Synthesis and photophysical properties of 8-arylbutadienyl 2′-deoxyguanosines

Article abstract of DOI:10.1016/j.tetlet.2010.11.053

We have developed novel push-pull-type 8-arylbutadienyl 2′-deoxyguanosine derivatives, ^ABG (1a) and ^CBG (1b). These nucleosides exhibit strong solvent polarity dependent fluorescence emission at long wavelength (ca. 490-550 nm). Thes

Full text of DOI:10.1016/j.tetlet.2010.11.053

Tetrahedron Letters 52 (2011) 491–494
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Tetrahedron Letters
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Synthesis and photophysical properties of 8-arylbutadienyl 20-deoxyguanosines
⇑
⇑
Yoshio Saito , Makio Koda, Yuta Shinohara, Isao Saito
Department of Chemical Biology and Applied Chemistry, School of Engineering, Nihon University, Koriyama, Fukushima 963-8642, Japan
a r t i c l e i n f o
a b s t r a c t
We have developed novel push–pull-type 8-arylbutadienyl 20-deoxyguanosine derivatives, ABG (1a) and
CBG (1b). These nucleosides exhibit strong solvent polarity dependent fluorescence emission at long
wavelength (ca. 490–550 nm). These environmentally sensitive fluorescent deoxyguanosines are power-
ful tools for structural studies of nucleic acids and also in molecular diagnostics.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Received 19 October 2010
Revised 8 November 2010
Accepted 10 November 2010
Available online 16 November 2010
Currently, fluorescence nucleosides are widely implemented as
reporter molecules for molecular recognition in diverse fields, such
as chemistry, biology, biotechnology and medicinal chemistry.1
Among these nucleosides, fluorescent guanosines are of greatest
importance owing to their unique supramolecular properties of
forming a variety of self-assembled structures and tetrameric com-
plexes of high biological interests.2 The design of environmentally
sensitive fluorescent guanosines is, therefore, of utmost impor-
tance, since they can function not only as fluorescent DNA probes
and fluorescence sensors, but also as fluorescent building blocks in
supramolecular chemistry.
Recently, we have reported push–pull-type fluorescent guano-
sines, AcG and CNG, which contain a covalently linked electron do-
nor–acceptor system consisting of guanosine as the electron
donor and pyrene fluorophore as the acceptor (Fig. 1).3 Although
these guanosine derivatives exhibited interesting solvatofluoro-
chromic properties, the steric bulkiness of the C8-substituents in
both AcG and CNG causes considerable destabilization of the DNA
duplex structure, and thus, they may not be applicable to the gen-
eral use as fluorescent DNA probes. A great demand accordingly re-
mains for further development of more simple, low-cost
solvatochromic fluorescence guanosine analogues, which can be
synthesized more easily. Therefore, we have designed simple gua-
The synthetic route of arylbutadienyl guanosines, ABG (1a) and
CBG (1b) is outlined in Scheme 1. E-b-bromostyrene derivatives,
4a–b, which contain an electron-withdrawing substituent in the
para-position of phenyl ring, were prepared from the correspond-
ing styrene derivatives.4 These bromostyrene analogues were cou-
pled with 8-vinyl guanosine derivative 35 via Pd(0)-mediated Heck
reaction to afford 6a–b.6 After deprotection of the DMF acetal
group with 28% aq NH4OH–methanol, two arylbutadienyl guano-
sine derivatives 1a–b containing electron-withdrawing substitu-
ents were obtained.7
Because of the low reactivity of bromostyrene derivatives with
electron-donating substituents, corresponding E-b-iodostyrene
derivatives 5a–b were used for the Pd-mediated cross-coupling
reactions. b-Iodostyrene derivatives, 5a and 5b, which were pre-
pared from the corresponding cinnamic acids,8 were coupled with
8-vinylguanosione 3 using Pd(PPh3)4 to afford 7a and 7b, respec-
tively. Deprotection of 7a–b with 28% aq NH4OH–methanol affor-
ded arylbutadienyl guanosine derivatives MBG (2a) and DABG (2b).
The photophysical properties of newly synthesized guanosine
derivatives 1a–b and 2a–b were examined. Initially, we measured
the fluorescence spectra of arylbutadienyl guanosines containing
electron-withdrawing substituents in various solvents of different
polarity. As shown in Figure 2, arylbutadienyl derivatives ABG (1a)
having longer conjugated system than 8-aryl or 8-arylethynyl
guanosines emitted strong fluorescence at a longer wavelength.
With excitation of ABG (1a) in 1,4-dioxane, strong fluorescence
emission at 494 nm was observed. Upon excitation of ABG (1a) in
ethyl acetate and acetonitrile, medium fluorescence emission was
observed at 510 and at 547 nm. In contrast, very weak fluorescence
emission was observed for ABG (1a) in polar solvents, such as eth-
anol (558 nm) and methanol (554 nm). Thus, ABG (1a) showed a
nosine derivatives, which contain a phenyl group
p-conjugated
with a butadiene linker at C8 position of guanosine. In addition
to the novel structure of these butadienyl nucleosides, to the best
of our knowledge, no report exists regarding the synthesis of a
fluorescent nucleoside containing butadiene linker. In constructing
such push–pull-type nucleosides, various substituents were intro-
duced into the arylbutadienyl guanosine derivatives and their
photophysical properties were examined. We herein report the
first synthesis of novel 8-arylbutadienyl 20-deoxyguanosines, ABG
(1a) and CBG (1b) and their photophysical properties in solvents
of different polarity.
considerably large solvatofluorochromicity (
D
k = 60 nm). A similar
k = 40 nm)
solvatofluorochromicity was observed with CBG (1b) (
D
(Table 1). These results indicated that push–pull-type arylbutadie-
nyl guanosines, such as ABG (1a) and CBG (1b) exhibited a remark-
able solvatofluorochromic property, as is evident from the
fluorescence colour image shown in Figure 2c.
⇑
Corresponding authors.
E-mail address: saitoy@chem.ce.nihon-u.ac.jp (Y. Saito).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.053

492
Y. Saito et al. / Tetrahedron Letters 52 (2011) 491–494
Figure 1. Structure of 8-arylbutadienyl guanosine derivatives.
R
X
O
4a
b
5a
b
: R = Ac, X=Br
: R =CN, X=Br
: R = OMe, X=I
: R =NMe2, X=I
O
N
R
N
N
NH
N
N
N
NH
N
N
N
HO
N
O
HO
NH
(a)
O
3
OH
OH
6a: R = Ac (36 %)
b: R = CN (57 %)
7a: R = OMe (30 %)
b: R = NMe2 (35 %)
O
N
R
N
(b)
N
NH2
HO
O
1a (ABG): R = Ac (58 %)
b (CBG): R = CN (89 %)
2a (MBG): R = OMe (88 %)
b (DABG): R = NMe2 (61 %)
OH
Scheme 1. Reagents and conditions: (a) 4 or 5, Pd(PPh3)4, CH3COONa, DMF, 100 °C, 8 h; (b) aq NH4OH, MeOH, 50 °C, 5 h.
Table 1
Photophysical properties of fluorescent guanosine derivatives
c
(Mꢀ1 cmꢀ1
)
/
Brightnessd
(e ꢁ /)
abs
max
a
fl
max
b
Compound
Solvent
e
k
(nm)
k
(nm)
ABG (1a)
1,4-Dioxane
CH3CN
MeOH
1,4-Dioxane
CH3CN
MeOH
1,4-Dioxane
CH3CN
MeOH
1,4-Dioxane
CH3CN
MeOH
399
392
388
395
387
381
354
352
342
352
349
343
25,500
21,000
38,300
18,600
18,900
24,900
21,400
21,300
23,200
14,200
13,800
14,700
494
547
554
486
526
522
429
441
438
429
443
438
0.59
0.57
0.015
0.75
0.47
0.32
0.71
0.68
0.56
0.70
0.75
0.58
15,200
12,000
589
14,000
9040
CBG (1b)
MBG (2a)
DABG (2b)
8070
15,200
14,500
13,200
9980
10,400
8590
a
b
c
Absorption spectra were measured at 25 °C using 1 cm path length cell (10
Fluorescence spectra were measured at 25 °C using 1 cm path length cell (10
The fluorescence quantum yields (/) were calculated by using 9,10-diphenylanthracene as a reference according to Ref. 9.
l
M). See Figures S1–S4.
l
M). See Figures 2 and 3 and S1–S2.
d
Brightness factors were calculated by
e ꢁ /.
The photophysical properties of arylbutadienyl derivatives with
arylbutadienyl substituted group. These results clearly indicate
that only push–pull-type arylbutadienyl derivatives exhibit highly
solvatofluorochromic properties as we expected.
We also examined the photoisomerization of these butadienyl
guanosines in each solvent. Although 8-phenylbutadienyl
guanosine having no substituent in the phenyl ring was gradually
electron-donating substituents were also investigated. As shown in
Figure 3, fluorescence quantum yields of MBG (2a) and DABG (2b)
are larger than those of ABG (1a) and CBG (1b). However, the red-
shift of fluorescence emission when solvent polarities were in-
creased was not large as that observed in the electron withdrawing

Y. Saito et al. / Tetrahedron Letters 52 (2011) 491–494
493
120
100
80
60
40
20
0
b 250
a
Methanol
Methanol
Ethanol
200
Ethanol
Acetonitorile
DMSO
Acetonitorile
DMSO
150
100
50
THF
THF
Ethyl acetate
1,4- Dioxane
Ethyl acetate
1,4- Dioxane
0
350
450
550
650
400
500
600
700
Wavelength (nm)
Wavelength (nm)
c
Figure 2. Fluorescence spectra of (a) ABG (1a, 10
l
M) and (b) CBG (1b, 10
l
M) in various solvents, (c) fluorescence colours of ABG (1a) in different solvents. The sample
solutions were illuminated with a 365 nm transiluminator.
180
a
250
b
Methanol
Ethanol
Methanol
Ethanol
160
140
120
100
80
60
40
20
200
150
100
50
Aetonitrile
DMSO
Acetonitrile
DMSO
THF
THF
Ethyl acetate
1,4- Dioxane
Ethyl acetate
1,4- Dioxane
0
0
300
400
500
600
300
400
500
600
Wavelength (nm)
Wavelength(nm)
Figure 3. Fluorescence spectra of (a) MBG (2a, 10
l
M) and (b) DABG (2b, 10
lM) in various solvents.
photoisomerized to a mixture of E- and Z-isomers, no appreciable
photoisomerization was observed in UV irradiation followed by
HPLC analyses in the case of electron withdrawing group- or
electron donating group-substituted arylbutadienyl guanosines
(Fig. S5–S9).
In summary, we have synthesized novel push–pull-type
8-arylbutadienyl guanosines for the first time. These newly synthe-
sized guanosine derivatives ABG (1a) and CBG (1b) possessing large
References and notes
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Tetrahedron symposium in print, 2007, 63.; (g) Wilson, J. N.; Kool, E. T. Org. Biomol.
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5487; (i) Sinkeldam, R. W.; Greco, N. J.; Tor, Y. Chem. Rev. 2010, 110, 2579.
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Chem., Int. Ed. 2000, 39, 1300; (b) Manet, I.; Francini, L.; Masiero, S.; Pieraccini, S.;
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125, 10830; For examples of DNA triplexes, see: (d) Moser, H. E.; Dervan, P. B.
Science 1987, 238, 645; For examples of guanine quadruplex formation, see: (e)
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4. James, A. B.; James, J. M.; Andre, B. C. Org. Lett. 2008, 10, 5485.
brightness factors (
e
ꢁ
U) exhibited a strong fluorescence depen-
dency on the solvent polarity at longer wavelengths without
photoisomerization. Such environmentally sensitive strong fluo-
rescent guanosines can be used as powerful tools for structural
studies of nucleic acids and in molecular diagnostics.
5. Saito, Y.; Matsumoto, K.; Takeuchi, Y.; Bag, S. S.; Kodate, S.; Morii, T.; Saito, I.
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Acknowledgement
6. Heck, R. F. Org. React. 1982, 27, 345.
7. Spectroscopic data for ABG (1a): 1H NMR (400 MHz, DMSO-d6) d 2.08 (ddd, J = 1.8,
5.9, 13.0 Hz, 1H), 2.58–2.67 (complex, 4H), 3.64–3.75 (complex, 2H), 3.85 (m,
1H), 4.43 (m, 1H), 5.18 (m, 1H), 5.30 (d, J = 4.0, 1H), 6.32 (dd, J = 5.9, 9.0 Hz, 1H),
6.52 (br, 2H), 6.94 (d, J = 15.8, 1H), 7.22–7.38 (complex, 3H), 7.66 (d, J = 8.4 Hz,
2H), 7.95 (d, J = 8.4 Hz, 2H), 10.96 (br, 1H); 13C NMR (DMSO-d6, 100 MHz) d 26.6
(2C), 61.5, 70.5, 82.6, 87.4, 116.9, 121.5, 126.5 (2C), 128.7 (2C), 131.4, 132.7,
133.1, 135.6, 141.4, 144.0, 151.7, 153.3, 156.3, 197.1; HRMS (ESI) m/z 460.1597
calcd for C22H23N5O5Na [M+Na]+, found 460.1575.
This work was supported by a Grant-in-Aid for Scientific re-
search of MEXT, Japanese Government.
Supplementary data
Spectroscopic data for CBG (1b): 1H NMR (400 MHz, DMSO-d6) d 2.08 (ddd, J = 1.8,
5.8, 13.0 Hz, 1H), 2.62 (ddd, J = 6.4, 9.0, 13.0 Hz, 1H), 3.64–3.75 (complex, 2H),
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.053.

494
Y. Saito et al. / Tetrahedron Letters 52 (2011) 491–494
3.85 (m, 1H), 4.43 (m, 1H), 5.19 (m, 1H), 5.30 (d, J = 4.0 Hz, 1H), 6.31 (dd, J = 5.8,
8. (a) Rajanna, K. C.; Reddy, N. M.; Reddy, M. R. J. Dispersion Sci. Technol. 2004, 25,
613; (b) Graven, A.; Jorgensen, K. A.; Dahl, S.; Stanczak, A. J. Org. Chem. 1994, 59,
3543.
9.0 Hz, 1H), 6.53 (br, 2H), 6.93 (d, J = 15.0 Hz, 1H), 7.24–7.39 (complex, 3H), 7.43
(d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 10.70 (br, 1H); 13C NMR (DMSO-d6,
100 MHz) d 24.6, 61.5, 70.5, 74.5, 82.6, 87.4, 109.5, 117.0, 119.0, 122.2, 124.5,
127.0 (2C), 132.3, 132.6 (2C), 141.5, 143.8, 151.7, 153.4, 156.3; HRMS (ESI) m/z
443.1439 calcd for C21H20N6O4Na [M+Na]+, found 443.1444.
9. Quantum yields (
U) were calculated according to following reference: Morris, J.
V.; Mahaney, M. A.; Huber, J. R. J. Phys. Chem. 1976, 80, 969.