Oligonucleotide analogues containing the internucleotide linker C3′-NH-CO-CH2-N(CH3)-C5′

Article abstract of DOI:10.1134/S1068162008040092

Oligonucleotide analogues were synthesized whose internucleoside linker contains an amide bond and a methylamino group (C3′-NH-CO-CH ₂-N(CH₃)-C5′). Melting curves for duplexes formed by modified oligonucleotides and natural oligonucleotides complementary to them were measured, and the melting temperatures and thermodynamic parameters of duplex formation were calculated. The introduction of one modified dinucleoside linker into the oligonucleotide only slightly decreases the melting temperatures of these duplexes compared with unmodified ones. The CD spectra of modified duplexes were studied, and their spatial structures are discussed.

Full text of DOI:10.1134/S1068162008040092

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2008, Vol. 34, No. 4, pp. 453–459. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © S.V. Kochetkova, N.A. Kolganova, E.N. Timofeev, V.L. Florent’ev, 2008, published in Bioorganicheskaya Khimiya, 2008, Vol. 34, No. 4, pp. 506–512.
Oligonucleotide Analogues Containing the Internucleotide
Linker C3'-NH-CO-CH2-N(CH3)-C5'
S. V. Kochetkova, N. A. Kolganova, E. N. Timofeev, and V. L. Florent’ev1
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, ul. Vavilova 32, Moscow, 119991 Russia
Received June 6, 2007; in final form, July 5, 2007
Abstract—Oligonucleotide analogues were synthesized whose internucleoside linker contains an amide bond
and a methylamino group (C3'-NH-CO-CH2-N(CH3)-C5'). Melting curves for duplexes formed by modified
oligonucleotides and natural oligonucleotides complementary to them were measured, and the melting temper-
atures and thermodynamic parameters of duplex formation were calculated. The introduction of one modified
dinucleoside linker into the oligonucleotide only slightly decreases the melting temperatures of these duplexes
compared with unmodified ones. The CD spectra of modified duplexes were studied, and their spatial structures
are discussed.
Key words: amide internucleotide bond, analogues, hybridization, oligonucleotides, thermal stability
DOI: 10.1134/S1068162008040092
INTRODUCTION
There are very few works devoted to the synthesis of
amide analogues of oligonucleotides containing inter-
nucleoside linkages of four atoms. To date oligonucle-
otides have been synthesized wherein one or several
dinucleotides are replaced by a dinucleoside residue
(A) [17], (B) [18], (C) [19−21], (D) or (E) [20, 21]
(Fig. 1). A detailed thermodynamic analysis of the
melting of duplexes formed by deoxyoligonucleotides
containing one modified dimer with complementary
natural ribooligonucleotides has been performed [21].
It was found that the modification (B) only slightly
decreases the stability of the duplex compared with the
natural, and modifications (C), (D), and (E), depending
on the sequence, either do not affect the duplex stability
or somewhat increase it. The X-ray analysis of a duplex
The therapy by synthetic analogues of oligonucle-
otides (“antisense” therapy) is a promising method in
the treatment of viral and oncological diseases [1–4].2
The idea of the method consists in the suppression of
gene translation by the specific binding of a synthetic
oligonucleotide to the corresponding region of mRNA.
Owing to high hybridization specificity, it is possible to
selectively suppress the expression of genes involved in
the pathogenesis of disease. However, the “antisense”
oligonucleotide should possess particular properties,
namely: it should be stable to intracellular nucleases
and, at the same time, specifically and firmly bind to the
target sequence on mRNA; it should readily penetrate
the cell membrane, have a low toxicity, and produce no containing one modification (E) showed that it does not
side effects. Over the past 15 years, a great number of disturb the stacking interaction of bases and helical
oligonucleotide analogues modified at the nucleic acid parameters of the duplex.
base, the carbohydrate residue, and the internucleotide
bond have been synthesized (see reviews [5–7]). Oligo-
nucleotide analogues wherein the phosphate internu-
cleotide bond is substituted for by an amide linkage
have received particular attention of investigators in the
last few years. In a natural oligonucleotide, the atoms
C3' of the preceding nucleoside and C5' of the next
nucleoside are linked through three atoms (C3'-O-P-O-
C5'). Therefore, the major efforts of investigators have
been directed toward the synthesis of oligonucleotide
analogues with amide internucleoside linkages of three
atoms [8–16].
This work is concerned with the synthesis of oligo-
nucleotide analogues containing an amide bond and an
aminomethyl group in the internucleoside unit of four
atoms [structure (F) in Fig. 1] and the study of their
physicochemical and hybridization properties.
We assumed that the introduction into the internu-
cleoside bond of an aminomethyl group carrying a pos-
itive charge at neutral pH values would increase the sta-
bility of a duplex formed by a modified and a natural
oligonucleotide due to electrostatic attraction.
RESULTS AND DISCUSSION
1
Corresponding author; phone: (499) 135-21-82, (499) 135-65-91;
The carboxy component (III) (scheme) was obtained by
the alkylation of 5'-deoxy-5'-methylaminothymidine (I)
[22] by the ethyl ester of bromoacetic acid with subsequent
fax: (499) 135-14-05; e-mail: flor@imb.ac.ru
2
Abbreviations: Im CO, carbonyldiimidazole; TEA, triethy-
2
lamine.
453

454
KOCHETKOVA et al.
saponification of ester. Protected 3'-deoxy-3'-aminothymi- dine (IV) was synthesized by the method described [23].
CH3
O
N
O
N
O
N
OH
O
H3C
CH3
HN
H3C
H3C
NH
NH
NH
O
O
(a)
(b)
O
N
O
N
O
H3C
H3C
O
O
O
OH
(I)
OH
(III)
OH
(II)
O
H C
3
NH
O
H C
3
(MeO )TrO
N
O
2
NH
O
O
(c)
(III) +(MeO )TrO
N
O
2
H C
3
O
HN
NH
O
N
N
O
NH
2
O
O
H C
3
(IV)
H C
3
(d)
NH
OH
(MeO )TrO
N
O
(V)
2
O
O
H C
3
HN
O
NH
N
N
O
O
H C
3
O
O
P
NC
(VI)
N(iPr)
2
(‡) BrCH2COOEt, TEA, DMF; (b) NaOH, Py/EtOH; (c) Im2CO, DMF; (d) NCCH2CH2OP(NiPr2)2, tetrazole.
The condensation of the carboxy component (III) ened singlet at 3.355 ppm from the protons of the
with the amino component (IV) in the presence of NCH2CO-group (broadening due to diastereotopism of
Im2CO gave dinucleoside (V). Finally, dinucleoside protons) as well as a triplet (1.172 ppm, 3J = 7.13 Hz)
3
(V) was converted to 2-cyanethyl-N,N-diisopropy- and a quartet (4.063 ppm, J = 7.13 Hz) of the ethyl
lphosphoamidite (VI) by the method described [22].
group. In the spectrum of acid (III), the signals from
the protons of the ethyl group are absent, with all other
signals being retained.
The structures of all compounds synthesized were
1
confirmed by H NMR spectra. Thus, the presence of
the ethoxycarbonylmethyl group in compound (II) was
We synthesized both the analogues of oligonucle-
confirmed by the presence in the spectrum of a broad- otides [X is the residue of the modified dinucleoside (F)
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 34 No. 4 2008

OLIGONUCLEOTIDE ANALOGUES
O
455
O
O
O
B
Thy
O
B
B
O
O
O
O
O
O
R
HN
O
O
O
CH3
CH3
NH
N
NH
O
O
NH
B
Thy
B
B
O
O
O
O
OCH3
O
O
O
(Ä)
(B)
(C): R = H
(D): R = CH3 (R)
(E): R = CH3 (S)
(F)
Fig. 1. Dinucleosides with the amide (3
5)-linkage of four atoms.
in Fig. 1] and natural oligonucleotides complementary duplexes (Fig. 3 and Table 2) enables some conclusions
to them (Table 1).
about the structure of the duplexes to be drawn. All
duplexes formed by modified oligonucleotides with the
complementary natural duplexes, irrespective of the
position of the modified bond in the strand and the
number of these bonds, have the spectrum shape very
similar to that of the corresponding natural oligonucle-
otide. It is seen from Fig. 3 that the spectrum of a
duplex containing even five nonphosphate internucleo-
side bonds in the modified strand insignificantly differs
The structures of all oligonucleotides synthesized
were confirmed by mass spectra (Table 1) and by PAGE
under denaturing conditions (Fig. 2).
As follows from Fig. 2, the modified oligonucle-
otides have a lower mobility in the electric field, which
is consistent with a decrease in the total negative charge
as the phosphate bond is substituted for by the amide.
A comparison of the CD spectra of modified
duplexes with those of the corresponding natural from the spectrum of the natural duplex. It has been
Table 1. Synthesized oligonucleotides and their mass spectra
Mass spectra, m/z [M + H]+
Code
Sequence 5'
3'
calculated
Modified oligonucleotides
3629.53
found
MS1
MS2
MS3
MS4
MS5
MS6
MS7
MS8
G-X-TT-TT-TT-TT-G
G-TT-X-TT-TT-TT-G
G-TT-TT-X-TT-TT-G
G-TT-TT-TT-X-TT-G
G-TT-TT-TT-TT-X-G
G-X-TT-TT-TT-X-G
G-X-X-X-X-X-G
3630
3629
3630
3631
3630
3618
3591
3701
3629.53
3629.53
3629.53
3629.53
3619.65
3589.99
3700.60
G-AA-GT-X-GA-CA-G
Natural oligonucleotides
S1
S2
S3
S4
G-TT-TT-TT-TT-TT-G
C-AA-AA-AA-AA-AA-C
G-AA-GT-TT-GA-CA-G
C-TG-TC-AA-AC-TT-C
3639.43
3649.51
3700.48
3581.40
3639
3549
3703
3581
* X, residue of thymidine dinucleoside with a modified internucleoside linkage [structure (F) in Fig. 1].
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 34 No. 4 2008

456
KOCHETKOVA et al.
∆ε
20
1
Natural duplex
Modified duplex
10
0
2
–10
–20
220
240
260
280
300
λ, nm
Fig. 2. Gel electrophoresis of oligonucleotides under dena-
turing conditions. The position of bands was determined
Fig. 3. CD spectra of a natural (S1·S2) and a modified
duplex (MS7·S2) at (1) 0°C and (2) 70°C (phosphate buffer,
pH 7, and 0.1 M NaCl).
from the absorption in UV light (~254 nm) after applying
the gel to a fluorescent support (TLC Kieselgel 60 F
254
plates).
were calculated (Table 3). In the calculation, the tem-
perature dependence of absorption of a duplex (Ad) and
a single strand (Ass) was taken into account. Because
the melting temperature for short duplexes depends on
concentration, the experimental melting temperatures
were recalculated with respect to the standard concen-
tration of strands of 10–5 M (column next to the last in
Table 3).
shown earlier that such double-humped CD spectra
with maxima at ~263 and ~285 nm are characteristic of
the B-form of oligo(dT) · oligo(dA)-sequences [24].
Thus, it can be assumed that the modification proposed
in this work does not practically distort the structure of
the DNA duplex.
The profiles of the thermal dissociation of natural
and modified duplexes were measured (Fig. 4a). The
experimental melting temperatures for duplexes were
determined from the derivative maxima after numerical
differentiation of experimental melting curves
(Fig. 4b).
As follows from the data in Table 3, one modifica-
tion decreases the melting temperature of the duplex on
the average by 2°ë; in this case, the additivity between
the decrease in the melting temperature of the duplex
From the curves obtained, the thermodynamic
parameters of duplex formation from single strands and the number of modified bonds is retained within the
Table 2. CD spectra of duplexes at 0°C*
Duplex
λmax, nm (∆ε*)
λmin, nm (∆ε*)
λmax, nm (∆ε*)
λmin, nm (∆ε*)
λmax, nm (∆ε*)
S1·S2
218.0 (19.6)
218.7 (21.8)
218.5 (22.5)
218.7 (23.4)
218.4 (22.2)
218.8 (22.4)
218.5 (21.9)
250.3 (–17.6)
250.1 (–19.2)
250.6 (–18.2)
250.5 (–17.7)
250.4 (–18.1)
250.5 (–19.0)
250.2 (–17.9)
250.8 (–16.4)
262.7 (1.5)
263.1 (2.0)
263.0 (1.9)
262.9 (2.1)
262.9 (2.1)
263.0 (1.7)
262.8 (1.9)
262.9 (2.2)
268.8 (–0.4)
269.2 (–0.1)
269.1 (–0.2)
269.2 (0.5)
269.1 (0.1)
269.3 (–0.5)
269.3 (–0.2)
270.2 (–2.1)
284.5 (4.7)
284.5 (6.1)
284.6 (6.0)
284.9 (5.6)
284.7 (5.2)
284.8 (5.9)
284.6 (5.5)
286.5 (4.4)
MS1·S2
MS2·S2
MS3·S2
MS4·S2
MS5·S2
MS6·S2
MS7·S2
219.2 (22.6)
–1
–1
* ∆ε = (ε – ε ) (ε, M cm ).
L
R
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OLIGONUCLEOTIDE ANALOGUES
457
60
limits of experimental error (–3.6°ë for two and
−10.0°ë for five bonds).
Thus, the oligonucleotides obtained form a rather
stable duplex with complementary natural oligonucle-
otides, and the structure of this duplex does not sub-
stantially differ from the structure of the natural duplex.
10
1.0
20
30
40
50
(b)
(a)
4
5
2
1
3
0.5
1.0
EXPERIMENTAL
The following preparations were used: pyridine,
chloroform, dimethylformamide (all of chemical
grade) (Khimmed, Russia); ethyl ester of bromoacetic
acid, thymidine, Im2CO (Fluka, Switzerland); and
dimethoxytrityl chloride (Aldrich, United States). Dim-
ethylformamide was dried by distillation over phospho-
rus pentoxide, and pyridine, over calcium hydride.
0.8
0.6
0.4
0.2
0
2
1
3
4
5
NMR spectra of substances in DMSO-d6 were mea-
sured on a Bruker AMXIII-400 spectrometer with an
operating frequency of 400 MHz. Duplex melting
curves were recorded on a UV 160-A spectrophotome-
ter (Shimadzu, Japan) equipped with a thermostating
accessory. The absorption of a duplex A260 was
recorded in steps of 0.5°ë. CD spectra were measured
on a J-715 spectropolarimeter (Jasco, Japan).
10
20
30
40
50
60
Temperature, °C
Modified and natural oligonucleotides were ana-
lyzed by MALDI spectrometry using an MS-30 mass
spectrometer (Kratos, Japan).
Fig. 4. (a) Experimental melting curves for natural
duplexes: 1, S3·S4 S4; 3, S1·S2 S2 and modified duplexes:
2, MS8·S4, 4, MS1·S2; 5, MS7·S2. (b) A derivative obtained
by numerical differentiation of the experimental curves. For
convenience of comparison, hyperchromism and the deriv-
ative are normalized to unity.
Oligonucleotides were synthesized by an ASM-
102U automatic DNA synthesizer (Biosun, Russia)
according to a standard protocol. Oligonucleotides
were purified by reverse-phase HPLC using columns
(25 × 4 mm2) of Hypersil C18 in 0.05 I TEAB buffer.
DMTr-protected oligomers were isolated using a gradi-
ent of acetonitrile from 10 to 50% in 30 min. Com-
purified using a gradient of acetonitrile concentration
from 0 to 25% (30 min) in a buffer indicated.
Denaturing gel electrophoresis of the oligonucle-
pletely unblocked oligonucleotides were additionally otides was carried out in 20% (acrylamide−bis-acryla-
.
Table 3. Thermodynamic parameters of formation of duplexes from single strands
∆S°,
Tmelt, °C,
reduce*
Duplex
c × 106, M
∆H°, kcal/mol
Tmelt, °C 0.5
∆Tmelt, °C
cal/mol–1 K–1
S1·S2
4.64
5.94
8.60
7.62
9.03
5.06
7.14
4.82
8.82
10.1
–96.1 2.0
–98.1 1.8
–100.7 1.0
–97.5 1.0
–99.3 0.9
–96.9 2.2
–98.8 1.2
–74.7 1.5
–86.8 0.6
–97.7 1.3
–287.6 6.3
–296.3 5.9
–305.0 3.2
–294.4 3.4
–300.3 3.0
–292.5 7.1
–300.0 4.0
–226.3 5.1
–249.2 2.0
33.8
32.4
32.8
32.5
32.6
32.2
31.5
23.2
44.0
42.6
35.6
33.6
33.1
33.1
32.8
33.8
32.2
25.4
44.4
42.6
MS1·S2
MS2·S2
MS3·S2
MS4·S2
MS5·S2
MS6·S2
MS7·S2
S3·S4
–2.0
–2.5
–2.5
–2.8
–1.8
–3.4
–10.0
MS8·S4
–284.8 4.3
–1.8
–5
Notes: * Recalculated with respect to the concentration value of 10 M.
** Difference between T
of the modified and natural duplexes.
melt
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 34 No. 4 2008

458
KOCHETKOVA et al.
mide 19 : 1) PAG in 100 mM Tris-borate buffer (pH 7) washed with a saturated NaHCO3 solution and water,
and 7 M urea.
and dried over anhydrous Na2SO4. The solvent was
evaporated, and the residue was dissolved in chloro-
form-0.1% Et3N and applied to a column of silica gel
(11 × 3.5 cm). The product was eluted with chloroform-
EtOH (gradient from 2 to 15% EtOH) with the addition
of 0.1% Et3N. The yield: 0.176 mg (52.4%) as a solid
Column chromatography was carried out using Kie-
selgel 60 (Merck, Germany). TLC was performed on
Kieselgel 60 F254 plates (Merck, Germany) in systems
(A) ethanol−chloroform 1 : 19, (B) ethanol−chloroform
1 : 4, and (C) iPrOH–NH4OH–H2O, 7 : 2 : 1.
Phosphoramidite (VI) was obtained by the method
described in [22] and used without isolation for the syn-
thesis of modified oligonucleotides.
5'-Deoxy-5'-N-methyl-N-ethoxycarbonylmethyl-
aminothymidine (II). TEA (0.46 ml, 3.3 mmol) and
ethyl ester of bromoacetic acid (0.55 g, 0.36 ml,
3.3 mmol) were added with stirring to a solution of
5'-deoxy-5'-methylaminothymidine (I) (0.77 g,
3 mmol) [22] in absolute DMF (5 ml), and the mixture
was kept overnight at room temperature under stirring.
The mixture was diluted with a saturated aqueous solu-
tion of NaHCO3 (10 ml) and extracted with chloroform
(5 × 10 ml). Chloroform extracts were combined, dried
over anhydrous Na2SO4, and the solvent was thor-
oughly evaporated. Compound (II) was obtained as a
dense oil. Yield: 0.97 g (94.7%); Rf 0.55 (B). 1H NMR:
11.301 (1 H, s, H3), 7.517 (1 H, d, br, J 1.05, H6), 6.121
(1 H, t, J 6.83, H1'), 4.120 (1 H, m, H3'), 4.063 (2 H, q,
J 7.13, CH2CH3), 3.795 (1 H, m, H4'), 3.355 (2 H, s, br,
1
foam; Rf 0.25 (B). H NMR: 5'-terminal nucleoside:
11.276 (1 H, s, H3), 7.510 (1 H, d, br, J 0.96, H6),
7.41−6.34 (13 H, m, Ar), 6.176 (1 H, t, J 6.26, H1'),
4.549 (1 H, m, H3'), 4.103 (1 H, m, H4'), 3.731 (6 H, s,
CH3, Thy), 3.931 (2 H, m, H5'), 2.312 (1 H, m, H2'a),
2.212 (1 H, m, H2'b), 1.471 (3 H, d, J 1.01, 5-CH3);
3'-terminal nucleoside: 11.235 (1 H, s, H3), 7.535 (1 H,
d, br, J 0.91, H6), 6.114 (1 H, t, J 6.77, H1'), 3.930
(1 H, m, H3'), 3.930 (1 H, m, H4'), 3.249 (2 H, s, br,
NCH2CO), 2.706 (1 H, dd, J 4.65, J 13.43, H5'a), 2.647
(1 H, dd, J 7.39, J 13.43, H5'b), 2.249 (3 H, s, NCH3),
2.146 (1 H, m, H2'a), 2.056 (1 H, m, H2'b), 1.768 (3 H,
d, J 0.98, 5-CH3).
EIMS: m/z 861.9 [M + Na]+. Calculated: 861.9
(C44H50N6O11Na).
ACKNOWLEDGMENTS
The authors are grateful to I. P. Smirnov (Institute of
NCH2CO), 2.746 (1 H, dd, J 4.99, J 13.45, H5'a), 2.682 Molecular Biology) for the measurement of mass spec-
tra.
This work was supported by the Russian Foundation
for Basic Research (project no. 05-04-49369).
(1 H, dd, J 7.17, J 13.45, H5'b), 2.358 (3 H, s, NCH3),
2.136 (1 H, m, H2'a), 2.046 (1 H, m, H2'b), 1.787 (3 H,
d, J 1.06, 5-CH3), 1.172 (3 H, t, J 7.13, CH3CH2).
5'-Deoxy-5'-N-methyl-N-carboxymethylaminothy-
midine (III). Six milliliters of 2 M NaOH in ethanol was
added under stirring to a solution of nucleoside (II)
(0.95 g, 2.8 mmol) in pyridine (6 ml) and ethanol (6 ml)
cooled to 0°ë, the reaction mixture was kept for 30 min at
room temperature, and an excess of Dowex 50 (Py-form)
(80−100 ml) was added to bind Na ions. The resin was fil-
tered off, washed with 50 ml of a 5% solution of pyridine
in H2O. The solvent was evaporated, and the residue was
reevaporated with ethanol (3 × 20 ml).Yield of pyridinium
salt (III) 0.88 g (80.5%) as a solid foam; Rf 0.32 (C).
1H NMR: 11.234 (1 H, s, H3), 7.546 (1 H, d, br, J 0.89,
H6), 6.134 (1 H, t, J 6.81, H1'), 4.147 (1 H, m, H3'), 3.840
(1 H, m, H4'), 3.263 (2 H, s, br, NCH2CO), 2.827 (1 H,
dd, J 4.79, J 13.42, H5'a), 2.765 (1 H, dd, J 7.20, J 13.42,
H5'b), 2.409 (3 H, s, NCH3), 2.142 (1 H, m, H2'a), 2.063
(1 H, m, H2'b), 1.797 (3 H, d, J 0.91, 5-CH3).
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