thus further
ligand design is needed to find even better ligand candidates
for Mn2+ ion complexation. DFT calculations confirmed that
the [Mn(PhDTA)]2- complex possesses one metal bound water
molecule (in agreement with the solid state structure of the
complex published previously37). As a result, we found a
Scheme 3. Synthesis of PhDTA. Reagents and conditions: i) BrCH2COOEt, DIPEA, NaI,
MeCN; ii) NaOH, EtOH; iii) HCl/H2O and crystallization.
ortho-Phenylenediamine-N,N,N’,N’-tetraacetate tetraethyl ester
(1). 1,2-Diaminobenzene (1.10 g, 10.2 mmol), ethyl-bromoacetate
(6.70 mL,10.1 g, 60.5 mmol), sodium iodide (1.30 g, 8.67 mmol) and
N,N-diisopropylethylamine (8.30 mL, 6.16 g, 47.7 mmol) were
mixed in acetonitrile (10 mL) and the mixture was refluxed under N2
atmosphere for 7 hours. After cooling to room temperature, the
reaction mixture was evaporated under reduced pressure. Water
(50 mL) was added to the residue and the mixture extracted with
chloroform (3×40 mL). The combined organic extracts were dried
with Na2SO4 and evaporated under reduced pressure resulting in a
brown oil, which was purified with flash silica gel chromatography
(petroleum ether:ethyl-acetate 10:1). Yield 2.90 g (62%).
ortho-Phenylenediamine-N,N,N’,N’-tetraacetic acid (PhDTA). The
ethyl ester precursor 1 (2.90 g, 6.41 mmol) was dissolved in ethanol
(40 mL) and NaOH (1.28 g, 32 mmol) dissolved in distilled water (5
mL) was added dropwise to the stirred reaction mixture. A white
precipitate was formed and the mixture was refluxed for 18 hours.
The white crystalline product was filtered with G3 filter crucible and
dissolved in water (2-3 mL). The pH was adjusted to pH=2 with
concentrated HCl and the precipitated white solid was isolated by
filtration and washed with cold distilled water (3×5 mL). Finally the
product was dried to constant mass. Yield 1.78 g (52%). 1H NMR
[360 MHz, D2O] δ 4,05 (8H, s, NCH2), 7,2-7,4 (4H, m, CHCH
aromatic); 13C NMR [100 MHz, D2O] δ 57,7 (4C NCH2), 123,2(2C CH
ring), 127,6 (2C CH ring), 141,0 (2C C ring), 174,7 (4C CO); MS (ESI)
m/z 481,300 (M+H)+ 35%; 503,282 (M+Na)+ 100%; 519,250 (M+K)+
13%.
o
relaxivity (r1 = 3.72 mM-1s-1 at 20 MHz and 25 C) very similar
to those determined earlier for the Mn2+ complexes formed
with EDTA as well as cis- or trans-CDTA ligands (Table 3). The
most important physicochemical parameters of the
[Mn(EDTA)]2-, [Mn(cis-CDTA)]2-, [Mn(trans-CDTA)]2- and
[Mn(PhDTA)]2- complexes are collected and compared in Table
3. As it can be seen form the data compared in Table 3 the
ortho-phenylenediamine building block represents an
attractive alternative to the trans-1,2-cyclohexanediamine unit
when tailoring inert open-chain based Mn2+ complexes for safe
MRI applications.
Table 3. Rate and stability constants characterizing the dissociation of the [Mn(EDTA)]2-
, [Mn(cis-CDTA)]2-, [Mn(trans-CDTA)]2- and [Mn(PhDTA)]2- complexes (I = 0.15 M NaCl, T
= 25 °C).
Equilibrium studies
EDTAa
12.46
cis-CDTAb
trans-CDTAa
PhDTA
11.79
The MnCl2, CaCl2, MgCl2, ZnCl2 and CuCl2 stock solutions were
prepared from the highest analytical grade chemicals, and their
concentrations were determined by complexometric titration with
standardized Na2H2EDTA and eriochrome black T indicator in the
presence of ascorbic acid and potassium hydrogen tartrate for
MnCl2, murexide indicator for CaCl2 and CuCl2, eriochrome black T
log K[Mn(L)]
pMnc
14.19
14.32
7.83
41d
7.82
22.5
3.85
0.47
8.68
14.0e
3.62
12.2
8.38
35.0f
3.72
19.1
kex298 (x107 s–1
)
r1p298 (mM-1s-1)g
3.20
0.076
t1/2 (h)h
for MgCl2
and xilenolorange in the presence of
a
b
c
hexamethylenetetramine for the ZnCl2 solution. The concentration
of the ligand stock solution was determined by pH-potentiometric
titrations. For determining the protonation constants of the ligand,
pH potentiometric titrations were carried out with 0.2 M NaOH,
using 0.002 M ligand solutions. The ionic strength was set to 0.15 M
by using NaCl. The titrated samples (starting volume of 6 mL) were
stirred mechanically and thermostated at 25 °C by a circulating
water bath (±0.1 °C). The protonation constants of the ligand (log
KiH) are defined as follows:
Ref. 23; Ref. 27; pMn values were calculated at pH=7.4 by using 0.01 mM
Mn2+ and ligand concentration as suggested by É. Tóth and o-workers, Ref. 15;
From Ref.43; e From Ref. 44; f From Ref. 45; g at 25 oC and 20 MHz; h The half-lives
(h) of dissociation were extrapolated to pH=7.4 by using 0.01 mM Cu2+ ion
concentration
d
Experimental Section
Synthesis
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[HiL]
KiH
=
(3)
only the solution of the complex was buffered, while in the
solution of exchanging Cu2+ the ionic strength was set. Under
[Hi-1L][H+ ]
where i = 1, 2, …, 5 and [Hi-1L] and [H+] are the equilibrium these conditions, the rate of the reaction can be expressed as
concentrations of the ligand (i = 1), protonated forms of the follows: -d[Mn(PhDTA)]2 tot/dt = kobs[Mn(PhDTA)]2 tot, where
−
−
ligand (i = 2, …, 5), and hydrogen ions respectively. To avoid kobs is the pseudo-first-order rate constant and
the effect of CO2, N2 gas was bubbled through the solutions [Mn(PhDTA)]2
is the total concentration of the Mn2+
−
tot
during the titrations process. The pH-potentiometric titrations complex. The kobs values were determined using the following
t)
+ Av, where At is the absorbance
were performed with a Metrohm 785 DMP Titrino titration equation: At = (Ar – Ap)e(-k
obs
workstation with the use of a Metrohm 6.0234.100 combined at time t, Ar is the absorbance of the reactants, Ap is the
electrode in the pH range of 1.8-12.0. For the calibration of the absorbance of the products.
pH meter, KH-phtalate (pH = 4.005) and borax (pH = 9.177) Determination of the relaxivity of the Mn2+ Complex
buffers were used, and the H+ concentrations were calculated The relaxation times of water protons were measured at 20
from the measured pH values by applying the method MHz with a Bruker Minispec MQ-20 NMR Analyzer. The
proposed by Irving et al.46 A solution of approximately 0.01 M temperature of the sample holder was set to 25.0 ± 0.2 °C and
HCl was titrated with a 0.2 M NaOH solution (0.15 M NaCl), controlled with the use of circulating water bath. The
and the differences between the measured and calculated pH longitudinal relaxation times (T1) were measured by using the
values (for the samples with pH < 2.4) were used to calculate inversion recovery method (180° – τ – 90°) by averaging 5-6
the [H+] from the pH values measured in the titration data points obtained at 8 different τ values. During the studies,
experiments. The measured points with pH > 11.0 of the acid- the concentration of the [Mn(PhDTA)]2- complex was 1.0 mM (I
base titration were used to calculate the ionic product of = 0.15 M NaCl) and the pH was varied in the range of 1.6 –
water which was found to be 13.867 under our experimental 10.6.
conditions. For the calculation of the equilibrium constants, Cyclic voltammetry Experiments
the PSEQUAD program was used.47 The protonation constants Cyclic voltammograms were recorded using
a 797 VA
of the PhDTA ligand were determined by titrating ligand Computrace potentiostat/galvanostat from Metrohm (Herisau,
solutions (acidified with a known volume of a standard HCl Switzerland) connected to a typical three electrode cell. A
solution) with 0.2 M NaOH at 0.15 M ionic strength in the 1.8 – glassy carbon rotating disk electrode (stirring rate of 2000
12.0 pH range. The log KiH values were calculated from 260 rpms) was used as working electrode, while the counter
V(mL)-pH data pairs. The stability constants of the metal electrode was a platinum rod. Potentials were measured using
complexes were determined using the direct pH- a Ag/AgCl reference electrode filled with 3 mol·L-1 KCl.
potentiometric method by titrating samples with 1:1 and 2:1 Solutions were purged with high purity (99.999%) nitrogen
metal-to-ligand ratios (the number of data pairs were between during 30 seconds prior recording the voltammograms. The
150-200), allowing 1 min for the sample equilibration to occur. starting and end potentials were 0.0 V, while the first vertex
In the presence of metal excess the titration was continued potential was set to +1.0 V. Sweep rates of 10 - 100 mV s-1
until the appearance of the precipitate (pH = 7 – 9). The were used.
stability constant of the Cu2+ complexes was too high to be Computational Details
determined by pH-potentiometry, hence
spectrophotometric method was
a
direct UV-vis
used.
The systems were fully optimized by using the hybrid GGA B3LYP48
The [Mn(PhDTA)(H2O)]2–·2H2O and [Mn(EDTA)(H2O)]2–·2H2O
spectrophotometric measurements were performed with a functional and the hybrid meta-GGA M062X49 functional along with
Cary 100 Bio spectrophotometer at 25 °C, using semimicro 1.0 the TZVP47 basis set. The nature of optimized geometries as true
cm cells. For the determination of the stability constant the energy minima was confirmed by frequency analysis. Hyperfine
absorbance was measured at 12 different acid concentrations coupling constants were calculated on the optimized structures by
(0.01 – 3.00 M) at 7 wavelengths between 650 and 800 nm using the EPR-III basis set for the ligand atoms51 and the aug-cc-
(the concentration of the complex was 4.0 mM). A pH-titration pVTZ-J basis set for Mn.52 Throughout this study bulk solvent effects
of [Cu(PhDTA)]2− was also performed in the pH range 1.50-12.0 were considered by using the integral equation formalism variant of
with a starting volume of 6 mL, cCu = cPhDTA = 2.0 mM.
the polarizable continuum model (IEFPCM).53 All calculations were
performed using the Gaussian 09 program package (revision
D.01).54
Kinetic Studies
The dissociation rates of the [Mn(PhDTA)]2 complex were
−
investigated at 25 °C and 0.15 M NaCl ionic strength by
spectrophotometry, in the presence of a high (10-40-fold)
excess of exchanging Cu2+ ion to ensure pseudo-first-order
conditions, using a Cary 100 Bio spectrophotometer at 300 nm
(using semimicro 1.0 cm cells). The concentration of the
Acknowledgements
Authors are grateful for the support granted by the H
Hungarian National Research, Development and Innovation
Office (NKFIH K-120224 project) and for the János Bolyai
Research Scholarship of the Hungarian Academy of Sciences
(Gy.T. and K.F.K.). The research was also supported in a part by
the EU and co-financed by the European Regional
complex was set to 2×
10-4 M, and the kinetic studies were
performed by using a noncoordinating buffer, N’-methyl
piperazine (NMP, log K2H = 4.92(0.02)) at 0.04 M concentration
to maintain constant pH in the samples. Before the kinetic runs
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Development Fund under the projects GINOP-2.3.2-15-2016- 19 A. Forgacs, R. Pujales-Paradela, M. Regueiro-Figueroa, L.
00008 and GINOP-2.3.3-15-2016-00004. Authors C. P.-I. and D.
E.-G. thank Ministerio de Economía y Competitivad (CTQ2015-
Valencia, D. Esteban-Gomez, M. Botta and C. Platas-
Iglesias, Dalton Trans., 2017, 46, 1546.
71211-REDT and CTQ2016-76756-P) and Centro de 20 M. Regueiro-Figueroa, G. A. Rolla, D. Esteban-Gomez, A. de
Supercomputación de Galicia (CESGA) for providing the
Blas, T. Rodriguez-Blas, M. Botta and C. Platas-Iglesias,
computer facilities. This work was carried out within the frame
Chem. Eur. J., 2014, 20, 17300.
of the COST CA15209 Action “European Network on NMR 21 J. S. Troughton, M. T. Greenfield, J. M. Greenwood, S.
Relaxometry”.
Dumas, A. J. Wiethoff, J. Wang, M. Spiller, T. J. McMurry
and P. Caravan, Inorg. Chem., 2004, 43, 6313.
22 E. M. Gale, I. P. Atanasova, F. Blasi, I. Ay and P. Caravan, J.
Am. Chem. Soc., 2015, 137, 15548.
Notes and references
23 F. K. Kálmán and Gy. Tircsó, Inorg. Chem., 2012, 51, 10065.
24 C. Vanasschen, M. Brandt, J. Ermert and H. H. Coenen,
Dalton Trans., 2016, 45, 1315.
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TOC Graphic
Equilibrium, dissociation kinetics,
relaxometric and
electrochemical properties of the [Mn(PhDTA)]2 complex
−
were investigated and the structure of the [Mn(PhDTA)]2
−
complex was studied by using DFT calculations.
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