Mechanostereoselective One-Pot Synthesis of Functionalized Head-to-Head Cyclodextrin [3]Rotaxanes and Their Application as Magnetic Resonance Imaging Contrast Agents

Article abstract of DOI:10.1021/acs.orglett.7b00153

A versatile, five-component, one-pot synthesis of cyclodextrin (CD) [3]rotaxanes using copper-catalyzed azide-alkyne cycloaddition has been developed. Head-to-head [3]rotaxanes of α-CD selectively functionalized by one or two gadolinium 1,4,7,10-tetraazac

Full text of DOI:10.1021/acs.orglett.7b00153

Letter
pubs.acs.org/OrgLett
Mechanostereoselective One-Pot Synthesis of Functionalized Head-
to-Head Cyclodextrin [3]Rotaxanes and Their Application as
Magnetic Resonance Imaging Contrast Agents
Jean Wilfried Fredy,†,∥ Jeremy Scelle,†,∥ Gregory Ramniceanu,‡ Bich-Thuy Doan,‡ Celia S. Bonnet,§
́
́
́
§
†
†
,†
,†
́
Eva Toth, Mickael Menand, Matthieu Sollogoub, Guillaume Vives,* and Bernold Hasenknopf*
́
́
̈
†Sorbonne Universites
Paris, France
́
, UPMC Univ Paris 06, CNRS, Institut Parisien de Chimie Molec
́
ulaire UMR 8232, 4 place Jussieu, 75005
‡Chimie ParisTech, CNRS, UMR8258 INSERM U1022 Unite
& Marie Curie, 75005 Paris, France
́
de Technologies Chimiques et Biologiques pour la Sante,
d’Orleans, Rue Charles Sadron, 45071 Cedex 2 Orlea
́
11 rue Pierre
§Centre de Biophysique Molec
́
ulaire, CNRS UPR4301, Universite
́
́
́
ns, France
S
* Supporting Information
ABSTRACT: A versatile, five-component, one-pot synthesis of
cyclodextrin (CD) [3]rotaxanes using copper-catalyzed azide−alkyne
cycloaddition has been developed. Head-to-head [3]rotaxanes of α-
CD selectively functionalized by one or two gadolinium 1,4,7,10-
tetraazacyclododecane-1,4,7-triacetic acid monoamide complexes
were obtained mechanostereoselectively. The magnetic resonance
imaging efficiency, expressed by the longitudinal proton relaxivity of the rotaxanes, was significantly improved as compared to the
functionalized CD. In vitro and in vivo preclinical studies showed a higher contrast and retention in the kidney than gadolinium
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid complex, demonstrating the potential of these rotaxanes as MRI contrast
agent.
upramolecular chemistry offers modularity and fast synthesis
pseudorotaxane in water and, after isolation or in situ, performing
Sof complex molecular objects. It is therefore well adapted to the stoppering reaction in aqueous solution to prevent
dethreading. These limitations have shown that (i) few CD
rotaxanes described in the literature contain two CDs and (ii)
polyrotaxanes assembled with already functionalized CDs remain
less explored and form a mixture of orientational mecha-
noisomers.8
Based on the polyammonium−CD polyrotaxanes described
by Wenz,6a,9 we have developed polyrotaxanes with Gd-
functionalized CDs1 that showed improved relaxivities compared
to small molecules. It was also possible to thread bodipy and Gd-
functionalized CDs simultaneously onto the polymer strand,
proving the viability of the approach to obtain bimodal agents
(fluorescence and MRI). However, they were obtained as a
statistical mixture of orientational mechanoisomers, and their
high toxicity prevented their use in vivo.
biological applications where multifunctional and modular
devices are needed. Furthermore, in view of in vivo applications
and eventual approval by regulatory agencies, the obtention of a
single molecular species is preferable. We are particularly
interested in the development of multimodal imaging agents
using such a modular supramolecular approach. Our concept
consists of preparing monofunctional molecular building units
that self-assemble in a modular fashion to produce multifunc-
tional imaging agents. A particularly appealing architecture for
this are polyrotaxanes composed of different rings threaded on a
common axle.1 However, efficient threading of functionalized
rings must be guaranteed, and different mechano isomers, i.e.,
diastereomers that differ in the orientation of the mechanically
bonded rings,2 can be obtained using this strategy.
In order to lower their toxicity, to test different functionalized
CDs, to obtain single isomeric compounds, and to better
understand the intrinsic role of the rotaxane architecture on the
MRI properties, we decided to investigate smaller [3]rotaxanes
as models for the above-mentioned polyrotaxanes. While various
synthetic strategies have been developed for multiple threading
of other macrocycles,10 in particular, the “active-metal template
strategy”,11 only a few methods yielding [3]rotaxanes of CDs
have been described. Anderson showed that reaction of 2,6-
While a large variety of macrocycles such as cucurbituril,
crown-ether, bis-paraquat, or calixarene have been reported to
produce rotaxanes,2,3 cyclodextrins (CDs) present the particular
advantages of being commercially available, cheap, and easily
functionalizable.4 Moreover, CDs are biocompatible and water-
soluble, which enables access to hydrosoluble rotaxanes with
potential applications in biology and medicine such as imaging.1,5
Native CDs have been widely used in rotaxanes or polyrotax-
anes6 since the synthesis of the first CD [2]rotaxane described by
Ogino.7 They are usually obtained by threading followed by an
end-capping reaction, with the hydrophobic effect as the driving
force for the self-assembly process. This requires forming the
Received: January 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00153
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Organic Letters
Letter
dimethylphenol with bis-diazonioazobenzene in the presence of
α-CD gave a tail-to tail [3]rotaxane.12 Takata has recently
reported another one-pot strategy to directly obtain head-to-
that they are part of the same supramolecular species. Moreover,
the diffusion coefficient is lower than the one of each separate
component, which is consistent with the larger molecular size of
the assembly. Since DMSO is a solvent that prevents the
formation of inclusion compounds with CD,13 the interlocked
structure forms a stable rotaxane. The integration of the 1H NMR
spectrum and mass spectrometry (see Figure S5) showed the
formation of a single symmetrical [3]rotaxane with two threaded
CDs. The 2D T-ROESY spectrum (transverse rotating-frame
Overhauser enhancement spectroscopy, Figure 1) provided
head [3]rotaxanes of α-CD by using isocyanate stoppers.13
A
solid-phase synthesis yielded a head-to-tail [3]rotaxane,14 and
the coupling of two pseudo[2]rotaxanes gave a tail-to-tail
[3]rotaxane.15 Fort prepared polyrotaxanes with lactose-
functionalized α-CD.8c Inspired by these results and the use of
click chemistry for the stoppering reaction of CD-rotaxa-
nes,8c,10a,16 we aimed at the development of a new general
mechanostereoselective synthetic strategy to produce function-
alized CD [3]rotaxanes as single isomers. Herein, we report a
versatile five-component one-pot synthesis that was applied to α-
CD mono or bifunctionalized by Gd(III) complexes (Scheme 1)
Scheme 1. Synthesis of Head-to-Head [3]Rotaxanes
Figure 1. T-ROESY spectrum of [3]rotaxane 6 (600 MHz, DMSO-d6).
further evidence for the formation of the interlocked structure
with correlation peaks between the central axle protons and inner
pointing CD protons H3 and H5. Moreover, the correlation peak
between H5 and protons Ho, Ht, and Hs as well as H6 and Ho
indicates that the CDs have their primary rim pointing to the
stoppers and their secondary rim pointing to each other, hence
adopting the head-to-head orientational mechanoisomery. This
orientation can be justified by the preferred establishment of
hydrogen bonds between the complementary secondary rims18
and is consistent with other [3]rotaxanes having an alkylene
axle.13
α-CD was then selectively functionalized by gadolinium
complex of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid
monoamide (Gd−DO3A-MA) complexes to act as MRI contrast
agent. The synthesis is based on a flexible approach using a
regioselective deprotection of perbenzylated CDs19 and a
CuAAC20 between protected mono21 and bis azido CDs22 and
propargyl-functionalized DO3A-MA followed by deprotection as
described in our previous publication.1 CDs selectively mono- or
difunctionalized on diametrically opposed A,D positions on the
primary rim by Gd−DO3A-MA complexes were obtained. As
MRI is not a very sensitive imaging technique, the difunction-
alized CD 8 is particularly interesting in order to increase local
Gd(III) concentration.23 Then, the same procedure was applied
for the synthesis of the functionalized CD rotaxanes (Scheme 1),
and the products were directly purified by size-exclusion
chromatography. The formation of the Gd−CD [3]rotaxanes
RotGd2 and RotGd4 was confirmed by mass spectrometry (see
Figures S6 and S7) with molecular ion peaks at m/z 1292.05 and
1706.14, respectively, corresponding to [M − 3H]3− ions. The
rotaxanes were obtained in 35−50% yield, which is suitable for a
five-component, one-pot reaction.
to obtain rotaxane-based MRI contrast agents. In vitro relaxivity
of these [3]rotaxanes and their use as biocompatible contrast
agents for in vivo imaging in mouse models are also reported.
Rotaxanes were synthesized in a one-pot strategy using a C12
alkyl chain as thread and click chemistry for the stoppering
reaction. The reaction conditions were optimized using native α-
CD (Scheme 1). The diazidododecane axle 3 was, in a first step,
mixed with native α-CD in water to yield a pseudorotaxane by the
hydrophobic effect. The formation of the inclusion complex can
be observed by the appearance of turbidity in the reaction
mixture. This is probably due to the formation of tubes of CD
pseudorotaxanes and their aggregation via intermolecular
hydrogen bonds as observed with other CD polyrotaxanes.17
In a second step, reactants for copper-catalyzed azide−alkyne
cycloaddition (CuAAC) and the stoppers were added to perform
the end-capping reaction. The dicarboxylic acid 5 was chosen
according to the literature,16a as it is described to be large enough
to prevent the dethreading of α-CD. Moreover, the carboxylate
groups enable the solubility of the rotaxane in water at
physiological pH, which is useful for potential in vivo studies.
Lanthanum analogues (7a and 8a) were also synthesized to
obtain further information on the interlocked structure by NMR
studies. As observed with native CD, the same diffusion
coefficient for the stoppers, functionalized CD and the axle in
water were observed in the DOSY spectra for RotLa2 1a and
1
The H DOSY spectrum (diffusion ordered NMR) of the
product 6 in DMSO showed the same diffusion coefficient for the
protons of the CD, axle, and stoppers (see Figure S1), indicating
B
DOI: 10.1021/acs.orglett.7b00153
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
RotLa4 2a (Figurea S2 and S3). For both rotaxanes, correlation
peaks between the inner cavity CD H3 and H5 and central axle
protons on the T-ROESY spectra (Figure S4) confirmed the
interlocked structure. Moreover, correlation between H5 and
triazolyl proton Ht indicates that the primary rim of the
functionalized CD is pointing to the stoppers. As observed with
native CD, this head-to-head configuration enables intra-
molecular hydrogen bonding between the two secondary rims
and seems inherently favored, even though in this case it also
avoids the steric hindrance between the substituents on the
primary rims.
(liver and kidney), and the MRI intensities of the regions were
plotted pre- and post-injection of the contrast agent at Gd
concentration of 50 μmol·kg−1. Comparison with commercial
Gd−DOTA as a reference was performed at the same
concentration of Gd. Figure 3 shows MRI cross sections where
The effect of the supramolecular assembly on the longitudinal
proton relaxivity of the Gd(III) complexes was then investigated
by 1H NMRD (nuclear magnetic relaxation dispersion) profiles
by measuring T1 at different magnetic fields. The profiles (Figure
2) were recorded in water at 37 °C for the two rotaxanes (1b and
Figure 3. (a) MRI cross sections of the kidneys (red arrow) pre- (left)
and postinjection (right, 40 min) of RotGd2. (b) Dynamic MRI signal
enhancement in renal cortex after CA injection.
the kidney regions are highlighted as expected for the
biodistribution of a molecular scaffold of a small size inferior to
5 nm.27 Comparison of the pre- and postcontrast images clearly
reveals the higher brightness of the kidney caused by RotGd2.
For further images of the liver with this CA and of kidney and
liver with RotGd4, see Figures S9 and S10. The peaks of
enhancement compared to the precontrast image were observed
at the same time, 6 min post-injection for all CA in the liver and
the kidney followed by a phase of decay (Figure 3b and Figure
S11). The absolute values at 21 min post-injection are highest for
RotGd2 (16% in the liver, 67% in the cortical region of the
kidney), followed by those of RotGd4 (9% and 28% respectively)
and Gd−DOTA (6% and 17%, respectively). After bloodstream
circulation with a complementary transitory visualization
through the vascular network in the liver, the CAs are excreted
from the kidney cortex to the bladder. After 40 min, the levels of
RotGd4 and Gd−DOTA came back to their precontrast values
and to 10% signal enhancement for RotGd2 in the liver,
indicating a hepatic wash out. However, a stronger retention in
the cortical region of the kidney was observed with enhancement
of 46% and 19% for RotGd2 and RotGd4, respectively (11% for
Gd−DOTA). Both rotaxanes behave similarly in the kidney
glomerular and tubular clearance with slower elimination than
the mononuclear complex Gd−DOTA. Due to the higher
concentration of RotGd2 than that of RotGd4 both injected for
an identical final Gd amount, RotGd2 takes longer to be
eliminated. This imaging study evidenced that both rotaxanes
display higher contrast enhancement than the commercial CA
Gd−DOTA over the full observation period without the typical
liver accumulation observed for macromolecular agents. Thus,
they improve the imaging properties without undesired liver
uptake. The relatively long circulation time opens the perspective
for vectorization toward other tissues than the kidney.
Figure 2. 1H NMRD profiles of aqueous solution of CD-Gd, CD-Gd2,
RotGd2, and RotGd4 at 37 °C.
2b) and compared to the corresponding CDs (7b and 8b). The
relaxivities per Gd are considerably higher for RotGd2 1b and
RotGd4 2b (12.30 and 15.70 mM−1·s−1 at 20 MHz, respectively)
than for the parent functionalized CDs (7.06 and 8.57 mM−1·s−1,
respectively) or Gd-DOTA24 (3.83 mM−1·s−1). The relaxivity
values are comparable to multimeric Gd−DOTA-functionalized
CD systems of similar size ([Gd−DOTA]7-β-CD: 12.2 mM−1·
s−1 at 60 MHz;25 Gd−DO3A-HP-β-CD: 7.82 mM−1·s−1 at 60
MHz;5 [Gd−DO3P]6.9-F0.1-β-CD: 21.6 mM−1·s−1 at 20 MHz26).
The NMRD profile shows an enhancement at medium field
(20−80 MHz) for the rotaxanes, which is not present for the
functionalized CDs. This hump is characteristic of macro-
molecular contrast agents (such as polymers or liposomes), and
it indicates that the interlocked architecture plays a crucial role in
the rotational dynamics and subsequently in the relaxivity
properties. The temperature dependence (Table S1) showing an
increased relaxivity with increasing temperature is also an
indication of the rigidity of the system. Indeed, it proves that
the relaxivity is limited by the water-exchange rate of the complex
and not by its rotation. It is most notable that our small rotaxanes
feature also those properties which were previously observed
with polyrotaxanes (CD−Gd/polyammonium PR: 16.4 mM−1·
s−1;1 CD−Gd2/polyammonium PR: 19.6 mM−1·s−1;1 Gd−
DO3A-HPCD/Pluronic PR: 22.8 mM−1·s−1 5 at 60 MHz). The
[3]rotaxanes behave indeed as a typical macromolecular contrast
agent with promising relaxation properties at relevant body
temperature.
The biodistribution of rotaxanes RotGd2 and RotGd4 was
then studied in vivo on BALB/c mice using adapted dynamic
MRI sequences at 7T. Several regions of interest were monitored
In summary, we have successfully developed a one-pot, five-
component mechanostereoselective synthesis of head-to-head
CD [3]rotaxanes leading to the first [3]rotaxanes with Gd−
C
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00153.
■
S
Experimental procedures, compound characterization
data, and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: guillaume.vives@upmc.fr.
*E-mail: bernold.hasenknopf@upmc.fr.
ORCID
Bernold Hasenknopf: 0000-0002-2518-1405
Author Contributions
∥J.W.F. and J.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(19) Lecourt, T.; Herault, A.; Pearce, A. J.; Sollogoub, M.; Sinay, P.
̈
■
Chem. - Eur. J. 2004, 10, 2960.
We thank Agnes
̀
Pallier, Universite
́
d’Orlea
́
ns, for performing
ICP measurements on the Gd3+-containing samples. Financial
support from UPMC (programme Emergence) and the LabEx
MiChem programme under reference ANR-11-IDEX-0004-02
and from the Ligue contre le Cancer are acknowledged. We
(20) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
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(21) Guieu, S.; Sollogoub, M. Angew. Chem., Int. Ed. 2008, 47, 7060.
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Buriez, O.; Sollogoub, M.; Amatore, C. Eur. J. Inorg. Chem. 2010, 2010,
4720. (b) Menand, M.; Adam de Beaumais, S.; Chamoreau, L.-M.;
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iot, Y.; Verpeaux, J.-N.;
thank also the Institut Weizmann Franca
fellowship to G.R. and the IDEX Programme interdisciplinaire,
Universite Paris Descartes SINON and Universite Paris
̧ is for the postdoctoral
́
́
́
Derat, E.; Blanchard, S.; Zhang, Y.; Bouteiller, L.; Sollogoub, M. Angew.
Chem., Int. Ed. 2014, 53, 7238.
Descartes. for the MRI equipment.
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