A rapid microwave-assisted procedure for easy access to Npolydentate ligands for potential application in α-RIT

Article abstract of DOI:10.1055/s-0029-1219813

Heterocycles bearing a hydrazine moiety react with bisaldehydes or bisketones to afford new Npolydentate ligands suitable for -radioimmunotherapy. We developed a fast and efficient method using microwave-assisted technology to obtain chelators with variab

Full text of DOI:10.1055/s-0029-1219813

LETTER
1215
A Rapid Microwave-Assisted Procedure for Easy Access to Nx Polydentate
Ligands for Potential Application in a-RIT
EasyAccess to
N
x Polyadentate
L
i
t
f
h
or Potentia
l
A
i
pplica
e
tion in
a
-
R
u
IT Mével,a Ewen Bodio,a Sylvain Grosjean,a Gilles Montavon,b Jean-Claude Meslin,a Karine Julienne,a David
Deniaud*a
a
Université de Nantes, CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR des Sciences
et des Techniques, 2, Rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France
Fax +33(2)51125402; E-mail: david.deniaud@univ-nantes.fr
Université de Nantes, Laboratoire SUBATECH, UMR CNRS 6457, Ecole des Mines de Nantes, 4, Rue A. Kastler, BP 20722,
44307 Nantes Cedex 3, France
b
Received 5 February 2010
sence of a stable isotope. The current approach for label-
ing biomolecules with 211At rests on covalent attachment
to a carbon atom.8 Unfortunately, a significant number of
studies has shown that astatinated radiopharmaceuticals
Abstract: Heterocycles bearing a hydrazine moiety react with bis-
aldehydes or bisketones to afford new Nx polydentate ligands suit-
able for a-radioimmunotherapy. We developed a fast and efficient
method using microwave-assisted technology to obtain chelators
with variable size and number of coordination centers which were can be stable to in vitro conditions, but generally more un-
stable in vivo.9–11 Nevertheless, clinical studies are in
fully characterized. The complexation efficiency with astatine will
progress in the US and in Sweden.12,13 Although it is clear
be assessed.
Key words: astatine, radioimmunotherapy, pyrimidinone, triazin-
one, chelating agent
that much of the chemistry ascribed to halogens is appli-
cable, the chemical similarity between astatine and its
nearest halogen neighbor, iodine, is not always obvious.
The general trend in the periodic system suggests that as-
Radioimmunotherapy (RIT) is a developing and promis- tatine is more metallic in character than iodine. Indeed, it
ing technique for the treatment of small tumors.1–3 It con- has been reported that astatine presents a metal-like be-
sists of injecting patients with a radiopharmaceutical able havior when existing under the oxidation states +I and
to target and selectively destroy tumor cells. The radionu- +III as At+ and AtO+ species.14,15 Different groups have
clides usually used are a or b– emitters with a short half- reported the formation of coordination complexes be-
life, attached to a vector (antibody or hapten) through a bi- tween AtO+ and N– or S– containing organic chelating
functional chelating agent.4–6 In order to minimize irradi- agents.16–18 The stability of these complexes is, however,
ation of healthy tissue whilst delivering radionuclides to not sufficient to use this chelation approach in RIT.
tumors, the metal complex between chelating agent and
radionuclide has to be stable in human serum.
These considerations brought us to develop new Nx poly-
dentate ligands with variable size and number of coordi-
Among the potential radionuclides, 211At has attracted in- nation centers. At the same time as a fundamental,
terest as a prospective candidate for a-radioimmunothera- theoretical, and pragmatic study around element astatine,
py applications due to its adequate physicochemical we led here a purely empirical approach. This paper re-
characteristics: a-emitter with a half-life of 7.2 hours, the ports the synthesis of chelating agents L1–8 containing het-
emission of high energy a particles (6.8 MeV), and ability erocyclic rings (Figure 1). Our expertise in the synthesis
to deposit large amounts of energy in a microvolume.7 As- of heterocycles led us to this choice of ligands. They
tatine is also an X-ray emitter allowing external imaging present a semirigid scaffold due to partial conjugation be-
of the radiopharmaceutical distribution. Nevertheless, the tween the linker and heterocycle. This characteristic is
chemistry of astatine remains in its infancy due to the ab- essential to preorganization, an important ligand proper-
(N)x
(N)x
ligands L1–4
ligands L5–8
N
N
N
N
N
N
N
N
HN
N
NH
N
HN
NH
x = 0,1, 2
N
N
N
N
O
O
O
O
CO2Me
CO2Me
Figure 1 Polydentate chelators prepared in the study
SYNLETT 2010, No. 8, pp 1215–1218
x
x.
x
x.
2
0
1
0
Advanced online publication: 07.04.2010
DOI: 10.1055/s-0029-1219813; Art ID: G04610ST
© Georg Thieme Verlag Stuttgart · New York

1216
M. Mével et al.
LETTER
ty.19,20 The degree of freedom is minimized, so that the
structure of the chelate before complexation is similar to
that in the complex. Preorganization provides high ther-
modynamic stability as well as increased kinetic inertness
of the metal complex.
MeNCS
SMe
N
SMe
N
Commercially available methylisothiocyanate was used
as the starting reagent for the synthesis of chelating agents
N
N
O
O
N
L1–8. The key step in this synthetic process was the prepa-
CO2Me
ration of the two corresponding hydrazino heterocyclic
rings 3 and 4 (Scheme 1). The intermediary pyrimidinone
1 and triazinone 2 were obtained in high yields according
to our previously described methodology.21,22 Nucleo-
philic displacement of the methylsulfanyl group of 1 and
2 with hydrazine was carried out using ethanol as solvent
to afford 2-hydrazonopyrimidine 3 and 2-hydrazonotriaz-
ine 4.23 The reaction was performed under microwave ir-
radiation in order to minimize reaction time and
secondary reactions. Indeed, with pyrimidinone 1, at room
temperature and after 20 hours, a byproduct (20%) result-
ing from double attack of hydrazine onto two hetero-
cycles, was observed.
1
2
MW (80 W), 110 °C,
quant
H2N
quant
NH2NH2, EtOH, 10 min
NH2
N
NH
HN
N
O
N
N
O
N
CO2Me
3
4
Scheme 1 Synthetic route to heterocyles 3 and 4
Finally, the heterocyclic rings 3 and 4 were converted into
the new polydentate ligands L1–8 with 4–6 coordination the N4 ligands in high yields.24 Microwave irradiation sig-
centers (N4, N5, and N6) by a double imination reaction nificantly improved yields and condensation reaction ki-
with dialdehydes 5, 8 or diketones 6, 7.24 These carbonyl netics compared to conventional thermal protocol.
compounds were commercially available except 5. This
latter compound was prepared by initial reduction (using
BH3·THF) of 5-tert-butylisophtalic acid to give the corre-
The N5-pentadentate ligands were prepared in a similar
way. Reaction of heterocyclic ring 3 or 4 with diacetylpy-
rimidine 7 led to the formation of ligands L5 and L6
sponding diol, which was subsequently oxidized (PCC/
(Scheme 3). The reaction proceeded at 130 °C in acetic
CH2Cl2) into the dialdehyde.25
acid under microwave irradiation affording the ligands in
To prepare N4-tetradentate ligands L1–4, two equivalents high yields.
of heterocyclic ring 3 or 4 were reacted with 1,3-
bis(formyl)-5-tert-butylbenzene (5) or butane-2,3-dione
(6, Scheme 2). The syntheses were performed under mi-
crowave irradiation at 110 °C in ethanol for dialdehyde 5
Finally, N6-hexadentate ligands L7 and L8 were analo-
gously prepared by condensation of 2,9-diformylphenan-
throline (8) and pyrimidine 3 or triazine 4 (Scheme 4).
These N6 ligands posses the rigidity imposed by the cen-
and at 130 °C in acetic acid for diketone 6 and afforded
t-Bu
t-Bu
t-Bu
N
N
N
N
N
N
N
N
3
4
HN
N
NH
N
HN
NH
80%
92%
N
N
N
N
O
O
5
O
O
O
O
MW (80 W), 110 °C
EtOH, 15 min
L2
L1
CO2Me
CO2Me
O
HN
N
N
N
NH
N
HN
N
N
N
NH
N
3
4
N
N
N
N
N
92%
82%
O
O
O
O
O
N
6
MeO2C
CO2Me
L3
L4
MW (250 W), 130 °C
MeCO2H, 15 min
Scheme 2 Tetradentate ligands L1–4 with pyrimidinone and triazinone scaffolds
Synlett 2010, No. 8, 1215–1218 © Thieme Stuttgart · New York

LETTER
Easy Access to Nx Polydentate Ligands for Potential Application in a-RIT
1217
N
N
N
N
N
N
N
N
N
N
3
4
HN
NH
HN
N
NH
N
N
85%
87%
N
N
N
N
O
O
7
O
O
O
O
MW (250 W), 130 °C
MeCO2H, 15 min
L6
L5
CO2Me
CO2Me
Scheme 3 Pentadentate ligands L5 and L6 with pyrimidinone and triazinone scaffolds
N
N
N
N
3
4
N
N
84%
85%
N
N
N
N
O
O
HN
N
NH
N
8
NH
HN
N
N
N
N
MW (80 W), 110 °C
EtOH, 15 min
N
N
N
N
O
O
O
O
CO2Me
L7
CO2Me
L8
Scheme 4 Hexadentate ligands L7 and L8 with pyrimidinone and triazinone scaffolds
(3) Liu, Z.; Jin, C.; Yu, Z.; Zhang, J.; Liu, Y.; Zhao, H.; Jia, B.;
Wang, F. Bioconjugate Chem. 2010, 21, 314.
(4) Remaud, P.; Faivre-Chauvet, A.; Gestin, J. F.; Morandeau,
L. WO 0240507, 2002.
(5) Friesen, C.; Glatting, G.; Koop, B.; Schwarz, K.;
Morgenstern, A.; Apostolidis, C.; Debatin, K.-M.; Reske, S.
Cancer Res. 2007, 67, 1950.
(6) Zalutsky, M. R.; Reardon, D.; Akabani, G.; Coleman, R.;
Friedman, A.; Friedman, H.; McLendon, R.; Wong, T.;
Bigner, D. J. Nucl. Med. 2008, 49, 30.
tral phenantroline ring and the flexibility of the heterocy-
clic arms.
All new ligands L1–8 were isolated with a high degree of
purity by simple filtration after microwave heating in
glass vial. Their structure was determined unequivocally
1
by complementary H/13C-2D NMR techniques (COSY,
HMQC, and HMBC).26
In conclusion, the synthesis of Nx-polydentate ligands
(N4, N5, and N6) was efficiently and simply performed by
use of microwave-assisted technology. These chelators
were prepared in 50–80% overall yield from methyl-
isothiocyanate. The described way of synthesis will be
easily adaptable to various starting heterocyclic struc-
tures. Study of the complexing ability of these new chelat-
ing agents toward astatine, suitable for a-radio-
immunotherapy, is in progress. According to the results of
this study we envision the synthesis of various analogues
of ligands L1–8 in order to adjust their structure (size, na-
ture, number of coordination centers, and heterocyclic
ring) to finally find out the ligand which would be best
suited for astatine.
(7) Lindegren, S.; Frost, S.; Bäck, T.; Haglund, E.; Elgqvist, J.;
Jensen, H. J. Nucl. Med. 2008, 49, 1537.
(8) Vaidyanathan, G.; Zalutsky, M. R. Curr. Radiopharm. 2008,
1, 177.
(9) Wilbur, D. S.; Chyan, M.-K.; Hamlin, D. K.; Perry, M. A.
Nucl. Med. Biol. 2010, 37, 167.
(10) Wilburg, S. Curr. Radiopharm. 2008, 1, 144.
(11) Boskovitz, A.; McLendon, R. E.; Okamura, T.; Sampson,
J. H.; Bigner, D. D.; Zalutsky, M. R. Nucl. Med. Biol. 2009,
36, 659.
(12) Zalutsky, M. R.; Reardon, D. A.; Pozzi, O. R.;
Vaidyanathan, G.; Bigner, D. D. Nucl. Med. Biol. 2007, 34,
779.
(13) Andersson, H.; Elgqvist, J.; Horvath, G.; Hultborn, R.;
Jacobsson, L.; Lensen, H.; Karlsson, B.; Lindgren, S.; Palm,
S. Clin. Cancer Res. 2003, 9, 3914S.
(14) Champion, J.; Alliot, C.; Huclier, S.; Deniaud, D.; Asfari, Z.;
Montavon, G. Inorg. Chim. Acta 2009, 362, 2654.
(15) Champion, J.; Alliot, C.; Renault, E.; Mokili, B. M.; Chérel,
M.; Galland, N.; Montavon, G. J. Phys. Chem. A 2010, 114,
576.
(16) Milesz, S.; Norseev, Y. V.; Szücs, Z.; Vasaros, L.
J. Radioanal. Nucl. Chem. Lett. 1989, 137, 365.
(17) Ludwig, R.; Fischer, S.; Dreyer, R.; Jacobi, R.; Beger, J.
Polyhedron 1991, 10, 11.
Acknowledgment
The authors thank the French National Research Agency (ANR)
(JCJC06_137852), the French Ministry of Education and CNRS for
financial support.
References
(1) Chatal, J.; Davodeau, F.; Cherel, M.; Barbet, J. J. Can. Res.
Ther. 2009, 5, 36.
(2) Cicone, F.; Baldini, R.; Cox, M. C.; Russo, E.; Torelli, F.;
Tofani, A.; Scopinaro, F. Anticancer Res. 2009, 29, 4771.
(18) Yordanov, A. T.; Deal, K.; Garmestani, K.; Kobayashi, H.;
Herring, B.; Waldmann, T. A.; Brechbiel, M. W. J. Labelled
Compd. Radiopharm. 2000, 43, 1219.
Synlett 2010, No. 8, 1215–1218 © Thieme Stuttgart · New York

1218
M. Mével et al.
LETTER
L3: mp 197–199 °C. IR (KBr): 3304, 1723, 1652, 1480,
(19) Martell, A. E.; Hancock, R. D.; Motekaitis, R. J. Coord.
Chem. Rev. 1994, 133, 39.
(20) Gouin, S. G.; Gestin, J. F.; Monrandeau, L.; Segat-Dioury,
F.; Meslin, J. C.; Deniaud, D. Org. Biomol. Chem. 2005, 3,
454.
(21) Kikelj, V.; Julienne, K.; Meslin, J. C.; Deniaud, D.
Tetrahedron Lett. 2009, 50, 5802.
(22) Robin, A.; Julienne, K.; Meslin, J. C.; Deniaud, D. Eur. J.
Org. Chem. 2006, 634.
1189, 1149 cm–1. 1H NMR (TFA): d = 2.40 (s, 6 H, CH3),
3.66 (s, 6 H, NCH3), 3.87 (s, 6 H, OCH3), 8.57 (s, 2 H,
CHpyr). 13C NMR (TFA): d = 10.7, 27.5, 52.3, 108.4, 145.0,
149.8, 155.1, 160.1, 162.3. MS (CI+): m/z = 447.3 [M + H]+.
L4: mp >250 °C. IR (KBr): 3434, 3071, 1691, 1622, 1494,
1291 cm–1. 1H NMR (TFA): d = 2.52 (s, 6 H, CH3), 3.61 (s,
6 H, NCH3), 8.53 (s, 2 H, CHtri). 13C NMR (TFA): d = 10.7,
33.9, 146.4, 155.8, 161.0, 162.2; MS (CI+): m/z = 333.0
[M + H]+.
(23) Sztanke, K.; Rzymowska, J.; Niemczyk, M.; Dybała, I.;
Kozioł, A. E. Eur. J. Med. Chem. 2006, 1373.
(24) General Procedure for Ligands L1–8
L5: mp 247–249 °C. IR (KBr): 3216, 1734, 1627, 1481,
1189, 1148 cm–1. 1H NMR (TFA): d = 2.73 (s, 6 H, CH3),
3.75 (s, 6 H, NCH3), 3.95 (s, 6 H, OCH3), 8.45 (d, 2 H,
J = 8.0 Hz, Har), 8.64 (s, 1 H, Hpyr), 8.81 (t, 1 H, J = 8.0 Hz,
Har). 13C NMR (TFA): d = 12.8, 27.9, 52.2, 104.9, 126.4,
146.3, 146.5, 148.1, 150.1, 154.1, 157.7, 163.4. MS
(MALDI): m/z = 524.52 [M + H]+, 546.33 [M + Na]+.
L6: mp 211–213 °C. IR (KBr): 3220, 1634, 1489, 1303, 1187
cm–1. 1H NMR (TFA): d = 2.74 (s, 6 H, CH3), 3.66 (s, 6 H,
NCH3), 8.55 (d, 2 H, J = 8.0 Hz, Har), 8.65 (s, 1 H, Htri), 8.85
(t, 1 H, J = 8.0 Hz, Har). 13C NMR (TFA): d = 12.4, 34.0,
126.9, 145.0, 146.1, 148.6, 150.9, 157.5, 162.9. MS (CI–):
m/z = 409.2 [M]+.
To a 10 mL microwave reaction vessel was placed
heterocyclic ring 3 or 4 (0.5 mmol) and dialdehyde 5 or 8 or
diketone 6 or 7 (0.25 mmol) in MeOH for L1,2,7,8 (4 mL) or
in AcOH for L3–6 (4 mL). The vial was heated (internal
temperature measured by fibre optic) in a microwave
synthesizer (MultiSYNTH®, Milestone S.r.l.) to 110 °C [2
min (110 W) ramp + 15 min irradiation (80 W)] for L1,2,7,8 or
to 130 °C [2 min (300 W) ramp + 15 min irradiation (250
W)] for L3–6. The solvent was removed under vacuum, and
the solid residue was washed with Et2O. The product was
filtered and dried under vacuum to afford ligands L1–8
.
(25) Hwang, S. H.; Moorefield, C.; Dai, L.; Newkome, G. Chem.
Mater. 2006, 18, 4019.
(26) Spectroscopic Data of Ligands L1–8
L7: mp >250 °C. IR (KBr): 1733, 1627, 1495, 1191, 1146
cm–1. 1H NMR (TFA): d = 3.66 (s, 6 H, NCH3), 3.86 (s, 6 H,
OCH3), 8.18 (s, 2 H, Har), 8.69 (s, 2 H, Hpyr), 8.72 (d, 2 H,
J = 8.5 Hz, Har), 8.84 (d, 2 H, J = 8.5 Hz, Har), 9.15 (s, 2H,
CH). 13C NMR (TFA): d = 28.7, 53.2, 107.8, 123.7, 129.0,
131.9, 137.5, 143.2, 146.4, 147.7, 150.0, 150.9, 151.0,
163.4. MS (MALDI): m/z = 597.41 [M + H]+, 619.22 [M +
Na]+.
L1: mp 243–244 °C. IR (KBr): 3245, 1733, 1628, 1480,
1193, 1147 cm–1. 1H NMR (TFA): d = 1.23 [s, 9 H,
C(CH3)3], 3.61 (s, 6 H, NCH3), 3.87 (s, 6 H, OCH3), 7.78 (s,
2 H, Har), 8.02 (s, 1 H, Har), 8.52 (s, 2 H, CH), 8.59 (s, 2 H,
CHpyr). 13C NMR (TFA): d = 27.3, 28.4, 33.4, 52.1, 106.5,
122.4, 130.3, 145.6, 148.9, 153.8, 155.7, 156.4, 162.7. MS
(MALDI): m/z = 551.42 [M + H]+, 573.31 [M + Na]+.
L2: mp 245–247 °C. IR (KBr): 3302, 1674, 1493, 1429,
1303, 1193 cm–1. 1H NMR (TFA): d = 1.37 [s, 9 H,
C(CH3)3], 3.68 (s, 6 H, NCH3), 8.12 (s, 2 H, Har), 8.30 (s, 1
H, Har), 8.50 (s, 2 H, CH), 8.52 (s, 2 H, CHtri). 13C NMR
(TFA): d = 28.5, 33.6, 33.7, 125.7, 130.1, 130.9, 146.3,
153.9, 154.4, 157.0, 161.3. MS (CI–): m/z = 436.2 [M]+.
L8: mp >250 °C. IR (KBr): 3212, 1623, 14932, 1306, 1186
cm–1. 1H NMR (TFA): d = 3.69 (s, 6 H, NCH3), 8.27 (s, 2 H,
Har), 8.69 (s, 2 H, Har), 8.61 (s, 2 H, Htri), 8.89 (d, 2 H, J = 8.6
Hz, Har), 9.06 (s, 2 H, CH), 9.29 (d, 2 H, J = 8.6 Hz, Har). 13
NMR (TFA): d = 33.9, 123.2, 128.0, 130.9, 136.3, 141.8,
147.1, 147.3, 149.7, 156.1, 162.7. MS (CI–): m/z = 482.2
[M]+.
C
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