Synthesis of a new chelating agent derived from phenylenediamine for application in radioimmunotherapy

Article abstract of DOI:10.1016/S0040-4039(02)00410-0

We report the synthesis of a new diethylenetriaminepentaacetic acid (DTPA) analogue, Ph-DTPA, possessing an aromatic rigid skeleton. This precursor of a bifunctional chelating agent was synthesized by elaboration of the intermediate N-(o-aminophenyl)ethyl

Full text of DOI:10.1016/S0040-4039(02)00410-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3003–3005
Synthesis of a new chelating agent derived from
phenylenediamine for application in radioimmunotherapy
Se´bastien G. Gouin,a,b Jean-Franc¸ois Gestin,b,c Alain Reliquet,a Jean Claude Meslina and
David Deniauda,*
aLaboratoire de Synthe`se Organique, UMR CNRS 6513, Faculte´ des Sciences et des Techniques, 2 rue de la Houssinie`re,
BP 92208, 44072 Nantes Cedex, France
bINSERM U463, Chimie des bioconjugue´s, 9 quai Moncousu, 44093 Nantes Cedex, France
cCHELATEC SAS, Institut de Biologie, 9 quai Moncousu, 44093 Nantes Cedex, France
Received 4 February 2002; accepted 27 February 2002
Abstract—We report the synthesis of a new diethylenetriaminepentaacetic acid (DTPA) analogue, Ph-DTPA, possessing an
aromatic rigid skeleton. This precursor of a bifunctional chelating agent was synthesized by elaboration of the intermediate
N-(o-aminophenyl)ethylenediamine and obtained in five steps with an overall yield of 42%. Preliminary complexation studies
between Ph-DTPA and 153Sm has been carried out. © 2002 Elsevier Science Ltd. All rights reserved.
For many years, complexes combining metals with
DTPA and its derivatives have been widely used in
magnetic resonance imaging (MRI),1–5 radiotherapy6–8
and radiodiagnosis.9 In particular, the gadolinium–
(DTPA) complex is currently used in clinical applica-
tions as a contrast agent in MRI.10,11 Moreover, many
complexes combining lanthanides with DTPA ana-
logues have proved stable enough for use in a physio-
logical medium as radiopharmaceuticals.12,13 Since the
introduction of this family of chelating agents, develop-
ments have been directed essentially at increasing the
stability of the resulting complexes.14,15 The most
promising results have been based on studies to
improve the rigidity of the chelating structure. The
introduction of a semi-rigid preformed skeleton, which
minimizes the freedom of donor atoms, has had a
significant effect on the stability of the metal complexes
formed.16 Notably, the teams of R. D. Hancock and
then M. W. Brechbiel have shown that DTPA ana-
logues with a semi-rigid structure of cyclohexyl (Cy-
DTPA),17,18 piperidinyl (PIP-DTPA) or azaparyl
(AZEP-DTPA)19 type prove considerably more stable
in vivo. On this basis, our recent research has been
directed at developing stereoisomer chelating agents
based on ethylenediaminetetraacetic acid analogues
with a cyclopentanic skeleton.20 The synthesis of the
DTPA analogue phenyleneethylenetriamine pentaacetic
acid (Ph-DTPA) reported here provides a chelating
agent even more rigid than Cy-DTPA and with an
aromatic skeleton (Scheme 1).
HO2C
HO2C
CO2H
N
N
N
N
N
HO2C
HO2C
N
HO2C
HO2C
N
HO2C
HO2C
N
N
CO2H
CO2H
HO2C
HO2C
HO2C
HO2C
DTPA
Cy-DTPA
Ph-DTPA 1
Scheme 1.
* Corresponding author. Tel.: +33-2-51-12-54-57; fax: +33-2-51-12-54-02; e-mail: david.deniaud@chimie.univ-nantes.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00410-0

3004
S. G. Gouin et al. / Tetrahedron Letters 43 (2002) 3003–3005
A bifunctional chelating agent is required for the
elaboration of bioconjugates suitable for cancer
radioimmunotherapy. The functional group commonly
used is the p-isothiocyanatobenzyl chain, which is
generally derived from nitrobenzene that must be
introduced during the synthesis of the complexing
molecule.21,22 The octadentate chelating agent Ph-
DTPA has a rigid structure, but is also easy to func-
tionalize directly on the aromatic cycle by means of
an isothyiocyanate group.
The key intermediate, N-(o-aminophenyl)ethylene-
diamine 5, was obtained with an excellent yield by
using the BH3–Me2S complex as a reducing agent,
followed by treatment with HCl gas.28,29 The prepara-
tion of triamine 5 was previously reported according
to a totally different synthesis strategy, which pro-
vided an overall yield of no more than 29%.30
According to the classical alkylation method, penta-
tert-butyl ester 6 was obtained through the action of
excess tert-butylbromoacetate in the presence of KI
and K2CO3 in acetonitrile.31 Finally, hydrolysis of the
ester functions was performed in basic medium,
providing Ph-DTPA 1 with a yield of 88% (Scheme
3).
The synthesis of Ph-DTPA 1 was performed in five
steps from the starting product, 1,2-phenylenediamine
(Scheme 2). The first step, described previously, which
consists in peptidic coupling of carbobenzyloxyglycine
and the aromatic amine in the presence of dicyclo-
hexylcarbodiimide, yields compound 2.23 The synthe-
sis of compound 4 implies the elimination of the Z
group. The usual deprotection method for benzyloxy-
carbonyl (HBr in acetic acid)24 could not be used. In
fact, substituted aniline 2 proved unstable in acid
medium, yielding quantitatively benzimidazole 3, a
product belonging to a pesticide class.25 The most
efficient method for achieving 4, which provided the
best yields (98%) without purification, involved the
use of palladium on charcoal as a catalyst under a
hydrogen atmosphere. This method proved more suit-
able than that described by M. R. Bermejo, which
uses cyclohexene as hydrogen source, providing yields
of no more than 80%.26,27
Preliminary complexation studies between Ph-DTPA
and 153Sm has been carried out. It shows that the
kinetic of complexation of 153Sm to 1 is adapted to
radioimmunotherapy.32 This was evident from the fact
that, on incubating for 45 min at 37°C a radioactive
153
solution containing a 1/1 molar ratio of
Sm/Ph-
DTPA, 56% of 153Sm chelating agent complex is
formed.33
In conclusion, a rigid DTPA analogue was synthe-
sized with a overall yield of 42% after five steps.
Studies of the complexing efficiency of this new
chelating agent with radioactive metals suitable for
radioimmunotherapy (90Y and 153Sm) are in progress.
H
H
N
NH2
NH2
N
HO2C-CH2-NHZ
DCC, THF
NHZ
NH2
Pd/C
O
O
NH2
H2, EtOH
NH2
2 (82%)
4 (98%)
BH3-SMe2
THF, HCl
HCl
H
N
H
N
NH2
NHZ
.3 HCl
N
NH2
5 (91%)
3 (98%)
Scheme 2.
CO2tBu
CO2H
CO2H
N
N
H
N
CO2tBu
CO2tBu
NH2
.3 HCl
N
N
N
CO2H
CO2H
CO2H
1 (88%)
BrCH2CO2tBu
1) NaOH 2M
2) HCl 6M
NH2
KI, K2CO3
CH3CN
CO2tBu
CO2tBu
6 (65%)
N
5
.3HCl
Scheme 3.

S. G. Gouin et al. / Tetrahedron Letters 43 (2002) 3003–3005
3005
19. Chong, H.-S.; Garmestani, K.; Bryant, H.; Brechbiel, M.
W. J. Org. Chem. 2001, 66, 7745–7750.
Acknowledgements
20. Gouin, S. G.; Gestin, J.-F.; Joly, K.; Loussouarn, A.;
Reliquet, A.; Meslin, J.-C.; Deniaud, D. Tetrahedron
2002, 58, 1131–1136.
21. Gestin, J. F.; Loussouarn, A.; Bardies, M.; Gautherot,
E.; Gruaz-Guyon, A.; Sa¨ı Maurel, C.; Bardet, J.; Curtet,
C.; Chatal, J. F.; Faivre Chauvet, A. J. Nucl. Med. 2001,
42, 146–153.
22. Brechbiel, M. W.; Gansow, O. A. J. Chem. Soc., Perkin
Trans. 1 1992, 1173–1178.
23. Hoyos, O. L.; Bermejo, M. R.; Fondo, M.; Garcia-Deibe,
A.; Gonzalez, A. M.; Maneiro, M.; Pedrido, R. J. Chem.
Soc., Dalton Trans. 1 2000, 3122–3127.
The authors are grateful to the French Ministry of
Education, the CNRS, and the ‘Ligue Nationale Contre
le Cancer’ for financial support.
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