An adamantane-based building block for DNA networks

Article abstract of DOI:10.1002/asia.201000887

DNA governs the storage and transfer of genetic information through generations in all living systems with the exception of some viruses. Its physicochemical nature and the Watson-Crick base pairing properties allow molecular constructions at nanometer le

Full text of DOI:10.1002/asia.201000887

FULL PAPERS
DOI: 10.1002/asia.201000887
An Adamantane-Based Building Block for DNA Networks
Richa Pathak and Andreas Marx*[a]
Abstract: DNA governs the storage
supramolecular arrays and scaffolds.
The tailor-made DNAs have been an
interesting material for such designed
nanoscale constructions. However, the
synthesis of specific structures with a
desired molecular function is still in its
and transfer of genetic information
through generations in all living sys-
tems with the exception of some virus-
es. Its physicochemical nature and the
Watson–Crick base pairing properties
allow molecular constructions at nano-
meter length, thereby enabling the
design of desired structural motifs,
which can self-assemble to form large
infancy and therefore has to be further
explored. To add a new dimension to
this approach, we have synthesized a
rigid three-way branched adamantane
motif, which is capable of forming
highly stable DNA networks. The
Keywords: adamantane · branched
DNA · DNA · oligonucleotides ·
self-assembly
moiety generated could serve as
a
useful building block for DNA-based
nanoconstructions.
Introduction
have appeared in the literature describing the generation of
DNA-based nanomechanical devices.[26–29] Despite these
novel accomplishments, there is still a need to expand the
limited directory of bDNA motifs for the exploration of
more versatile and sophisticated arrangements to achieve a
greater role of DNA in the macroscopic world.
In recent years, we have reported asymmetrical bDNA by
employing a nucleotide analog as a branch point. By varying
the protection-group protocols, bDNA constructs were gen-
erated, which were further used in the generation of func-
tional DNA networks by the polymerase chain reaction.[30–31]
However, to the best of our knowledge there are no reports
for the synthesis and utilization of a robust, three-way
branched adamantane motif for generation and utilization
as bDNA.
Therefore, in our continuing efforts and to add a new di-
mension to the branch point tool box with yet another very
useful variation to our study, we envisioned the synthesis of
a rigid, compact, symmetric, and a three-way branched junc-
tion as a new bDNA construct. Among the several potential
possibilities for a rigid core, the adamantane framework was
our structure of choice, as it possesses a Td symmetric nu-
cleus that represents a strong tetrahedral core, which can be
selectively functionalized at the tertiary carbon positions,
and it represents the best known examples for rigid and
high-order molecular constructions in the literature.[32–35]
Adamantane belongs to a class of rigid hydrocarbons proc-
essing a high order of symmetry, and is therefore particular-
ly important for use in nanotechnology because the new
functionalities could be incorporated at a particular and a
The first reports of branched DNA (bDNA) by Seeman in
1982 opened a new era in the field of DNA nanobiotechnol-
ogy,[1] and since then this area has been continuously ex-
plored towards construction of objects for nanobiotechnolo-
gy. Branched DNA occurs naturally when homologous chro-
mosomes pair up, and the aligned strands of DNA break to
crossover and form a Holliday junction. It consists of four
DNA strands bound together, and this results in four
double-helical arms flanking a branch point.[2] In contrast,
synthetic DNA complexes are designed to have fixed
branch points consisting of a variable number of arms.[3–10]
Numerous branch points have been reported in the litera-
ture for various applications. In principle, DNA is a tool for
generating complex materials with nanoscale features.[11–18]
In this context, DNA-hybrid structures originating from
small molecule-DNA hybrids (SMDHs), forming caged
dimers possessing three or more DNA strands around a cen-
tral core, have been generated.[19–20]
Several distinct DNA objects have been synthesized in
various geometries such as triangles, pyramids, cubes, and
complicated polyhedra.[21–25] Additionally, several reports
[a] Dr. R. Pathak, Prof. Dr. A. Marx
Department of Chemistry and Konstanz Research School
of Chemical Biology University of Konstanz
Universitꢀtsstrasse 10, 78457 Konstanz (Germany)
Fax : (+49)7531-88-5140
E-mail: Andreas.Marx@uni-konstanz.de
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Chem. Asian J. 2011, 6, 1450 – 1455

specific intramolecular distance within the adamantane core.
In recent years, tetrahedral adamantane tectons possessing
nucleosidic sticky ends were synthesized, thereby making
use of click chemistry.[36] In this study, we have worked on a
new three-way adamantane branch point that allows the at-
tachment of three DNA strands at a fixed distance and fixed
interval in a very compact format (Figure 1). We herein
present an expeditious synthesis for branched oligonucleo-
tides, in which the trifunctional adamantane linker connects
three oligonucleotide strands.
Having accomplished the synthesis of 9, we next synthesized
the branched oligonucleotide bDNA-I in a 3’ to 5’ direction
as depicted in Scheme 2. Having synthesized DNA strand
A, we tried to manually couple the phosphoramidite build-
ing block 9 by using syringe techniques described earli-
er.[41–42] Thus, the column containing DNA was connected to
a syringe equipped with the phosphoramidite 9 and an
empty syringe. By pushing 9 from one syringe to the other it
can react with the free hydroxy group of the DNA. After-
wards, the column was reinstalled for the synthesis of two
parallel B branches commencing from the incorporated
building block 9 and terminating with a 5’ end.
However, owing to the poor yields obtained by the above
procedure, we proceeded with completely automated DNA
synthesis and increased the coupling time for the incorpora-
tion of 9 to 10 minutes. Gratifyingly, this resulted in a better
coupling reaction. When the synthesis was accomplished,
the bDNA was cleaved from the solid support and purified
by HPLC. The 4,4’-dimethoxytrityl (DMT) group of the last
incorporated nucleoside was deprotected manually after
RP-HPLC purification. After lyophilisation, the identity of
the purified bDNA was confirmed by ESI mass spectrome-
try.
To investigate whether the branched DNA construct
bDNA-I was able to form a duplex with complementary
DNA, we conducted thermal denaturation studies. The
melting temperature (Tm) obtained for the bDNA-I was co-
operative and comparable with the linear control C-I
(Figure 2).
Figure 1. Structure and molecular model depicting DNA duplexes at-
tached to three-way adamantane branch point.
Results and Discussion
To synthesize the three-way adamantane-based bDNA, we
first generated 1,3,5-triethynyladamantane 4 from adaman-
tane 1 (Scheme 1), and this required some modifications of
reported procedures.[37] Next, we carried out the synthesis of
6 wherein the nucleoside 5 was selectively coupled to only
one branch of adamantane 4. We chose to modify the C5
position in the 2ꢂ-deoxyuridine, as such modifications do not
significantly interfere with the Watson–Crick base pairings.
A palladium-catalyzed cross coupling reaction of the 5’-ace-
tylated nucleoside 5[38] with 4 afforded compound 6. During
this reaction, we investigated that only very slow addition of
the nucleoside 5 to the adamantane derivative 4 leads to ex-
clusive formation of 6, however, in all other attempts we
ended up with mixtures of products as analyzed by TLC.
Furthermore, the palladium-catalyzed cross coupling reac-
tion of the adduct 6 with the protected nucleoside 7[39] was
accomplished by following two simultaneous Sonogashira
couplings, which yielded the trifunctionalized adamantane
building block 8 in good yields. Compound 8 was then treat-
ed with 2-cyanoethyl N,N,N’,N’-tetraisopropylphosphordia-
midite in the presence of tetrazole in anhydrous tetrahydro-
furan (THF).[40] This reaction gratifyingly yielded the de-
sired phosphoramidite 9 in excellent yield after 20 hours.
Figure 2. Duplex-formation capability of bDNA-I a) Sequences used.
b) Melting profile of bDNA-I (empty squares) and DNA-I (full squares)
with complementary strand C-1.
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Scheme 1. a) Fe, Br2, 708C, 12 h; b) vinyl bromide, anhydrous DMF, Ar, ꢀ288C, 3 h; c) tBuOK, DMSO, 48 h; d) CuI, [Pd
ACHTUNGTRENNUNG
Ar, RT, 12 h; e) CuI, [PdACHTUGNTRENNNUG
08C!RT, 20 h.
In the next step to investigate the formation of 3D net-
works as shown in Figure 3, we synthesized short and self-
complimentary monomers bDNA-II-IV by using a combina-
heating the samples from 108C to 958C and the UV absorb-
ance was monitored at 260 nm. It was observed that melting
temperatures for bDNA-II, bDNA-III, and bDNA-IV were
drastically elevated in comparison to the control sequences
C-II, C-III, and C-IV (Figure 4).
In fact, we were unable to detect any melting behaviour
for the short self-complementary sequences, 5’-CG-3’ (C-II)
and 5’-TTAA-3’ (C-III). Figures 2 and Figure 4 represent the
various Tm values for the oligonucleotides I–IV. On the
other hand, it was also noted that slow heating and cooling
at 18C per minute is more favorable for bDNA-II, as no
characteristic melting was observed for it at 28C per minute.
Additionally, reproducibility was also noted for the Tm
values by repeating the experiment with the same sample,
thus indicating the consistency and stability of DNA net-
work formation. Furthermore, these elevated temperatures
assert towards the formation of stable duplexes between the
neighbouring bDNA monomers and generation of a larger
adamantane-based DNA network. Altogether, it could be
Figure 3. Graphic representation for the formation of DNA networks.
tion of 3’- and 5’-phosphoramidites.[43] We envisioned that
such monomers had the potential to form a duplex structure
by interacting with the neighbouring monomers, eventually
leading to the generation of a bigger DNA network. Thus,
we carried out thermal denaturation studies to assert our as-
sumptions. The melting temperature was ascertained by
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Chem. Asian J. 2011, 6, 1450 – 1455

A. Marx and R. Pathak
Scheme 2. General strategy for the synthesis of bDNA (A, B=DNA strands).
ried out by the microanalysis facility at the University of Konstanz. NMR
spectra were recorded by using Bruker avance 400 (1H: 400; 13C: 101,
31P: 162 MHz) spectrometers. Chemical shifts are given in parts per mil-
lion and tetramethyl silane was used as the external standard. Electro-
spray ionization ion-trap (ESI-IT) mass spectra were recorded by using a
Bruker Daltonics esquire 3000+ instrument in positive or negative mode
with a flow rate of 3 mLminꢀ1. High-resolution ESI-TOF mass spectra
were recorded by using a micrOTOF II (Bruker Daltonics). DNA oligo-
nucleotide synthesis was carried out by using an Applied-Biosystems 392
DNA/RNA synthesizer. Reverse-phase HPLC was performed by using a
Prominence HPLC (Shimadzu) instrument equipped with a Nucleosil-
100-5 C18 column (250 L 4 mm, Macherey–Nagel). A binary gradient
system (triethyl ammonium acetate buffer (0.1 m, pH 7.0/CH3CN, 258C)
was used.
proposed that multiple interactions are responsible for ele-
vating the melting temperatures of the bDNA-II-IV. The
rigid adamantane core is also providing the desired force
needed for the DNA duplex alignment, and thereby leading
to the formation of DNA networks.
Conclusions
In conclusion, we have demonstrated a general and robust
synthetic protocol for the generation of an adamantane-
based building block for DNA networks. The results pre-
sented here show that a rigid three-way organic framework
can promote DNA network formation. We have shown that
two base pairs are sufficient to form networks by self-assem-
bly. These results corroborate earlier findings by using four-
way branching points.[44] DNA networks and future tuning
of the properties of the networks by chemical manipulations
of the branching units might be important constructs for
DNA-based nanobiotechnology.
Compound (3)
AlCl3 (0.93 g, 9.0 mmol) was added portionwise to a stirred solution of 2
(2.6 g, 6.9 mmol) in DCM (20 mL) at ꢀ288C. The mixture was stirred for
15 minutes. This was followed by the continuous purging of vinyl bromide
until completion was indicated on the TLC. The reaction mixture was
slowly warmed to room temperature and extracted with DCM (200 mL)
and 5% HCl in water (150 mL). The organic layer was dried over anhy-
drous magnesium sulfate and concentrated under reduced pressure. The
crude compound 3 was used without further purification.
Compound (4)
Experimental Section
Potassium tert-butoxide (1.5 g, 13.3 mmol) was added portionwise to a
stirred solution of 3 (1.5 g, 2.2 mmol) in DMSO (15.0 mL) at 08C. The
mixture was allowed to stir at room temperature for 48 h. The reaction
mixture on completion was extracted with DCM (200 mL) and 5% HCl
in water (100 mL). The organic layer was dried over anhydrous magnesi-
um sulfate and concentrated under reduced pressure. The crude com-
General
All synthetic reactions were performed under an inert atmosphere. Dry
solvents were purchased from Fluka and were stored over molecular
sieves and used without further purification. Elemental analysis was car-
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Adamantane-Based Building Block
FULL PAPERS
ture was continuously stirred until completion was indicated on TLC
(12 h). It was then evaporated to dryness and was further diluted with
MeOH (20 mL). Subsequently the reaction mixture was filtered and the
filtrate was concentrated under reduced pressure. The crude product was
purified by RP-MPLC on a C18 column (CH3CN/water 1:1) to give com-
1
pound 8 (0.415 g, 76%) as a yellow oil; H NMR (400 MHz, CDCl3): d=
1.80–1.82 (m, 1H, CH), 2.05–2.07 (m, 21H, 6 x CH2, 3 x CH3), 2.28–2.37
(m, 2H, H-2’), 2.50–2.59 (m, 4H, 2 x H-2’), 2.8 (brs, 1H, CHOH), 3.37
(dd, 2H, J=3.3 Hz, J=10.7 Hz, H-5’), 3.45 (dd, 2H, J=2.6 Hz, J=
10.6 Hz, H-5’), 3.81 (s, 12H, OCH3), 4.12–4.15 (m, 1H, H-3’), 4.18–4.19
(m, 2H, H-4’, H-3’), 4.27 (dd, 1H, J=3.5 Hz, J=12.1 Hz, H-5’), 4.34 (dd,
1H, J=4.2 Hz, J=12.2 Hz, H-5’), 4.44–4.48 (m, 1H, H-3’), 5.43–5.44 (m,
2H, 2 x H-4’), 6.27–6.32 (m, 3H, 3 x H-1’), 6.93 (d, 8H, J=8.8 Hz, ArH),
7.26–7.30 (m, 2H, ArH), 7.35–7.39 (m, 4H, ArH), 7.40–7.44 (m, 8H,
ArH), 7.54–7.56 (m, 4H, ArH), 7.88 (s, 1H, =CH), 8.08 ppm (s, 2H, =
CH); 13C NMR (101 MHz, CDCl3): d=20.0, 20.3, 27.8, 30.2, 30.4, 37.9,
40.0, 45.1, 45.5, 54.7, 63.4, 63.5, 70.8, 71.7, 72.3, 74.8, 84.2, 84.7, 84.8, 85.3,
86.7, 98.7, 98.9, 99.8, 100.3, 113.2, 113.3, 126.9, 128.0, 128.1, 130.0, 130.1,
135.7, 135.8, 141.4, 144.8, 149.4, 149.5, 158.6, 158.7, 161.0, 161.1, 169.8,
169.9 ppm; (ESIMS): m/z (%): 1616.9 [Mꢀ1]ꢀ. HR-ESIMS: m/z: calcd
for C91H88N6O22: 1616.5952; found: 1616.7298.
Compound (9)
Tetrazole (12 mL, 2.0 mmol) was added to a stirred solution of 8 (0.11 g,
1.0 mmol) in anhydrous THF (5.0 mL) at 08C under an argon atmos-
phere and was stirred for 5 minutes. Subsequently 2-cyanoethyl
N,N,N’,N’-tetraisopropylphosphordiamidite (43 mL, 2.0 mmol) was added
and the reaction mixture was continued to stir for 20 h or until comple-
tion was evident from TLC. The reaction mixture was then diluted with a
saturated solution of NaHCO3 (30 mL) and extracted with EtOAc
(40 mL). The organic layer was dried over anhydrous magnesium sulfate
and concentrated under a nitrogen atmosphere under reduced pressure.
The crude compound was purified by means of flash column chromatog-
raphy on silica gel (40% EtOAc in hexane) to give compound 9 (0.12 g,
Figure 4. Network-formation capability of self-complementary bDNA
a) Sequences used. b) Melting profile of self-complementary bDNA-IV.
n.t.=no cooperative transition was observed.
91%) as
a
colorless oil; 31P NMR (162 MHz, CDCl3): d=148.6,
148.8 ppm; mass (ESIMS): m/z: 1816.1 [Mꢀ1]ꢀ.
pound was purified by means of flash column chromatography on silica
gel (0.5% EtOAc in hexane) to give compound 4 (0.28 g, 60%) as a
white solid; m.p. 82–858C.
General Procedure for the Synthesis of bDNA
The synthesis of bDNA oligonucleotides was performed by using an Ap-
plied Biosystems 392 DNA synthesizer with a 3’-CPG support (1000m)
and commercially available 3’-O-2-CE phosphoramidites (CE=cyanoeth-
yl) on a 0.2 mmol scale. After insertion of branch point 9, DNA synthesis
was continued and standard coupling conditions were utilized in the case
of the 3’- and 5’-CE phosphoramidites, whereas for the insertion of
branch point 9, the coupling times were extended to 10 minutes by using
9 (0.1m) in CH3CN. The extension of each branch was terminated by first
cleaving the respective DMT group and subsequently passing capping
mixtures A (acetic anhydride/pyridine/THF) and B (N-methylimdida-
zole/pyridine/THF) over the solid support for 3ꢃ15 s. At the end of the
synthesis, the DMT group was retained (“trityl ON’’), which allowed
failed sequences to be removed by means of reverse-phase HPLC with a
binary gradient of CH3CN in triethylammonium acetate buffer (pH 7.0).
The desired bDNA containing the DMT group was collected, deprotect-
ed by using 80% AcOH, purified by using means of reverse-phase
HPLC with a binary gradient of CH3CN in triethylammonium acetate
buffer (pH 7.0), and characterized by using ESIMS.
Compound (6)
CuI (0.05 g, 0.25 mmol), tetrakis(triphenylphosphine)palladium(0)
(0.15 g, 0.12 mmol), and anhydrous triethyl amine (1.0 mL, 7.6 mmol)
were added to a stirred solution of 4 (0.53 g, 2.5 mmol) in anhydrous
THF (5.0 mL). The mixture was allowed to stir for 10 minutes. A solution
of 5 (0.67 g, 2.5 mmol) in anhydrous THF (5.0 mL) was added to this
mixture over a duration of 15 minutes. The reaction mixture was continu-
ously stirred until completion was indicated on TLC (12 h). It was then
evaporated to dryness and diluted with MeOH (15.0 mL), subsequently
filtered, and concentrated under reduced pressure. The crude compound
was purified by RP-MPLC on a C18 column (CH3CN/water 1:1) to give
compound 6 (0.50 g, 42%) as a yellow solid; m.p. 2208C; 1H NMR
(400 MHz, CDCl3): d=1.69–1.75 (m, 4H, 2 x CH2), 1.86–1.91 (m, 5H,
CH, 2 x CH2), 1.98 (s, 4H, CH, CH3), 2.06 (s, 3H, CH, CH2), 2.10–2.14
(m, 3H, CH2, 1H of H-2’), 2.39 (ddd, 1H, J=5.0 Hz, J=6.3, J=11.3 Hz,
H-2’), 2.71 (d, 1H, J=4.1 Hz, CHOH), 4.07–4.08 (m, 1H, H-5’), 4.25 (dd,
1H, J=3.0 Hz, J=12.3 Hz, H-5’), 4.31–4.35 (m, 2H, H-4’, H-3’), 6.17 (t,
1H, J=6.1 Hz, H-1’), 8.01 ppm (s, 1H, =CH); 13C NMR (101 MHz,
CDCl3): d=14.2, 21.1, 21.2, 27.8, 29.8, 30.7, 40.3, 40.4, 46.1, 46.2, 60.5,
63.6, 68.4, 71.1, 84.6, 85.7, 89.9, 100.2, 100.6, 141.3, 149.4, 161.6, 170.7,
171.3 ppm; (ESIMS): m/z: calcd for C27H28N2O6: 477.1 [M+H]+; found:
499.1 [M+Na]+.
UV-melting analysis
UV-melting curves were aquired on a Cary 100 Bio spectrophotometer.
The heating and cooling curves were detected at 260 nm at the gradients
of 28C/minꢀ1 or 18C/minꢀ1. The melting temperatures were determined
from the extremum of the first derivative of 75 or 95-point curves.
Compound (8)
ESI measurements
7 (0.471 g, 0.7 mmol), CuI (0.024 g, 0.12 mmol), and tetrakis(triphenyl-
phosphine)palladium(0) (0.074 g, 0.06 mmol) were added to a stirred so-
lution of 6 (0.153 g, 0.32 mmol) in anhydrous THF (10.0 mL) and the
mixture was allowed to stir for 10 minutes. This was followed by the addi-
tion of anhydrous triethyl amine (0.4 mL, 3.2 mmol). The reaction mix-
The purified bDNA molecules and oligonucleotide templates (50–
100 pmol) were dissolved in a solution of 2-propanol (20%) containing
NEt3 (1%).[45] The mass measurements were carried out by using an Es-
quire 3000+ (Bruker) instrument and nitrogen was used as the nebulizing
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Chem. Asian J. 2011, 6, 1450 – 1455

A. Marx and R. Pathak
gas (12 psi) at 3008C. The samples were injected into the system with the
aid of a syringe pump (180 mLhꢀ1).
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Received: December 10, 2010
Published online: April 15, 2011
Chem. Asian J. 2011, 6, 1450 – 1455
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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