Potential supramolecular cyclodextrin dimers using nucleobase Pairs

Article abstract of DOI:10.1055/s-0029-1217988

The synthesis of six new cyclodextrin derivatives having nucleobase moiety is described. These two moieties are linked by different spacers, such as aminoethyl and 1,2,3-triazolyl groups. Example of association constants for complexation of adenine and thymine derivatives: KAT=385 M(-1;) using NMR methodology is reported. Study of interaction between four cyclodextrin derivatives and one adamantyl guest is described by ITC.

Full text of DOI:10.1055/s-0029-1217988

LETTER
2875
Potential Supramolecular Cyclodextrin Dimers Using Nucleobase Pairs
a
a
b
c
c
d
P
F
otentia
l
Supr
l
o
ular Cyclode
r
xtrinDi
i
s
an Hamon, Bruno Violeau, Frédéric Turpin, Mathilde Bellot, Laurent Bouteiller, Florence Djedaini-Pilard,
a
Christophe Len*
a
Université de Poitiers, UMR 6514 CNRS, Synthèse et Réactivité des Substances Naturelles,
40 Avenue du Recteur Pineau, 86022 Poitiers Cedex, France
Fax +33(5)49453501; E-mail: christophe.len@univ-poitiers.fr
Biocydex, 40 Avenue du Recteur Pineau, 86022 Poitiers Cedex, France
Université Paris 6, UMR 7610 CNRS, 4 Place Jussieu, 75252 Paris, France
Université de Picardie Jules Verne, UMR 6219 CNRS, Laboratoire des Glucides, 33 Rue Saint Leu, 80039 Amiens, France
b
c
d
Received 11 June 2009
having a nucleobase such as adenine and thymine and
their potential application for the formation of supramo-
lecular CD dimers. The target compounds 8, 9, 11, and 12
Abstract: The synthesis of six new cyclodextrin derivatives having
nucleobase moiety is described. These two moieties are linked by
different spacers, such as aminoethyl and 1,2,3-triazolyl groups.
Example of association constants for complexation of adenine and had three major structural variations and were novel CD
–
1
thymine derivatives: KAT = 385 M using NMR methodology is re- derivatives. First modulation was the glycone moiety:
ported. Study of interaction between four cyclodextrin derivatives amino-b-CD, azido-b-CD, or amino-permethylated b-CD
and one adamantyl guest is described by ITC.
derivatives. Second variation was the nature of the linker:
Key words: click chemistry, nucleobase, cyclodextrin
aminoethyl group or 1,2,3-triazol-4-ylmethyl group.
Third modulation was the nucleobase: adenine or thy-
mine.
Cyclodextrins (CD) are a family of cyclic oligosaccha-
N-Alkylation of pyrimidine bases gave predominantly
N1-monosubstituted and N1,N3-bis-substituted deriva-
tives. In order to prepare regioselectively the N1-alkylated
pyrimidine, silylation of the nucleobase was developed.
Coupling of dibromoethane with silylated thymine (1) in
rides composed of a-(1→4)-linked D-glucopyranose units
4
in C chair conformation. The most common CD have
1
six, seven, and eight glucopyranose units and are referred
to as a-, b-, and g-CD, respectively. As a consequence of
the structure, the molecule is hydrophilic and features a
conical cavity that is essentially hydrophobic in nature.
This property enables them to be successfully used as
presence of NaI at 105 °C without solvent furnished the
22–25
bromide 2
in 32% yield. Coupling of propargyl bro-
mide with silylated thymine at 80 °C in acetonitrile gave
1
–3
4–6
7,8
drug carrier, separation reagents, enzyme mimics,
26,27
the alkyne 3
in 89% yield. The N9-alkylated adenine
9
,10
11,12
photochemical sensors, catalysis,
host–guest inter-
25
26,27
derivatives 5 and 6
were obtained from unprotected
1
3
14
actions, and molecular recognition. In comparison
with CD monomers, CD dimers tethered by a spacer of
different sizes and shapes have two hydrophobic cavities
in a close vicinity. This property may afford distinctly
different apparent association abilities and molecular se-
adenine (4). Starting from 4, selective alkylation with di-
bromoethane and propargyl bromide using K CO in
2
3
DMF gave the derivatives 5 and 6 in 40 and 39% yields,
respectively (Scheme 1).
1
5
2
8
The desired CD derivative 8a was obtained in 14% yield
by the reaction of b-CD derivative 7a with an excess of
bromide 2 in anhydrous DMSO at 50 °C for 16 hours
1
6
lectivities. Various structural architectures of covalent
CD dimers could be prepared but one challenge will be to
obtain supramolecular CD dimers with noncovalent inter-
actions such as H bonding, staking, electrostatic, and
charge-transfer interactions. The equilibrium between the
noncovalent dimers and the corresponding monomers
could permit to modulate the association. Unexpectedly,
these molecular organization behaviors have not been ex-
tensively investigated. The supramolecular assembly
could be obtained by association of nucleobases such as
adenine and thymine or guanine and cytosine. Few exam-
ples of CD derivative having nucleobase were described
in the literature but only the study of CD monomers were
(
Scheme 2). Starting from b-CD derivative 7a and per-
O
O
O
NH
(i)
NH
(ii)
NH
N
O
N
H
O
N
O
Br
2
1
3
NH2
NH2
NH2
N
N
N
(iii)
(iv)
N
N
N
1
7–21
reported.
In this paper, we reported our preliminary
N
N
H
N
N
N
N
work regarding the synthesis of different CD monomers
Br
5
4
6
Scheme 1 Reaction conditions: (i) HMDS, (NH ) SO , reflux, 12 h
4
2
4
SYNLETT 2009, No. 17, pp 2875–2879
Advanced online publication: 24.09.2009
DOI: 10.1055/s-0029-1217988; Art ID: G16909ST
x
x
.x
x
.2
0
0
9
then BrC H Br, NaI, 105 °C, 25 h (32%); (ii) BSA, MeCN, reflux, 12
2
4
h then HCCCH Br, reflux, 16 h (89%); (iii) BrC H Br, K CO , DMF,
2
2
4
2
3
r.t., 24 h (40%); (iv) HCCCH Br, K CO , DMF, r.t., 24 h (39%).
2
2
3
©
Georg Thieme Verlag Stuttgart · New York

2
876
F. Hamon et al.
LETTER
O
NH
N
O
NH2
HN
O
O
RO
O
RO
O
O
O
RO
RO
OR
OR
OR
OR
O
O
OR
OR
RO
RO
ORO
O RO
O
O
O
OR
O
OR
RO
RO
(i)
RO
RO
O
O
OR
RO
OR
RO
O
O
OR
OR
RO
OR
OR
RO
O
OR
O
O
O
OR
O
OR
OR
O
RO
RO
O
O
RO
RO
O
O
OR
OR
7
a R = H
8a R = H
8b R = Me
7
b R = Me
Scheme 2 Reaction conditions: (i) 2, Et N, DMSO, 50 °C, 16 h.
3
methylated analogue 7b, application of this procedure af- 1H NMR investigations were developed to estimate if the
2
9
forded the cyclodextrin derivatives 8b, 9a,b in 16%, nucleobase moiety was oriented inside the CD cavity or
3
8%, and 44% yields, respectively (Scheme 2 and outside. Liu et al. described the self inclusion of the nucle-
Figure 1).
obase into the b-CD cavity with nucleobase-modified b-
17
CD. In our case, the ROESY spectrum of 8, 9, 11, and
2 in D O showed the lack of NOE interactions between
In order to modulate the nature of the linker, the Huisgen
1
2
1
,3-dipolar cycloaddition of alkynes 3 and 6 and azide 10
(
i) the thymine protons (H6/CH ) and (ii) the adenine pro-
3
was used for the synthesis of the target compounds 11 and
tons (H2/H8) with the interior protons (H3/H5) of b-CD
cavity, respectively. These results showed that the nucle-
obase moiety of 8, 9, 11, and 12 was outside the b-CD
cavity probably due to the presence of a linker: amino-
ethyl or 1,2,3-triazol group.
1
2 (Scheme 3).
1
,2,3-Triazo-4-yl compound 1130 was prepared in 41%
yield by treatment of azido derivative 10 with alkyne 3 in
the presence of CuI in aqueous t-BuOH solution. Applica-
tion of this procedure with the azido compound 10 and
3
1
alkyne 6 furnished the CD derivative 12 in 67% yield.
O
NH2
NH
N
N
N
O
N
N
N
N
N
N
N
N3
N
O
O
O
HO
O
HO
O
HO
O
O
O
O
HO
HO
HO
OH
OH
OH
OH O
HO
OH O
HO
OH
O
OH
OH
OH
OHO
OHO
OHO
HO
O
O
O
O
OH
O
OH
O
OH
HO
HO
HO
HO
HO
HO
O
O
O
OH
HO
OH
HO
OH
HO
O
O
O
OH
OH
OH
HO
OH
OH
(i)
HO
OH
OH
(ii)
HO
OH
OH
O
O
O
O
OH
O
OH
O
OH
O
O
O
HO
HO
HO
O
O
O
HO
HO
HO
O
O
O
OH
OH
OH
11
10
12
Scheme 3 Reaction conditions: (i) 3, CuI, H O, t-BuOH, MW, 85 °C, 40 min (41%); (ii) 6, CuI, H O, t-BuOH, MW, 85 °C, 40 min (67%).
2
2
Synlett 2009, No. 17, 2875–2879 © Thieme Stuttgart · New York

LETTER
Potential Supramolecular Cyclodextrin Dimers
2877
H2N
N
N
N
N
HN
O
RO
O
O
RO
OR
OR
O
RO
OR
O
OR
O
O
OR
RO
RO
O
OR
RO
O
OR
RO
OR
OR
O
O
O
OR
O
RO
RO
O
OR
a R = H
b R = Me
9
9
Figure 1 CD derivatives 9a and 9b having adenine nucleobase
Figure 2 Supramolecular cyclodextrin dimers 8b and 9b using
The self-assembly property of CD derivatives 8b and 9b
1
nucleobase pairs and the corresponding H NMR spectra in CDCl
3
was studied by NMR spectroscopy in CDCl . The self ag-
3
(25 mM, 500 MHz) with temperature variation from 283 K to 328 K.
gregation for compounds 8b and 9b was shown by NMR
titrations performed at 298 K. The association constant for
notable that the mixture of 11 and 12 gave no significant
enhancement of the association constant (Figure 4). This
is probably due to the unfavorable hydrogen-bond forma-
tion between individual nucleobases (thymine and ade-
nine) in water. Apparently, in water the presence of the
guest dimer 13 (Figure 3) is not sufficient to drive the for-
mation of noncovalent cyclodextrin dimer through a sin-
gle base as designed.
homodimerization of 8b and 9b in CDCl was K = 22
3
TT
–
1
–1
M and K = 16 M , respectively. Based on the NMR
AA
experiment data, the interactions between 8b and 9b in so-
lution have been demonstrated, strong chemical shifts of
signals of aromatic protons of both nucleobase moieties
fully supporting the formation of hetero dimer (Figure 2).
From 283 K to 328 K, remarkable shifts of both the thy-
mine imino proton from d = 11.3–9.5 ppm and the adenine
amino proton from d = 6.3–5.9 ppm were noticed. The as-
sociation constant for hetero dimerization of 8b and 9b in
O
H
N
–
1
N
a 1:1 stoichiometry was KAT = 385 M . These different
values of K are in agreement with those obtained in the
same experimental conditions for adenine and thymine
N
N
H
O
O
O
3
2,33
O–
O–
alone.
In our case, the presence of cyclodextrin does
not affect the interactions between nucleobases (AA, TT,
or AT) in CDCl3.
1
3
Figure 3 Bisadamantyl derivative 13
Adamantyl moiety has been selected as guest model since
complexation of adamantyl derivatives with CD has been
3
4
In conclusion, nucleobase and cyclodextrin moieties were
linked by aminoethyl and 1,2,3-triazol groups to provide
six novel potential supramolecular elements. The appar-
ent association constant between two nucleobase-
appended permethylated cyclodextrin derivatives was de-
well documented.
ITC experiments were carried out for measuring the ther-
modynamic parameters associated with the inclusion pro-
3
5
cess of bisadamantyl derivative 13 in several CD hosts,
in pure water at 298 K (Table 1).
–1
termined by NMR in CDCl (K = 385 M ) supporting
3
AT
The experimental values for the guest/host ratio (n) were the formation of supramolecular hetero dimer of modified
compatible with the expected ones. The association con- cyclodextrins. The association constant between these
stants were slightly superior for the derivatives having nu- two novel cyclodextrin derivatives and one bisadamantyl
3
3
–1
cleobase moiety than for pure b-CD (78·10 vs. 46·10 M , guest in water was determined but no significant improve-
Table 1). These marginally enhanced binding abilities ment was observed with regard to the parent compounds.
may result from additional interactions involving the nu- In this study, the two desired interactions are orthogonal
cleobase and/or the triazole ring with the guest 13. It was in the sense that AT and host–guest association occur in
Synlett 2009, No. 17, 2875–2879 © Thieme Stuttgart · New York

2
878
F. Hamon et al.
LETTER
Table 1 Apparent Association Constants and Thermodynamic Parameters Deduced from ITC for the Different Hostsa
3
–1
0
–1
-1
0
–1
Entry
Host
b-CD
7a
[Host] (mM)
na
K (·10 M )
DH (kJ mol )
–45.3 ± 0.3
–49.0 ± 0.2
–51.1 ± 0.3
–50.3 ± 0.3
–51.1 ± 0.3
TDS° (kJ.mol )
DG (kJ mol )
–26.7 ± 0.1
–26.8 ± 0.1
–27.8 ± 0.1
–27.7 ± 0.1
–27.8 ± 0.1
a
1
2
3
4
0.8
0.50 (1/2)
0.43 (1/2)
0.43 (1/2)
0.43 (1/2)
0.43 (1/2)
46 ± 2
50 ± 3
77 ± 2
74 ± 2
78 ± 2
–18.6 ± 0.4
–22.2 ± 0.3
–23.3 ± 0.4
–22.6 ± 0.4
–23.3 ± 0.4
0.8
11
0.8
12
0.8
5
11 + 12
0.4 + 0.4
a
Different hosts: b-CD, 7, 11, and 12 with the guest: bisadamantyl derivative 13 {[13] = 4.0 mM} in pure H O at 298 K.
2
b
n: molar ratio (guest/host) of both components in the complex. The values in parentheses are theoretical values for the formation of complexes
with all the binding sites of both guest and host occupied.
chloroform and water, respectively. Therefore, a screen-
ing of other solvents might result in a functioning system.
Moreover, extension of this preliminary work to the syn-
thesis of other novel cyclodextrin derivatives bearing nu-
cleic acid oligomers, to strengthen the interaction in
water, will be reported in due course.
(8) Kataky, R.; Mogan, E. Biosens. Bioelectron. 2003, 18, 1407.
(
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(
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14) Hamada, F.; Kondo, Y.; Ishikawa, K.; Ittto, H.; Suzuki, I.;
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(
(
15) (a) Aime, S.; Gianolio, E.; Arena, F.; Barge, A.; Martina, K.;
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(
Figure 4 Calorimetric titration curve of 11 (a), 12 (b), 11 + 12 (c)
or pure water (d) with 13 in water at 298 K. 5 mL injections of 13
Lett. 2000, 41, 6869. (e) Baugh, S. D. P.; Yang, Z.; Leung,
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{
[13] = 4.0 mM} into host solution {[host] = 0.8 mM}
Acknowledgment
2001, 7, 3603. (g) Liu, Y.; Li, L.; Zhang, H. Y.; Song, Y.
J. Org. Chem. 2003, 68, 527.
17) Liu, Y.; Zhang, Q.; Chen, Y. J. Phys. Chem. B 2007, 111,
This work was supported by (i) the CNRS program; (ii) regional
program from the Région Poitou-Charentes, France, and (iii) Bio-
cydex.
(
(
(
(
(
(
(
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References and Notes
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22) Kato, Y.; Nishizawa, S.; Teramae, N. Org. Lett. 2002, 4,
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(
4) Bhushan, R.; Kumar, R. J. Chromatogr., A 2002, 62, 2667.
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Synlett 2009, No. 17, 2875–2879 © Thieme Stuttgart · New York

LETTER
Potential Supramolecular Cyclodextrin Dimers
2879
(
26) Lock, L.; Pohlsgaard, J.; Jepsen, A. S.; Hansen, L. H.;
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(s, 1 H), 4.44 (br s, 2 H), 3.88–3.51 (m, 26 H), 3.64–3.62 (m,
21 H), 3.55–3.52 (m, 21 H), 3.41–3.32 (m, 14 H), 3.41–3.40,
(m, 21 H), 3.24 (br s, 2 H), 3.05 (br s, 2 H) ppm. C NMR
1
3
(
(
(125 MHz, D O): d = 155.5, 152.4, 149.3, 142.6,118.5,
2
97.7–96.5, 80.9–76.5, 71.1–70.7, 60.0–58.0, 48.1, 47.5, 43.2
+
28) Selected Physical Data of Compound 8a
ppm. ESI-HRMS: m/z calcd [M + H] : 1575.7673; found:
1
MP 200 °C (decomp.). H NMR (500 MHz, D O): d = 7.48
1575.7654.
2
(
s, 1 H), 5.14–5.08 (m, 7 H), 4.30–4.10 (m, 3 H), 4.03–3.81
(30) Selected Physical Data of Compound 11
1
(
m, 25 H), 3.72–3.50 (m, 15 H), 3.47 (m, 2 H), 3.39 (m, 1 H),
Mp 200 °C (decomp.). H NMR (500 MHz, D O): d = 8.10
2
1
3
1
1
6
.91 (s, 3 H) ppm. C NMR (125 MHz, D O): d = 166.8,
(s, 1 H), 7.66 (s, 1 H), 5.20 (s, 1 H), 5.10–5.03 (m, 9 H), 4.63
(s, 1 H), 4.30 (s, 1 H), 4.08–3.50 (m, 37 H), 3.01 (s, 1 H),
2.70 (s, 1 H), 1.92 (s, 3 H) ppm. C NMR (125 MHz, D O):
2
53.0, 142.2, 111.5, 102.0–101.0, 83.3–80.8, 71.5–70.5,
1
3
7.5, 60.5–59.5, 48.8, 47.6, 45.0, 11.3 ppm. ESI-HRMS:
2
+
m/z calcd [M + H] : 1286.4522; found: 1286.4581.
d = 167.1, 152.2, 142.4, 126.5, 111.2, 101.9–101.4, 83.2–
(
29) Selected Physical Data of Compound 8b
80.5, 73.0–70.4, 60.3, 59.1, 51.4, 42.9, 11.3 ppm. ESI-
1
+
Mp 200 °C (decomp.). H NMR (500 MHz, D O): d = 7.56
HRMS: m/z calcd [M + Na ]: 1346.4246; found: 1346.4211.
2
(
s, 1 H), 5.36–5.24 (m, 5 H), 4.00 (s, 2 H), 3.89–3.54 (m, 33
(31) Selected Physical Data of Compound 12
1
H), 3.64–3.62 (m, 21 H), 3.55–3.52 (m, 21 H), 3.43–3.37 (m,
Mp 200 °C (decomp.). H NMR (500 MHz, D O): d = 8.29
2
7
1
1
5
H), 3.41–3.40 (m, 21 H), 3.23 (br s, 2 H), 3.18 (br s, 2 H),
(s, 1 H), 8.26 (s, 1 H), 7.99 (s, 1 H), 5.60 (s, 2 H), 5.15–5.00
(m, 7 H), 4.97 (d, 1 H), 4.59 (dd, 1 H), 4.11 (t, 1 H), 4.00–
1
3
.94 (s, 3 H) ppm. C NMR (125 MHz, D O): d = 166.8,
2
1
3
52.4, 143.1, 110.6, 97.6–96.6, 81.4–75.9, 71.2–69.6, 59.9–
3.40 (m, 37 H), 2.78 (d, 1 H), 2.60 (d, 1 H) ppm. C NMR
8.1, 48.5, 47.4, 47.0, 11.43 ppm. ESI-HRMS: m/z calcd
(125 MHz, D O): d = 155.6, 152.7, 148.9, 142.6, 142.1,
2
+
[M + H] : 1566.7532; found: 1565.7573.
125.9, 118.6, 101.9, 81.3–80.4, 73.1–70.6, 60.0–58.8, 51.2,
+
Selected Physical Data of Compound 9a
38.4 ppm. ESI-HRMS: m/z calcd [M + Na ]: 1355.4362;
1
Mp 200 °C (decomp.). H NMR (500 MHz, D O): d = 8.52
found: 1355.4363.
2
(
s, 1 H), 8.40 (s, 1 H), 5.17–5.10 (m, 7 H), 4.38 (s, 2 H),
(32) Sartorius, J.; Schneider, H.-J. Chem. Eur. J. 1996, 2, 1446.
(33) Salas, M.; Gordillo, B.; Gonzalez, F. J. ARKIVOC 2003, (xi),
72.
(34) Carrazana, J.; Jover, A.; Meijide, F.; Soto, V. H.; Tato, J. V.
J. Phys. Chem. B. 2005, 109, 9719; and references cited
therein.
4
1
1
8
.00–3.50 (m, 39 H) 3.31 (t, 1 H), 3.11 (m, 2 H), 2.95 (d,
1
3
H), 2.77 (m, 1 H) ppm. C NMR (125 MHz, D O): d =
2
55.4, 152.2, 149.5, 142.5, 118.5, 102.0–101.7, 101.0, 83.5,
1.2–80.1, 73.1–70.2, 60.3–59.9, 48.2, 47.0, 43.2 ppm. ESI-
+
HRMS: m/z calcd [M + H] : 1295,4637; found: 1295.4574.
Selected Physical Data of Compound 9b
(35) Tellini, V. H. S.; Jover, A.; Garca, J. C.; Galantini, L.;
Meijide, F.; Tato, J. V. J. Am. Chem. Soc. 2006, 128, 5728.
1
Mp 200 °C (decomp.). H NMR (500 MHz, D O): d = 8.31
2
(s, 1 H), 8.23 (s, 1 H), 5.29–5.24 (m, 5 H), 5.17 (s, 1 H), 4.98
Synlett 2009, No. 17, 2875–2879 © Thieme Stuttgart · New York

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