Positive variation of the MRI signal via intramolecular inclusion complexation of a C-2 functionalized β-cyclodextrin

Article abstract of DOI:10.1039/c6ob02583h

The synthesis of a new contrast agent based on a β-cyclodextrin scaffold and bearing a flexible lipophilic spacer arm on its secondary face is reported. Intermolecular host-guest inclusion complexes were known to undergo an enhancement of the contrast imaging. We extend this concept to intramolecular complexation. Inter- and intramolecular interactions are compared by NMR spectroscopy, circular dichroism and magnetic resonance imaging using hydrocinnamic acid and adamantane carboxylic acid as external guests. This positive variation of the observed relaxivity is a key element of new strategies aiming at developing smart molecular MRI probes.

Full text of DOI:10.1039/c6ob02583h

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Biomolecular Chemistry
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Positive variation of the MRI signal via intramolecular
inclusion complexation of a C-2 functionalized
β-cyclodextrin†
I. Zgani,a H. Idriss,a,b C. Barbot,a F. Djedaïni-Pilard,c S. Petit,d M. Hubert-Roux,a
F. Estoura and G. Gouhier*a
Cite this: DOI: 10.1039/c6ob02583h
Received 24th November 2016,
Accepted 12th December 2016
DOI: 10.1039/c6ob02583h
www.rsc.org/obc
The synthesis of a new contrast agent based on a β-cyclodextrin undergo chemical modifications, the size and shape of the
scaffold and bearing a flexible lipophilic spacer arm on its second- cavity of this kind of macrocycle play an essential role in the
ary face is reported. Intermolecular host–guest inclusion com- formation of host–guest inclusion complexes with lipophilic
plexes were known to undergo an enhancement of the contrast molecules by hydrophobic interactions, H-bonding and van
imaging. We extend this concept to intramolecular complexation. der Waals forces in aqueous media or polar solvents.2
Inter- and intramolecular interactions are compared by NMR spectro- Cyclodextrins have been already identified as the support of
scopy, circular dichroism and magnetic resonance imaging using gadolinium for MRI imaging applications. They were used as
hydrocinnamic acid and adamantane carboxylic acid as external polyfunctionalizable scaffolds bearing one to seven DOTA or
guests. This positive variation of the observed relaxivity is a key DTPA units.3 The higher molecular weight of the contrast
element of new strategies aiming at developing smart molecular MRI agent so formed exerts a positive effect on the MRI signal by
probes.
decreasing the rotation rate in water. Thus, it enhances the
contrast of images by increasing the water proton relaxation
rates (relaxivity r1). These properties were used to develop new
MRI probes4 based on polyrotaxanes5 or nanoparticules.6
Other contrast agents have also been developed using 3,6-
anhydro-α-cyclodextrin substituted by carboxylate ligands.7
In vivo studies on rats were performed on a tumor model and no
nephrotoxicity or hemolysis was reported.8 We have also pre-
viously synthesized new MRI probes based on a β-cyclodextrin
bearing seven carboxylate functions on its primary side.
Thanks to the cyclic oligosaccharide, we observed a positive
effect on the MRI signal which could be attributed to the influ-
ence of the secondary hydration sphere.9
The cyclodextrins’ host properties were also exploited to
modify the MRI signal by inclusion of organic molecules
inside their internal cone in aqueous medium. Indeed, non-
covalent interactions between the cyclodextrin cavity and hydro-
phobic compounds also act positively on the relaxivity value.
Thus the influence of the formation of an intermolecular
inclusion complex in MRI was described between DOTA and
DTPA bearing one to three lipophilic aromatic groups in the
presence of β-cyclodextrins,10 polymers of β-cyclodextrins11 or
nanoparticules of β-cyclodextrins.12 Surprisingly a higher relax-
ivity was observed even in case of a weak host–guest associ-
ation constant. This correlation between relaxivity and binding
constant values was confirmed with a dimer and trimer of
cyclodextrins in the presence of DTPA functionalized with one
to three cyclohexyl groups.13 Host–guest interactions were
Introduction
Magnetic Resonance Imaging (MRI) is widely used for human
non-invasive imaging of deep tissues despite its low sensitivity.
To improve this weak detection threshold, 35% clinical scans
are performed by administration of contrast agents. Currently,
ten millions of diagnostics are carried out annually using a
probe to increase the efficiency of the medical diagnosis. The
most important class of contrast agents for MRI is represented
by gadolinium Gd(III) chelates such as cyclic DOTA or linear
DOPA developed in 1988.1 Indeed, the free gadolinium atom is
toxic and has to be polycoordinated by organic chelates.
Cyclodextrins are natural and chiral cyclic oligosaccharides
composed of (α-1,4)-linked D-glucose units that can be used as
an anchor for various ligands of Gd(III). Besides their ability to
aNormandie Univ, COBRA, UMR 6014, FR 3038, INSA Rouen, CNRS,
IRIB IRCOF 1 rue Tesnière, 76821 Mont-Saint-Aignan, France.
E-mail: geraldine.gouhier@univ-rouen.fr; Fax: +33-235522959; Tel: +33-235522909
bLebanese International University, Biological and Chemical Sciences,
P.O. Box 146404 Mazraa, Mousaytbeh, Beyrouth, Lebanon
cUniversity of Picardie Jules Verne, LG2A UMR CNRS 7378, France
dNormandie Univ, SMS, EA 3233, Place E. Blondel, 76821 Mont Saint Aignan Cedex,
France
†Electronic supplementary information (ESI) available: Experimental data, syn-
thesis, NMR spectra and relaxivity data. See DOI: 10.1039/c6ob02583h
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recently applied to target tumor using a modified macrocyclic
DOTA with the adamantane group. This self-assembly under-
went a significant increase of the relaxivity from 3.17 to
6.36 mM−1 s−1 14
.
Self-inclusion studies of various arms linked to cyclo-
dextrins into their cavities have been reported in the
literature.15–21 The β-cyclodextrin and a flexible pendant intro-
duced into the C2 position underwent the most efficient mole-
cular sensing.16a,c,17a,d This balance can be influenced by
various parameters such as temperature,17a,c,18a,19b pH,16a,20
concentration17b,18b,d or solvent polarity.17b,c,18a,b,21 However,
the impact on the MRI signal of intramolecular inclusion com-
plexation has never been studied. To evaluate this effect, we
developed an innovative strategy to obtain a new contrast
agent based on a β-cyclodextrin bearing a lipophilic spacer.
Such a functionalized pendant can constitute a future anchor
site for a biological target in order to achieve a smart MRI
molecular probe.22
Fig. 2 Molecular modeling of the contrast agent 3(Gd).
With the aim of showing the role of the intramolecular
inclusion process and the secondary hydroxyl groups of the
oligosaccharide, a comparative study was carried out with
three contrast agents denoted as 1(Gd), 2(Gd) and 3(Gd). They
are composed of seven acetate functions introduced on the
primary face of the β-cyclodextrin (Fig. 1). The secondary side
of 2(Gd) was permethylated, and a flexible pendant was also
introduced into the secondary position of 3(Gd) in addition to
the methyl groups in the remaining positions.
Fig. 3 Contrast agents 1(Gd), 2(Gd) and 3(Gd) in the presence of a
host–guest inclusion complex: (a) no inclusion, (b) and (d) inter-
molecular and (c) intramolecular. The bowl in red represents the gadoli-
nium atom, and the guests 4 and 5 are represented in blue and red
shapes, respectively. Two water molecules fill the inner sphere.9
Contrast agents 1(Gd) and 2(Gd) were previously described
and analyzed.9 Since gadolinium is noncoordinated, two water
molecules fill the inner sphere.9 In the case of 3(Gd), the
pendant was introduced by using a biologically stable ether
function at the C-2 position. A molecular modelling approach
proved that a linker involving three carbon atoms is flexible
enough to form an intramolecular complex (Fig. 2).23 The
pendant was functionalized at its end with a carboxylic acid
function as the future site of the anchor of a biological target.
To evaluate the role of the pendant in the MRI efficiency of
3(Gd) (Fig. 3c), the relaxivities were measured with contrast
agents 1(Gd) and 2(Gd) in the absence (Fig. 3a) and in the
presence of an external guest (Fig. 3b and d). The first chosen
external guest is hydrocinnamic acid 4 with a chemical struc-
ture close to that of the flexible arm introduced into the crown
of 3(Gd).
The in and outside isomerism was considered using
adamantane carboxylic acid 5 as a second lipophilic guest. It is
characterized by a high association constant value and it is
assumed to totally displace the complexation equilibrium.24
Thus, this second guest tends to disadvantage the intra-
molecular inclusion to the benefit of an intermolecular
inclusion complex (Fig. 3d). The impact of such an inclusion
is studied hereafter by NMR spectroscopy and circular
dichroism.
Results and discussion
Synthesis of contrast agent 3(Gd)
Hydroxyl groups present at the C2-, C3-, and C6-positions
compete with the reagent and make selective modifications
extremely difficult. Among the three types of hydroxyl groups,
those at the C6-position which correspond to primary alcohols
are the most nucleophilic (pKa: 15–16), those at the C2-posi-
tion are the most acidic (pKa: 12.1), and those at the C3-posi-
tion are the least accessible. All these factors make the second-
ary side less reactive and harder to selectively functionalize
than the primary face.25 We developed a methodology to
control the position and the number of substitutions on the
secondary face from a native β-cyclodextrin.26 Without any
protection step, a designed spacer arm 6 † was regioselectively
introduced into the native cyclodextrin in 18% yield using
sodium hydride in DMSO (Scheme 1).† The follow-up of the
Fig. 1 Structures based on the β-cyclodextrin scaffolds 1, 2 and 3.
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Intramolecular inclusion complex study
In order to confirm the intramolecular inclusion of the aro-
matic moiety of 3, we compared the 1H NMR spectra at various
concentrations of this non-metaled compound ranging
between 6.1 mM (likely to generate an intermolecular process)
to 188 μM (enabling an intramolecular inclusion). Indeed, the
structure of the formed supramolecular entities depends on
the concentration of the solution.17b,18b,d The multiplet corres-
ponding to the aromatic area initially observed at a con-
centration of 6.1 mM (Fig. 4a) underwent a major modification
at a higher dilution (from 750 μM to 188 μM, Fig. 4b) to turn
into a broad singlet.
The addition of adamantane carboxylic acid 5 as a com-
petitive guest at 188 μM (MRI concentration level) led to a
strong shielding of the aromatic signal (Fig. 4c). These NMR
modifications confirm that the flexible arm stands outside the
cavity of the cyclodextrin 3 in the presence of adamantane acid
5 that prevents the inclusion complex formation.
Temperature can play a key role in the stability of the
inclusion complex.17a,c,18a,19b Thus, NMR analyses of com-
pound 3 were done at various temperatures, i.e. 25 °C, 50 °C
and 70 °C (Fig. 5a–c) and 6.1 mM. We observed deformation
and deshielding of signals corresponding to aromatic protons
from 7.2 (a) to 7.5 (b) and 7.7 ppm (c), respectively. The higher
the temperature the more the deshielding of signals in the aro-
matic area was important. The increase of temperature modi-
Scheme 1 Synthesis of the contrast agent 3(Gd).
reaction by HPLC-MS revealed an intramolecular transesterifi-
cation reaction with another hydroxyl group of the cyclodextrin
as a side reaction which explains the lower yield than expected.
1
The C-2 regioselectivity was confirmed by 400 MHz H NMR.†
The spectrum analysis showed three characteristic peaks at
4.98 ppm (H′-1), 3.81 ppm (H′-3) and 3.22 ppm (H′-2). The
attribution of the proton signal H′-1, H′-2 and H′-3 was possi-
ble, thanks to COSY NMR study. The corresponding carbons
(C′-1, C′-2 and C′-3) were set to HMQC NMR. The proton
H′-1 correlates with a carbon at 100.77 ppm (C′-1), the signal at
81.15 ppm is related to C′-2, and the one at 71.8 ppm with
C′-3. A correlation between the methylene protons of the
spacer arm (α-CH2) and the carbon C′-2 could not be high-
1
lighted due to an overlapping with the H signals of the cyclo-
Fig. 4 1H NMR spectra of 3 (aromatic area) in the absence of adaman-
tane acid 5 at 6.1 mM (a) and at 188 μM (b) and in the presence of 1 eq.
of 5 at 188 μM (c), pH 7.4, 25 °C.
dextrin (H-2, H-4, H-5 and H-6). The substitution step led to a
shielding of the C′-1 and C′-3 signals (1.61 ppm and 0.8 ppm
respectively) while the signal of the substituted carbon C′-2
was shielded (+8.3 ppm). These observations are in agreement
with the previous results published by Masurier et al.26
The next step was the protection of primary alcohols by silyl
groups. Afterwards, the residual hydroxyl groups were deproto-
nated using an excess of sodium hydride and the permethyl-
ation step was performed by addition of methyl iodide in tetra-
hydrofuran. The subsequent deprotection step of the primary
face by ammonium fluorine in methanol was quantitative.
Seven ester functions were then introduced by the action of
ethyl diazoacetate in the presence of tetrafluoroboric acid in
dichloromethane with 36% yield.9 After saponification of 3,
the contrast agent 3(Gd) was obtained by addition of gadoli-
nium chloride hexahydrate.
Fig. 5 Evolution of 1H NMR aromatic signals as a function of tempera-
ture of 3 at 6.1 mM.
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The conformation (a) (Scheme 2) observed at high concen-
trations could be due to an inter-supramolecular assembly
which could lead to an intramolecular complex (b) at high
dilutions. The behavior of a flexible and functionalized
pendant grafted on position C-2 of a β-cyclodextrin has been
only studied by Park by circular dichroism and NMR spectro-
scopy.28 The authors also observed two conformations depend-
ing on the concentration used, assigned to the formation of a
self-inclusion or a head-to-head type dimer. The formation of
different types of inclusion complexes was shown to depend
on the concentration and temperature. The assignment of an
intermolecular complex at high concentrations justifies the
hypothesis of an intramolecular complex at weaker concen-
trations, consistent with an IRM examination.
Fig. 6 Circular dichroism measurement of 3(Gd) in the absence (curve
a) and in the presence of 1 eq. of adamantane acid 5 (curve b), H2O,
25 °C, 0.2 mM.
Host–guest intermolecular study
fied the signal shape to give a symmetric signal at 70 °C, indi-
cating a dissociation of the inclusion complex. So, the entities
formed at 6.1 mM underwent a disaggregation due to weaker
binding forces at high temperature.
A circular dichroism study was then carried out with the
contrast agent 3(Gd). Indeed, this experiment can provide
information on the inclusion conditions into the cyclodextrin
cavity.27 The analysis was performed at 0.2 mM (close to MRI
concentration conditions).
To prove the inclusion between hydrocinnamic acid 4 and the
β-cyclodextrin derivative 2, 1H NMR experiments were firstly
performed at various concentrations of 4.† The gradual
addition of 4 in the medium (0.12 to 1.5 equivalents versus 2)
led to a shielding of the signals related to the protons H-3 and
H-5 of the macrocycle, and showing the interaction between
compounds 4 and 2. To study the inclusion mode of 4, the
lanthane derivative 2(La)9 was used since it is closer to the
structure of contrast agent 2(Gd).
In the presence of one equivalent of hydrocinnamic acid 4
versus 2(La) only the methyl group in the alpha position of the
aromatic group undergoes a shielding of 0.2 ppm (2.6 ppm to
2.4 ppm) and complex signals were observed around the aro-
matic area. A ROESY NMR experiment showed a spatial corre-
lation between the aromatic proton and the internal H-3
(3.6 ppm) of the oligosaccharide (Fig. 7). No correlation was
detected between the protons of the aliphatic chain of the acid
4 and the internal protons of the macrocycle. Consequently,
only the aromatic part is included in the cavity through the
secondary face of 2(La). It can be noticed that similar NMR
experiments were carried out in the absence of lanthane with
compound 2 and similar correlations were observed.†
The transition negative band in the wavelength range of
1
200–230 nm corresponding to a transition of type Bb (Fig. 6a)
proved an orthogonal intramolecular inclusion towards the
axis of the cyclodextrin cavity. Addition of one equivalent of
adamantane carboxylic acid 5 in the medium led to a modifi-
cation of the signal that turns positive (Fig. 6b). This change
revealed a variation of the environment of the cavity. Due to its
higher affinity for the hydrophobic cavity of cyclodextrin, 5 per-
turbs the initial equilibrium and forces the formation of an
intermolecular inclusion (Scheme 2).24 The positive band indi-
cates that the adamantane acid 5 stands parallel to the axis of
the cyclodextrin 3(Gd). Thus, the aromatic linker could be
oriented above the cavity of the cyclodextrin as a cap-like con-
formation and could not be totally included directly due to the
high polarity of the carboxylate function.
Three states can exist in equilibrium: the open form “self-
unlocked” (a), the closed form “self-locked” (b) and the ada-
mantane complex form (c) (Scheme 2).
Scheme 2 Competitive study: open (a), closed (b) and adamantane (c)
forms.
Fig. 7 Zoom of the aromatic proton area of the NMR ROESY spectrum
of the inclusion complex 2(La) + 4, 25 °C, pH 7.4, D2O.
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thesized. The positive influence of self-inclusion complex for-
mation on the MRI signal was proved. The phenomenon was
compared to intermolecular complexes using a similar external
guest structure.
A higher enhancement of the relaxivity
value was observed for the intramolecular inclusion complex. In
perspective, new contrast agents will be designed to optimize
the variation of the signal using an adapted pendant to improve
the inclusion inside the cavity. The functionalized spacer arm
will become the key intermediate to fix specific biological
targets in the future and to achieve new smart molecular MRI
probes.29
Acknowledgements
Fig. 8 Relaxivity values for contrast agents 1(Gd), 2(Gd), and 3(Gd) in
the absence and in the presence of the hydrocinnamic acid guest 4.
We are grateful to Region Haute-Normandie via the FEDER
network for the Post-doctoral fellowship (I. Z.), the French
Ministry of Research for the PhD grant (H. I.), BPI and the
Institute for Research and Innovation in Biomedicine of
Rouen for their financial support.
Relaxivity comparison study
The relaxivity study was performed with contrast agents 1(Gd),
2(Gd) and 3(Gd) at 0.5 Tesla (minispec mq20) with solution
concentrations varying from 1 to 0.0625 mM in TRIS buffer at
pH 7.4. The results obtained are summarized in Fig. 8.
Notes and references
At the concentration levels used, the contrast agent 3(Gd) is
mainly under its intramolecular form (Scheme 2b). Compared
to the relaxivity value of 2(Gd) (r1 = 4.7 mM−1 s−1), 3(Gd) shows
26% increase (r1 = 5.94 mM−1 s−1). The addition of one equi-
valent of hydrocinnamic acid 4 versus 2(Gd) improved the
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