Modular construction of dynamic nucleodendrimers

Article abstract of DOI:10.1002/anie.201402400

Isoguanosine-containing dendritic small molecules self-assemble into decameric nucleodendrimers as observed by 1D NMR spectroscopy, 2D DOSY, and mass spectrometry. In particular, apolar building blocks readily form pentameric structures in acetonitrile while the presence of alkali metals promotes the formation of stable decameric assemblies with a preference for cesium ions. Remarkably, co-incubation of guanosine and isoguanosine-containing nucleodendrons results in the formation of decameric structures in absence of added salts. Further analysis of the mixture indicated that guanosine derivatives facilitate the formation, but are not involved in decameric structures; a process reminiscent of molecular crowding. This molecular system provides a powerful canvas for the rapid and modular assembly of polyfunctional dendritic macromolecules.

Full text of DOI:10.1002/anie.201402400

Angewandte
Chemie
DOI: 10.1002/anie.201402400
Supramolecular Chemistry
Modular Construction of Dynamic Nucleodendrimers**
Valentina Abet, Robert Evans, Florian Guibbal, Stefano Caldarelli, and Raphaꢀl Rodriguez*
Dedicated to Professor Max Malacria on the occasion of his 65th birthday
Abstract: Isoguanosine-containing dendritic small molecules
self-assemble into decameric nucleodendrimers as observed by
1D NMR spectroscopy, 2D DOSY, and mass spectrometry. In
particular, apolar building blocks readily form pentameric
structures in acetonitrile while the presence of alkali metals
promotes the formation of stable decameric assemblies with
a preference for cesium ions. Remarkably, co-incubation of
guanosine and isoguanosine-containing nucleodendrons
results in the formation of decameric structures in absence of
added salts. Further analysis of the mixture indicated that
guanosine derivatives facilitate the formation, but are not
involved in decameric structures; a process reminiscent of
molecular crowding. This molecular system provides a power-
ful canvas for the rapid and modular assembly of polyfunc-
tional dendritic macromolecules.
structures resembling G-quadruplex nucleic acids.[6] While
particular guanine-rich oligonucleotides readily form G-
quadruplex structures at physiological conditions, self-assem-
bled dendrimers involving multiple building blocks are
entropically disfavored and heavily rely on solvent polarity,
temperature, and the presence of organic (e.g. aromatic
template) and inorganic stabilizers (e.g. metal ions).[1] This
dependency provides the opportunity to design tunable
supramolecular devices.[7] For example, it has been shown
that such assemblies can serve as thermo-, photo-, and
metallo-responsive structures, which can be exploited for
the purpose of drug delivery.[8]
Herein, we describe the synthesis and self-assembly of
isoguanosine-containing dendritic derivatives named “nucle-
odendrons” (iG-NDs). Seminal work from Davis has shown
that a low-molecular-weight lipophilic isoguanosine residue
could self-assemble as pentamers around alkali metals.[9] This
property mainly relies on a network of hydrogen bonds
dominated by a larger bond angle compared to the one
observed for guanosine residues. Based on this, we reasoned
that high-molecular-weight iG dendritic building blocks could
self-assemble in a dynamic and controllable manner to form
“nucleodendrimers”. This work hypothesis was formulated on
the ground that specific monomers might confer distinct
physicochemical properties to the corresponding assembly
based on different shape, polarity, metal ion preferences, and
overall size. We anticipated that the hydrophobic nature of
the dendritic core would help drive and modulate the stability
of the structure in polar solvents, despite higher costs in
entropy compared to its G counterpart. Moreover, the central
channel being wider for pentameric structures compared to
that of G-quartets, the former was expected to be poorly
affected by electrostatic repulsion imposed by oxygen lone
pairs laying inside the central cavity as is the case for G-
quadruplex structures. A representative scheme of putative
assemblies is depicted in Figure 1.
D
endrimers are globular macromolecules harboring a high
density of peripheral functional groups.[1] As a result, den-
dritic structures exhibit unique physicochemical properties
and have found widespread applications spanning from
catalysis to molecular sensing.[2] The polymeric nature of
these structures makes their syntheses challenging, often
resulting in the production of polydisperse mixtures. In
pioneering work, Zimmerman et al. have shown that den-
dritic macromolecules can readily arise from the self-assem-
bly of monomers in organic solvents by means of noncovalent
interactions (e.g. hydrogen bonding).[3] Betancourt and
Rivera have shown that guanosine (G) residues embedded
with an extended aromatic surface form hexadecameric self-
organized structures in the presence of potassium ions.[4]
Guanosine is known to form square-planar assemblies (e.g.
G-quartet), composed of four guanosine residues engaged in
a Hoogsteen-type hydrogen-bond network.[5] G-quartets have
the ability to pile-up and form multilayered higher-order
[*] Dr. V. Abet, F. Guibbal, Dr. S. Caldarelli, Dr. R. Rodriguez
Centre de Recherche de Gif
A series of monomers were prepared from isoguanosine,
first protected as an acetonide, then acylated on the 5’-OH
using 6-azidohexanoic acid in the presence DCC/DPTS to
provide the corresponding iG-azide building block in 79%
yield. Three generations of alkyne-containing side chains
either protected or harboring free primary alcohols, making
up for the core of the assembly, were prepared in solution and
coupled to iG-azide by means of a copper catalyzed alkyne/
azide cycloaddition (see the Supporting Information).[10,11]
This short synthetic procedure gave rise to a series of six
nucleodendrons of variable size and polarity, readily available
for self-assembly studies (Figure 1C).
Institut de Chimie des Substance Naturelles du CNRS
Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
E-mail: raphael.rodriguez@cnrs.fr
Homepage: http://rodchembiolab.com
Dr. R. Evans
Chemical Engineering and Applied Chemistry
Aston University, Birmingham, B4 7ET (UK)
[**] This research was funded by the Centre National de la Recherche
Scientifique and the Institut de Chimie des Substances Naturelles.
We thank N. Birlirakis for fruitful discussions, N. Elie and O. Gimello
for assistance with MS analyses.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402400.
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Figure 1. Molecular structures of: A) iG-pentamer, B) iG-decamer, and
C) iG-derived nucleodendrons (iG-ND); 1, 2 and 3 indicate generation
number; P indicates acetonide-protected ND.
Nucleodendrons were independently dissolved and sub-
jected to NMR spectroscopy. Our search for a suitable solvent
revealed that CD3CN provided the best results in terms of
solubility and spectral resolution of the sample peaks.
Because of its low viscosity, diffusion-ordered spectroscopy
(DOSY) data were acquired using a convection-compen-
sated, bipolar-paired double-stimulated echo protocol and
were processed as previously described.[12] Interestingly, when
iG-ND-1 or iG-ND-1P were dissolved in CD3CN in the
absence of a metal template, weak NH1 and NH6a signals
were observed at 13.7 and 10.7 ppm, respectively (Fig-
ure 2A). These signals, characteristic of a hydrogen-bond
network, indicated that iG building blocks interact with one
another in solution, to form a symmetrical structure as
opposed to random aggregates as previously observed for
G derivatives.[5,9,13] In line with this, DOSY data indicated
that a range of small-sized species formed, producing NMR
spectra with many overlapping peaks that renders simple
DOSY analysis intractable.[14] Diffusion coefficients could be
measured using isolated signals and suggested that iG-ND-
Figure 2. A) 1H NMR spectra (500 MHz, CD3CN, 298 K), arrows indi-
cate weak 1H signals. a) iG-ND-1P; b) iG-ND-1P after addition of 0.2
mol equiv CsI; c) (iG-ND-1P)P; d) (iG-ND-1P)P after addition of 0.2
mol equiv CsI. B) 2D DOSY spectra (600 MHz, CD3CN, 298 K) of iG-
ND-1P with 0.2 mol equiv CsI; C) ESI mass spectra of iG-ND-1P in
the presence of CsI; D) Schematic representation of dynamic nucleo-
dendrimer formation.
preformed pentamers operate as suitable receptors for Cs+
ions. DOSY experiments revealed a diffusion coefficient of
3.9 ꢀ 10À10 m2 sÀ1 for the largest species of the mixture (Fig-
ure 2B), consistent with the formation of a higher-order
decameric structure as depicted in Figure 1B, with a predicted
coefficient of 3.9 ꢀ 10À10 m2 sÀ1. In agreement with this, mass
spectrometry analysis revealed the mass of Cs+-containing
decameric species (Figure 2C).[16] As a control experiment,
a nucleodendron where both the aromatic amine and
carbonyl groups were protected ((iG-ND-1P)P, see the
Supporting Information), thereby preventing hydrogen-
bond formation, was not able to form structured assemblies
1
formed an assembly with an experimental diffusion
coefficient of 5.3 ꢀ 10À10 m2 sÀ1. This compares well to a theo-
retical value of 5.5 ꢀ 10À10 m2 sÀ1 for a pentameric assembly.[15]
DOSY spectra indicated the presence of a significant amount
of smaller oligomeric species, reflecting the dynamic and
reversible nature of these structures. Addition of CsI to
a solution containing iG-ND-1P resulted in significant
sharpening of the proton signals associated with a moderate
downfield shift of the hydrogen-bonded NH6a signal (from
10.7 to 11.1 ppm) (Figure 2A). This data indicated the
formation of a tighter assembly, further suggesting that
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as demonstrated by the absence of spectral evolution upon
addition of CsI (Figure 2A). Dynamic self-assembly was
observed for other monomers of the series, prompting us to
propose a general model whereby nucleodendrons exist as
multimeric species in dynamic equilibrium with a cyclic
pentameric assembly, which upon addition of a template is
driven towards the formation of a more stable decameric
entity as depicted in Figure 2D. The fact that these structures
exhibited a single set of proton signals above 10 ppm supports
the notion that the heart of self-assembled nucleodendrimers
display a high level of symmetry.
Further analysis of this system revealed a marked depend-
ency on the size and polarity of the nucleodendrons to self-
assemble. We found that increasing the generation number
significantly impaired the ability of monomers to form stable
structures in the unprotected series. For example, a compara-
tive NMR analysis of first and second generations showed
that while the first generation formed a decameric structure in
the presence of CsI, the proportion of structured species was
considerably decreased for its second-generation counterpart
(Figure 3A). Given that a low-molecular-weight lipophilic
observed the general trends of: iG-ND-1P > iG-ND-2P >
iG-ND-3P and iG-ND-1 > iG-ND-2 @ iG-ND-3 in the pres-
ence of CsI.[17] In particular, iG-ND-3 was resistant to self-
assembly in the presence of equimolar amounts of CsI
whereas its protected analogue formed structures in the
absence of CsI, reaching the size of small proteins almost
quantitatively in the presence of 1 mol equiv CsI (ca. 15 kDa).
The size of the cavity within isoguanosine assemblies is
suitable to accommodate Cs+ and K+ ions.[13] Therefore, we
next evaluated the ability of both ions to induce the formation
of nucleodendrimers and to compete each other out after
assembly. To do so, iG-ND-1 was first incubated with KI.
Interestingly, we observed a new set of NH signals at 14.1 and
10.5 ppm, distinct from those obtained in the presence of CsI,
but still representative of a hydrogen-bonded supramolecular
assembly. Remarkably, addition of
a substoichiometric
amount of CsI shifted the mixture composition towards the
decamer containing Cs+, for which the chemical shifts were
identical to the ones observed when iG-ND-1 was directly
incubated with CsI (Figure 3C). In contrast, when iG-ND-
1 was first incubated with CsI prior to addition of an
equimolar amount of KI, no evolution of the mixture
composition was observed. This data demonstrated that
isoguanosine-based nucleodendrimers show a preference for
Cs+ ions reflecting a cavity size that is more suitable for its
larger ionic radii, leading to a more stable structure as
compared to potassium-containing assemblies.[13] Most impor-
tantly, our data indicate that monomers or preformed
pentamers are in dynamic equilibrium allowing template
exchange, leading to distinct nucleodendrimers.
We then explored the capacity of G- and iG-NDs to form
hybrids species based on a previous finding showing that
oligonucleotides containing either G or iG have the ability to
form heterodimeric assemblies.[18] To do so, G-NDs were
synthesized, and sequentially incubated either with CsI or KI.
Consistent with previous reports on guanosine containing
oligonucleotides, G-NDs were resistant to CsI and did not
form any well-defined assembly (Figure 4A). In contrast,
addition of potassium resulted in the appearance of a series of
poorly resolved imino signals near 12 ppm indicating the
formation of hydrogen-bonded structures devoid of a pre-
dominant species exhibiting a clear symmetry. Strikingly,
mixing iG-ND-3P with G-ND-1 resulted in the appearance of
a signal at 11.1 ppm at the expense of the one at 10.7 ppm in
absence of salts, suggesting the formation of the homodeca-
meric iG-containing nucleodendrimer (Figure 4B). This
structure did not significantly evolve upon addition of
excess CsI, whereas signals corresponding to the K+ contain-
ing structure emerged as a result of KI addition (Figure 4B).
These results support the idea that nucleodendrimers com-
prising exclusively iG were predominent. The absence of an
extra set of imino proton corresponding to G residues further
corroborates the fact that G-ND-1 was not involved in
a putative hybrid species per se. Additionally, we failed to
identify proton signals of either free or structured G-ND-
1 previously identified (Figure 4A). Together, these results
demonstrate that G-derived nucleodendrons facilitate the
formation of a decameric iG-containing nucleodendrimer in
absence of salts, without forming hybrid G/iG nucleodentritic
Figure 3. 1H NMR spectra (500 MHz, CD3CN, 298 K). A) a) iG-ND-1;
b) iG-ND-1 after addition of 0.2 mol equiv CsI; c) iG-ND-2; d) iG-ND-2
after addition of 0.2 mol equiv CsI; B) a) iG-ND-3P after addition of
0.2 mol equiv CsI; b) iG-ND-3 after addition of 0.2 mol equiv CsI;
C) a) iG-ND-1; b) iG-ND-1 after addition of 0.1 mol equiv KI; c) iG-ND-
1 after addition of 0.1 mol equiv KI followed by addition of 0.1
mol equiv CsI.
isoguanosine requires the presence of cations to self-assem-
ble,[13] our data support the idea that the hydrophobic nature
of the dendritic side chain constitute a driving force for the
assembly of nucleodendrimers in acetonitrile, whereas steric
hindrance impacts on the ability of higher generations to self-
assemble. Consistent with this, we observed that protected
nucleodendrons had a stronger propensity to self-assemble
compared to their non-functionalized analogues, strengthen-
ing the notion that the polarity of individual dendrons affects
their capacity to self-assemble (Figure 3B). Overall, we
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Figure 4. 1H NMR spectra (500 MHz, CD3CN, 298 K). A) a) G-ND-1;
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Received: February 13, 2014
Published online: && &&, &&&&
Keywords: cesium · dendrimers · isoguanosine ·
.
NMR spectroscopy · self-assembly
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Communications
Supramolecular Chemistry
Dendritic macromolecules: Isoguano-
sine-containing dendritic small mole-
cules self-assemble into isoguanosine-
containing dendrimers named nucleo-
dendrimers (see picture). The building
blocks alone form pentameric structures
while the presence of alkali metals pro-
motes the formation of stable decamers.
This system provides a powerful canvas
for the rapid and modular assembly of
polyfunctional dendritic macromolecules.
V. Abet, R. Evans, F. Guibbal, S. Caldarelli,
R. Rodriguez*
&&&& — &&&&
Modular Construction of Dynamic
Nucleodendrimers
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