A modified uridine for the synthesis of branched DNA

Article abstract of DOI:10.1016/j.tet.2007.04.080

Branched DNA constructs have found wide application in DNA-based nanotechnology. Several reports describe the generation of branched DNA structures with variable numbers of arms to self-assemble with pre-designed architectures. Branched DNA is generated b

Full text of DOI:10.1016/j.tet.2007.04.080

Tetrahedron 63 (2007) 8576–8580
A modified uridine for the synthesis of branched DNA
*
Madhavaiah Chandra, Sascha Keller, Yan Luo and Andreas Marx
Fachbereich Chemie, Universita€t Konstanz, Universita€tsstrasse 10, M 726, 78457 Konstanz, Germany
Received 20 March 2007; revised 23 April 2007; accepted 24 April 2007
Available online 29 April 2007
Abstract—Branched DNA constructs have found wide application in DNA-based nanotechnology. Several reports describe the generation of
branched DNA structures with variable numbers of arms to self-assemble with pre-designed architectures. Branched DNA is generated by
using designed rigid crossover DNA molecules as building blocks. Alternatively, branched DNAs can also be generated by using synthetic
branch points derived either from nucleoside or non-nucleoside building blocks. Herein, we report the synthesis of modified uridine deriva-
tives as branching monomer for the synthesis of branched DNA and first studies of their self-assembling properties.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
RNA cleavage activity.5 Interestingly, another kind of
branching point was utilized to generate branched nucleic
acids by employing 40-, 30-, and 50-modified thymidine deri-
vatives. In these examples TBDMS and tetrahydropyrane
(THP) were used as orthogonal protecting groups for
DMTr.6 Recently, von Kiedrowski and co-workers reported
a novel class of branched oligonucleotides that were con-
structed with the aid of a trifunctional linker.7 We have also
reported a modified cytidine-based branching monomer to
generate unsymmetrical branched DNA and reported first
insights into their property to self-assemble.8
There is a need to expand synthetic approaches for the gener-
ation of branched DNA, since their pivotal role in DNA-
based nanotechnology and material science.1 To generate
such branched DNA, two basic strategies are followed: either
linear oligonucleotides are constructed to result in rigid
crossover constructs or covalent DNA branches aregenerated
employing suitably modified branching monomers. Obvi-
ously, these branching monomers have to be designed in
a way to be suited for automated standard solid phase synthe-
sis. In this direction, a polyhydroxy phosphoramidite was
synthesized for generating oligonucleotide dendrimers and
these were employed as polylabelled DNA probes and as
primer in PCR.2 A ribonucleoside branching point (adeno-
sine based) was utilized to generate ‘Y’ and ‘V’ shaped
RNA and DNA with the length of 18 and 21 nucleotides. In
this approach the tert-butyldimethylsilyl (TBDMS) group
was utilized for protection of the additional hydroxyl func-
tion orthogonal to 4,40-dimethoxytrityl (DMTr).3 In another
approach, the levulinyl (Lev) group was used as protecting
group orthogonal to DMTr that can easily be deprotected
under mild basic or buffered conditions using N2H4, under
which other base sensitive protective groups remain intact.
By using this strategy, Horn and co-workers synthesized
a modified cytosine based branching monomer. This branch-
ing point was utilized to generate large comb and fork shaped
branched DNAs, which were subsequently employed as
signal amplifiers in nucleic acid quantification assays.4
Herein, we report the synthesis of novel 20-hydroxyl modi-
fied uridine derivative as branching monomer for the synthe-
sis of branched DNA. First studies of their self-assembling
properties are also included.
2. Results and discussion
The synthesis of modified uridine branching monomer is de-
picted in Scheme 1. The starting precursor 1 was synthesized
according to the literature procedures starting from uridine.9
Brown et al. first synthesized 1 for the generation of DNA
signaling probes termed HyBeacons.9 In this case, the 20-
hydroxyethyl group was protected with fluorenylmethoxy-
carbonyl (Fmoc), which was deprotected after automated
oligonucleotide synthesis on solid support under mild basic
conditions and subsequently coupled with a dye phosphor-
amidite. However, this approach was not yet employed for
the synthesis of branched nucleic acids.
€
Recently, Muller et al., used the same branching point to gen-
erate an artificial hairpin ribozyme, which was shown to have
Afterward, 1 was coupled with levulinic acid in the presence
of 2-chloro-1-methylpyridinium iodide and 1,4-diazabicy-
clo[2.2.2]octane to give 2. The tetraisopropyldisiloxane
30,50-hydroxy protection group was cleaved by using
Keywords: DNA; Oligonucleotide; Nucleoside; Phosphoramidite; Branched
DNA.
* Corresponding author. Tel.: +49 (0)7531 88 5139; fax: +49 (0)7531 88
5140; e-mail: andreas.marx@uni-konstanz.de
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.080

M. Chandra et al. / Tetrahedron 63 (2007) 8576–8580
8577
O
O
N
O
N
NH
NH
NH
N
O
O
O
O
HO
O
Si
O
a
b
Si
O
O
O
O
Si
Si
O
O
OH O
O
O
OLev
OLev
OH
1
2
3
O
N
O
N
NH
NH
O
O
DMTrO
O
DMTrO
c
d
O
O
O
O
OH
O
NC
P
OLev
OLev
N(i-Pr)2
4
5
Scheme 1. Synthesis of uridine-based branching monomer. Reactions and conditions: (a) 2-chloro-1-methylpyridinium iodide, 1,4-diazabicyclo[2.2.2]octane,
levulinic acid, CH3CN/dioxane, 15 h, 98%; (b) TBAF/AcOH, THF, 30 min, 95%; (c) 4,40-dimethoxytriphenylmethyl chloride, DMAP, pyridine, 9 h, 80%;
(d) N,N-diisopropylethylamine, 2-cyanoethoxy-N,N-diisopropylaminochlorophosphine, CH2Cl2, 3 h, 77%.
tetrabutylammonium fluoride (TBAF) in the presence of
acetic acid to yield compound 3. Diol 3 was subsequently
treated with DMTr chloride in the presence of a catalytic
amount of 4-dimethyaminopyridine (DMAP) to give 50-O-
(4,40-dimethoxytriphenylmethyl)-20-O-(2-levulinyl-hydroxy-
ethyl)-uridine (4) in 80% yield. Phosphitylation by treatment
with 2-cyanoethoxy-N,N-diisopropylaminochlorophosphine
yielded the corresponding phosphoramidite 5.
O
N
NH
NC
O
P
O
O
AcO 5'-DNA O
O
O
O
O
OLev
3'-DNA O
P
O
O
CN
The synthetic strategy of branched DNA using 5 is shown in
Scheme 2.
N2H4
After insertion of the branching monomer by usage of 5,
DNA synthesis was continued to yield the 50-O-DNA seg-
ment. The 50-O-terminal DMTr was cleaved on the DNA
synthesizer and the 50-hydroxyl group subsequently acety-
lated by using the standard capping conditions. Then, the
levulinyl protection group at the 20-O-hydroxyethyl group
was removed by using 0.5 M N2H4 (10 mL of 1:1 AcOH/
pyridine). Subsequently, the DNA synthesis was continued
to yield the respective DNA segment starting from the 20-
O-ethoxy group of the branching monomer. According to
the DMTr deprotection, the insertion yield of the modified
uridine branch monomer is >98%. For the synthesis of
unmodified nucleotides standard b-cyanoethyl phosphor-
amidites were employed and gave the best yields. Interest-
ingly, usage of commercial phosphoramidites that bear
acetyl groups to protect nucleobase functionalities resulted
in very poor yield of desired branched DNA. This is proba-
bly due to the incompatibility of acetyl protection with the
conditions required for levulinyl deprotection.
O
N
NH
NC
O
P
O
O
AcO 5'-DNA O
O
O
O
O
OH
3'-DNA O
P
O
O
CN
DNA synthesis
O
N
NH
NC
O
O
O
AcO 5'-DNA O
P
O
O
CN
O
P
O
O
O
5'-DNA ODMTr
O
3'-DNA O
P
O
O
O
To investigate the self-assembling properties of branched
DNAs, we have synthesized two different branched DNAs,
b-DNA A and b-DNA B (46-mer) employing 5 and the strat-
egy is depicted in Scheme 2. Each of the branches is com-
posed of 15-mer oligonucleotides (Fig. 1). All branches
are designed in such a way that the end segment (10-mer)
of each branch of b-DNA A is complementary to the 10-
mer end segment of b-DNA B branches. Thus, the 10-mer
CN
(i) NH3
(ii) AcOH
b-DNA
Scheme 2. Synthesis of b-DNA using 5.

8578
M. Chandra et al. / Tetrahedron 63 (2007) 8576–8580
(a)
(B)
(A)
A
B
A+B
ATC AGT GTT AAG GCC-5'
(c)
3'-TAG GAG GAA
GCA TCG -B- ATC GTA TGG CTC GCT-5'
b-DNA A
(b)
(a')
ATC CGG GCC TTA
ACA-5'
(c')
1
2
3
3'-CTT CCT CCT
ACA GTC-B- ATC GAA GCG AGC CAT-5'
(b')
b-DNA B
Figure 1. Synthesized b-DNA and their self-assembly. (A) b-DNA synthesized employing 5; (B) 8% native PAGE analysis of radioactively labeled b-DNA.
Lane 1: b-DNA A; lane 2: b-DNA A; lane 3: b-DNA A+b-DNA B.
end segments (a, b, c) of b-DNA are complementary to the
10-mer end segments of b-DNA B (a0, b0, c0).
was performed on a prominence-line HPLC (Shimadzu) with
a Nucleosil-100-5-(250/4)-C18-column from Macherey–
Nagel and a binary gradient system (TEAA—buffer
(0.1 M), acetonitrile).
In order to gain first insights into the non-covalent self-
assembling properties of these branched DNA, both b-DNAs
were 32P-labeled by using T4 polynucleotide kinase under
standard conditions. Afterward, A and B were mixed in
1:1 ratio and heated up to 95 ꢀC for 5 min and slowly cooled
to 4 ꢀC (0.1 ꢀC/min). The samples were then analyzed by
native polyacrylamide gel electrophoresis (see Fig. 1B).
The exclusive formation of a slower migrating reaction
product was observed. As judged from the migration mobil-
ity of the reaction products, the chosen set-up resulted in the
formation of dimeric structures rather than the formation of
any higher order structures.
4.1.1. 30,50-O-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)-
20-O-(2-levulinyl-hydroxyethyl)-uridine (2). To the stirred
solution of 1 (2.00 g, 3.77 mmol) in dry 1,4-dioxane
(40 mL), the suspension of 2-chloro-1-methylpyridinium
iodide (1.90 g, 7.44 mmol) in dry acetonitrile (20 mL)
was added with constant stirring, at room temperature. To
this, the mixture of 1,4-diazabicyclo[2.2.2]octane (2.07 g,
18.5 mmol) and levulinic acid (1.71 g, 14.7 mmol) in 1,4-di-
oxane (40 mL) was added dropwise with constant stirring.
Stirring was continued for 9 h at room temperature. Solvent
was evaporated under reduced pressure and the residue was
dissolved in dichloromethane. The organic layer was washed
with 10% sodium bicarbonate followed by brine and dried
over anhydrous magnesium sulfate. The crude compound
was purified by silica gel column chromatography (55%
ethyl acetate in petroleum ether) to give 2 as an oil
(2.30 g, 98%). Rf: 0.45 (66% ethyl acetate in petroleum
3. Conclusions
In conclusion, we have shown the synthesis of branched
DNAs using a novel 20-O-modified uridine branching mono-
mer and investigated first self-assembling properties of the
derived branched DNA oligonucleotides.
1
ether). H NMR (CDCl3): d 7.89 (d, J¼8.0 Hz, 1H, H-6);
5.75 (s, 1H, H-10); 5.67 (d, J¼8.0 Hz, 1H, 5-H); 3.87–4.29
(m, 9H, H-50, H-40, H-30, H-20, CH2CH2–O); 2.57–2.64 (m,
2H, CH2-Lev); 2.73–2.78 (m, 2H, CH2-Lev); 2.18 (s, 3H,
CH3–CO); 1.01, 1.10 (m, 28H, (CH3)2CH–Si). 13C NMR
(CDCl3): d 206.6, 172.6, 163.6, 149.8, 139.6, 101.4, 89.0,
82.6, 81.6, 69.1, 68.3, 63.7, 59.3, 37.9, 29.8, 27.9, 17.4–
4. Experimental section
4.1. General
i
i
All temperatures quoted are uncorrected. All reagents are
commercially available and used without further purifica-
tion. Solvents are purchased over molecular sieves (Fluka)
and used directly without further purification unless other-
wise noted. All reactions were conducted under rigorous
exclusion of air and moisture. NMR spectra were recorded
on a Bruker AC 250 Cryospec and Jeol JNA-LA-400 (1H:
250 MHz, 13C: 62.5 MHz, 31P: 160.0 MHz). The solvent
signals were used as references and the chemical shifts con-
verted to the TMS scale and are given in parts per million (d).
High resolution electrospray ionization-Fourier transform
ion cyclotron mass spectrometry (ESI-FTICR) was recorded
on a Bruker Daltonics Apex II in positive mode. DNA oligo-
nucleotides were synthesized on an Applied Biosystems 392
DNA/RNA-synthesizer employing standard phosphorami-
dite strategy. Flash chromatography: Merck silica gel G60
(230–400 mesh). Thin layer chromatography: Merck pre-
coated plates (silica gel 60 F254). Reversed-phase HPLC
16.8 (m, PrC); 13.4–12.5 (m, PrC). ESI-MS (m/z) calcd
for C28H48N2O10Si2 [M+Na]+: 651.2745; found: 651.2744.
4.1.2. 20-O-(2-Levulinyl-hydroxyethyl)-uridine (3). To
the stirred solution of 2 (2.10 g, 3.33 mmol) in dry THF
(30 mL), acetic acid (0.50 g, 8.33 mmol) followed by tetra-
butylammonium fluoride (1 M in THF, 8.5 mL, 8.5 mmol)
was added dropwise at room temperature. Stirring was con-
tinued for 1 h and the solvent was evaporated under reduced
pressure. The crude compound was purified by silica gel col-
umn chromatography (5% methanol in dichloromethane) to
give 3 (1.22 g, 95%) as an oil. Rf: 0.3 (10% methanol in di-
1
chloromethane). H NMR (CDCl3 and CD3OD): d 7.95 (d,
J¼8.1 Hz, 1H, H-6); 5.76 (d, J¼2.7 Hz, 1H, H-10); 5.62
(d, J¼8.1 Hz, 1H, H-5); 4.16–4.21 (m, 2H, H-20, H-30);
3.43–3.96 (m, 7H, H-40, H-50, CH2CH2–O); 2.67–2.72 (m,
2H, CH2-Lev); 2.47–2.52 (m, 2H, CH2-Lev); 2.11 (s, 3H,
CH3–CO). 13C NMR (CDCl3 and CD3OD): d 207.6, 172.8,

M. Chandra et al. / Tetrahedron 63 (2007) 8576–8580
8579
164.1, 150.4, 138.9, 101.8, 88.3, 84.3, 82.3, 68.6, 68.1, 63.3,
60.0, 37.7, 27.7, 23.7. ESI-MS (m/z) calcd for C16H22N2O9
4.2. General procedure for the synthesis of branched
DNA
[M+Na]+: 409.1223; found 409.1225.
The synthesis of branched DNA oligonucleotides was per-
formed on an Applied Biosystems 392 DNA synthesizer,
4.1.3. 50-O-(4,4-Dimethoxytrityl)-20-O-(2-levulinyl-hy-
droxyethyl)-uridine (4). Compound 3 (1.20 g, 3.11 mmol)
was coevaporated twice with dry pyridine and re-dissolved
in dry pyridine (30 mL). To this DMAP (5 mg, 0.04 mmol)
was added at 0 ꢀC. Then DMTrCl (1.25 g, 3.69 mmol) in
dry pyridine (10 mL) was added dropwise at the same
temperature over the period of 1 h. Stirring was continued
at room temperature over night. After this time, methanol
(5 mL) was added to quench the reaction. The solvent was
evaporated under reduced pressure and the remainder coeva-
porated twice with toluene. The crude compound was puri-
fied by silica gel column chromatography (70–80% of
ethyl acetate in petroleum ether containing 1% of triethyl-
amine) to give compound 4 (1.70 g, 80%) as white crystals.
Rf: 0.2 (80% of ethyl acetate in petroleum ether containing
1% triethylamine). 1H NMR (CD3OD): d 8.01 (d,
J¼8.1 Hz, 1H, H-6); 7.23–7.36 (m, 9H, Ar-H); 6.82 (d,
J¼8.7 Hz, 4H, Ar-H); 5.84 (d, J¼2.2 Hz, 1H, H-10); 5.12
(d, J¼8.1 Hz, 1H, H-5); 4.39–4.44 (dd, J¼5.2 Hz,
J¼7.7 Hz, 1H, H-30); 4.20–4.24 (m, 2H, H-40, –CH2O–);
3.84–4.04 (m, 4H, H-50, H-20, –CH2O); 3.44–3.45 (m, 2H,
–OCH2–); 2.72 (t, J¼6.0 Hz, 2H, CH2-Lev); 2.46–2.51 (m,
2H, CH2-Lev); 2.10 (s, 3H, –COCH3). 13C NMR
(CD3OD): d 209.6, 174.5, 166.2, 160.3, 152.0, 146.0,
136.9, 136.6, 131.6, 131.5, 114.3, 102.3, 88.2, 84.2, 83.9,
69.9, 64.7, 62.9, 55.8, 38.7, 29.7, 28.9. ESI-MS (m/z) calcd
for C37H40N2O11 [M+Na]+: 711.2530; found: 711.2527.
0
˚
by using 3 -CPG support (1000 A) and commercially avail-
able 30-O-2-(cyanoethyl)-phosphoramidites on 0.2 mmol
scale. After insertion of 5, DNA synthesis was continued
and standard coupling conditions were utilized in case of
standard phosphoramidites, whereas for the insertion of
branch point 5, the coupling times were extended to 10 min
using 0.12 M of 5 in acetonitrile and it was coupled twice
without capping step after the first coupling step in the syn-
thetic cycle. The extension of the branch was terminated by
first cleaving of the respective DMTr group and subsequently
passing the capping mixture A (acetic anhydride/pyridine/
tetrahydrofuran) and B (N-methylimidazole/pyridine/tetra-
hydrofuran) for 3ꢁ15 s over the solid support. Then the auto-
mated synthesis was temporarily interrupted and the column
was detached from the synthesizer. The levulinyl group was
deprotected manually with the aid of syringes; by utilizing
10 mL of the deprotection solution (0.5 M of hydrazine in
1:1 mixture of pyridine and acetic acid) for 55 min. After-
ward the column was thoroughly washed with acetonitrile
(30 mL) followed by CH2Cl2 (30 mL). Then the column
was reinstalled and the synthesis was continued from the
branch point. At the end of the synthesis, the DMTr group
was retained (‘trityl ON’), which allowed to purify from
failure sequences by RP-HPLC with a binary gradient of
acetonitrile in triethylammonium acetate buffer (pH 7.0).
The desired branched DNAwith DMTr group was collected,
deprotected by using 80% AcOH, followed by purification
over preparative polyacrylamide gel and characterization
by ESI-MS.
4.1.4. 50-O-(4,40-Dimethoxytrityl)-20-O-(2-levulinyl-hy-
droxyethyl)-uridine-30-O-(2-cyanoethyl)-N,N-diisopro-
pylphosphoramidite (5). To the stirred solution of 4 (0.43 g,
0.62 mmol) in dichloromethane (8 mL), at 0 ꢀC N,N-di-
isopropyl-N-ethylamine (0.53 mL, 3.10 mmol) was added
dropwise. Subsequently N,N-diisopropylethylamine and
2-cyanoethoxy-N,N-diisopropylaminochlorophosphine
(0.28 mL, 1.25 mmol) were added dropwise at the same
temperature. Stirring was continued for 4 h at room temper-
ature, and then dry methanol (0.5 mL, 20 mmol) was added
to quench the reaction. The reaction mixture was diluted
with dichloromethane and washed with cold water followed
by brine solution. The organic layer was dried over anhy-
drous magnesium sulfate and the solvent was evaporated un-
der reduced pressure. The crude compound was purified by
silica gel column chromatography (80% ethyl acetate in
petroleum ether containing 1% of triethylamine) to give 5
(0.43 g, 77%) as an oil. Rf: 0.66 (80% of ethyl acetate in
petroleum ether containing 1% triethylamine). 1H NMR
(CD3OD): d 8.10 (d, J¼8.0 Hz, H-6); 7.20–7.44 (m, 9H,
Ar-H); 6.83 (d, J¼8.7 Hz, 4H, Ar-H); 5.86 (d, J¼1.5 Hz,
1H, H-10); 5.16 (d, J¼8.0 Hz, 1H, H-5); 3.72–4.22 (m,
10H); 3.72 (s, 6H, –OCH3); 3.50–3.58 (m, 2H); 2.68–2.83
(m, 5H); 2.46–2.55 (m, 2H, CH2-Lev); 2.09 (s, 3H,
–CH3CO); 1.10–1.26 (m, 12H, H-iPr). 13C NMR (CD3OD):
d 209.2, 174.2, 166.1, 160.2, 151.9, 145.9, 136.5, 131.5,
129.5, 1290.0, 128.9, 128.2, 114.2, 102.0, 88.1, 83.6, 83.5,
82.5, 71.0, 69.6, 64.9, 62.1, 61.4, 60.2, 55.8, 46.6, 38.6,
29.8, 28.9, 25.3, 23.2, 20.4. 31P NMR (CD3OD): d 151.34,
150.00. ESI-MS (m/z) calcd for C46H57N4O12P [M+Na]+:
911.3609; found: 911.3604.
4.3. Radioactive labeling of branched DNA
b-DNA of 10 pmol was dissolved in a solution (46 mL,
25 ꢀC) containing Tris–HCl (79.5 mM, pH 7.6), magnesium
chloride (11.4 mM), dithiothreitol (5.7 mM), and 4 mL of
g-32P-ATP (2.0 mM). To this T4 polynucleotide kinase
(2 mL, 10 U/mL) was added and incubated at 37 ꢀC for 1 h.
The reaction was stopped by heating the solution to 95 ꢀC
for 5 min, followed by purification with a G-25 column.
4.4. Self-assembly and native polyacrylamide gel
electrophoresis
Equimolar molar amounts of b-DNA A and b-DNA B (radio
activelyphosphorylatedandnon-phosphorylated)weremixed
in a buffer containing, Tris–HCl (50 mM), MgCl2 (10 mM),
and DTT (10 mM). The gel was prepared with 8% acrylamide
(29:1, acrylamide/bisacrylamide) in a buffer containing Tris–
HCl (70 mM, pH 8), boric acid (70 mM), EDTA (1.5 mM),
and magnesium acetate (12.5 mM). The samples were loaded
on to gel suspended in loading buffer (50% of glycerol, 0.3%
of xylene cyanol, and bromophenol blue as tracking dyes).
The gel was run for 14 h, 4 ꢀC, and 30 V.
Acknowledgements
M.C. gratefully acknowledges support by the Alexander von
Humboldt-Stiftung. The assistance of Dr. Karl-Heinz Jung

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M. Chandra et al. / Tetrahedron 63 (2007) 8576–8580
Seeman, N. C. Angew. Chem., Int. Ed. 1998, 37, 3220; (o)
Mirkin, C. A.; Letsinger, R. L.; Mucic, R. C.; Storhoff, J. J.
Nature 1996, 382, 607; (p) Seeman, N. C. J. Theor. Biol. 1982,
99, 237.
in manuscript preparation and Reinhold Weber in recording
the HRMS data is kindly acknowledged.
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