Supramolecular Helices via Self-Assembly of 8-Oxoguanosines

Article abstract of DOI:10.1021/ja0364827

The cooperative effect of solvophobic interactions and hydrogen bonding has been exploited to self-assemble supramolecular helical architectures of 8-oxoguanosines in different environments. This self-assembly into helical structures is completely different from that of the parent guanosines which, in the same experimental conditions, form flat, ribbonlike structures. While optical microscopy and X-ray diffraction suggest a chiral columnar aggregate in the LC phase, NMR and Circular Dichroism reveal the presence of a helical structures in solution. Scanning Tunneling Microscopy made it possible to visualize hexagonally arranged G-quartets on graphite, which are sections of the helices packed with their long axis perpendicular to the basal plane of the substrate. Due to their rectifying electrical properties, such helices are interesting for fabricating (opto)electronic biodevices.

Full text of DOI:10.1021/ja0364827

Published on Web 11/07/2003
Supramolecular Helices via Self-Assembly of
8
-Oxoguanosines
†
†
‡
§
Tatiana Giorgi, Stefano Lena, Paolo Mariani, Mauro A. Cremonini,
†
†
|
,|,#
Stefano Masiero, Silvia Pieraccini, J u¨ rgen P. Rabe, Paolo Samor `ı ,*
,
†
,†
Gian Piero Spada,* and Giovanni Gottarelli*
Alma Mater Studiorum-UniVersit a` di Bologna, Dipartimento di Chimica Organica “A.
Mangini”, Via San Donato 15, 40127 Bologna, Italy, UniVersit a` Politecnica delle Marche,
Istituto di Scienze Fisiche and INFM Istituto Nazionale per la Fisica della Materia, Via Ranieri
6
5, 60131 Ancona, Italy, Alma Mater Studiorum-UniVersit a` di Bologna, Dipartimento di
Scienze degli Alimenti, Via RaVennate 1020, 47023 Cesena, Italy, Department of Physics,
Humboldt UniVersity Berlin, Newtonstrasse 15, D-12489 Berlin, Germany, and Istituto per la
Sintesi Organica e la FotoreattiVit a` , Consiglio Nazionale delle Ricerche, Via Gobetti 101,
40129 Bologna, Italy
Received June 3, 2003; E-mail: giovanni.gottarelli@unibo.it; gianpiero.spada@unibo.it; samori@isof.cnr.it
Abstract: The cooperative effect of solvophobic interactions and hydrogen bonding has been exploited to
self-assemble supramolecular helical architectures of 8-oxoguanosines in different environments. This self-
assembly into helical structures is completely different from that of the parent guanosines which, in the
same experimental conditions, form flat, ribbonlike structures. While optical microscopy and X-ray diffraction
suggest a chiral columnar aggregate in the LC phase, NMR and Circular Dichroism reveal the presence of
a helical structures in solution. Scanning Tunneling Microscopy made it possible to visualize hexagonally
arranged G-quartets on graphite, which are sections of the helices packed with their long axis perpendicular
to the basal plane of the substrate. Due to their rectifying electrical properties, such helices are interesting
for fabricating (opto)electronic biodevices.
Introduction
frame, one major goal is to use cooperatively weak interactions
2,3
for generating self-organized helical assemblies. This approach
allows for the construction of synthetic supramolecular helices,
simultaneously exploiting solvophobic interactions and hydrogen
bonding, thereby replicating the interactions that contribute to
the formation of the double-stranded helical structure of DNA.3
Lipophilic guanosine derivatives
Harmonizing the functionalities of individual moieties in a
supramolecular network represents a versatile approach for
developing well-defined polymeric architectures with pre-
1
programmed conformations and tailored properties. In this
†
Alma Mater Studiorum-Universit a` di Bologna, Dipartimento di
Chimica Organica “A. Mangini”.
‡
Universit a` Politecnica delle Marche.
Alma Mater Studiorum - Universit a` di Bologna, Dipartimento di
§
Scienze degli Alimenti.
|
Humboldt University Berlin.
Istituto per la Sintesi Organica e la Fotoreattivit a` .
#
(
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(
e.g., 1-3) are capable of self-assembling into different
structures depending on the experimental conditions. In the
presence of certain ions, they can form G-quartet-based octamers
or columnar aggregates (supramolecular polymers) depending
on the concentration of the ion and nucleobase. The ions act as
templates and they are located between the quartets (Figure 1).
In these assembled structures, both syn and anti orientations of
1
1 899. Fenniri, H.; Mathivanan, P.; Vidale, K. L.; Sherman, D. M.;
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002, 41, 2828. Schenning, A. P. H. J.; Kilbinger, A. F. M.; Biscarini, F.;
4,5
the base around the glycosidic bond have been observed.
Cavallini, M.; Cooper, H. J.; Derrick, P. J.; Feast, W. J.; Lazzaroni, R.;
Leclere, P.; McDonell, L. A.; Meijer, E. W.; Meskers, S. C. J. J. Am. Chem.
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10.1021/ja0364827 CCC: $25.00 © 2003 American Chemical Society
J. AM. CHEM. SOC. 2003, 125, 14741-14749
9
14741

A R T I C L E S
Giorgi et al.
Figure 2. Structural motifs of the two ribbonlike supramolecular assemblies
of guanosine derivatives in the absence of cations.7
,8
electrodes, are photoconductive.12 More interestingly, these
1
3
ribbons also display rectifying properties. A field effect
transistor, based on this supramolecular structure, has been
14
recently described. Furthermore, crystals of the ribbon obtained
1
5
from derivative 3 generate second harmonics. It is worth
noticing that ribbon II is dipolar and that in the crystal, due to
the parallel packing of the ribbons, these dipoles are parallel.8
In an effort to modify and enhance these unique electronic
properties, we broadened our scope to investigate 8-substituted
lipophilic G-derivatives. Here, we report the synthesis of
different 8-substituted guanosines and the study of their self-
assembly behavior under different environmental conditions.
Figure 1. Donor/acceptor sites in the guanine moiety (a), the G-quartet
arrangement (b) and the columnar ion-directed self-assembly (c). A
simplified sketch of syn and anti conformations (d).
6
Sessler has recently shown that attaching a sterically demand-
ing group to the C(8)-position (derivative 4), enables the mole-
cules to self-associate into G-quartets, both in the solid state
and in solution, even in the absence of the template metal
cations. Only the syn stereochemistry was observed for the
G-quartets formed from 4.
8
-Oxo derivatives 5 and 6 are models for 8-oxoguanine, a
1
6,17
species formed during DNA oxidation.
Interestingly, 8-ox-
(
4) Marlow, A. L.; Mezzina, E.; Spada, G. P.; Masiero, S.; Davis, J. T.;
Gottarelli, G. J. Org. Chem. 1999, 64, 5116. Forman, S. L.; Fettinger, J.
C.; Pieraccini, S.; Gottarelli, G.; Davis, J. T. J. Am. Chem. Soc. 2000, 122,
4060. Mezzina, E.; Mariani, P.; Itri, R.; Masiero, S.; Pieraccini, S.; Spada,
G. P.; Spinozzi, F.; Davis, J. T.; Gottarelli, G. Chem. Eur. J. 2001, 7, 388.
Shi, X.; Fettinger, J. C.; Davis, J. T. Angew. Chem., Int. Ed. 2001, 40,
2827. Wong, A.; Fettinger, J. C.; Forman, S. L.; Davis, J. T.; Wu, G. J. J.
Am. Chem. Soc. 2002, 124, 742.
5) The same is true for water-soluble compounds in the solid state and in
solution; see, for example: Kang, C.; Zhang, X.; Ratliff, R.; Moyzis, R.;
Rich, A. Nature 1992, 356, 126. Laughlan, G.; Murchie, A. J. H.; Norman,
D. G.; Moore, M. H.; Moody, P. C. E.; Lilley, D. M. J.; Luisi, B. Science
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W.; Lau, F. W.; Feigon, J. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 10 546.
6) Sessler, J. L.; Sathiosatham, M.; Doerr, K.; Lynch, V.; Abboud, K. H.
Angew. Chem., Int. Ed. 2000, 39, 1300.
In the absence of metal templates, guanosines without a C(8)-
substituent self-assemble, both in solution and in the solid state,
(
into ribbonlike architectures (Figure 2) with an anti orientation
of the base around the glycosidic bond.7-9
These ribbon structures are interesting: they are the building
blocks for new lyotropic mesophases formed in organic
(
solvents.8
,10,11
In the solid state, the ribbons, by bridging gold
14742 J. AM. CHEM. SOC.
9
VOL. 125, NO. 48, 2003

Supramolecular Helices of 8-Oxoguanosines
A R T I C L E S
oguanines possess oxidation potentials (Eox) that are even lower
than those of guanines,1
7,18
which have the lowest Eox of the
primary DNA nucleobases. This lowered Eox for 5 and 6 should
further enhance the conductive properties of guanosine based
architectures.
Moreover, we have extended our studies to include the
8-methylthio substituent (7), in an attempt to further enhance
the dipolar character of guanosine. Finally, the 8-bromo
derivative 8 was used as a reference compound, the syn
conformation of 8-bromoguanosine being reported in the
1
9,20
literature.
Of these compounds (5-8), only the 8-oxo derivatives 5 and
self-assemble to give lyotropic mesophases in organic solvents.
6
This is basically correlated to the presence of a new lactamic
function in the five-membered ring which generates new
hydrogen bonding architectures. Although optical microscopy
and X-ray diffraction allowed us to cast light on the behavior
of 5 and 6 in the liquid crystalline phase, NMR and Circular
Dichroism were employed to investigate the formation of
supramolecular assemblies in solution. The use of Scanning
Tunneling Microscopy also made it possible to gain insight into
the self-assembly at surfaces.
The results indicate the formation of a continuous helical
structure. This structure is interesting as it is a new architecture
formed by a biologically important molecule; furthermore, the
helix could explain the rectifying properties of cast films of
Figure 3. Optical textures of the two LC phases observed for 6 in heptane
at c ) 8 (a) and 15% (w/w) (b) (Magnification 250×).
8
-oxoguanosine derivatives.13
Liquid Crystalline Phases of 8-Oxo Derivatives. Among
the 8-substituted derivatives 5-8, only the 8-oxo compounds 5
and 6 displayed lyotropic liquid crystalline properties. The LC
properties of 5 and 6 were, however, quite different from those
of the 8-unsubstituted derivatives reported in ref 8. Optical
2
1
microscopy reveals the presence of two birefringent phases,
depending on the percentage of 5 and 6 in heptane or hexane:
they exist at c ) 2-12 and c > 12% (w/w) (c being the weight
of the guanosine derivative over the total weight of the sample).
(
7) Gottarelli, G.; Masiero, S.; Mezzina, E.; Pieraccini, S.; Rabe, J. P.; Samor `ı ,
P.; Spada, G. P. Chem. Eur. J. 2000, 6, 3242.
Figure 4. Low-angle X-ray diffraction profiles obtained for derivative 6
in hexane at c ) 3% (full line) 10% (dotted line) and 20% (dashed line).
(
8) Giorgi, T.; Grepioni, F.; Manet, I.; Mariani, P.; Masiero, S.; Mezzina, E.;
Pieraccini, S.; Saturni, L.; Spada, G. P.; Gottarelli, G. Chem. Eur. J. 2002,
8
, 2143.
(9) Araki, K.; Takasawa, R.; Yoshikawa, I. Chem. Commun. 2001, 1826.
X-ray diffraction experiments confirm the presence of two
different phases (see next paragraph). In contrast, unsubstituted
G-derivatives show only a single phase with two-dimensional
square symmetry, based on the previously described G-ribbons.8
X-ray diffraction measurements have been performed as a
function of the concentration of 5 or 6 in hexane. The
experimental diffraction data for the two systems are practically
superimposable, thus only the results obtained from 6 will be
described. Typical low angle X-ray diffraction profiles obtained
at different compositions are shown in Figure 4, whereas Figure
5 shows a complete scattering profile obtained at high concen-
tration.
(
10) Also, lipophilic derivatives of folic acid give ribbonlike assembled species
and liquid crystalline phases: Kato, T. Science 2002, 295, 2414, and
references therein.
(
(
(
11) Gottarelli, G.; Masiero, S.; Mezzina, E.; Pieraccini, S.; Spada, G. P.; Mariani,
P. Liq. Cryst. 1999, 26, 965.
12) Rinaldi, R.; Branca, E.; Cingolani, R.; Masiero, S.; Spada, G. P.; Gottarelli,
G. Appl. Phys. Lett. 2001, 78, 3541.
13) Rinaldi, R.; Branca, E.; Cingolani, R.; De Felice, R.; Calzolari, A.; Molinari,
E.; Masiero, S.; Spada, G. P.; Gottarelli, G.; Garbesi, A. Ann. N. Y. Acad.
Sci. 2002, 960, 184. Rinaldi, R.; Maruccio, G.; Biasco, A.; Arima, V.;
Cingolani, R.; Giorgi, T.; Masiero, S.; Spada, G. P.; Gottarelli, G.
Nanotechnology 2002, 13, 398.
(
14) Maruccio, G.; Visconti, P.; Arima, V.; D’Amico, S.; Biasco, A.; D’Amone,
E.; Cingolani, R.; Rinaldi, R.; Masiero, S.; Giorgi, T.; Gottarelli, G. Nano
Lett. 2003, 3, 479.
(
15) Gottarelli, G.; Taliani, C.; Spada, G. P., manuscript in preparation.
16) Kasai, H.; Yamaizumi, Z.; Berger, M.; Cadet, J. J. Am. Chem. Soc. 1992,
(
1
14, 9692. Miller, J. H.; Fan-Chiang, C.-C. P.; Straatsma, T. P.; Kennedy,
M. A. J. Am. Chem. Soc. 2003, 125, 6331.
The analysis has been carried out considering separately the
low and the high angle diffraction regions, since from the
(
17) Burrows, C. J.; Muller, J. G. Chem. ReV. 1998, 98, 1109. White, B.; Smyth,
M. R.; Stuart, J. D.; Rusling, J. F. J. Am. Chem. Soc. 2003, in press.
18) Berger, M.; Anselmino, C.; Mouret, J.-F.; Cadet, J. J. J. Liq. Cromatogr.
(
1
990, 13, 929. Goyal, R. N.; Jain, N.; Garg, D. K. Bioelectrochem. Bioenerg.
997, 43, 105. Ikeda, H.; Saito, I. J. Am. Chem. Soc. 1999, 121, 10 836.
(21) Although the picture of the high-concentration phase shows a “herringbone”
texture observed in many hexagonal phases, including those formed by
guanylates (see, e.g., Spada, G. P.; Carcuro, A.; Colonna, F. P.; Garbesi,
A.; Gottarelli, G. Liq. Cryst. 1988, 3, 651) and DNA (see, e. g., Livolant,
F.; Levelut, A. M.; Doucet, J.; Benoit, J. P. Nature 1989, 339, 724), the
micrograph of the more diluted system does not show textures typical
enough to allow an unambiguous assignment.
1
(
19) Saenger, W. Principles of Nucleic Acid Structure; Springer-Verlag: New
York, 1984; p 21. See also: Dias, E.; Battiste, J. L.; Williamson, J. R. J.
Am. Chem. Soc. 1994, 116, 4479. Altona, C.; Sundaralingam, M. J. Am.
Chem. Soc. 1972, 94, 8205.
(
20) Polissiou, M.; Theophanides, T. Inorg. Chim. Acta 1987, 195.
J. AM. CHEM. SOC.
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VOL. 125, NO. 48, 2003 14743

A R T I C L E S
Giorgi et al.
Figure 6. Dependence on concentration of the dimension of the unit cell
measured in the two derivatives 5 (square) and 6 (circle) in hexane.
Figure 5. X-ray diffraction profile obtained from derivative 6 in hexane
at c ) 20%. The low angle diffraction peaks have been indexed according
to a 2D hexagonal packing (in the inset, the diffraction profile in the 2θ
region between 2 and 12° has been expanded for clarity); the high angle
peak referring to the 8-oxoguanosine stacking is indicated by the arrow.
The large band centered at ca. 19.5° (around 4.6 Å) reflects the disordered
nature of the hexane and of the aliphatic side chains.
26
former, the crystalline lattice and symmetry, as well as informa-
tion on the long-range organization of the structure elements,
can be derived. From the high-angle region, information on the
short-range arrangement inside the structural elements can be
obtained.2
2,23
For concentrations of 6 ranging between 3 and
1
2%, a diffuse band was observed in the low angle X-ray
diffraction profile. The position, width, and intensity of this
broad band changes with the concentration, indicating that
removal of the solvent determines both a continuous decrease
of the repetition distance and an increase of the sample’s long-
range order. This result indicates of the presence of a poorly
ordered liquid crystalline phase of a nematic or cholesteric
nature. No peaks were detected in the high angle region,
suggesting that order inside the structural elements is low. The
low concentration of scattering particles in this condition might
also explain this absence of diffraction peaks.
Figure 7. Representation of the hexagonal phase with the quantities defined
in the text.
discotic nature of the mesophase, characterized by the regular
stacking of 8-oxoguanosine, probably bonded in quartets, at the
typical distance of 3.4 Å.
At concentrations of 6 higher than 12%, a series of diffraction
peaks appear in the X-ray profile. According to the birefringent
viscous liquid observed in the same concentration range by
polarizing microscopy, the characteristic diffraction confirms
the liquid-crystalline nature of the sample, as both thermotropic
and lyotropic liquid crystals show an intrinsic long-range
Therefore, the ordered liquid crystalline phase possesses a
columnar hexagonal structure, with parallel elongated columnar
elements (rods) consisting of stacked oxoguanosines. These rods
are embedded in a hydrocarbon matrix formed by the hexane
solvent and by the aliphatic side chains, which are responsible
for the broad scattering band observed at about 4.4 Å (2θ about
2
2-25
disorder.
In particular, the low-angle X-ray diffraction
2
0°). The absence of extra peaks in the low-angle X-ray
region is dominated by a very strong peak, whose position
depends on the solvent concentration. Higher order diffraction
peaks can be detected using very long exposure times (see
Figure 5): at least 2 more peaks were detected, providing help
diffraction profile indicates the absence of a long-range three-
dimensional order. In other words, no correlation exists in the
direction perpendicular to the two-dimensional cell.
According to the lattice symmetry, the dimensions of the unit
22,23
in the assessment of the lattice symmetry.
The peak
22
cell a have been derived for 5 and 6: the observed values as
reciprocal spacings are, in fact, in the ratio of 1:x3:x4,
indicating a two-dimensional hexagonal packing of the structural
elements. A characteristic peak, centered at about 3.4 Å, is
observed in the high angle region. According to previous
a function of the concentration are reported in Figure 6. From
these data, some important structural information can be derived.
In the hexagonal structure (see Figure 7), the projection on the
plane perpendicular to the rod axis defines the two-dimensional
lattice, i.e., the unit cell a corresponds to the inter-columnar
distance. Assuming the columns have a circular section with
radius R (the radius of the guanosine column) and a length L,
the relation between the cross-sectional area of the cylinder and
the 2-dimensional hexagonal unit cell surface is as follows2
2
4,25
results,
the presence of this peak indicates the columnar,
(
22) Luzzati, V. In Biological Membranes; Chapman, D., Ed.; Academic
Press: London, 1968; p 71.
(
23) Gottarelli, G.; Spada, G. P.; Mariani, P. In Crystallography of Supramo-
lecular Compounds; Tsoucaris, G., Atwood, J. L., Lipkowski, J., Eds.;
Kluwer: Netherlands, 1996; p 307.
2,23
(24) Mariani, P.; Mazabard, C.; Garbesi, A.; Spada, G. P. J. Am. Chem. Soc.
1
989, 111, 6369. Bonazzi, S.; Capobianco, M.; De Morais, M. M.; Garbesi,
2
2
A.; Gottarelli, G.; Mariani, P.; Ponzi Bossi, M. G.; Spada, G. P.; Tondelli,
L. J. Am. Chem. Soc. 1991, 113, 5809.
π R L ) C (x3/2)a c
(1)
v
(
25) Pieraccini, S.; Gottarelli, G.; Mariani, P.; Masiero, S.; Saturni, L.; Spada,
G. P. Chirality 2001, 13, 7.
where cv is the volume concentration of the lipophilic guanosine
14744 J. AM. CHEM. SOC.
9
VOL. 125, NO. 48, 2003

Supramolecular Helices of 8-Oxoguanosines
A R T I C L E S
derivative (obtained from the weight concentration, using 0.92,
3
27
0
.95, and 1.45 cm /g as the specific volume for 5, 6 and
hexane, respectively), and C is the average interaxial distance
between rod centers (normal to the 2D cell plane). The ratio
L/C gives essentially the fraction of solvent in the C direction.
For rodlike elements having an infinite length, L/C ) 1 and
-1/2
the concentration dependence of the unit cell is cV . For finite
rodlike objects undergoing isotropic swelling (i.e., on dilution,
the interparticle distances uniformly increase in all three
dimensions) L/C ) R/a, and thus
a ) (2πR /x3) cv-1/3
3
1/3
(2)
Therefore, cv exponents -1/2 and -1/3 can be considered as
fingerprints of interparticle distances decreasing in a plane (2D
swelling) or isotropically in the volume around the particles in
all three dimensions (3D swelling), respectively. It should be
noticed that if the length of the rod particles depends on the
concentration, or if the interparticle distances change anisotro-
Figure 8. Room temperature H NMR spectra of derivative 6 in (a) DMSO-
d and (b) CDCl .
6
3
whereas the H(2) protons (also singlet) are shifted slightly
upfield. NMR spectra recorded at low temperature first show
broadening of the H(2) signal, which eventually splits into two
signals at δ 8.50 (H-bonded) and δ 5.44 ppm (free) (see the
Supporting Information). This behavior is substantially identical
to that observed in ref 6 for the generation of free quartets from
pically with concentration, then the a on cv power law
dependence can be even slower.28 The dependence on concen-
tration of the hexagonal unit cell a (Figure 6) shows that the
rods move apart as dilution proceeds; however, the cv depen-
dence is ca. -1/8, which suggests that the aggregates have a
finite length and that they grow as a function of the concentration
and/or are subjected to anisotropic swelling.
4
. The NMR lines are, in all cases, sharp. This, together with
the absence of LC phases, indicates that the G-quartets formed
from 8, without metal templates, do not stack to give large
columnar aggregates. These data also demonstrate that the
energy price required for 8 to adopt an anti conformation,
necessary for ribbon formation, is not compensated by the
Self-Assembly in Solutions of 8-Substituted Derivatives.
In the 8-unsubstituted guanosines, the base can adopt a syn or
6
4,5,8
hydrogen bonds formed in this arrangement.
an anti orientation depending on the environment.
In parti-
8
-Methylthio Derivative 7. A behavior similar to 8 was
cular, structures based on G-quartets show an alternation of both
conformations, as the base is substantially free to rotate. In the
ribbon structure, only the anti conformation has been observed.
observed also for 8-methylthio derivative 7 in which the splitting
of the H(2) signal occurs at a temperature (-90 °C in CD2Cl2)
lower than that of the 8-bromo derivative. Also in this case,
NMR spectra in CDCl3 do not show line-broadening on
changing the concentration; the formation of lyomesophases has
not been observed either.
Therefore, the absence of self-assembled ribbon structures
and the formation of G-quartets, without metal templates, seems
to be a quite general behavior for 8-substituted guanosines.6
8
-Bromoguanosine Derivative 8. 8-bromoguanosine is re-
1
9
ported to adopt a syn conformation in the crystalline state.
This conformation appears to be the most abundant one also in
acqueous solution on the basis of simple NMR chemical shift
2
0
considerations, and has been confirmed here via HSQMBC
2
9
experiments. These experiments indicate a predominant syn
conformation also for derivative 8 in CDCl3 and DMSO-d6
solution. NMR data in CDCl3 solutions do not show broadening
of the bands even at high concentrations, providing evidence
that no large species are formed (in contrast, broadening of the
bands was observed for G-derivatives forming ribbons and LC
phases). With respect to the spectrum recorded in DMSO-d6,
CDCl3 solutions exhibit a downfield shift of the H(1) proton
signal (singlet), indicating the formation of hydrogen bonding,
8
-Oxo Derivatives 5 and 6. The 8-oxo compounds show at
-4
-2
-1
every concentration (10 -10 mol L ) and temperature (10-
5 °C) investigated very broad NMR signals in CDCl3 (trace b
4
in Figure 8). Moreover, signals in the spectra recorded in CD2-
ClCD2Cl at higher temperatures are also very broad. Thus, no
detailed information on solution conformation can be obtained.
However, some information can be deduced from NMR, starting
from the spectrum in pure DMSO-d6, by titration with CDCl3.
In pure DMSO (trace a in Figure 8), the H(1) and H(7) amide
protons are nearly superimposed at δ 10.8 ppm, whereas the
exocyclic H(2) amino protons are at δ 6.5 ppm. By adding
CDCl3, the spectrum is unchanged until a high percentage (97,
98, 99%) of CDCl3 is present: at these concentrations, the H(2)
amino protons undergo a large upfield shift (ca. 1.2 ppm), while
the H(1) and H(7) amidic protons eventually form a broad band
(
26) The best fit lines have been obtained by using a modified form of eq 1,
which include the possibility of a not uniform swelling in the three
dimensions, as expressed by L/C ) Rκ/a. The fitting equation is then a )
1
/3 1/3
-µ
1/3
R (2π/x3)
κ
c
v
. The fitting parameters were Rκ ) 19.9 Å and µ
1/3
)
-0.12 for derivative 5 and Rκ ) 17.1 Å and µ ) -0.12 for derivative
6
. Note that R is expected to be not higher than 10-12 Å: therefore, the
κ values are larger than 1 and indicate that the swelling mainly occurs at
the end-to-end distance between the helices.
(
27) The volume of the guanosine derivatives was estimated by summing up
the value of the base, the sugar moiety and the chains. As a reference, the
3
specific volume of guanylic acid is 0.651 cm /g (Iball, J.; Morgan, C. H.;
3
0
at ca. δ 11.2 ppm. These data indicate that the NH2 group is
not involved in H-bonding, whereas the lactam groups are
involved in H-bonding. Furthermore, the large upfield shift of
the amino protons supports the presence of a stacked supramo-
lecular structure.
Wilson, H. R. Nature 1963, 199, 688).
(
28) Amaral, L.; Gulik, A.; Itri, R.; Mariani, P. Phys. ReV. A 1992, 46, 3548.
Mariani, P.; Amaral, L. Q. Phys. ReV. E 1994, 50, 1678.
(
29) 3
JCH coupling constants (Williamson, R. T.; M a´ rquez, B. L.; Gerwick, W.
H.; K o¨ v e´ r, K. E. Magn. Res. Chem. 2000, 38, 265) between H
1 4 8
′ and C /C
in CDCl and DMSO-d for compound 8 were 5.13/3.83 and 4.75/4.32
3
6
Hz, respectively. These values agree with a syn conformation according to
the theoretical DFT Karplus relationships for unsubstituted guanosine
proposed by Munzarov a´ and Sklen a´ rˇ (Munzarov a´ , M. L.; Sklen a´ rˇ , V. J.
Am. Chem. Soc. 2003, 125, 3649).
CD spectra of derivative 6 under different experimental
conditions have been recorded (Figure 9). Although the CD
J. AM. CHEM. SOC.
9
VOL. 125, NO. 48, 2003 14745

A R T I C L E S
Giorgi et al.
Figure 9. CD and absorption spectra of 6 in methanol (dotted line), and
hexane (full line), c ) 0.5 mM. As a comparison, the CD spectrum of the
quartet-based columnar aggregate obtained in CCl3CH2Cl from 1 in the
+
25
presence of K (dashed line) is reported.
signal is very weak in methanol, the bands are more intense in
chloroform (not shown). In hexane, below the critical concentra-
tion for obtaining the first mesophase, the CD spectrum is
dramatically different and characterized by very intense bands.
The latter spectrum does not change with concentration in the
range 0.05-5 mM, indicating that the population of the chirally
assembled species is independent of concentration. At concen-
trations higher than the critical concentration, the intensity
further increases and all bands are monosignated, a typical
behavior for a cholesteric phase.31
Figure 10. Donor/acceptor amide groups in the 8-oxoguanine moiety (a);
architecture of the ribbonlike structure (b), the 8-oxo G-quartet (c) and the
helical structure (d).
G-quartets (see Figure 9). On the other hand, guanosine ribbons
display only a very weak CD spectrum.
In the case of guanine columns, a detailed analysis of the
33
CD spectrum was reported: CD bands are associated with
As the assignments of the electronic transitions of 8-oxogua-
nine are not available, no detailed analysis of the CD spectrum
can be attained. Nevertheless, a few issues can be considered:
exciton coupling of in-plane polarized transitions of adjacent
quartets. Because out-of-plane polarized transitions with high
intensity are unlikely also for the 8-oxo derivative, the chiral
structure detected here does not seem to be composed of a stack
of 8-oxo G-quartets, because a similar structure should display
CD spectra with intensities similar to those of G-stacks.
(i) The intensity of the features in hexane (but also in
chloroform) is remarkable and compatible only with a “highly”
chiral structure.
(ii) The intensity does not change with concentration (below
The tautomeric form of the five membered ring of 8-oxo
the critical concentration) or temperature, indicating a notable
stability of the architecture.32
34
derivatives is a lactam. We have, therefore, two amide-like
groups present in 5 and 6 (Figure 10). This opens up new
(iii) The g-factor (ratio between CD and absorption intensities)
possibilities for the formation of strong amide-amide hydrogen
for the 8-oxo compound 6 is much higher than for the chiral
columnar structures of guanosine derivatives based on a pile of
35
bond pairings that are not possible in guanine. In particular,
(
32) Even if the length of the supramolecular helix is undetermined and/or
possibly changing with concentration, the intensity and shape of the CD
spectrum is not expected to vary with this length. This was observed for
“covalent” polymers, e. g. polypeptides (Sreerama, N.; Woody, R. W. In
Circular Dichroism: Principles and Applications; Berova, N., Nakanishi,
K., Woody, R., Eds.; Wiley: New York, 2000; p 601) and DNA (Johnson,
W. C. In Circular Dichroism: Principles and Applications; Berova, N.,
Nakanishi, K., Woody, R., Eds.; Wiley: New York, 2000; p 703).
(
30) The possible existence of tautomers has been taken into account, but no
evidence for such equilibria has been observed. In particular, NOESY and
ROESY spectra of 2-N-3′,5′-O-tripropanoyl-8-oxo-2′-deoxyguanosine showed
a strong cross-peak between H(1) and H(2) and no cross-peaks relating
H(7) with any sugar protons. Furthermore, no significant shift of the relevant
protons was observed for 5 and 6 at different temperatures, whereas
integration of each of these signals accounted satisfactorily for the expected
number of protons.
(33) Gottarelli, G.; Masiero, S.; Spada, G. P. Enantiomer 1998, 3, 429.
(34) Uesugi, S.; Ikrhara, M. J. Am. Chem. Soc. 1977, 99, 3250. Culp, S. J.;
Cho, B. P.; Kadlubar, F. F.; Evans, F. E. Chem. Res. Toxicol. 1989, 2,
416.
(
31) Gottarelli, G.; Spada, G. P. In Circular Dichroism: Principles and
Applications; Berova, N., Nakanishi, K., Woody, R., Eds.; Wiley: New
York, 2000; p 547.
14746 J. AM. CHEM. SOC.
9
VOL. 125, NO. 48, 2003

Supramolecular Helices of 8-Oxoguanosines
A R T I C L E S
Figure 11. STM current image of 5 at the solid-liquid interface. Dashed
lines indicate the HOPG axis underneath. Bias voltage 0.684 V (tip positive);
average tunneling current 21 pA; scan rate 14 line/s.
amide-amide interaction can be of two types: (i) the lactam
in the six-membered ring is bound to those in the six-membered
ring, and those in the five-membered rings are bound similarly,
leading to the generation of a ribbonlike structure (Figure 10b);
and (ii) formation of H-bonds between five- and six-membered
rings. This latter arrangement leads to either a quartet (Figure
10c) or to a continuous helix (Figure 10d).
Our data suggest that the helix is the most likely supramo-
lecular structure for the 8-oxo derivatives 5 and 6. Another piece
of evidence in support of a helix comes from the fact that the
quartets of 8-methylthio and 8-bromo derivatives (7 and 8), as
Figure 12. CPK models of a continuous helix (a) and of a stacked quartet-
based assembly (b) formed by twelve molecules of the model 9-methyl-
6
well as that reported by Sessler (4), without added ions do not
8-oxoguanine.
stack to form a columnar structure. Therefore, a pile of quartets
(
Figure 10c) without metal templates seems very unlikely for 5
obtaining a section that can appear in STM imaging as a quartet
array of bright spots.
3
6
and 6.
Self-Assembly at Surfaces. Figure 11 displays the constant
height STM image of 5 at the graphite-solution interface. It
reveals an array of quartets that are packed according to a unit
cell of a ) (3.8 ( 0.2) nm, b ) (3.4 ( 0.2) nm, R ) (59 (
Discussion
The 8-oxoguanosine derivatives 5 and 6 could self-assemble
under diverse environments according to different motifs (shown
in Figure 10). A careful examination of the data reported above
indicates that the continuous helix must be the most populated
structure because of the following:
3
)°. This is consistent with a hexagonal motif. The a vector is
at 22° from the nearest neighbor axis in the HOPG lattice (see
dashed lines).37 The bright spots corresponding to higher
tunneling probability can be assigned to the conjugated guanine
core since the energy difference between their HOMO and the
Fermi-level of HOPG is smaller than for the sugar and for the
aliphatic side chains.38
(i) The structure of the cholesteric and hexagonal liquid
crystalline phases is typical of columnar aggregates, and not of
flat ribbonlike structures. On the other hand, other authors,
as well as our group have never found cholesterics or hexagonal
10
The visualized quartet is not in disagreement with the helical
models as it could represent a section of a helical architecture
LCs with ribbon like architecture.
6
(ii) As indicated by Sessler’s results, and those presented in
(ca. four repeats per turn, Figure 10d). Note that by selecting
this work, classical G-quartets are unable to give columnar
aggregates by stacking in the absence of metal templates.
the tunneling parameters in STM experiments at the solid-
liquid interface, one can tune the tip-substrate gap, allowing
one or more adlayers to fit in the gap and scraping away the
upper layers. In this way, one would shave off part of the helix,
(iii) The CD spectrum strongly indicates a helical structure.
(iv) Only a subtle structural deformation is needed to change
a planar quartet into a continuous helix. The formation of a
continuous helix, rather than a stack of G-quartets in the case
of guanosine-5′-phosphate has been proposed. The structures
obtained after molecular dynamics calculations of two as-
semblies of twelve molecules of 9-methyl-8-oxoguanine are
displayed in Figure 12: the energy of the two structures is the
(
35) Pranata, J.; Wiersche, S. G.; Jorgensen, W. L. J. Am. Chem. Soc. 1991,
39
1
13, 2810.
(36) Extraction experiments of aqueous potassium (or sodium) picrate with 5
gave negative results. It is therefore very unlikely that 8-oxo compounds
can capture Na+ or K+ from the surroundings. Furthermore, in ESI-MS
+
we have not observed signals corresponding to [M + Na] species. [M +
+
Na] species were instead observed for compound 1.
(
37) The STM visualization of the missing quartet in the self-assembled crystal
(
see the Supporting Information) provides unambiguous evidence that the
(39) Walmsley, J. A.; Burnett, J. F. Biochemistry 1999, 38, 14 063. Davies, D.
R. Annu. ReV. Bioch. 1967, 36, 321. Sasisekharan, V.; Zimmerman, S. B.;
Davies, D. R. J. Mol. Biol. 1975, 92, 171. Audet, P.; Simard, C.; Savoie,
R. Biopolymers 1991, 31, 243.
visualized arrangement is not an imaging artifact.
(
38) Lazzaroni, R.; Calderone, A.; Br e´ das, J. L.; Rabe, J. P. J. Chem. Phys.
1
997, 107, 99.
J. AM. CHEM. SOC.
9
VOL. 125, NO. 48, 2003 14747

A R T I C L E S
Giorgi et al.
same (within the method accuracy).40 There are, therefore, no
compelling energetic reasons for choosing the quartet structure.
Moreover, we have previously shown that placing the 8-oxo
assembled species between two facing Au electrodes, gives a
substrate. The lattice of the underlying HOPG has been monitored
during the measurements by simply changing the tunneling parameters;
this permitted the calibration of the piezo in the xy plane in situ. Unit
cells were averaged on several images after their correction for the
piezo drift (using SPIP Scanning Probe Image Processor, Version 1.720,
Image Metrology ApS, Lyngby, Denmark). STM current images with
a submolecular resolution have been recorded using average tunneling
1
3,41
hybrid system that displays rectifying electrical behavior.
This rectification requires a dipolar character for the supramo-
lecular architecture, which would exist in a helix but would be
very unlikely in a stack of quartets.
currents (I
10-30 lines/s.
′,5′-O-Didecanoyl-8-oxo-2′-deoxyguanosine (5). 8-Oxo-2′-deoxy-
guanosine (Berry & Associate) (0.53 mmol) was dried over P in
vacuo for 2 h at 50 °C and then suspended in MeCN (12 mL).
Redistilled Et N (1.2 mmol), DMAP (0.1 mmol) and decanoic anhydride
t
) ) 10-30 pA, tip voltage (U
t
) ) 0.4-1.2 V and scan rates
)
3
Conclusions
2
O
5
In summary, the cooperative effect of hydrogen bonding and
solvophobic interactions induces the 8-oxoguanosines 5 and 6
to self-associate into a helical architectures both in the liquid
crystalline phase, in solution and at surfaces. These arrange-
ments, which are markedly different from the structures obtained
by the spontaneous self-assembly of guanosine derivatives
unsubstituted at the C(8) position, are of interest, not only for
their optical properties, but also for their ability to rectify
currents, making them potential building blocks for the con-
struction of nanoscale bio-electronic devices and circuits.
3
(1.17 mmol) were added, and the resulting mixture was stirred overnight
at r.t. Methanol (0.5 mL) was then added, and stirring was continued
for 20 min. The mixture was filtered and the precipitate washed several
2
times with small portions of MeCN and Millipore H O to afford
1
analytically pure 5 as a white solid in a 25% yield. H NMR (200
MHz, DMSO-d ): 0.98 (t, 6H Me); 1.25 (m, 12H aliphatic CH ’s);
.55 (m, CH CO); 2.30 (dd, H2′); 3.28 (m, H2′); 4,05-4.19 (m, H4′,
6
2
1
2
H5′); 4.35 (m, H5′); 5,39 (m, H3′); 6.02 (t, H1′); 6.49 (bs, NH
2
); 10.75
-
(
s, NH). ESI-MS (CHCl
3
/MeOH): 590.10 (100, [5-H] ).
2
′,3′,5′-O-Tridecanoyl-8-oxoguanosine (6). 8-Oxoguanosine was
Experimental Procedures
43
obtained by catalytic hydrogenation (10% Pd/C) of benzyloxy
derivative in EtOH-H O (1:1, v/v). 8-Oxoguanosine (218 mg, 0.73
2
CD spectra were recorded with a JASCO J-710 spectropolarimeter
using cells of the appropriate path-length. NMR spectra were recorded
with Varian instruments at 300 or 400 MHz.
44
mmol) was dissolved in 12 mL of anhydrous acetonitrile. To this
solution distilled triethylamine (2.1 mmol), decanoic anhydride (2.1
mmol) and a catalytic amount of DMAP were added. The mixture was
stirred for 12 h at r.t. and the crude, after evaporation in vacuo of the
solvent, was applied to a silica gel column. After washing with a mixture
of dichloromethane-acetone (9:1), to remove the decanoic acid, 2′,3′,5′-
O-tridecanoil-8-oxoguanosine was eluted with a mixture of dichlo-
romethane-methanol (95:5). The product, after evaporation of the
solvent, was crystallized from methanol to give 0.12 g (0.16 mmol,
X-ray diffraction experiments were performed using a 3.5 kW Philips
PW1830 X-ray generator equipped with a Guinier-type focusing camera
operating in a vacuum: a bent quartz crystal monochromator was used
to select the Cu-KR1 radiation (λ ) 1.54 Å). The explored s range
-1
extended from 0.01 to 0.35 Å (s ) 2 sin θ/λ, where 2θ is the scattering
angle). The samples were mounted in a vacuum-tight cells with thin
mica windows. To reduce the spottiness arising from possible macro-
scopic monodomains, the cells were continuously rotated during
exposure. The sample cell temperature was controlled with an accuracy
of 0.5 °C by using a circulating thermostat. The diffraction patterns
were recorded on a curved detector INEL CPS120. In each experiment,
a number of sharp or broad reflections were observed and their spacings
measured following the usual procedure. In some cases, the X-ray
diffraction profiles were recorded after solvent loss due to partial
evaporation in order to follow the general trend of the structural
parameters. Therefore, in such cases, the sample concentration, which
was determined by gravimetric measurements, is only indicative.
The STM investigation has been carried out at the solid-liquid
1
6
22% yield). H NMR (200 MHz, DMSO-d ): 10.84 (s, 2H, NH), 6.53
(bs, 2H, NH ), 6.02 (m, 1H, H2′), 5.70 (d, 1H, H1′), 5.57 (t, 1H, H3′),
2
4.35 (m, 1H, H5′), 4.21-4.08 (m, 2H, H4′-H5′′), 2.39-2.23 (m, 6H,
CH CO), 1.60-1.38 (m, 6H, CH -CH CO), 1.34-1.12 (m, 36H, CH ),
2
2
2
2
-
0.85 (t, 9H, CH ). ESI-MS (CHCl /MeOH): 761.1 (100, [6-H]
3
3
).
′,3′,5′-O-Tridecanoyl-8-methyltioguanosine (7). 8-Mercaptogua-
nosine (Sigma) (0.95 mmol) was dried over P in vacuo for 2 h at
0 °C and then suspended in DMF (4.5 mL) in the presence of K CO
1.24 mmol). Dimethyl sulfate (1.14 mmol) was added and the resulting
2
2 5
O
5
(
2
3
mixture was stirred for 3 h at 75 °C. The reaction mixture was then
cooled, and acetone (60 mL) was added. The reaction mixture was
filtered and the precipitate was re-crystallized from water to afford
analytically pure 8-methyltioguanosine as a white solid in a 63% yield.
ESI-MS (MeOH): 328.0 (100, [M-H ]). The product was used in
the subsequent step without any further purification. 8-Methyltiogua-
4
2
interface using a picoAmp Nanoscope IIIa setup (Digital Instrument)
with the E scanner. Pt/Ir (85-15%) tips have been prepared from a
0.25 mm thick wire by mechanical cutting or by electrochemical etching
+
using a solution of NaCN (6 N) + KOH (2 N). Almost saturated
solutions of 5 in 1,2,4-trichlorobenzene have been applied to the basal
plane of the freshly cleaved highly oriented pyrolitic graphite (HOPG)
nosine (0.85 mmol) was dried over P
then suspended in MeCN (15 mL). Redistilled Et
O
2 5
in vacuo for 2 h at r.t. and
N (2.79 mmol),
3
DMAP (0.1 mmol) and decanoic anhydride (2.79 mmol) were added,
and the resulting mixture was stirred for 5 h at RT. Methanol (1 mL)
was then added, and stirring was continued for 20 min. The mixture
was concentrated and then chromatographed on silica (eluent: dichlo-
(
40) Calculations were performed with MacroModel 7.0 (Schr o¨ dinger) using a
stochastic dynamics method with the force field AMBER* in vacuo at
constant temperature (300 K).
(
41) In the experiments reported in ref 13, the gold nanoelectrodes are at a
distance of 60 nm and probe an array of helical structures, which are very
12-14
romethane/methanol from 99:1 to 97:3) to afford analytically pure 7
probably, though not necessarily, disordered. In the case of G-ribbons,
1
in the crystal structure the ribbons are dipolar and the dipoles are parallel
to each other. Unfortunately, we do not have the crystal structure of the
present 8-oxoguanosine derivatives, but the helices do not necessarily have
to be antiparallel.
in a 50% yield. H NMR (200 MHz, CDCl
3
): 0.98 (m, 9H, Me); 1.33-
2.41 (m, 24H, CH
2
); 2.75 (s, 3H, MeS); 4,31-4.37 (m, H4′, H5′); 4.51
(m, H5′); 5,73 (bs, NH
2
); 5.91-5.94 (m, H3′, H1′); 6.14 (dd, H2′);
(
42) Rabe, J. P.; Buchholz, S. Science 1991, 253, 424. Cyr, D. M.; Venkataraman,
B.; Flynn, G. W. Chem. Mater. 1996, 8, 1600. Claypool, C. L.; Faglioni,
F.; Goddard, W. A., III; Gray, H. B.; Lewis, N.; Marcus, R. A. J. Phys.
Chem. B 1997, 101, 5978. Qiu, X.; Wang, C.; Zeng, Q.; Xu, B.; Yin, S.;
Wang, H.; Xu, S.; Bai, C. J. Am. Chem. Soc. 2000, 122, 5550. Gesqui e` re,
A.; Abdel-Mottaleb, M. M. S.; De Feyter, S.; De Schryver, F. C.;
Schoonbeek, F.; van Esch, J.; Kellogg, R. M.; Feringa, B. L.; Calderone,
A.; Lazzaroni, R.; Br e´ das, J. L. Langmuir 2000, 16, 10385. Isoda, S.;
Nemoto, T.; Fujiwara, E.; Adachi, Y.; Kobayashi, T. J. Crys. Growth 2001,
-
1
2.2 (s, NH). ESI-MS (CHCl
3
/MeOH): 790.8 (100, [7-H] ).
45
2′,3′,5′-O-Tridecanoyl-8-bromoguanosine (8). 8-Bromoguanosine
600 mg, 1.66 mmol) was dissolved in 10 mL of anhydrous acetonitrile.
(
(43) Bowles, W. A.; Schneider, F. H.; Lewis, L. R.; Robins, R. K. J. Med.
Chem. 1963, 6, 471.
(44) Ikehara, M.; Muneyama, K. Chem. Pharm. Bull. 1966, 14, 46. Holmes,
R.; Robins, R. K. J. Am. Chem. Soc. 1965, 87, 1772.
2
29, 574. Samor ´ı , P.; Rabe, J. P. J. Phys.: Cond. Matter 2002, 14, 9955.
1
4748 J. AM. CHEM. SOC. VOL. 125, NO. 48, 2003
9

Supramolecular Helices of 8-Oxoguanosines
A R T I C L E S
To this solution was added distilled triethylamine (4.98 mmol), decanoic
anhydride (4.98 mmol), and a catalytic amount of DMAP. The mixture
was stirred for 12 h. at RT, and the crude, after evaporation in vacuo
of the solvent, was applied to a silica gel column. After washing with
a mixture of dichloromethane-acetone (9:1), to remove the decanoic
acid, 2′,3′,5′-O-tridecanoyl-8-bromoguanosine was eluted with a mixture
of dichloromethane-methanol (95:5). The product, after evaporation of
Acknowledgment. This paper is dedicated to Professor
Stephen F. Mason on the occasion of his 80 birthday. This
work has been supported by MIUR (PRIN 2001 project), FIRB
Nomade project) and the University of Bologna. Research in
Berlin on the self-assembly of supramolecular nanostructures
was financed by the EU-TMR project SISITOMAS (project
reference FMRX970099). Moreover, support from the British-
Italian Partnership Program (British Council-CRUI) is grate-
fully acknowledged. We thank Dr. Paola Franchi (University
of Bologna) for molecular dynamics calculations.
th
(
the solvent, was crystallized from ethanol to give 0.6 g (0.70 mmol,
1
4
2% yield) of the title compound as a white solid. H NMR (200 MHz,
DMSO-d
.84 (d, 1H, H1′), 5.67 (t, 1H, H3′), 4.45-4.17 (m, 3H, H5′, H5′′,
H4′), 2.40-2.22 (m, 6H, CH CO), 1.53-1.46 (m, 6H, CH -CH CO),
). ESI-MS (CHCl
6 2
): 11.00 (s, 1H, NH), 6.61 (bs, 2H, NH ), 6.02 (m, 1H, H2′),
5
2
2
2
1
.24-1.20 (m, 36H, CH
2
), 0.84 (t, 9H, CH
3
3
/
Supporting Information Available: H NMR spectra of 8 and
a STM current image of 5. This material is available free of
charge via the Internet at http://pubs.acs.org.
-
MeOH): 823.1, 825.1 (47, 53 [8-H] ).
(
45) Long, R. A.; Robins, R. K.; Townsend, L. B. In Synthetic Procedures in
Nucleic Acid Chemistry; Zorbach, W. W., Tipson, R. S., Eds.; Wiley-
Interscience: New York, 1968; Vol. 1, p 228.
JA0364827
J. AM. CHEM. SOC.
9
VOL. 125, NO. 48, 2003 14749