The Readout of Base-Pair Information in Adenine-Thymine α- D -Arabinonucleosides

Article abstract of DOI:10.1002/chem.201403998

Structurally modified nucleosides are central players in the field of nucleic acid chemistry. Adenine-thymine (AT) pyrimido[4,5-d]pyrimidine furanosyl and pyranosyl arabinonucleosides have been synthesized for the first time. Single-crystal X-ray diffraction analysis reveals novel base pairs that, in synergy with the sugar residues, direct the emergence of distinct networks containing channels and cavities. The microscopic noncovalent connections can be translated into macroscopic levels in which robust organogels are formed by the furanoside but not the pyranoside. The influences of the sugars are also displayed by the different shaped superstructures of the free nucleosides in solution. The readout of the information in the base moiety is therefore tailored by the sugar configuration, and the interplays exert subtle effects on the structures, from solid to gel and to the solution state. The potential for forming these appealing base pairs and higher structures enables these intriguing nucleosides to serve as unique building blocks in various areas or to construct innovative nucleic acid structures.

Full text of DOI:10.1002/chem.201403998

DOI: 10.1002/chem.201403998
Full Paper
&
Self-Assembly
The Readout of Base-Pair Information in Adenine–Thymine a-d-
Arabinonucleosides
Shiliang He,[a] Hang Zhao,[a, b] Xiurong Guo,[a] Xiaoping Xu,[b] Xinglong Zhou,[a] Jiang Liu,[a, b]
Zhihua Xing,[a] Ling Ye,[b] Lu Jiang,[b] Qianming Chen,*[b] and Yang He*[a]
Abstract: Structurally modified nucleosides are central play-
ers in the field of nucleic acid chemistry. Adenine–thymine
(AT) pyrimido[4,5-d]pyrimidine furanosyl and pyranosyl arabi-
nonucleosides have been synthesized for the first time.
Single-crystal X-ray diffraction analysis reveals novel base
pairs that, in synergy with the sugar residues, direct the
emergence of distinct networks containing channels and
cavities. The microscopic noncovalent connections can be
translated into macroscopic levels in which robust organo-
gels are formed by the furanoside but not the pyranoside.
The influences of the sugars are also displayed by the differ-
ent shaped superstructures of the free nucleosides in solu-
tion. The readout of the information in the base moiety is
therefore tailored by the sugar configuration, and the
interplays exert subtle effects on the structures, from solid
to gel and to the solution state. The potential for forming
these appealing base pairs and higher structures enables
these intriguing nucleosides to serve as unique building
blocks in various areas or to construct innovative nucleic
acid structures.
Introduction
saccharides as backbones) offered insights into Nature’s choice
of pentose over other sugar alternatives as the carbohydrate
building block for the genetic system.[2b–f] The focus on the di-
versities of base-pair motifs[2g] expanded the genetic alphabet
by enzymatically incorporating different artificial base-modified
nucleosides into genomes.[2h,i] Certain types of nucleoside ana-
logues have been developed into efficient therapeutic agents
against tumors and viruses by modifing the sugar and/or base
moieties.[3] The specific molecular recognition of nucleobases
has been explored extensively to construct nanoscale architec-
tures ranging from monomeric supramolecular complexes[4a–f]
to polymeric DNA origami.[4g,h] Inspired by these works and
especially fired up by Lehn and co-workers’ research on the ro-
sette structure of the Janus type guanine–cytosine (J-GC)
base,[4a] we have synthesized tridentate (J-GC) and bidentate
(J-adenine–thymine, J-AT) ribonucleosides and evaluated their
biological and supramolecular self-assembly properties.[5] Dif-
ferences in the hydrogen-bonding patterns of the base pair
and/or the position of glycosylation led to different supra-
molecular nanoflowers or nanobundles in the solution
state.[5c,d] Later on, we found that both the sugar and base
components and the interplay between them were determinis-
tic factors for the complex self-assembly of J-AT derivatives.[5f]
This drove us to expand our study to other sugar systems as
a part of systematic investigation. With the consideration that
arabinose is the epimer of ribose with the reversed configura-
tion at the first chiral center and given the biological/medicinal
importance of arabinonucleosides,[6] it was logical for us to
select this sugar as the first candidate.
The elucidation of the double-helix structure of DNA[1] by
Watson and Crick, based on Chargaff’s observation of the
equal ratios of purines and pyrimidines in DNA and the X-ray
data of Franklin and Wilkins, has brought about explosive ad-
vances in various scientific fields. In particular, the establish-
ment of the base-pair-based flow of genetic information in
processes of replication, transcription, and translation has revo-
lutionized many aspects of biology. Apart from biological
areas, chemists’ attempts to exploit the diverse structures and
the rich chemistry from both the sugar residues and the heter-
ocyclic moieties of nucleosides/nucleotides/nucleic acids to
create unnatural entities with various properties have acceler-
ated the evolution from genetic to generic materials that cross
many areas of chemistry, including basic research[2] and medici-
nal[3] and nanotechnology applications.[4] The systematic inves-
tigation of Eschenmoser and co-workers on the chemical etiol-
ogy of the nucleic acid structure (by using four- to six-carbon
[a] S. He,+ Dr. H. Zhao,+ Dr. X. Guo,+ X. Zhou, J. Liu, Z. Xing, Prof. Dr. Y. He
Institute for Nanobiomedical Technology and Membrane Biology
Regenerative Medicine Research Center, West China Hospital
West China Medical School, Sichuan University
No. 1, Keyuan 4th Road, Gaopengdadao, Chengdu 610041 (China)
E-mail: heyangqx@scu.edu.cn
[b] Dr. H. Zhao,+ X. Xu, J. Liu, Prof. Dr. L. Ye, Prof. Dr. L. Jiang, Prof. Dr. Q. Chen
State Key Laboratory of Oral Diseases
West China Hospital of Stomatology, Sichuan University
No. 14, Section 3, Renminnan Road, Chengdu 610041 (China)
E-mail: qmchen@scu.edu.cn
[+] These authors contributed equally to this work.
During the initial design, the bidentate adenine–thymine nu-
cleosides were thought to form either Watson–Crick or reverse
Watson–Crick base pairs, which would lead to either a cyclic
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403998.
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structure or a linear structure (Figure S1 in the Supporting In-
formation). Afterwards, the experimental evidence revealed
that reverse Watson–Crick base pairs are indeed formed by
sugar-protected or free J-AT ribonucleosides. Thus, we sup-
posed that the corresponding arabinonucleosides would also
form the same base pairs because the base moiety stores the
same information of hydrogen-bonding patterns. Surprisingly,
completely different scenarios were observed: the neighboring
amino group of the adenine ring and oxo group of the thy-
mine ring form a quasi-Hoogsteen face to participate in the
base-pair formation, and the N1 atom of the thymine ring is
also a potential acceptor site. Herein, we report the critical de-
tails of how the readout of the information stored in the base
moiety (by which face to form base pairs) is tailored by the
spatial arrangements of the sugar substituents and how the
microscopic interactions can be translated into higher
structures.
regioisomers were obtained, in accordance with their theoreti-
cal higher reactivity (in the context of intermediate 4 bearing
trimethylsilyl groups) calculated by density functional theory
(DFT).[5d] With regard to the anomeric center, a isomers were
exclusively formed due to the directing effect of the 1,2-acety-
loxonium ion in the course of nucleophilic attack at the C1’ po-
sition. The two products were finally identified to be furano-
side 1a and pyranoside 1b. The coexistence of the five-mem-
bered furanoside and six-membered pyranoside has been re-
ported for normal pyrimidine arabinonucleoside synthesis,[10]
albeit mainly by spectroscopic characterizations. Such a phe-
nomenon was verified here unambiguously by X-ray analysis
of single crystals of compounds 1a and 1b obtained from ab-
solute methanol and ethanol, respectively. The nucleobases are
planar, adopt the anti conformation around the glycosidic
bonds (c(O4’–C1’–N8–C9)=153.8(3)8 for 1a and c(O5’–C1’–
N8–C9)=127.1(3)8 for 1b), and located at
a positions
(Figure 1).
The most striking structural difference resides in their sugar
components: 1a adopts a five-membered furano configura-
tion, whereas 1b exhibits a six-membered pyrano configura-
tion. The sugar puckering, defined by pseudorotation phase
angles (P),[11] of 1a falls into the South range with a C3’-exo
puckering (3T4, P=212.8(4)8, tm =24.3(3)8; Figure 1a), which
slightly deviates from the common C2’-endo puckering for
other O- or N-glycosides of arabinofuranose.[12] For 1b, the six-
membered pyranose ring adopts
Results and Discussion
Synthesis and monomeric structures
To synthesize the J-AT arabinonucleoside, we adopted the Vor-
brueggen (or silyl-Hilbert–Johnson) reaction[7] by coupling sily-
lated J-AT base moiety 4 with the corresponding arabino-sugar
donor in the presence of Friedel–Crafts catalyst (Scheme 1).
a
perfect chair conformation
with the nucleobase on the
equatorial position. The ramifica-
tions of the distinct configura-
tions and conformations are the
rather different spatial arrange-
ments of the substituents in
each case. The acetoxy groups
stemming from the C2’, C3’, and
C5’ positions of 1a stretch paral-
lel to the base plane (Figure 1;
Figure S2a and b in the Support-
ing Information), and the 3’-ace-
toxy group is opposed to the 5’-
acetoxy group with a torsion
angle of d(C5’–C4’–C3’–O3’)=
148.3(6)8 (Figure S2b in the Sup-
porting Information), similar to
Scheme 1. Synthesis of J-AT a-d-arabinonucleoside analogues 1a, 1b, 2a, and 2b. R: TMS. i) HMDS, TMSCl, reflux;
ii) Ac2O, NaOAc, 1108C, 96%; iii) dry acetonitrile/dry 1,2-dichloroethane (1:1), SnCl4, 808C, 3 h, 52% total yield;
iv) 0.2m MeONa/MeOH, reflux, 72% for 2a, 70% for 2b. TMS: trimethylsilyl; HMDS: hexamethyldisilazane.
The sugar donor, per-O-acetylated d-arabinose, was
obtained in a one-pot reaction by direct acetylation of d-arabi-
nose in hot acetic anhydride in the presence of sodium ace-
tate.[8] This straightforward route is much shorter than the gen-
erally adopted three-step Guthrie–Smith method[9] but has not
yet been commonly employed in the synthesis of peracetylat-
ed arabinose. Next, this syrup was coupled with silylated base
moiety 4 with SnCl4 as the catalyst because it gave a much
higher yield than the weaker Lewis acid trimethylsilyl trifluoro-
methanesulfonate (TMSOTf) in this case, and two products
were obtained. Although the existence of the four ring nitro-
gen atoms might have posed regiochemical problems, only N8
that between the 3’-OH and 5’-OH groups of natural B-DNA
(1568), which direct the orientation of the sugar–phosphate
backbone. However, for 1b, the 5’-OH group participated in
aminal formation with the 4’-acetoxy group on the sugar ring
instead. The 2’-acetoxy group of 1b stretches along a direction
almost perpendicular to the base plane, and there is a bending
relationship between the 3’- and 4’-acetoxy groups (d(O4’–C4’–
C3’–O3’)=À50.4(9)8; Figure S2d–f in the Supporting Informa-
tion).
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vertical direction, the base moieties still formed a side-by-side
arrangement wrapped in channels composed of sugar walls
(Figure 2d). There were no head-to-head connection between
the bases, so the width of the vertical linear base tape of 1b
(4.2 ꢁ) is narrower than that of 1a (12.3 ꢁ), and the lower
number of base pairs in 1b will naturally lead to overall
weaker interactions along this linear tape compared with
those in 1a.
Figure 2. Different views of the overall supramolecular assemblies of com-
pounds 1a and 1b. a) Side view of the 1a solid superstructure showing the
infinite stepwise linear extension and zigzag channels. b) Perspective view of
the 1a solid superstructure showing the infinite base tapes and sugar chan-
nels perpendicular to the paper plane direction. c) A portion of the 3D net-
work structure of compound 1b showing the blocked base-pair extension
along the paper plane direction. d) Perspective view of the 1b assembly
showing the stacked base tapes and channels along the direction perpen-
dicular to the paper plane, with the central channel highlighted with bolder
bond radii. H bonds are not shown for clarity. The unit-to-unit distances
shown are in ꢁ. Atoms are color coded as in Figure 1.
Figure 1. Structures of the monomeric nucleosides. a) Compound 1a with
a sugar moiety with the furanosyl configuration and S-type (C3’-exo) sugar
puckering. b) Compound 1b with a sugar moiety with the pyranosyl config-
uration and chair conformation. Atoms are color coded as follows: red:
oxygen; blue: nitrogen; gray: carbon; white: hydrogen.
Overall supramolecular structures in the solid state
The spatial orientations of the sugar substituents have pro-
found effects on the overall supramolecular solid state. For 1a,
along the paper plane direction, the adjacent base moieties
are joined head-to-head and the sugar residues are joined tail-
to-tail (Figure 2a). Together, these act as noncovalent synthons
to construct an infinite stepwise linear extension with a step
height of 5.3 ꢁ and a step length of 23.0 ꢁ. Accordingly, zigzag
channels with a width of 3.7 ꢁ were formed between these
neighboring layers. Perpendicular to the paper plane direction
(Figure 2b), the individual monomers are also joined in a side-
by-side manner to form a straight infinite linear extension of
base tapes and rectangular channels encircled by sugars. Over-
all, a well-organized noncovalently cross-linked 3D network
with linear extension in two directions is produced. For 1b,
along the paper plane direction (Figure 2c), although the
sugar residues were still joined tail-to-tail, the adjacent base
moieties were blocked to form head-to-head base pairs, which
was caused by the perpendicular relationship between the 2’-
acetoxy group and the base moiety. Thus, the infinite linear ex-
tension of base pairs is terminated along this direction. In the
Details of base pairs
By looking closer, one can see drastically distinct detailed hy-
drogen-bond connectivities of the base pairs of 1a and 1b
(Figure 3). Although many base-pair motifs (of canonical or ar-
tificial pyrimidines or purines) have been investigated,[2g,11] the
base-pair patterns of the pyrimido[4,5-d]pyrimidine nucleo-
sides have not been explored systematically up to now due to
the limited compound numbers. Initially, we supposed 1a and
1b may form either Watson–Crick or reverse Watson–Crick
base pairs based on the rationale that they have only Watson–
Crick faces (Figure S1 in the Supporting Information) and no
real Hoogsteen faces and based on the previous experimental
evidence that reverse Watson–Crick base pairs were exclusively
adopted by several J-AT ribonucleoside derivatives.[5b,f] Surpris-
ingly, neither 1a nor 1b adopted the expected base-pair
motifs and they were also different from each other.
For 1a, two types of base arrangement coexist: head-to-
head and side-by-side (Figure 3a). The head-to-head base pair
is connected through two symmetric hydrogen bonds (N11À
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tides, which have potential for gene inhibition, activation, and
therapy.[14]
Compound 1b (Figure 3b) adopts a different base-pair pat-
tern, which has only side-by-side relationships. This unusual
base pair is formed through a bifurcated hydrogen bond be-
tween the amino group of the adenine ring with the C2 car-
bonyl function (O13) and the ring nitrogen atom (N1) of the
thymine ring (N11ÀH11A···O13 and N11ÀH11B···N1), which is lo-
cated on neither a Watson–Crick nor a quasi-Hoogsteen face.
Such an interaction involving the N1 atom of the thymine ring
has never been found before because (in the pyrimidine
series) it is always occupied by the sugar residue and not avail-
able as a hydrogen-bond acceptor. These two intermolecular
hydrogen bonds form the repeated unit by connecting adja-
cent nucleobases side by side to form an infinite one-dimen-
sional tape with p–p stacking between upper and lower layers
(Figure 2d; Figure S4 in the Supporting Information) in an
opposite manner.
Details of sugar–sugar connections
The sugar–sugar arrangements are also quite different be-
tween 1a and 1b. For 1a (Figure 4a), the sugar residues form
an infinite tandem zigzag linear arrangement with an alternat-
ing reversed orientation of the pentofuranose ring and pro-
truding bases on the outside (reminiscent of Pauling and
Corey’s unfortunate DNA model with a central sugar backbone
and radially projecting bases[15]). In this linear arrangement,
three adjacent sugar residues are held together as the repeat-
ed unit with two types of van der Waals contacts: 1) Contacts
between the 2’- and 3’-acetyl groups with atomic distances of
4.30 and 3.91 ꢁ for C21’–C31’ and C22’–C32’, respectively; in
this case, two symmetrical 2’- and 3’-acetyl contacts together
with the upper and lower bases formed a noncovalently en-
closed cavity (Figure 4a1); and 2) contacts between 3’-acetyl
Figure 3. Two distinct base-pair motifs. a) A detailed view of the unusual
base pairs in the solid state of 1a; the head-to-head and side-by-side ar-
rangements are highlighted with red and purple shading, respectively, and
the repeated triplet unit is represented with a triangle. b) The base-pair pat-
tern of 1b. H bonds are shown with dashed lines. The repeated intermolecu-
lar hydrogen bonds connecting adjacent molecules are highlighted in
green; the intramolecular hydrogen bonds are highlighted in blue. The unit-
to-unit distances shown are in ꢁ. Atoms are color coded as in Figure 1.
H11A···O12) between adjacent opposing molecules (like a base
pair of DNA between two opposite strands), in which the N11À groups and C4’ÀC5’ bonds with atomic distances of 4.28 and
H11A moiety forms a donating bifurcated geometry (with an
intramolecular hydrogen bond). As a whole, a rectangular hy-
drogen-bond arrangement is formed here by two intermolecu-
lar and two intramolecular hydrogen bonds. So, this part is
also capable of forming base pairs like the Hoogsteen face of
adenine.[13] The exocyclic carbonyl group (O12 atom from the
thymine ring) can also act as an acceptor group in lieu of the
N7 atom of adenine, so this face can be taken as, in fact,
a quasi-Hoogsteen face (the detailed geometry parameters are
compared in Figure S3 in the Supporting Information). The
side-by-side base pair is actually connected by one base,
3.75 ꢁ for C31’–C4’ and C32’–C5’, respectively (Figure 4a2). In
the case of compound 1b (Figure 4b), the bending relation-
ship between the 3’- and 4’-acetoxy groups instead leads to
the formation of two channels. The bigger one, trapping two
stacked base tapes, is formed by CÀH···O type weak hydrogen
bonds of the 2’-acetyl group with the 5’-methylene group
(C5’À5’···O21’; Figure 4b1; Figure S5b in the Supporting Infor-
mation). This wrapped channel structure is enforced by two
hydrogen bonds connecting the base and sugar together
(N3ÀH3···O5’ and C5’ÀH5’B···O13; Figures S4 and S5 in the
Supporting Information). The smaller channel was formed by
through a methanol molecule bridge (N11ÀH11B···O1S, O1SÀ CÀH···O type weak hydrogen bonds of C5’ÀH5’···O21’ and
H4S···O13), with the neighboring base. More interestingly,
within this neighboring base, the O13 and N3 atoms form ad-
ditional two intermolecular hydrogen bonds (N3ÀH1···O13)
with the aforementioned opposite base through the Watson–
Crick face, which results in a symmetric homopyrimidine T–T
base pair, rather than a Watson–Crick A–T base pair. In general,
a coplanar triplet unit is formed, the repeating of which results
in an infinite linear base tape in this direction. Triplets are in-
teresting structures involved in triplex-forming oligonucleo-
C32’ÀH32B···O41’ (Figure 4b2; Figure S5c in the Supporting
Information).
Gelation of compound 1a
One of the crucial differences between these two compounds
is that the base tape of 1a consisted of more hydrogen bonds
(and was thus more stable than that of 1b) and extends in
crossing directions in space. To see if these microscopic fea-
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gel morphologies (Figure 5; Fig-
ures S6–S9 in the Supporting In-
formation). The critical gelation
concentration of 1a was rather
low: 0.4–0.6 wt% in 1, 2-di-
chloroethane, dichloromethane,
and chloroform, which indicates
that 1a falls into the range of
supergelators.[17] At a concentra-
tion of 1 wt%, the 1a/1,2-di-
chloroethane system formed
a rather robust gel with a sol–
gel transition temperature (Tgel
)
of 918C, which is higher than
the boiling point of the solvent
itself (838C). The mechanical
properties of the gels of com-
pound 1a were characterized by
rheological measurements; dy-
namic strain sweep and oscilla-
tory frequency sweep experi-
ments confirmed their typical
viscoelastic natures (Figure S10
in the Supporting Information).
The solvent selectivity of 1a was
analyzed by correlating gelation
abilities with Hildebrand (d) and
Hansen (dd, dp, dh) parameters[18]
(Table S2 in the Supporting Infor-
mation). A narrow favorable dh
domain (dh accounts for hydro-
gen-bonding interactions) for
gelation was established (Fig-
ure S11 in the Supporting Infor-
mation), which indicated that
the self-assembly of 1a is hydro-
Figure 4. Different sugar–sugar arrangements in the 1a and 1b self-assemblies. a) The infinite tandem zigzag
linear sugar arrangement in the 1a assembly, highlighted with bolder bond radii and represented with green
arrows, consisted of a repeated three-molecule unit with two types of intermolecular van der Waals contacts,
which are highlighted with red and purple ovals, respectively. a1) A detailed view of the symmetrical van der
Waals contacts between the 2’- and 3’-acetyl groups from adjacent sugar residues of 1a and the resultant cavity
structure. a2) A detailed view of the symmetrical van der Waals contacts between the 3’-acetyl group and the
C4’ÀC5’ bond from adjacent sugar residues of 1a. b) The bending of the substituent groups on the sugar rings of
1b constitutes two types of channels, which are highlighted with bolder bond radii. b1) A detailed view of the in-
teractions between the 2’-acetyl group and 5’-methylene group from adjacent 1b molecules. b2) A detailed view
of the interactions between the 3’- and 4’-acetoxy groups from adjacent 1b molecules. The van der Waals con-
tacts of interest are highlighted in yellow; the intermolecular hydrogen bonds are highlighted in green. The unit-
to-unit distances shown are in ꢁ. Atoms are color coded as in Figure 1.
gen-bond-interaction
depen-
dent, in accordance with the in-
formation obtained from the
crystal structure. On the basis
that J-AT has the potential to
base pair with adenine and thy-
tures were able to be translated into macroscopic properties,
the gelation behaviors of compounds 1a and 1b were investi-
gated in 20 different organic solvents. Low-molecular-weight
gelators have drawn much attention recently for building
nanoscale soft materials due to the well-defined and fine-tuna-
ble chemical structures of their discrete molecular compo-
nents. The prerequisite for gelation is the spontaneous self-as-
sembly of small molecules into entangled fibrous structures re-
sulting from molecular-level recognition.[16] From this perspec-
tive, 1a could act as an organogelator by its cross-linked infin-
ite linear tapes and 1b may not gelate solvent because one of
its linear structures is truncated (Figure 2c). As expected
(Table S1 in the Supporting Information), 1b could not gelate
any of the investigated solvents, whereas 1a acted as a very
strong gelator in chloroalkanes, with similar microscopic xero-
mine/uracil in competition with its self-complementary associa-
tion, the molecular recognition of the 1a organogel was also
investigated through titration experiments. The results indeed
supported the capability of 1a to base pair with adenine or
uracil derivatives (Table S3 in the Supporting Information), be-
cause the addition of guanine or cytosine derivatives did not
influence the gel stability within the saturated concentrations
whereas addition of adenine or thymine derivatives destabi-
lized the gel system.
Supramolecular self-assemblies of compounds 2a and 2b in
the solution state
Supramolecular morphogenesis is a fundamentally important
process in a variety of fields ranging from structural biology to
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Conclusions
In parallel with natural selection, the chemical evolution of nu-
cleosides in chemists’ hands has not seen its end yet, and
novel structures obtained through a myriad of modifications
always lead to the emergence of new properties. We have
found that a new type of J-AT ribonuleosides can form com-
plex-shaped superstructures. It is of great interest to investi-
gate the relationship between their microscopic and macro-
scopic structures systematically. For this purpose, the corre-
sponding pyrimido[4,5-d]pyrimidine arabinonucleosides were
synthesized, and some new phenomena were found. The first
striking difference was the coexistence of furanosyl and pyra-
nosyl sugar configurations. The configuration determined the
spatial arrangement of the substituents, which in turn exhibit-
ed restrictions on the base-pair patterns; consequently, two
novel base-pair motifs (through a quasi-Hoogsteen face or the
N1 atom of the thymine ring) were adopted by the furanosyl
or pyranosyl nucleosides. These unique orchestrating interac-
tions led to the formation of certain higher structures: two
elaborate supramolecular solids containing hollow channels
and cavities and the robust organogels formed by compound
1a. In addition, the two free nucleosides also formed morpho-
logically different self-assemblies in the solution state. Evident-
ly, the microscopic interactions (the chemical information
stored in the hydrogen-bonding patterns) were translated into
the higher structures at different levels.
Figure 5. Gelation experiments: a) 1a in 1,2-dichloroethane (1 wt%) formed
a robust gel; b) 1b in 1,2-dichloroethane (1 wt%) did not undergo gelation.
c) SEM image of the 1a xerogel prepared in 1,2-dichloroethane.
material chemistry. Previously, the mechanistic process of the
formation of the flower-shaped superstructures has been ad-
dressed in detail for free J-AT ribonucleosides in water, and the
central role of the 2’-OH group has been established.[5f] By
closer inspection of the molecular structures of the J-AT ribo-
and arabinonucleosides (Figure S13 in the Supporting Informa-
tion), one can see the sugar configurations of them, and the
relative spatial relationship between the base moiety and the
2’-OH group is the same (just with the opposite direction
around the the C1’ÀC2’ bond). Therefore, it is very interesting
and necessary to investigate whether the same complex supra-
molecular morphology will still be reproduced by the corre-
sponding J-AT arabinonucleosides. The free nucleosides 2a and
2b were obtained by treatment of 1a and 1b with 0.2m
sodium methoxide. The unmasking of the hydroxy groups
made them more water soluble, and consequently, the mor-
phologies of the supramolecular assemblies in solution state
were investigated. Compound 2a indeed formed flower-
shaped superstructures in aqueous solution, with uniform di-
ameters of approximate 20 mm and the petal thicknesses of
about 80 nm (Figure S12 in the Supporting Information), which
gave us further experimental evidence for our earlier observa-
tions and conclusions. In addition, apart from the general simi-
larity with the flower of the J-AT ribonucleoside, a subtle differ-
ence between them should be noticed: the petals of the mi-
croflower of 2a were cross-linked with each other, whereas
those of the ribonucleosides were discrete (Figure S13 in the
Supporting Information). This difference might indicate the ef-
fects of the spatial arrangement of the 3’-OH and 5’-OH
groups in both cases. In comparison, 2b under the same con-
ditions could not form the flower-shaped morphology, which
indicated the influence of the six-membered configuration. It
formed microspheres instead, with average diameters of about
25 mm and with a porous structured surface consisting of inter-
weaved nanobundles. Of course, the high-resolution elucida-
tion of the atomic connectivities for the morphological differ-
ences between compounds 2a and 2b and the J-AT ribonu-
cleosidea currently remains a challenge because crystals of the
free nucleosides suitable for X-ray structure determination
have not yet been obtained.
Initially, by following the concept of two-faced, Janus type
guanine–cytosine derivatives,[4a] we synthesized the corre-
sponding ribonucleosides of J-GC and J-AT and supposed that
they would form self-complementary base pairs dominantly
through Watson–Crick faces. However, on closer inspection, we
see that, apart from the Watson–Crick faces, the A–T pyrimido-
[4,5-d]pyrimidine does have two more faces with hydrogen-
bonding capabilities that could easily escape notice: the quasi-
Hoogsteen face and the N1 atom of the thymine ring. From
this point, the A–T pyrimido[4,5-d]pyrimidine base is more
than just a Janus type molecule. More importantly, how the
programmed hydrogen-bonding information of this nucleo-
base is read turns out to be tailored by the sugar counterparts.
Selective noncovalent hydrogen bonds in complementary base
paring are the basis of the genetic information flows in DNA
replication, in RNA transcription, or between codon and antico-
don in protein translation. It was proposed that the four can-
onical nucleobases (the primary information layer) alone are
neither sufficient for the complex functions of RNA nor suffi-
cient for the encoding of heritable genetic information in DNA,
and the numerous noncanonical nucleobases that exist in
them (as a secondary information layer) play indispensible
roles, especially for the functions of RNA.[19] Up to now, most
of the research on the expression of the specific hydrogen-
bonding information has focused on only the nucleobases
themselves. The research into how the interplay between the
sugar counterparts and the base moieties influences the read-
out of the hydrogen-bonding pattern information is generally
overlooked. Now that we have found that the sugar can direct
the same base to form completely different base pairs and can
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even lead to the formation of completely distinct higher struc-
tures, this prompts us to raise an interesting conjecture: is the
expression of genetic information in the complex biological
context also influenced (under certain circumstances, through
internal or external factors) by orchestrating between the
sugar backbone (through certain modification or even the exis-
tence of noncanonical sugar configurations) and the base se-
quence? Further investigation on this question might produce
some interesting findings about whether or not there exists
a third layer of information in RNA or DNA.
Rheological studies
Rheological studies were carried out with a stress-controlled rhe-
ometer (TA Instruments, AR 2000ex) equipped with steel parallel-
plate geometry (20 mm diameter). The gap distance was fixed at
0.025 mm. The gel was scooped onto the plate of the rheometer.
Strain sweep at a constant frequency (6.28 radsÀ1) was performed
in the 0.01–100% range to determine the linear viscoelastic region
(LVR) of the gel sample. Oscillatory frequency sweep was obtained
at 0.1–100 radsÀ1 at a constant strain of 0.1%, well within the
linear regime determined by the strain sweep, to ensure that the
calculated parameters corresponded to an intact network struc-
ture. All measurements were carried out at a constant temperature
(208C). The rheometer had a built-in computer and the US-200
software converted the torque measurements into the storage
modulus (G’) and loss modulus (G’’) values.
Finally, besides the theoretical interest, the novel base pairs
formed by 1a and 1b indicate their potential applications to
serve as new synthons and molecular tectons to widen the
complex matters in supramoleular chemistry[20] through the
high malleability of the hydrogen-bonding patterns. In addi-
tion, the regular cavities/channels featured in the solid-state
structures of 1a and 1b, in which specific-sized and -shaped
guest species might reside, suggests that they could act as effi-
cient solid-state host–guest clathrates for molecule sensing,
pharmacological usages, or template-synthesis purposes.[21]
The recognition of these new-type nucleosides with neutral
guest molecules in the solid state and the specific interactions
with charged ions in the solution state are currently under
investigation.
SEM imaging of xerogels
Gels (2 wt%) of compound 1a were freeze-dried with an EYEL4
FDU-2100 freezing drier for 24 h. The resulting xerogel samples
were fractured and coated with gold. The surface morphology was
observed with a JSM-7500F instrument.
SEM imaging of aqueous solutions
SEM imaging of the supramolecular self-assemblies of 2a and 2b
in water was performed with a high-resolution INSPECT F50 instru-
ment. All SEM images were obtained without staining. Samples
were prepared by dissolving the appropriate compounds in H2O
(0.2 mgmLÀ1), heating the solutions to 1008C, and then allowing
them to cool to room temperature for 48 h.
Experimental Section
General
Crystallographic study
All chemicals were commercially available. The solvents and re-
agents were analytically pure. The solvents 1, 2-dichloroethane and
acetonitrile were purified by distillation from P2O5. Thin-layer chro-
matography (TLC) was performed on aluminum sheets covered
with silica gel 60 F254 (0.2 mm, Merck, Germany). Flash column
chromatography (FC) was carried out with silica gel 60 (Haiyang
chemical company, P. R. China) at 0.4 bar. NMR spectra were re-
corded on a Bruker AV II spectrometer (Bruker, Germany) at
400 MHz and 600 MHz; the chemical shift (d) values in ppm are rel-
ative to Me4Si as the internal standard. High-resolution mass spec-
tra were measured with a mass analyzer (Q-TOF, Bruker, Germany).
The UV absorption spectra were recorded on a DU-800 spectropho-
tometer (Beckman, US.
X-ray-quality colorless crystals of 1a and 1b were obtained by
slow evaporation from absolute ethanol and methanol, respective-
ly. Proper-sized single crystals were stabilized into a tiny glass tube
including mother liquor with epoxy resin to minimize solvent loss.
Crystal data were collected at 296 K on a Bruker Apex II instrument.
CCDC 997732 (1a) and 940971 (1b) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Crystal data for 1a: C18H23N5O10; formula weight: 469.41; triclinic;
PÀ1; a=10.3546(9), b=10.7846(9), c=10.9259(1) ꢁ; a=64.985(5),
b=89.469(6), g=79.184(6)8; V=1082.64(16) ꢁ3; Z=2; Dx =
1.461 gcmÀ3
; ; Rint =0.0340; GOF=1.073; R1 =
m=0.126 mmÀ1
0.0554; wR2 =0.1327 for 2614 data with I>2s(I).
Crystal data for 1b: C17H19N5O9; formula weight: 437.37; ortho-
rhombic; P21212; a=15.183(2), b=16.916(2), c=7.8583(1) ꢁ; a=
90, b=90, g=908; V=2018.3(5) ꢁ3; Z=4; Dx =1.439 gcmÀ3; m=
0.118 mmÀ1; Rint =0.0231; GOF=1.041; R1 =0.0336; wR2 =0.0855
for 3750 data with I>2s(I).
Gelation tests
Compound 1a/1b (5 mg) was added to a screw-capped glass sam-
pler vial, to which solvent (100 mL) was added in one portion. The
vial was heated to promote the dissolution of the mixture. The so-
lution was then gradually allowed to cool to room temperature to
see if a gel was formed. If the sample was insoluble at the boiling
point of the solvent, solvent (100 mL each time) was added until
the total volume reached 1000 mL. Gelation was considered to
have occurred if a homogeneous substance that exhibited no grav-
itational flow was obtained. The sol–gel transition temperature
(Tgel) was assumed to be the temperature at which the gel started
to flow if the sealed vial containing the gel was immersed inversely
in a thermostatted oil bath with the temperature rising at a rate of
2,3,5-Tri-O-acetyl-d-arabinose (6)
NaOAc (2.0 g, 24 mmol) was suspended in Ac2O (30 mL), and the
mixture was heated to reflux at 1108C for about 3 min. d-(À)-Arabi-
nose (5; 5.0 g, 33 mmol) was then added in portions. After 10 min,
the reaction was accomplished (as monitored by TLC). The mixture
was then poured into ice water (300 mL) and neutralized by addi-
tion of solid NaHCO3. The mixture was extracted with CH2Cl2 (3ꢂ
120 mL). The combined organic phases were dried and concentrat-
18C minÀ1
.
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ed. The residue was then purified by FC to afford a colorless syrup
(10.0 g, 96%). HRMS (ESI+): m/z calcd for C13H18O9: 341.0849 [M+
Na]+; found: 341.0850.
J=11.1 Hz, 3’-H), 3.88–3.92 (1H, m, 2’-H), 4.74–4.75 (1H, d, J=
6.6 Hz, OH), 5.03–5.04 (1H, d, J=5.5 Hz, OH), 5.36–5.37 (1H, d, J=
5.2 Hz, OH), 5.88–5.89 (1H, d, J=9.4 Hz, 1’-H), 8.55 (1H, s, CH), 9.11
(2H, s, NH2), 10.81 ppm (1H, s, NH); 13C NMR (150 MHz, [D6]DMSO):
d=69.04, 69.67, 70.41, 73.65, 83.25, 87.19, 152.81, 157.01, 158.29,
161.77, 165.49 ppm; HRMS (ESI+): m/z calcd for C11H13N5O6:
334.0764 [M+Na]+; found: 334.0765.
5-Amino-8-(2,3,5-tri-O-acetyl-a-d-arabinofuranosyl)pyrimido-
[4,5-d]pyrimidine-2,4-(3H,8H)-dione (1a) and 5-amino-8-
(2,3,5-tri-O-acetyl-a-d-arabinopyranosyl)pyrimido[4,5-d]pyri-
midine-2,4-(3H,8H)-dione (1b)
5-Amino-8-(a-d-arabinopyranosyl)pyrimido[4,5-d]pyrimi-
dine-2,4-(3H,8H)-dione (2b)
Compound 3 (2.0 g, 11.2 mmol) was suspended in hexamethyldisi-
lazane (HMDS) (150 mL), and the mixture was stirred at 1408C for
about 3 min. Trimethylsilyl chloride (TMSCl) (2 mL, 15.8 mmol) was
then added, and the reaction was stirred with heating at reflux
until the mixture was clear. After evaporation of the solution to
remove the HMDS, the resulting silylated base, 4, was dissolved in
dry 1,2-dichloroethane (60 mL), to which the syrup of tetraacetylat-
ed d-arabinose (6; 1.8 g, 5.7 mmol) suspended in dry acetonitrile
(60 mL) was added. SnCl4 (1.8 mL, 13.6 mmol) was added as the
catalyst at 08C. After the mist vanished, the reaction flask was
moved to an oil bath and stirred at 808C with exclusion of mois-
ture. After 3 h, saturated NaHCO3 aqueous solution (120 mL) was
added at 08C to quench the reaction; CH2Cl2 (3ꢂ120 mL) was used
to extract the organic phase. After being dried with anhydrous
Na2SO4, the organic phase was evaporated. The residue was ap-
plied to FC (CH2Cl2:isopropanol, 98:2) to furnish compounds 1a
(1370 mg, 28%) and 1b (1220 mg, 25%).
Compound 1b (130 mg, 0.3 mmol) was suspended in 0.2m
NaOMe/MeOH (9 mL), and the mixture was heated to reflux at
708C for about 30 min. After cooling to room temperature, the so-
lution was neutralized with diluted acetic acid to pH 6.5, and a pre-
cipitate formed. The precipitate was filtered and washed with
methanol (3ꢂ4 mL) and water (1ꢂ3 mL). The target compound 2b
was obtained as a white powder by vacuum drying (65 mg, 70%).
UV (MeOH): lmax (e)=251 (17000), 277 nm (5600 dm3 molÀ1 cmÀ1);
1H NMR (400 MHz, [D6]DMSO): d=3.59–3.60 (2H, d, J=2.3 Hz, 5’-
H2), 3.98–3.99 (1H, d, J=2.0 Hz, 3’-H), 4.20 (1H, s, 4’-H), 4.36–4.40
(1H, m, 2’-H), 5.11 (1H, s, OH), 5.43–5.44 (1H, d, J=2.8 Hz, OH),
5.85–5.86 (1H, d, J=3.3 Hz, OH), 6.07 (1H, d, J=1.6 Hz, 1’-H), 8.41
(1H, s, CH), 8.92–8.94 (2H, d, J=7.2 Hz, NH2), 10.79 ppm (1H, s,
NH); 13C NMR (150 MHz, [D6]DMSO): d=61.85, 76.14, 80.61, 87.46,
90.21, 93.89, 151.69, 157.03, 158.04, 162.16, 165.35 ppm; HRMS
(ESI+): m/z calcd for C11H13N5O6: 334.0764 [M+Na]+; found:
334.0766.
Compound 1a: UV (MeOH): lmax (e)=233 (17000), 250 (30000),
277 nm (7200 dm3 molÀ1 cmÀ1); 1H NMR (400 MHz, [D6]DMSO): d=
1.86 (3H, s, OAc), 1.99 (3H, s, OAc), 2.20 (3H, s, OAc), 4.03–4.07
(1H, dd, J1 =13.1 Hz, J2 =1.7 Hz, 5’-Ha), 4.21–4.25 (1H, d, J=
13.2 Hz, 5’-Hb), 5.25–5.35 (2H, m, 4’-H and 3’-H), 5.51–5.55 (1H, dd,
J1 =10.0 Hz, J2 =3.3 Hz, 2’-H), 6.48–6.51 (1H, d, J=8.8 Hz, 1’-H),
8.57 (1H, s, CH), 9.14–9.15 (1H, d, J=3.3 Hz, NHa), 9.21–9.22 (1H, d,
J=3.2 Hz, NHb), 10.84 ppm (1H, s, NH); 13C NMR (150 MHz,
[D6]DMSO): d=20.43, 20.86, 21.11, 67.02, 68.19, 69.50, 70.31, 79.91,
86.67, 152.26, 156.81, 157.69, 161.48, 165.32, 169.86, 170.29,
170.50 ppm; HRMS (ESI+): m/z calcd for C17H19N5O9: 460.1081 [M+
Na]+; found: 460.1080.
Acknowledgements
We thank the National Natural Science Foundations of China
(document nos.: 81321002, 20772087, 81061120531, and
30930100), ISTCPC (2012DFA31370), and the Open Foundation
(SKLODOF2014OF04) of the State Key Laboratory of Oral Dis-
eases of Sichuan University for the financial support.
Compound 1b: UV (MeOH): lmax (e)=250 (31000), 277 nm
Keywords: base pairs
supramolecular chemistry
·
nucleosides
·
self-assembly
·
1
(7300 dm3 molÀ1 cmÀ1); H NMR (400 MHz, [D6]DMSO): d=2.01 (3H,
s, OAc), 2.07 (3H, s, OAc), 2.11 (3H, s, OAc), 4.16–4.20 (1H, dd, J1 =
12.1 Hz, J2 =6.4 Hz, 5’-Ha), 4.32–4.36 (1H, dd, J1 =12.1 Hz, J2 =
4.1 Hz, 5’-Hb), 4.98–5.02 (1H, m, 4’-H), 5.26–5.28 (1H, m, 3’-H), 5.66–
5.67 (1H, t, J=3.3 Hz, 2’-H), 6.29 (1H, d, J=3.0 Hz, 1’-H), 8.55 (1H,
s, CH), 9.01 (1H, d, J=3.5 Hz, NHa), 9.07 (1H, d, J=3.5 Hz, NHb),
10.81 ppm (1H, s, NH); 13C NMR (150 MHz, [D6]DMSO): d=20.99,
21.04, 25.93, 63.35, 75.24, 78.82, 83.01, 87.49, 91.19, 152.03, 156.69,
157.83, 162.06, 165.28, 169.88, 169.90, 170.58 ppm; HRMS (ESI+):
m/z calcd for C17H19N5O9: 460.1081 [M+Na]+; found: 460.1079.
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Published online on September 26, 2014
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