EDTA and DTPA modified ligands as sequestering agents for uranyl decorporation

Article abstract of DOI:10.1016/j.tet.2011.11.065

Synthesis of modified EDTA and DTPA ligands and determination of their binding affinities for the uranyl cation are described. Thanks to a screening method, based on a chromophoric complex displacement procedure, chelating properties were studied in aqueous media under various pH conditions for evaluation of their in vivo uranyl-removal efficacy. Each ligand showed a more or less pronounced affinity for uranium. Specific ligands based on EDTA or DTPA analogues containing sulfocatecholamide (CAMS) were found to exhibit a significant affinity towards uranyl ion in acidic, neutral or basic conditions.

Full text of DOI:10.1016/j.tet.2011.11.065

Tetrahedron 68 (2012) 1163e1170
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
EDTA and DTPA modified ligands as sequestering agents for uranyl decorporation
a
a
b
b
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ꢀ c
a,b,
*
Antoine Leydier , Yi Lin , Guilhem Arrachart , Raphael Turgis , Delphine Lecercle ,
a
c
a
ꢀ ꢀ
ꢀ
Alain Favre-Reguillon , Frederic Taran , Marc Lemaire , Stephane Pellet-Rostaing
ICBMS, Institut de Chimie et Biochimie Moleculaires et Supramoleculaires, CNRS, UMR 5246, Universite de Lyon , INSA, CPE, Laboratoire de Catalyse et Synthese Organique,
a
ꢀ
ꢀ
ꢀ
ꢁ
43 Bd du 11 novembre 1918, Villeurbann F-69622, France
b
ꢀ
ꢀ
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ICSM, Institut de Chimie Separative de Marcoule, CNRS/CEA/UM2/ENSCM, UMR 5257, Universite Montpellier 2, Laboratoire de Tri ionique par des Systemes Moleculaire
ꢀ
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auto-assembles, site de Marcoule, 30207 Bagnols sur Ceze, France
c Service de Chimie Bio-organique et de Marquage, iBiTec-S, CEA-Saclay 91191 Gif sur Yvette, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of modified EDTA and DTPA ligands and determination of their binding affinities for the uranyl
cation are described.
Received 5 September 2011
Received in revised form 4 November 2011
Accepted 23 November 2011
Available online 27 November 2011
Thanks to a screening method, based on a chromophoric complex displacement procedure, chelating
properties were studied in aqueous media under various pH conditions for evaluation of their in vivo
uranyl-removal efficacy. Each ligand showed a more or less pronounced affinity for uranium. Specific
ligands based on EDTA or DTPA analogues containing sulfocatecholamide (CAMS) were found to exhibit
a significant affinity towards uranyl ion in acidic, neutral or basic conditions.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Ligands for decorporation therapy need specific properties, such
as a strong association with the toxic metal, selectivity in relation to
Development and exploitation of radionuclides in the nuclear
industry led to consider the risks incurred using these highly toxic
compounds. Uranium is a natural radioactive heavy metal, with dif-
ferentisotopic compositions (natural, depleted, enriched), commonly
used in nuclear industry either for civilian or military applications.1
At each step of the fuel cycle: extraction, concentration, purifi-
cation, enrichment or recycling, workers can be subjected to ura-
nium contamination. Accidental internal contamination by
inhalation or through skin lesions is the major risk for workers,
whether acute and/or repeated.
biological cations, non-toxicity and good availability. Most efficient
uranophile chelating functions are oxygen-containing ligands14 like
multidentate sulfocatecholamides (CAMS),15 hydroxylpyridones
(HOPO),16 carbamoylmethylphosphine oxide (CMPO),17 calixarene
derivatives18 or bisphosphonate sequestering agents.19
Polycarboxylic acids, such as EDTA (ethylenediaminetetraacetic
acid) and DTPA (diethylenetriaminepentaacetic acid), due to their
relative efficiencies in treatments for other ‘hard’ metals decorpo-
ration like plutonium, have quickly been considered as possible
candidates in decorporation of uranium contamination.
Inside the body, uranium creates risks both as a toxic heavy
metal and as radioactive material in the case of chronic exposition.
The hexavalent uranyl ion (UO22þ, U (VI)) was found to be the most
stable form in vivo.2,3 After contamination it is rapidly transferred
through the blood stream to deep organs, such as kidneys and
bones that assimilate it strongly.4e7
To avoid these effects, heavy metals must be eliminated from
the body by administrating non toxic chelating agents.8,9 Many li-
gands are reported to efficiently complex uranyl ion but, only a few
ligands are able to decorporate U(VI) in vivo, promote its excretion,
and efficiently prevent or reduce deposition into target organs.10e13
As recently described by Sammartano et al. speciation of EDTA
and DTPA suggest that they represent good candidates for the
formation of 1:1:0 complexes in the physiological pH range.20
DTPA is recognized as a chelating agent that accelerates the
excretion of plutonium in early treatment after an accident but its
effectiveness remains limited for uranium decorporation. Due to
the lack of selectivity, these ligands have often been administered
through calcium or zinc salts during decorporation treatment.21
In this paper, we focused on the preparation of new chelating
agents based on EDTA and DTPA skeletons as potential sequestering
agents for uranyl chelation.
In order to increase the affinity regarding uranyl ion, we
designed and synthesized a series of modified water-soluble EDTA
and DTPA using various substituted amines (Scheme 1). Evaluation
of the complexation constants with uranyl ions was then studied
* Corresponding author. Tel.: þ33 (0) 4 72 44 85 07; fax: þ33 (0) 4 72 43 14 08;
e-mail address: stephane.pellet-rostaing@cea.fr (S. Pellet-Rostaing).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.065

1164
A. Leydier et al. / Tetrahedron 68 (2012) 1163e1170
Table 1
EDTA and DTPA derivatives (yields %)
Amine scaffolds
EDTA ligands
DTPA ligands
a
1a (95%)
2a (62%)
b
c
1b (93%)
1c (94%)
2b (92%)
2c (77%)
d
e
1d (80%)
1e (69%)
2d (85%)
2e (66%)
f
1f (74%)
1g (67%)
2f (95%)
2g (97%)
g
Scheme 1. General synthesis of EDTAeDTPA derivatives.
h
1h (76%)
2h (80%)
using a method based on competitive uranium binding with sul-
fochlorophenol (SCP).3
a
Reactions performed in the presence of NEt3.
2. Results and discussion
2.1. Synthesis
and by 13C NMR with the C-SO3H carbon atoms found at around
145 ppm.
The ligands were synthesized in good yields according to Table 1.
Before modification, EDTA (1) or DTPA (2) can be easily converted
into their dianhydrides by reaction with acetic anhydride.22 EDTA-
or DTPA-bisanhydride, were reacted with a twofold amount of the
corresponding commercially amines (aeg) in dry DMF (Scheme 1).
The products (Table 1) were isolated and characterised (1H, 13C
NMR, HRMS analysis) from the crude mixture by recrystallisation
from methanol and acetone and were used without further
purification.
The dibenzyl-aminocatecholamide derivatives (1h and 2h) were
synthesized in four steps starting from the products 3 and 4, re-
spectively (Scheme 2).
In a first step N-(2-azidoethyl)phthalimide (5) was prepared
from N-(2-bromoethyl)phthalimide (3) using sodium azide.
Coupling reaction of 5 with acid chloride derivative of 6 fol-
lowed by a treatment with hydrazine afforded the desired amine h
in a 52% overall yield. Acid chloride derivative was obtained by the
reaction of oxalyl chloride with 2,3-bis(benzyloxy)benzoic acid (6)
starting from the 2,3-dihydroxybenzoic acid (4).23
2.2. Complexation studies
Determination of conditional constant provides a quantitative
measurement of the ligand affinity towards the uranyl cation. The U
(IV)eEDTA and U (IV)eDTPA complexes have been investigated in
many studies and association constants determined.9,20 In the
presence of polyaminocarboxylate, the formation of stable uranyl
soluble species occurs in a wide range of pH (independently from
ionic medium and ionic strength). Stability constant (log Kconcd) for
EDTA and DTPA towards uranium U (IV) was evaluated to 13.7 and
11, respectively.9,24 Complexes in solution are well defined25 and
exhibit good complexing constant26 in regards to uranium and
physiological pH range. Unfortunately, beside these values, EDTA
and DTPA appear to be poor ligands for uranium decorporation.
The binding abilities for uranyl cation of the water-soluble se-
questering agent based on EDTA or DTPA derivatives were de-
termined by UV spectrophotometry in aqueous media under
various pH conditions: acidic, neutral and basic (pH 5.5, 7.4 and
9.0). This method is essentially based on the spectral behaviour and
complexation properties of a chromophoric probe with respect to
the uranyl cation.27 A screening method was performed using the
method developed by Taran et al.3 based on competitive uranium
binding with sulfochlorophenol (SCP) as chromogenic chelate. Af-
finity constants towards uranyl ion were determined through
a competitive displacement between the ligand and complex
UO2SCP.
Deprotection under mild conditions of the hydroxyl groups was
achieved after coupling with EDTA or DTPA backbone. Un-
fortunately, total deprotection of catechol benzyl ester could not be
achieved when DTPA was used (2h). Hydrogenolysis of the catechol
1h led to EDTA-CAM (8). Sequestering agent based on sulfoca-
techolamide (CAMS) ligands was prepared by sulfonation of 8 in
20% oleum followed by precipitation in diethyl ether, which gave
the desired disulfonated compound EDTA-CAMS (9) in 71% yield
(Scheme 3).
The addition of a stronger ligand than SCP displaces the equi-
librium towards the formation of UO2-ligand (Fig. 1) decreases the
absorbance value and changes the colour of the medium. The ligand
Structure of 9 was confirmed by 1H NMR with chemical shifts at
7.3 and 7.6 ppm corresponding to the two residual aromatic protons

A. Leydier et al. / Tetrahedron 68 (2012) 1163e1170
1165
Scheme 2. Synthesis of N-(2-aminoethyl)-2,3-bis(benzyloxy)benzamide h.
complexation constant (Kconcd) was evaluated in comparison to
values of complexes Kconcd SCP/UO2.
Globally, whatever the commercial amine (aeg) and pH studied
the EDTA and DTPA ligands were not able to displace more than 20%
of the SCP/UO2 complex and exhibited Kconcd comparable to the
original polyaminocarboxylate (Table 2). We observed a Kconcd en-
hancement in basic conditions in accordance with previous
findings.28
Scheme 3. Deprotection and sulfonation of EDTA-CAM.
A moderated increase on the Kconcd value was observed for the
EDTA-CAM ligand (8) but with displacement of only about 20%, this
value remains too low compared to expected values.
their affinities towards the uranyl cation. Their binding abilities
were investigated using UV spectrophotometry in aqueous media
under physiological pH (close to neutral) as well as under acidic and
basic conditions. In regard to decorporation applications the best
uranophile ligand was found to be the EDTA-CAMS 9, which ex-
hibits significant association constants under the range of pH
studied. With respect to the results obtained with the EDTA-CAMS
a new efficient synthetic route for deprotection of DTPA-CAM and
its sulfonation is under investigation before a possible evaluation of
their in vivo efficiency.
Only the EDTA-CAMS ligand (9) displayed significant displace-
ment and a larger complexation efficiency with a value about 1017
at pH¼7.4 close to values already observed in CAMS derivatives. It
appears that EDTA-CAMS exhibits sufficient affinities with respect
to uranium decorporation at physiological pH: acidic pH of 5.5
corresponding to that of kidney and blood pH (pH¼7.4). For EDTA-
CAMS the binding properties were found similar to those observed
with 5-LICAMS, which is a well known ligand, which displays
in vivo uranyl-removal capabilities.19
4. Experimental part
4.1. General
3. Conclusion
A family of sequestering agents based on EDTA and DTPA moi-
eties were synthesized and fully characterised in order to evaluate
Amines aeg are commercially available, dianhydride EDTA29
and DTPA30 were synthesized as previously described. All the

1166
A. Leydier et al. / Tetrahedron 68 (2012) 1163e1170
Fig. 1. UV spectra of SCPeUO2 and SCP following addition of increased amounts of EDTA-CAMS ligand.
Table 2
Kconcd of ligandeUO22þ at several pH values (displacement value range)
aluminium plates. Flash chromatographies were carried out on
Merck Silica Si60 (40e63 m
m). 1H, 13C NMR spectra were recorded
Log Kconcd UeL/(pH)
on a Bruker AC-200 (200.13 MHz for 1H, 50.32 MHz for 13C) or AC-
300 FT (300.13 MHz for 1H, 75.46 MHz for 13C) spectrometer;
chemical shifts (d) are given in parts per million and coupling
5.5
<8 (0e20%)
<8 (0e20%)
7.4
<13 (0e20%)
<13 (0e20%)
9
1
2
<16 (0e20%)
<16 (0e20%)
constants (J) in Hertz. Elemental analysis (C, H, N, S, O and F) was
obtained from the Service Central d’Analyse of the CNRS (Solaize).
High resolution mass spectra: HR LSIMS (Liquid Secondary Ionisa-
tion Mass Spectrometry: Thioglycerol), HR CIMS (Isobutan) and HR
EIMS were carried out on a Finnegan MAT 95xL by the UCBL Centre
de Spectroscopie de Masse.
1a
2a
<8 (0e20%)
<8 (0e20%)
<13 (0e20%)
13.9 (0e20%)
17 (0e20%)
16.7 (0e20%)
1b
2b
<8 (0e20%)
<8 (0e20%)
<13 (0e20%)
13.64 (0e20%)
17.1 (0e20%)
16.4 (0e20%)
1c
2c
<8 (0e20%)
<8 (0e20%)
<13 (0e20%)
<13 (0e20%)
17.0 (0e20%)
<16 (0e20%)
1d
2d
<8 (0e20%)
<8 (0e20%)
<13 (0e20%)
<13 (0e20%)
17.3 (0e20%)
<16 (0e20%)
4.2. Synthesis of amine h
4.2.1. N-(2-Azidoethyl)phthalimide (5)31. A mixture of 2.6 g of N-(2-
1e
2e
<8 (0e20%)
<8 (0e20%)
<13 (0e20%)
14.21 (0e20%)
<16 (0e20%)
16.4 (0e20%)
bromoethyl)phthalimide (3,10.2 mmol), 0.87
g
of NaN3
1f
2f
<8 (0e20%)
<8 (0e20%)
<13 (0e20%)
<13 (0e20%)
<16 (0e20%)
<16 (0e20%)
(13.4 mmol), in 30 mL of dry DMF was refluxed for 18 h under ar-
gon. The mixture was evaporated to dryness; the residue was dis-
solved in 50 mL of dichloromethane and washed subsequently with
2ꢀ50 mL of water, 50 mL of brine, dried over MgSO4, filtered,
concentrated and dried under vacuum to give pure compound 5
(2.12 g, 90%) as pearly white solid.
1g
2g
<8 (0e20%)
<8 (0e20%)
<13 (0e20%)
13.25 (0e20%)
16.6 (0e20%)
16.9 (0e20%)
8
9
10 (0e20%)
11.2 (20e40%)
14.2 (0e20%)
16.4 (40e60%)
17.6 (0e20%)
18.6 (40e60%)
1H NMR (CDCl3, 300 MHz, 25 ꢁC)
2H, AreH), 3.88 (t, J¼6 Hz, 2H, CH2), 3.56 (t, J¼6 Hz, 2H, CH2).
13C NMR (CDCl3, 75 MHz, 25 ꢁC)
d
¼7.85 (m, 2H, AreH), 7.70 (m,
d
¼168.4 (ArC), 134.6 (ArCH),
organic reagents used were pure commercial products from
Aldrich, Acros, Fluka, Avocado, Lancaster and Maybridge. The sol-
vents were purchased from Carlo Erba, Acros, ProLabo, Fulka and
Aldrich. THF was distilled from sodium/benzophenone under ni-
trogen before use. CH2Cl2, was dried and distilled from CaH2. Thin
layer chromatography (TLC) was performed on silica gel backed
132.2 (ArC), 123.8 (ArCH), 49.3 (CH2), 37.2 (CH2).
4.2.2. 2,3-Bis(benzyloxy)benzoic acid (6)32. A mixture of 10.15 g of
2,3-bis(hydroxy)benzoic acid acid (4, 65.86 mmol), 1.2 mL benzyl-
bromide (100 mmol), 41 g anhydrous K2CO3 (100 mmol) in 220 mL
acetone was refluxed for 24 h, then evaporated. The residue was

A. Leydier et al. / Tetrahedron 68 (2012) 1163e1170
1167
dissolved in 150 mL methanol; 15 g of LiOHeH2O were carefully
added. The mixture was then refluxed for 3 h. After cooling, the
mixture was concentrated, 3 N HCl was carefully added at 0 ꢁC until
pH¼2. After 24 h, white crystals were filtered, washed sub-
sequently with 5ꢀ50 mL of water, dried under vacuum to give pure
compound 6 (20 g, 91%) as white powder.
hydrochlorite (3.78 g, 19.9 mmol), triethylamine (2.8 mL, 20 mmol)
in dry DMF (60 mL) was heated at 70 ꢁC under stirring under argon.
After 18 h the brown mixture was filtered, concentrated, 30 mL
ethanol were added, then 100 mL chloroform to give white crystals.
The supernatant was taken off; the residue was triturated twice
with 100 mL chloroform to give after filtration and drying under
vacuum compound 1a (5.8 g, 95%) as white crystals.
1H NMR (DMSO-d6, 300 MHz, 25 ꢁC)
d
¼7.76 (dd, J¼7.7 Hz,1.7 Hz,
1H, AreH), 7.38e7.52 (m,10H, AreH), 7.20e7.36 (m, 2H, AreH), 5.26
(s, 2H, OeCH2), 5.22 (s, 2H, OeCH2).
1H NMR (D2O, 300 MHz, 25 ꢁC)
d
¼6.72e6.77 (m, 4H, AreH), 6.61
(dd, J¼8.1 Hz, 1.9 Hz, 2H, AreH), 3.54 (s, 4H, NeCH2eCO), 3.40 (m,
8H, NeCH2eCO and NHeCH2eCH2eAr), 2.82 (s, 4H,
NeCH2eCH2eN), 2.68 (t, J¼6.4 Hz, 4H, NHeCH2eCH2eAr). 13C
13C NMR (CDCl3, 75 MHz, 25 ꢁC)
d
¼166.0 (ArC), 151.8 (ArC), 147.6
(ArC), 136.3 (ArC), 135.2 (ArC), 129.7 (ArCH), 129.6 (ArCH), 129.2
(ArCH), 129.0 (ArCH), 128.2 (ArCH), 125.4 (ArCH), 124.8 (ArCH),
123.5 (ArC), 119.4 (ArCH), 77.5 (CH2), 71.9 (CH2).
NMR (DMSO-d6, 75 MHz, 25 ꢁC)
d
¼172.3 (C]O), 169.8 (C]O), 145.9
(ArC), 144.4 (ArC), 130.9 (ArC), 120.1 (ArCH), 116.9 (ArCH), 116.4
(ArCH), 57.6 (CH2), 55.7 (CH2), 52.5 (CH2), 40.5 (CH2), 35.4 (CH2).
HRMS (ESI): calcd for C26H34N4O10Naþ: 585.2167; found:
585.2169. Anal. Calcd (%) for C26H34N4O10$2H2O: C, 52.17; H,
6.40; N, 9.36; O, 32.07; found: C, 51.77; H, 6.50; N, 9.66.
4.2.3. N-(N-(2-(2,3-Bis(benzyloxy)-1-carboxamido))ethyl)phthali-
mide (7). A mixture of 1.314 g of N-(2-azidoethyl)phthalimide (5,
6.07 mmol), 1.71 g of PPh3 (6.5 mmol), in 30 mL of toluene was
stirred until the end of N2 release. Water (0.4 mL) was added and
the mixture stirred for 1 h (Solution A).
4.3.2. EDTA-bis(3,4-dimethoxyphenylethylamine) (1b). A mixture of
EDTA dianhydride (2 g, 7.84 mmol), 2-(3,4-dimethoxyphenyl)ethyl
amine (2.9 g, 16 mmol), in dry DMF (20 mL) was heated at 70 ꢁC
under stirring under argon. After 18 h the brown mixture was con-
centrated, 5 mL chloroformwereadded, then 100 mL diethyl ether to
give a white solid. The supernatant was taken off; the residue was
triturated twice with 50 mL diethyl ether to give after filtration and
drying under vacuum compound 1b (4.5 g, 93%) as white crystals.
1 mL of oxalyl chloride (11.6 mmol) was added dropwise to
a solution of 2,3-bis(benzyloxy)benzoic acid (6, 2.53 g, 7.5 mmol) in
CH2Cl2 (30 mL). After adding a drop of DMF, the mixture was stirred
until the end of HCl release. After evaporation of solvents and re-
sidual oxalyl chloride, the residue was dissolved in 30 mL of dry
CH2Cl2 and added dropwise to Solution A in NEt3 (1.4 mL,10 mmol),
the mixture was stirred overnight. The mixture was washed sub-
sequently with 2ꢀ50 mL HCl 1 N, 2ꢀ50 mL of water, 100 mL of
brine, dried over MgSO4, filtered, concentrated and purified by
silica gel column chromatography (EtOAc 1/Cyclohexan 1) to give
compound 7 (1.99 g, 62%) as white powder.
1H NMR (DMSO-d6, 300 MHz, 25 ꢁC)
d
¼8.01 (br s, 2H, NH),
6.68e6.80 (m, 6H, AreH), 3.70 (m, 12H, OeCH3), 3.19e3.22 (m, 12H,
NeCH2eCH2eN and NeCH2eCO), 2.63 (s, 8H, NCH2eCO). 13C NMR
(DMSO-d6, 75 MHz, 25 ꢁC)
d (ppm): 173.0 (C]O), 170.6 (C]O), 149.0
1H NMR (CDCl3, 300 MHz, 25 ꢁC)
2H, AreH), 7.67 (m, 3H, AreH), 7.25e7.45 (m, 12H, AreH), 7.12 (m,
2H, AreH), 5.13 (s, 2H, OeCH2), 5.10 (s, 2H, OeCH2), 3.78 (t, J¼6 Hz,
2H, CH2), 3.46 (m, 2H, CH2). 13C NMR (CDCl3, 75 MHz, 25 ꢁC)
d
¼8.14 (br s, 1H, NH), 7.78 (m,
(ArC),147.6(ArC),132.1 (ArC),120.7(ArCH),112.7(ArCH),112.2(ArCH),
57.9 (CH2), 55.8 (CH3), 55.7 (CH3), 55.6 (CH2), 52.7 (CH2), 40.5 (CH2),
35.2 (CH2). HRMS (ESI): calcd for C30H42N4O10Naþ: 641.2793;
found: 641.2791. Anal. Calcd (%) for C30H42N4O10: C, 58.24; H, 6.84;
N, 9.06; O, 25.86; O, 42.88; found: C, 58.22; H, 6.84; N, 9.06.
d
¼168.6 (ArC), 166.0 (ArC), 152.1 (ArC), 147.2 (ArC), 136.8 (ArC),
134.3 (ArCH), 132.4 (ArC), 129.2 (ArCH), 129.1 (ArCH), 129.0 (ArCH),
128.9 (ArCH), 128.6 (ArCH), 127.5 (ArC), 124.7 (ArCH), 123.7 (ArCH),
123.6 (ArCH), 117.4 (ArCH), 76.6 (CH2), 71.6 (CH2), 40.0 (CH2), 38.0
(CH2). HRMS (ESI): calcd for C31H26N2O5Naþ: 529.1739; found:
529.1737. Anal. Calcd (%) for C31H26N2O5: C, 73.50; H, 5.17; N, 5.53;
O, 15.79; found: C, 73.38; H, 5.21; N, 5.61.
4.3.3. EDTA-bis(4-carboxylphenylamine) (1c)34. A mixture of EDTA
dianhydride (0.534 g, 2.08 mmol), 4-aminobenzoic acid (0.572 g,
4.17 mmol), in dry DMF (20 mL) was heated at 70 ꢁC under stirring
under argon. After 18 h the brown mixture was filtered, concen-
trated, recrystallized from water to give after filtration and drying
under vacuum compound 1c (1 g, 94%) as white crystals.
4.2.4. N-(2-Aminoethyl)-2,3-bis(benzyloxy)benzamide (h)33. A mix-
ture of 1.014 g of N-(2-(2,3-bis(benzyloxy)-1-carboxamido)ethyl)
phthalimide 7 (2 mmol), 2 mL hydrazine monohydrate (41 mmol),
in 40 mL ethanol was refluxed overnight. The mixture was filtered,
evaporated to dryness; the residue was dissolved in 100 mL of
dichloromethane washed subsequently with 2ꢀ50 mL of water,
100 mL of brine, dried over MgSO4, filtered, evaporated to dryness
to give amine h (0.71 g, 94%) as hygroscopic yellow oil.
1H NMR (DMSO-d6, 300 MHz, 25 ꢁC)
d
¼12.58 (br s, 4H, CO2H),
10.40 (s, 2H, NH), 7.87 (d, J¼8.9 Hz, 4H, AreH), 7.77 (d, J¼8.9 Hz, 4H,
AreH), 3.51 (s, 4H, NeCH2eCO), 3.49 (s, 4H, NeCH2eCO), 2.83 (s,
4H, NeCH2-CH2eN). 13C NMR (DMSO-d6, 75 MHz, 25 ꢁC)
d¼173.4
(C]O), 170.7 (C]O), 167.3 (C]O), 143.1 (ArC), 130.7 (ArCH), 125.5
(ArC), 118.7 (ArCH), 58.5 (CH2), 55.7 (CH2), 52.5 (CH2). HRMS (ESI):
calcd for C24H26N4O10Naþ: 553.1541; found: 553.1543. Anal.
Calcd (%) for C24H26N4O$10H2O: C, 52.55; H, 5.15; N, 10.21; O,
32.09; found: C, 52.60; H, 5.01; N, 10.13.
1H NMR (CDCl3, 300 MHz, 25 ꢁC)
d
¼8.02 (br s, 1H, NH), 7.64 (m,
2H, AreH), 7.24e7.38 (m, 10H, AreH), 7.04 (m, 4H, AreH), 5.04 (s,
2H, OeCH2), 4.98 (s, 2H, OeCH2), 3.22 (m, 2H, CH2), 3.46 (br s, 2H,
4.3.4. EDTA-PAS (1d)34. A mixture of EDTA dianhydride (0.696 g,
2.72 mmol), 4-aminosalicylic acid sodium salt dihydrate (0.1.18 g,
5.57 mmol), 100 mg MgSO4, in dry DMSO (20 mL) was heated at
70 ꢁC under stirring under argon. After 18 h the brown mixture was
filtered, concentrated, recrystallized from water/acetone to give
after filtration and drying under vacuum compound 1d (1.4 g, 80%)
as white powder.
CH2). 13C NMR (CDCl3, 75 MHz, 25 ꢁC)
d
¼165.9 (ArC), 152.1 (ArC),
147.2 (ArC), 136.8 (ArC), 129.3 (ArCH), 129.2 (ArCH), 129.1 (ArCH),
129.0 (ArCH), 128.6 (ArCH), 127.8 (ArC), 124.8 (ArCH), 123.6 (ArCH),
117.4 (ArCH), 76.8 (CH2), 71.7 (CH2), 43.1 (CH2), 41.8 (CH2). HRMS
(ESI): calcd for C23H24N2O3Naþ: 377.1865; found: 377.1863. Anal.
Calcd (%) for C23H24N2O3$H2O$2CH2Cl2: C, 53.21; H, 4.64; N,
4.96; O, 11.34; found: C, 53.21; H, 4.91; N, 4.70.
1H NMR (D2O, 300 MHz, 25 ꢁC)
d
¼7.53 (d, J¼8.5 Hz, 2H, AreH),
6.85 (d, J¼2.1 Hz, 2H, AreH), 6.76 (dd, J¼8.5 Hz, 2.1 Hz, 2H, AreH),
3.88 (s, 4H, NeCH2eCO), 3.62 (s, 4H, NeCH2eCO), 3.30 (s, 4H,
4.3. Synthesis of EDTA sequestering agents
NeCH2eCH2eN). 13C NMR (D2O, 75 MHz, 25 ꢁC)
d¼174.9 (C]O),
174.6 (C]O), 168.2 (C]O), 160.7 (Cq-O), 141.4 (ArC), 131.4 (ArCH),
114.5 (ArC), 111.6 (ArCH), 107.8 (ArCH), 58.3 (CH2), 57.9 (CH2), 52.5
(CH2). HRMS (ESI): calcd for C24H24N4O12Naꢂ: 583.1294; found:
4.3.1. EDTA-bis(3-hydroxytyramine) (1a). A mixture of EDTA dia-
nhydride (2.54 g, 9.92 mmol), 2-(3,4-dihydroxyphenyl)ethyl amine

1168
A. Leydier et al. / Tetrahedron 68 (2012) 1163e1170
583.1291. Anal. Calcd (%) for C24H24N4Na2O12$2H2O: C, 44.87; H,
4.39; N, 8.72; Na, 7.16; O, 34.86; found: C, 44.92; H, 4.16; N, 8.39.
(s, 2H, OeCH2eAr), 3.17e3.38 (m, 8H, CH2), 2.77 (s, 2H, CH2). 13
NMR (DMSO-d6, 75 MHz, 25 ꢁC)
¼172.6(C]O), 171.1(C]O),
C
d
167.2(C]O), 152.3(ArC), 145.8(ArC), 137.6(ArC), 131.1(ArC),
129.3(ArCH), 129.2(ArCH), 129.1(ArCH), 129.0(ArCH), 128.6(ArCH),
125.2(ArCH), 121.7(ArCH), 116.9(ArCH), 75.9(CH2), 71.0(CH2),
57.6(CH2), 55.9(CH2), 52.4(CH2), 39.5(CH2), 39.2(CH2). HRMS
(ESI): calcd for C56H60N6O12Naþ: 1031.4167; found: 1031.4168.
Anal. Calcd (%) for C56H60N6O12$2H2O: C, 64.36; H, 6.17; N, 8.04;
O, 21.43; found: C, 64.13; H, 6.07; N, 8.36.
4.3.5. EDTA-bis(diethanolamine) (1e)35. A mixture of EDTA dia-
nhydride (1.228 g, 4.79 mmol), diethanolamine (1.02 g, 9.70 mmol),
in dry DMF (20 mL) was heated at 70 ꢁC under stirring under argon.
After 18 h the brown mixture was concentrated, 5 mL methanol
were added, then 50 mL acetone to give a white solid. The super-
natant was taken off; the residue was triturated twice with 50 mL of
acetone to give after filtration and drying under vacuum compound
1e (1.54 g, 69%) as very hygroscopic white crystals.
4.3.9. EDTA-CAM (8). A mixture of EDTA-O-benzyl CAM (1h)
(554 mg, 0.55 mmol) and Pd/C (10%) (43 mg), in THF (15 mL) was
stirred under H2 atmosphere for 96 h. The resulting mixture was
filtered over Celite, evaporated to dryness, then dried under vac-
uum to give compound 8 (264 mg, 74%) as white powder.
1H NMR (D2O, 300 MHz, 25 ꢁC)
d
¼4.35 (NeCH2eCOOH), 3.81 (s,
4H, NeCH2eCONH), 3.75 (m, 8H, s, 4H, CH2eOH), 3.51 (m, 4H, s,
4H, NeCH2eCH2eN), 3.49 (m, 8H, CONHCH2eCH2). 13C NMR (D2O,
75 MHz, 25 ꢁC)
d
¼171.8 (C]O), 168.0 (C]O), 58.8 (CH2), 58.6
(CH2), 57.7 (CH2), 56.6 (CH2), 52.0 (CH2), 49.9 (CH2), 48.3 (CH2).
HRMS (ESI): calcd for C18H34N4O10Naþ: 489.2173; found:
489.2172. Anal. Calcd (%) for C18H34N4O10$2H2O: C, 43.02; H,
7.62; N, 11.15; O, 38.21; found: C, 43.46; H, 7.75; N, 10.88.
1H NMR (DMSO-d6, 300 MHz, 25 ꢁC)
d
¼8.21 (br s, 1H, NH),
7.16e7.44 (m, 3H, AreH), 3.13e3.36 (m, 8H, CH2), 2.74 (s, 2H, CH2).
13C NMR (DMSO-d6, 75 MHz, 25 ꢁC)
d
¼172.9 (C]O), 170.4 (C]O),
166.7 (C]O), 148.3 (ArC), 146.1 (ArC), 121.1 (ArCH), 120.2 (ArCH),
119.7 (ArCH), 116.9 (ArCH), 58.1 (CH2), 55.2 (CH2), 52.4 (CH2), 39.2
(CH2), 38.9 (CH2).
4.3.6. EDTA-di-(amidodiacetic acid) (1f)36. A mixture of EDTA dia-
nhydride (0.51 g, 1.99 mmol), iminodiacetic acid (0.53 g,
3.98 mmol), in dry DMF (20 mL) was heated at 70 ꢁC under stirring
under argon. After 18 h the brown mixture was concentrated, 5 mL
methanol were added, then 50 mL acetone to give a white solid. The
supernatant was taken off; the residue was triturated twice with
50 mL acetone to give after filtration and drying under vacuum
compound 1f (0.77 g, 74%) as white crystals.
4.3.10. EDTA-CAMS (9). EDTA-CAM (8) (343 mg, 0.53 mmol) was
added portionwise to a solution of oleum (H2SO4/SO3 20%, 2 mL) at
0
ꢁC under stirring. The resulting white solution was allowed to
warm to room temperature and stirred overnight. The mixture was
then poured in Et2O (20 mL). The resulting precipitate was filtered
off under argon and dried under vacuum to give compound 10a
(304 mg, 71%) as a hygroscopic grey powder.
1H NMR (D2O, 300 MHz, 25 ꢁC)
d
¼4.29 (s, 4H, NeCH2eCO), 3.94
(s, 4H, NeCH2eCO), 3.56 (s, 4H, NeCH2eCO), 3.41 (s, 4H,
1H NMR (DMSO-d6, 300 MHz, 25 ꢁC)
d
¼8.21 (br s, 1H, NH), 7.6 (s,
1H, AreH), 7.3 (s, 1H, AreH), 3.19e3.53 (m, 8H, CH2), 2.67 (s, 2H,
CH2). 13C NMR (DMSO-d6, 75 MHz, 25 ꢁC)
NeCH2eCO), 2.78 (s, 4H, NeCH2eCH2eN). 13C NMR (D2O, 75 MHz,
25 ꢁC)
d
¼172.3 (C]O), 171.4 (C]O), 170.8 (C]O), 170.5 (C]O), 55.4
d
¼172.7 (C]O), 170.1
(CH2), 54.8 (CH2), 51.2 (CH2), 50.3 (CH2), 49.3 (CH2). HRMS (ESI):
calcd for C18H26N4O14Naþ: 545.1338; found: 545.1340. Anal.
Calcd (%) for C18H26N4O14: C, 41.38; H, 5.02; N, 10.72; O, 42.88;
found: C, 41.27; H, 4.89; N, 10.97.
(C]O), 167.2 (C]O), 148.4 (ArC), 146.4 (ArC), 144.5 (ArC), 121.2
(ArCH), 119.9 (ArCH), 117.5 (ArCH), 57.8 (CH2), 55.2 (CH2), 52.5
(CH2), 39.2 (CH2), 39.0 (CH2).
4.4. Synthesis of DTPA sequestering agents
4.3.7. EDTA-di-3-carboxylpropylamide (1g). N,N0-1,2-Ethanedigly-
cine-bis(N-(carboxymethyl)-1.10-di(4-carboxy)propyl)amide.
A mixture of EDTA dianhydride (1.228 g, 4.79 mmol), amino-
butyric acid (0.989 g, 9.59 mmol), in dry DMF (20 mL) was heated at
70 ꢁC under stirring under argon. After 18 h the brown mixture was
concentrated, 5 mL of water was added, then 50 mL acetone to give
yellow oil. The supernatant was taken off, the treatment was re-
peated twice, and the yellow oil was dried under vacuum to give
compound 1g (1.5 g, 67%) as yellow foam.
4.4.1. DTPA-bis(3-hydroxytyramine) (2a)37. To
a solution of 3-
hydroxytyramine hydrochloride (0.99 g, 5.2 mmol) in DMF
(50 mL), 0.74 mL of triethylamine (11.3 mmol) was added followed by
0.85 g of DTPA dianhydride (5.6 mmol). After 24 h under stirring at
75 ꢁC, the mixture was concentrated and the precipitate formed was
filtered off. The filtrate was evaporated and the residue was dissolved
in ethanol. Addition of chloroform led to a precipitate and compound
2a (0.98 g, 62%) was obtained as white powder after filtration.
1H NMR (CD3OD, 300 MHz, 25 ꢁC)
d¼3.72 (s, 4H,
1H NMR (D2O, 300 MHz, 25 ꢁC)
d
¼6.76 (d, J¼8.1 Hz, 2H, AreH),
NeCH2eCOOH), 3.62 (s, 4H, NCH2eCONH), 3.21 (t, J¼7.1 Hz, 4H,
CONHeCH2eCH2), 2.32 (t, J¼7.1 Hz, 4H, COOHeCH2eCH2), 2.13 (s,
4H, NeCH2eCH2eN), 1.74 (q, J¼7.1 Hz, 4H, CH2eCH2eCH2). 13C
6.70 (d, J¼1.7 Hz, 2H, AreH), 6.57 (dd, J¼1.7 and 7.8 Hz, 2H, AreH),
3.70 (s, 4H, NCH2CO2H), 3.58 (s, 4H, NCH2C(O)NHꢂ), 3.52 (s, 2H,
NCH2CO2H), 3.38 (t, J¼6.4 Hz, 4H, NCH2CH2N), 3.11 (t, J¼6.7 Hz, 4H,
NHCH2CH2Ar), 2.97 (t, J¼6.7 Hz, 4H, NHCH2CH2Ar), 2.61 (t,
NMR (CD3OD, 75 MHz, 25 ꢁC)
(C]O), 57.0 (CH2), 56.9 (CH2), 56.4 (CH2), 51.8 (CH2), 39.1 (CH2),
31.5 (CH2), 24.2 (CH2). HRMS (ESI): calcd for C18H30N4O10Naþ:
641.2793; found: 641.2789.
d
¼178.3 (C]O), 172.6(C]O), 169.1
J¼6.4 Hz, 4H, NCH2CH2N). 13C NMR (D2O, 75 MHz, 25 ꢁC)
¼172.4
d
(C]O), 171.9 (C]O), 168.3 (C]O), 144.3 (ArC), 142.8 (ArC), 132.2
(ArC), 121.5 (ArCH), 117.0 (ArCH), 116.5 (ArCH), 56.9 (CH2), 56.5
(CH2), 51.8 (CH2), 51.3 (CH2), 40.9 (CH2), 34.0 (CH2). ES-MS found:
664.0 ([MþH]þ).
4.3.8. EDTA-O-benzyl CAM (1h). A mixture of EDTA dianhydride
(0.252 g, 1 mmol), N-(2-aminoethyl)-2,3-bis(benzyloxy)benzamide
h (0.74 g, 2 mmol), in dry DMF (20 mL) was heated at 70 ꢁC under
stirring under argon. After 16 h the brown mixture was concen-
trated, 5 mL chloroform then 200 mL of diethyl ether were added,
to give a white precipitate. The residue was filtered was triturated
twice with 20 mL diethyl ether to give after filtration compound 1h
(0.77 g, 76%).
4.4.2. DTPA-bis(3,4-dimethoxyphenylethylamine) (2b)38. To a sus-
pension of DTPA dianhydride (2 g, 5.6 mmol) in acetonitrile, the
solution of 2-(3,4-dimethoxyphenyl)ethylamine (2.28 g,
21.6 mmol) in acetonitrile (30 mL) was added. After stirring of 24 h
at 75 ꢁC, the solvent was evaporated. The residue was purified by
crystallisation in water to give compound 2b (3.73 g, 92%) as white
powder after filtration.
1H NMR (DMSO-d6, 300 MHz, 25 ꢁC)
(d, J¼6.2 Hz, 2H, AreH), 7.33 (d, J¼6.2 Hz, 3H, AreH), 7.23e7.30 (m,
6H, AreH), 7.08 (t, J¼6.2 Hz, 2H, AreH), 5.10 (s, 2H, OCH2eAr), 4.94
d
¼8.23 (br s, 1H, NH), 7.42
1H NMR (D2O, 300 MHz, 25 ꢁC)
(dd, J¼1.5 and 8.3 Hz, 2H, AreH), 3.71 (s, 12H, OCH3), 3.68 (s, 12H,
d
¼6.75e6.77 (m, 4H, AreH), 6.66

A. Leydier et al. / Tetrahedron 68 (2012) 1163e1170
1169
OCH3), 3.32 (t, J¼6.8 Hz, 4H, NCH2CH2N), 3.04 (s, 4H, NCH2C(O)
NHꢂ), 2.96 (s, 4H, NCH2CO2H), 2.88 (s, 2H, NCH2CO2H), 2.64 (t,
J¼6.8 Hz, 4H, NCH2CH2N), 2.43 (br s, 4H, NHCH2CH2Ar), 2.29 (br s,
O), 172.9 (C]O), 172.0 (C]O), 171.4 (C]O), 171.3 (C]O), 169.0 (C]
O), 61.2 (CH2), 55.0 (CH2), 52.1 (CH2), 51.2 (CH2), 50.5 (CH2), 49.6
(CH2). ES-MS found: 624 ([MþH]þ).
4H, NHCH2CH2Ar). 13C NMR (D2O, 75 MHz, 25 ꢁC)
d¼179.5 (C]O),
179.3 (C]O), 174.5 (C]O), 148.4 (ArC), 147.0 (ArC), 132.6 (ArC),
121.7 (ArCH), 112.7 (ArCH), 112.1 (ArCH), 59.4 (CH2), 58.7 (CH2),
56.0 (OCH3), 52.7 (CH2), 52.5 (CH2), 40.5 (CH2), 34.4 (CH2). ES-MS
found: 718 ([MꢂH]ꢂ).
4.4.7. DTPA-di-3-carboxylpropylamide (2g)42. 1 g of DTPA dianhy-
dride (2.8 mmol) was mixed with 4-aminobutyric acid (0.58 g,
5.6 mmol) in 30 mL of DMF. After 24 h under stirring at 75 ꢁC, the
mixture was evaporated to dryness. Residue was purified by
recrystallisation in a mixture of water/acetone. Compound 2g
(1.53 g, 97%) was obtained as yellow hygroscopic powder after
filtration.
4.4.3. DTPA-bis(4-carboxylphenylamine) (2c)39. 1 g of DTPA dia-
nhydride (2.8 mmol) was mixed with 4-aminobenzoic acid (0.85 g,
6.2 mmol) in 25 mL of DMF. After 24 h under stirring at 75 ꢁC, the
solution was evaporated to dryness. Residue was purified by
recrystallisation in a mixture of water/ethanol to give compound 2c
(1.37 g, 77%) as yellow powder after filtration.
1H NMR (D2O, 300 MHz, 25 ꢁC)
d
¼3.76 (s, 4H, NCH2C(O)NHꢂ),
3.59e3.63 (s, 6H, NCH2CO2H), 3.27 (m, 4H, NCH2CH2N), 3.17 (m,
8H, NCH2CH2NþNCH2), 2.30 (m, 4H, CH2), 1.70 (m, 4H, CH2). 13C
NMR (D2O, 75 MHz, 25 ꢁC)
d
¼178.3 (C]O), 172.6 (C]O), 172.5 (C]
1H NMR (D2O, 300 MHz, 25 ꢁC)
J¼8.7 Hz, 4H, AreH), 7.77 (d, J¼8.9 Hz, 4H, AreH), 3.72 (s, 2H,
NCH2CO2H), 3.50e3.55 (br s, 8H, NCH2CO2Hþ, NCH2C(O)NHꢂ),
3.05e3.20 (m, 8H, NCH2CH2N). 13C NMR (D2O, 75 MHz, 25 ꢁC)
d
¼10.38 (s, 2H, NH), 7.85 (d,
O), 168.8 (C]O), 57.2 (CH2), 57.0 (CH2), 52.0 (CH2), 51.5 (CH2), 39.0
(CH2), 30.6 (CH2), 24.1 (CH2). ES-MS found: 564 ([MþH]þ).
4.4.8. DTPA-O-benzyl CAM (2h). A mixture of DTPA dianhydride
(0.365 g, 1 mmol), N-(2-aminoethyl)-2,3-bis(benzyloxy)benzamide
(0.74 g, 2 mmol), in dry DMF (15 mL) was heated at 80 ꢁC under
stirring under argon. After 48 h the brown mixture was concen-
trated, 5 mL of methanol, then 200 mL of acetone were added to
give a white precipitate. The residue was filtered was triturated
twice with 20 mL ether to give after filtration compound 2h (0.92 g,
80%).
d
¼179.7 (C]O), 179.4 (C]O), 175.2 (C]O), 140.1 (ArC), 132.9
(ArCH), 130.3 (ArCH), 120.9 (ArC), 59.6 (CH2), 52.9 (CH2), 52.0
(CH2), 37.0 (CH2), 29.5 (CH2). ES-MS found: 632 ([MþH]þ).
4.4.4. DTPA-PAS (2d)40. 0.357 g of DTPA dianhydride (1 mmol) was
mixed with p-aminosalicylic (PAS) sodium (0.457 g, 2.25 mmol) in
5 mL of DMSO. After 2 h under stirring at room temperature, a so-
lution of NaOH in methanol was added for neutralisation. Addition
of ethanol gave a precipitate. Compound 2d (0.66g, 85%) was ob-
tained as white powder after filtration.
1H NMR (CD3OD, 300 MHz, 25 ꢁC)
AreH), 7.23e7.38 (m, 10H, AreH), 7.14 (t, J¼6.2 Hz, 1H, AreH), 5.13
(s, 2H, OeCH2eAr), 5.06 (s, 2H, OeCH2eAr), 3.23 3.40 (m, 11H,
CH2), 2.86 (s, 2H, CH2). 13C NMR (DMSO-d6, 75 MHz, 25 ꢁC)
d
¼7.48 (d, J¼6.3 Hz, 2H,
1H NMR (D2O, 300 MHz, 25 ꢁC)
d
¼7.67 (d, J¼8.5 Hz, 2H, AreH),
7.05 (d, J¼1.9 Hz, 2AreH), 6.91 (dd, J¼1.9 and 8.5 Hz, 2H, AreH),
d
¼175.0 (C]O), 173.9 (C]O), 169.2 (C]O), 153.8 (ArC), 147.7 (ArC),
3.32 (s, 4H, NCH2C(O)NHꢂ), 3.21 (s, 6H, NCH2CO2H), 2.79 (m, 8H,
138.6 (ArC), 130.8 (ArC), 130.4 (ArCH), 130.1 (ArCH), 130.0 (ArCH),
129.9 (ArCH), 129.7 (ArCH), 129.5 (ArCH), 126.1 (ArCH), 123.1
(ArCH), 118.4 (ArCH), 77.5 (CH2), 72.5 (CH2), 58.9 (CH2), 56.8
(CH2), 56.6 (CH2), 55.1 (CH2), 51.6 (CH2), 40.7 (CH2), 40.5 (CH2).
HRMS (ESI): calcd for C60H68N7O14þ: 1110.4824; found:
1110.4820.
NCH2CH2N). 13C NMR (D2O, 75 MHz, 25 ꢁC)
d
¼179.8 (C]O), 175.5
(C]O), 173.5 (C]O), 160.8 (ArC), 141.8 (ArC), 131.7 (ArCH), 115.0
(ArC), 112.0 (ArCH), 108.1 (ArCH), 59.7 (CH2), 59.4 (CH2), 52.6
(CH2), 52.3 (CH2). ES-MS found: 664 ([MþH]þ).
4.4.5. DTPA-bis(diethanolamine) (2e)41. To a solution of DTPA dia-
nhydride (2 g, 5.6 mmol) in CH3CN (60 mL), the solution of
diethanolamine (1.19 g, 11.2 mmol) in CH3CN (40 mL) was added
slowly. The mixture was stirred in atmosphere argon at 80 ꢁC for
48 h. After decantation, residue was filtered, diluted in water. Ad-
dition of acetone gave a viscous precipitate, which was isolated by
filtration. Further purification through emberlite IR-120 with water
as eluent gave compound 2e (2.1 g, 66%) as hygroscopic white
powder after evaporation and dryness in vacuum.
References and notes
1. Craft, E.; Abu-Qare, A.; Flaherty, M.; Garofolo, M.; Rincavage, H.; Abou-Donia, M.
J. Toxicol. Env. Heal. B 2004, 7, 297e317.
2. Hamilton, J. G. Rev. Mod. Phys. 1948, 20, 718e728.
3. Sawicki, M.; Siaugue, J.-M.; Jacopin, C.; Moulin, C.; Bailly, T.; Burgada, R.;
Meunier, S.; Baret, P.; Pierre, J.-L.; Taran, F. Chem.dEur. J. 2005, 11,
3689e3697.
4. Diamond, G. L.; Morrow, P. E.; Panner, B. J.; Gelein, R. M.; Baggs, R. B. Fundam.
Appl. Toxicol. 1989, 13, 65e78.
1H NMR (D2O, 300 MHz, 25 ꢁC)
d
¼4.49 (s, 4H, NCH2C(O)Nꢂ),
5. Leggett, R. W. Health Phys. 1989, 57, 365e383.
6. Morrow, P. E.; Gibb, F. R.; Leach, L. J. Health Phys. 1966, 12, 1217e1223.
3.91 (s, 4H, NCH2CO2H), 3.76 (t, J¼5.2 Hz, 8H, NHCH2CH2OH), 3.59
(t, J¼6.2 Hz, 4H, NCH2CH2N), 3.48e3.52 (m, 10H, NH-
CH2CH2OHþNCH2CO2H), 3.1 (t, J¼6.25 Hz, 4H, NCH2CH2N). 13C
7. Finkel, M. P. Proc. Soc. Exp. Biol. Med. 1953, 83, 494e498.
ꢀ
8. Henge-Napoli, M.-H.; Stradling, G. N.; Taylor, D. M. Radiat. Prot. Dosim. 2000, 87,
11e18.
NMR (D2O, 75 MHz, 25 ꢁC)
d
¼176.8 (C]O), 172.6 (C]O), 169.0 (C]
9. Ansoborlo, E.; Amekraz, B.; Moulin, C.; Moulin, V.; Taran, F.; Bailly, T.; Burgada,
ꢀ
R.; Henge-Napoli, M.-H.; Jeanson, A.; Den Auwer, C.; Bonin, L.; Moisy, P. C. R.
O), 61.2 (CH2), 60.9 (CH2), 59.9 (CH2), 58.8 (CH2), 56.6 (CH2), 55.9
(CH2), 52.1 (CH2), 51.8 (CH2), 50.6 (CH2). ES-MS found: 568.2
([MþH]þ).
Chimie 2007, 10, 1010e1019.
10. Durbin, P. W.; Kullgren, B.; Ebbe, S. N.; Xu, J.; Raymond, K. N. Health Phys. 2000,
78, 511e521.
11. Martinez, A. B.; Cabrini, R. L.; Ubios, A. M. Health Phys. 2000, 78, 668e671.
12. Fukuda, S.; Iida, H.; Ikeda, M.; Yan, X.; Xie, Y. Health Phys. 2005, 89, 81e88.
13. (a) Xu, J.; Raymond, K. N. Inorg. Chem. 1999, 38, 308e315; (b) Durbin, P. W.;
Kullgren, B.; Xu, J.; Raymond, K. N. Radiat. Prot. Dosim. 1994, 53, 305e309; (c)
Durbin, P. W.; Kullgren, B.; Xu, J.; Raymond, K. N. Radiat. Prot. Dosim. 1998, 79,
433e443; (d) Durbin, P. W.; Kullgren, B.; Xu, J.; Raymond, K. N. Health Phys.
1997, 72, 865e879.
4.4.6. DTPA-di-(amidodiacetic acid) (2f). 729 mg of DTPA dianhy-
dride (2.04 mmol) was mixed with iminodiacetic acid (543 mg,
4.08 mmol) in 15 mL of dry DMF. After 24 h under stirring at 80 ꢁC,
the mixture was evaporated to dryness. Residue was purified by
recrystallisation in a mixture of methanol/acetone. Compound 2f
(1.2 g, 95%) was obtained as yellow hygroscopic powder after
filtration.
14. Gorden, A. E. V.; Xu, J.; Raymond, K. N.; Durbin, P. Chem. Rev. 2003, 103,
4207e4282.
ꢀ
15. Leydier, A.; Lecercle, D.; Pellet-Rostaing, S.; Favre-Reguillon, A.; Taran, F.;
Lemaire, M. Tetrahedron 2008, 64, 6662e6669.
16. Bailly, T.; Burgada, R. C.R. Acad. Sci. 1998, 1, 241e245; Leydier, A.; Lecercle, D.;
1H NMR (DMSO-d6, 300 MHz, 25 ꢁC)
d
¼11.0 (br s, CO2H), 4.13 (s,
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