Synthesis of a novel bifunctional chelating agent for actinium complexation

Article abstract of DOI:10.1016/S0040-4039(00)01208-9

A novel bifunctional chelating agent for actinium was synthesized in eight steps. Bimolecular cyclization between an iminodiester and a polyamine was achieved through the action of a molar equivalent of sodium methoxide. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01208-9

Tetrahedron Letters 41 (2000) 7207±7209
Synthesis of a novel bifunctional chelating agent for actinium
complexation
Ali Ouadi,a,b,c,* Anthony Loussouarn,c Patricia Remaud,c Laurence Morandeau,c
Christos Apostolidis,b Claude Musikas,a Alain Faivre-Chauvetc
and Jean-Francois Gestinc
a
Â
Unite Mixte de Recherche 6457, Laboratoire Subatech-Ecole des Mines de Nantes, 4 rue Alfred Kastler, BP 20722,
44307 Nantes cedex 3, France
bEuropean Institute for Transuranium Elements, Postfach 2340, D-76125 Karlsruhe, Germany
c
Â
Chimie des Bioconjugues, U. 463 INSERM, 9 Quai Moncousu, 44093 Nantes Cedex, France
Received 18 May 2000; accepted 13 July 2000
Abstract
A novel bifunctional chelating agent for actinium was synthesized in eight steps. Bimolecular cyclization
between an iminodiester and a polyamine was achieved through the action of a molar equivalent of sodium
methoxide. # 2000 Elsevier Science Ltd. All rights reserved.
Immunotherapy with radiolabeled antibodies should allow fairly speci®c targeting of some
cancers.1,2 One promising candidate for such applications3 is 225Ac, an a-emitter. The very short
range (<100 mm) of a particles and their high energy transfer should be conducive to ecient
destruction of tumor cells, whereas normal cells should be relatively spared. The development of
new bifunctional chelating agents (BCAs) is essential for this purpose, but no suitable BCA has
been reported for 225Ac.4 6
Our investigations, in agreement with other studies,5 indicated that HEHA (1,4,7,10,13,16-
hexaazacarboxylmethyl-1,4,7,10,13,16-hexaazacyclooctadecane) was the best candidate for 225Ac
complexation (Scheme 1), which led us to synthesize the C-functionalized analogue.
We prepared 2-(4-isothiocyanatobenzyl)-1,4,7,10,13,16-hexakis (2-carboxymethyl)hexaaza-
cyclooctadecane, which is functionalized at C-2 on the ring by an isothiocyanate termination for
covalent attachment to biomolecules (Scheme 2).
A commercial product, 4-nitrophenylalanine 1, was used as starting material. Treatment of 1
with HCl gas in methanol yielded 4-nitrophenylalanine methyl ester hydrochloride. N-((methoxy-
carbonyl)methyl)-4-nitrophenylalanine methyl ester was prepared by reacting 3 equivalents of
* Corresponding author. Fax: 49 7247 951 593; e-mail: ouadi@itu.fzk.de
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01208-9

7208
Scheme 1. HEHA
Scheme 2. Reagents: (i) MeOH/HClg; (ii) NEt3/BrCH2CO2Me/THF; (iii) NaOMe/tetraethylenepentamine/MeOH/
re¯ux; (iv) BH3/THF; (v) Na2CO3/BrCH2CO2tBu/DMF; (vi) SnCl2/MeOH; (vii) TFA; (viii) CSCl2
methylbromoacetate and triethylamine with 1 equivalent of 4-nitrophenylalanine methyl ester.
Treatment with tetraethylenepentamine in the presence of sodium oxide in re¯uxing methanol
induced macrocyclization, producing the cyclic diamide 2 in a 50% yield.7 Reduction with BH3
a€orded after treatment with HCl gas and puri®cation by anion-exchange chromatography 2-(4-
nitrobenzyl)-1,4,7,10,13,16-hexaazacyclooctadecane 3 in a 55% yield. The hexa-t-butyl ester 4
was prepared by reacting 6 equivalents of tert-butyl bromoacetate and 11 equivalents of sodium
carbonate with 1 equivalent of hexaazacyclooctadecane. The nitrobenzyl function was selectively
reduced by using tin chloride in ethanol to obtain the aminobenzyl compound. Cleavage of the
ester groups with tri¯uoroacetic acid, followed by puri®cation on an ion-exchange chromatography
column, gave p-aminobenzyl-HEHA 5,8 and treatment with thiophosgene yielded the ®nal com-
pound, p-isothiocyanatobenzyl-HEHA 6.
Construction of the polyazamacrocycle ring is crucial for the successful synthesis of a macrocycle
BCA. However, previously reported cyclization methodologies9 14 proved unsatisfactory in our

7209
hands. The reaction between N-methoxycarbonylmethyl-p-nitrophenylalanine methyl ester and
tetraethylenepentamine, upon re¯uxing in methanol for several days in the absence of sodium
methoxide, failed to yield the desired product. Therefore, an improved procedure was developed
for the bimolecular cyclization between an iminodiester and a polyamine through the action of a
molar equivalent of sodium methoxide. A 50% yield was obtained, which enabled us to prepare
the bifunctional dioxoaza macrocycle without any need for high dilution. This method is simple
and easy to perform, allowing the preparation of functionalized macrocyclic polyamines of
varying ring sizes.
References
1. Couturier, O.; Faivre-Chauvet, A.; Filippovich, I. V.; Thedrez, P.; Saõ-Maurel, C.; Bardies, M.; Mishra, A. K.;
Gauvrit, M.; Blain, G.; Apostolidis, C.; Molinet, R.; Abbe, J. C.; Bataille, R.; Wijdenes, J.; Chatal, J. F.; Cherel,
M. Clin. Cancer. Res. 1999, 5, 3165±3170.
2. Macklis, R. M.; Kinsey, B. M.; Kassis, A. I.; Ferrara, J. L.; Atcher, R. W.; Hines, J. J.; Coleman, C. N.; Adelstein,
S. J.; Burako€, S. J. Science 1988, 240, 1024±1026.
3. Kaspersen, F. M.; Bos, E.; Doornmalen, A. V.; Geerlings, M. W.; Apostolidis, C.; Molinet, R. Nucl. Med.
Commun. 1995, 16, 468±476.
4. Davis, I. A.; Glowienka, K. A.; Boll, R. A.; Deal, K. A.; Brechbiel, M. W.; Stabin, M.; Bochsler, P. N.; Mirzadeh,
S.; Kennel, J. S. Nucl. Med. Biol. 1999, 26, 581±589.
5. Deal, K. A.; Davis, I. A.; Mirzadeh, S.; Kennel, J. S.; Brechbiel, M. W. J. Med. Chem. 1999, 42, 2988±2992.
6. Grote Gansey, M. H. B.; de Haan, A. S.; Bos, E. S.; Verboom, W.; Reinhoudt, D. N. Bioconj. Chem. 1999, 10,
610±623.
7. Preparation of 2: Sodium (20 mmol) was dissolved in dry methanol (100 ml) at room temperature under a nitrogen
atmosphere, and tetraethylenepentamine (18 mmol) and N-((methoxycarbonyl)methyl)-4-nitrophenylalanine
methyl ester (18 mmol) were then added to this solution. After the solution was re¯uxed for 72 h, the solvent
was removed and the residue was puri®ed on silica gel chromatography with chloroform:methanol:NH3 (aq)
(75:20:5), a€ording a brown powder with a yield of 50%.
8. All compounds gave satisfactory spectroscopic and analytical data. Representative data for selected compounds
are: compound 2: MS (M+1): 422, IR (Kr, cm^1): 3287 (NH), 3287±2842 (Ar±C±H), 1656 (CˆO), 1517 and 1345
(NO2), 1H NMR (250 MHz, CDCL3): ꢀ 8.17 (d, 2H), 7.57 (s, NH amide), 7.40 (d, 2H), 7.27 (s, NH amide), 3.14±
3.48 (m, 9H), 2.6±2.9 (m, 11H), 13C NMR (CDCl3): CO: 175, 145, 130, 123, 55, 52, 40; compound 3: MS (M+1):
394, IR (Kr, cm^1): 3428 (NH), 2961±2759 (Ar±C±H), 1518 and 1349 (NO2), 1H NMR (250 MHz, CDCL3): ꢀ 8.06
(d, 2H), 7.27 (d, 2H), 2.3±2.9 (m, 25H); compound 5: MS (M+1): 712, 1H NMR (250 MHz, D2O): ꢀ 7.08 (d, 2H),
6.80 (d, 2H), 2.5±4.0 (m, 37H).
9. Richman, J. E.; Atkins, T. J. J. Am. Chem. Soc. 1974, 96, 2268±2270.
10. Vellacio Jr., F.; Penzar, R. V.; Kemp, D. S. Tetrahedron Lett. 1977, 6, 547±550.
11. Tabushi, I. Tetrahedron Lett. 1977, 12, 1049±1052.
12. Moi, M. K.; Meares, C. F. J. Am. Chem. Soc. 1988, 110, 6266±6267.
13. Krakowiack, K. E.; Bradshaw, J. S.; Izatt, R. M. J. Heterocycl. Chem. 1990, 27, 1585±1589.
14. McMurry, T. J.; Brechbiel, M.; Kumar, K.; Gansow, O. A. Bioconj. Chem. 1992, 3, 108±117.