Photoswitchable unsymmetrical ligand for DNA hetero-mismatches

Article abstract of DOI:10.1002/ejoc.200900323

Photoswitchable DNA-binding ligands should be useful for controlling diverse biological functions involving DNA and reversible assembly of DNA-based nanostructures. In work directed towards the development of photoswitchable ligands with various sequence

Full text of DOI:10.1002/ejoc.200900323

FULL PAPER
DOI: 10.1002/ejoc.200900323
Photoswitchable Unsymmetrical Ligand for DNA Hetero-Mismatches
Chikara Dohno,[a] Tsuyoshi Yamamoto,[a] and Kazuhiko Nakatani*[a]
Keywords: DNA / Mismatch / Azobenzenes / Photoswitch / Nanostructures / Ligand design
Photoswitchable DNA-binding ligands should be useful for
controlling diverse biological functions involving DNA and
reversible assembly of DNA-based nanostructures. In work
directed towards the development of photoswitchable li-
gands with various sequence specificities, we have elabo-
rated an efficient synthesis of photoswitchable unsymmetri-
cal ligands possessing pairs of different base recognition ele-
ments. A novel photoswitchable ligand incorporating an acy-
lated aminonaphthyridine and an azaquinolone as its base
recognition elements can bind to the CAG/CAG sequence in
response to light stimuli.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
pression.[1,2] We have developed a series of synthetic ligands
Small molecules that recognize specific DNA sequences and that selectively bind to DNA bulges,[3] mismatch base
structures are promising therapeutic agents and molecular pairs,[4] and trinucleotide repeats.[5] Integration of photo-
tools for investigation and regulation of specific gene ex- chromic moieties into the ligands enables us to control the
Figure 1. (a) Structure of NA and its mode of binding to the CAG/CAG sequence. (b) Structures of NCAA and NAA and retro-synthesis
of NCAA. Ns denotes (2-nitrophenyl)sulfonyl.
ligand binding in a reversible manner through external light
[a] Department of Regulatory Bioorganic Chemistry, The Institute
stimuli.[6,7] Photoswitchable mismatch binding ligands
of Scientific and Industrial Research (SANKEN), Osaka Uni-
(photoswitchable MBLs) can control DNA hybridization
and secondary structure in response to light stimuli because
the ligand binding alters the stability of double-stranded
DNA.[6] The photoswitchable functions of such ligands
versity,
8-1 Mihogaoka, Ibaraki 567-0047, Japan
E-mail: nakatani@sanken.osaka-u.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900323.
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should be useful for controlling diverse biological functions with NBS to the corresponding azobenzene derivative 8.
involving DNA and for the construction of DNA-based Reduction of the ester moiety 8 then gave the azobenzene
nanoarchitectures.
derivative 1. The doubly functionalized azobenzene unit 1
A photoswitchable MBL consists of three parts: a photo- can be further converted into the unsymmetrically function-
chromic azobenzene group, base recognition elements, and alized dialdehyde equivalent 9. Compound 9 is also a useful
a connecting linker between them.[6] The first photoswitch- intermediate for the synthesis of photoresponsive hetero-
able MBL was a C2-symmetric compound targeting the GG dimeric ligands.
homo-mismatch, and was synthesized by a double reductive
amination of naphthyridine units with a symmetrical azo-
benzene dialdehyde.[6] Here we report the synthesis, based
on the coupling of two different base recognition elements
onto an unsymmetrically functionalized azobenzene unit,
of a photoswitchable MBL (naphthyridine-carbamate-and-
azaquinolone-functionalized azobenzene, NCAA) designed
to target a GA hetero-mismatch. The synthetic scheme de-
scribed here should be useful for the preparation of libraries
of photoswitchable MBLs targeting hetero-mismatches.
We have previously developed the ligand naphthyridine-
azaquinolone (NA, Figure 1a), possessing two different
base recognition elements.[5] The two heterocycles in NA,
an acylated aminonaphthyridine and an azaquinolone, can
form complementary hydrogen bonds with guanine and ad-
enine, respectively (Figure 1a). NA binds to a GA mis-
match,[4] and more strongly to a CAG/CAG sequence. A
key intermediate for the synthesis of NCAA is the unsym-
metrically substituted azobenzene derivative 1, which could
be modified with various combinations of recognition ele-
ments in a stepwise manner (Figure 1b). For evaluation of
the linker length connecting between the base recognition
groups and the photochromic azobenzene group, the pho-
toresponsive ligand naphthyridine-azaquinolone-function-
alized azobenzene (NAA, Figure 1b) was also synthesized.
Scheme 1. Synthesis of the azobenzene unit.
For the adenine recognition element we had previously
synthesized the 7-aminomethyl-8-azaquinolone derivative
15 (Scheme 2) through bromination of the 7-methyl-8-aza-
quinolone 10, but the bromination of 10 was poor in terms
both of chemical yield and reproducibility.[10] An improved
synthesis of 15 is shown in Scheme 2. The key step is the
Results and Discussion
NCAA was synthesized from three building blocks: the rearrangement of the N-oxide 11 to the corresponding hy-
photochromic azobenzene unit 1, the guanine-recognizing droxymethyl derivative 12.[11] The azaquinolone N-oxide 11
naphthyridine derivative 2, and the adenine-recognizing was readily prepared by oxidation of 10 with m-CPBA. The
azaquinolone derivative 3 (Figure 1b). The key azobenzene [3,3] sigmatropic rearrangement resulting in the oxidation
derivative 1 bears two functional groups with different oxi- of the C7-methyl group was conducted with trifluoroacetic
dation states, alcohol and aldehyde, at its two para posi- anhydride and subsequent hydrolysis of the trifluoroacetyl
tions. The hydroxymethyl and formyl groups are used for group to provide the alcohol 12 in 98% yield over two steps.
coupling reactions with base recognition elements through The alcohol 12 was converted into the iodide 14 in two
the Fukuyama–Mitsunobu reaction[8] and reductive amin- steps. Nucleophilic substitution of the iodide 14 with liquid
ation, respectively. In this synthetic scheme, the two func- ammonia gave 15. The desired azaquinolone building block
tional groups are both eventually converted into secondary 3 was obtained by coupling of 15 with β-alanine derivative
amino groups connected to the base recognition elements. 16, in which the carboxyl group was activated as a penta-
Secondary amino groups are effective for DNA binding be- fluorophenyl ester. The synthesis of the naphthyridine de-
cause the positive charges on the ammonium groups in- rivative 2, possessing a 2-nitrobenzenesulfonamide (nosyl
crease the affinity to DNAs and the solubility in water.
amide) moiety, from 2-amino-7-methyl-1,8-naphthyridine is
The azobenzene derivative 1 was synthesized from com- straightforward.[6]
mercially available methyl p-bromobenzoate (4, Scheme 1).
Coupling of the first base-recognition element 2 onto the
The aryl hydrazide 5 was obtained through a Pd-catalyzed azobenzene unit was carried out through a Fukuyama–Mit-
amidation reaction with tert-butyl carbazate.[9] Coupling sunobu reaction (Scheme 3).[8] The naphthyridine carb-
between 5 and the bromobenzene derivative 6 was ac- amate derivative 2, containing a nosyl-protected/activated
complished by use of Pd(OAc)2/P(tBu)3 as catalyst in 75% amine, underwent efficient monoalkylation with 1 under
yield,[9] and the resulting diarylhydrazide 7 was oxidized Mitsunobu conditions to give 18 in 91% yield. The N,N-
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Photoswitchable Unsymmetrical Ligand for DNA Hetero-Mismatches
Figure 2. UV/Vis spectra of NCAA (30 µ) in sodium cacodylate
(pH = 7.0, 10 m) and NaCl (100 m). The sample was irradiated
with 360 nm light for the indicated periods.
Scheme 2. Synthesis of the azaquinolone building block.
An absorption band observed at around 320 nm before
photoirradiation represents the summation of the absorp-
disubstituted sulfonamide was removed, and the resulting tion bands of an azobenzene π–π* transition and two
secondary amine was protected with a tBoc group to give heterocycles. Upon exposure to 360 nm light, the band in-
20. The acetal of 20 was readily removed by treatment with tensity at 320 nm decreased and the absorbance at around
pTsOH to give the aldehyde 21.
430 nm increased concurrently, with isosbestic points at 277
Coupling of the second base-recognition element 3 was and 385 nm. These spectral changes are characteristic of
carried out by reductive amination between 21 and 3 with trans to cis photoisomerization of azobenzenes.
use of NaBH3CN. Removal of the tBoc group in 22 gave
the target compound NCAA as a hydrochloride salt.
Photoisomerization of NCAA was further analyzed by
HPLC (Figure 3). Under ambient room-light conditions,
NAA was synthesized similarly by use of the azobenzene NCAA exists predominantly as the trans form (91%, Fig-
unit 9.[12]
ure 3a). Irradiation with 360 nm light for 5 min in sodium
Photoisomerization of NCAA in aqueous sodium caco- cacodylate buffer (pH = 7.0, 10 m) and NaCl (100 m)
dylate buffer (pH = 7.0, 10 m) and NaCl (100 m) was resulted in the formation of the equilibrium mixture of 67%
monitored by UV/Vis absorption spectroscopy (Figure 2).
cis isomer (Figure 3b). The mixture was converted back
Scheme 3. Synthesis of NCAA.
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C. Dohno, T. Yamamoto, K. Nakatani
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into the original state (92% trans isomer, Figure 3c) without
any by-products by irradiation at 430 nm for 5 min. Ther-
mal cis-to-trans isomerization of NCAA was slow (Ͻ10%
after 100 h incubation at 20 °C) and negligible under physio-
logical conditions.
Figure 4. CD spectra of DNA (2.3 µ) containing a CAG/CAG
sequence in the presence of NCAA. (a) CD spectra were measured
during titration with photoirradiated (67% cis) NCAA (0, 1.1, 2.3,
4.5, 9.1, 13.6, 18.2, 36.3 45.4 µ). Inset: titration with NCAA with-
out photoirradiation (91% trans). (b) Photoswitching of the NCAA
binding. Solid line: CD spectra after 360 nm irradiation. Dashed
line: subsequent 430 nm irradiation. Dotted line: subsequent
360 nm irradiation.
Figure 3. HPLC analysis of the photoisomerization of NCAA. The
peak with the longer retention time is attributed to trans-NCAA.
(a) Before irradiation, (b) after 360 nm irradiation for 5 min, (c)
subsequent irradiation at 430 nm for 5 min.
Conclusions
We have synthesized a new photoswitchable DNA-bind-
ing ligand containing two different base-recognition ele-
ments, NCAA, through the use of the bifunctional azoben-
zene derivative 1 as a key intermediate. NCAA recognized
DNA duplex containing a CAG/CAG sequence, and the
binding was reversibly regulatable by successive photoirra-
diation. The bifunctional azobenzene derivative 1 is a useful
intermediate for the synthesis of photoswitchable MBLs
containing various combinations of linkers and base-re-
cognition elements. A set of photoswitchable ligands for
various mismatch DNA sequences should be useful molecu-
lar tools for the regulation of DNA functions and the re-
versible assembly of DNA-based nanostructures.
Having established that NCAA undergoes reversible
isomerization by UV and visible light, we next examined
the interaction of NCAA with DNA. Figure 4a shows CD
spectra of the DNA duplex 5Ј-(CTAA CAG AATG)-3Ј/5Ј-
(CATT CAG TTAG)-3Ј, containing a target CAG/CAG
binding sequence, in the presence of NCAA. With increas-
ing concentrations of cis-NCAA, the induced CD bands de-
rived from the ligand binding were observed at 320 and
430 nm (Figure 4a). At around 320 nm the CD bands are
biphasic, suggesting an exciton coupling between naphthyr-
idine and azaquinolone chromophores. In marked contrast,
no induced CD band was observed in the presence of trans-
NCAA (Figure 4a, inset). These results indicate that the cis
isomer of NCAA made a significant contribution to binding
with the CAG/CAG sequence, whereas the trans isomer did
not. Similar CD spectra were observed with NAA, with its
different linker structure.[12] The induced CD bands gener-
ated by cis-NCAA disappeared as a result of cis-to-trans
isomerization after subsequent irradiation at 430 nm (Fig-
ure 4b). The binding of NCAA to the DNA duplex can be
controlled reversibly and repeatedly through a combination
of UV and visible-light irradiation.
The sequence selectivity of the NCAA binding was inves-
tigated by use of DNA duplexes 5Ј-(CTAA CXG AATG)-
3Ј/5Ј-(CATT CYG TTAG)-3Ј containing single mismatch
sites (X/Y). As would be expected from the base-recognition
properties of the acylated aminonaphthyridine and azaqui-
nolone, binding of cis-NCAA was also observed for the
CAG/CGG sequence as well as the CAG/CAG sequence,
but not for the other sequence.[12] The binding of NCAA to
the DNA duplex occurs in a sequence-selective manner,
which can be engineered by the combinations of base-re-
cognition moieties.
Experimental Section
General: Flash chromatography was performed with Wakogel (C-
300). 1H NMR and 13C NMR spectra were recorded with JEOL
LA-600 (600 MHz, 150 MHz) or JEOL LA-400 (400 MHz,
100 MHz) spectrometers with solvent resonances as the internal
standards (1H NMR, CDCl3 at δ = 7.26 ppm and CD3OD at δ =
3.31 ppm; 13C NMR, CDCl3 at δ = 77.2 ppm and CD3OD at δ
= 49.0 ppm) at room temperature unless otherwise noted. High-
resolution ESI mass spectrometry analysis was performed with a
JEOL JMS-T100LC AccuTOF mass spectrometer. Photoirradia-
tion was carried out with an ASAHI SPECTRA LAX-102 instru-
ment fitted with an appropriate band path filter.
tert-Butyl 2-[4-(1,3-Dioxolan-2-yl)phenyl]-1-[4-(methoxycarbonyl)-
phenyl]hydrazinecarboxylate (7): Compound 5 (1.17 g, 4.4 mmol),
2-(4-bromophenyl)-1,3-dioxolane (6; 884 mg, 3.9 mmol), palladi-
um(II) acetate (0.20 mmol), tri-tert-butylphosphane (0.22 mmol),
Cs2CO3 (1.9 g, 5.9 mmol), and toluene (30 mL) were placed under
argon in an oven-dried flask. The mixture was stirred at room tem-
perature for 20 min and was then heated at reflux and stirred for
an additional 14 h. The resulting mixture was allowed to cool to
room temperature and diluted with CHCl3. After filtration, the or-
ganic phase was concentrated in vacuo. The residue was purified
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Photoswitchable Unsymmetrical Ligand for DNA Hetero-Mismatches
by flash chromatography (AcOEt/hexane, 1:4) on silica gel to give
sulting mixture was heated at reflux for 18 h. The mixture was di-
rectly dried with MgSO4, and the solution was concentrated in
1
7 as a colorless oil (1.21 g, 75%). H NMR (600 MHz, CDCl3): δ
= 7.98 (d, J = 8.8 Hz, 2 H, Ar-H), 7.70 (d, J = 8.8 Hz, 2 H, Ar- vacuo. The crude mixture was purified by flash chromatography on
H), 7.35 (d, J = 8.5 Hz, 2 H, Ar-H), 6.76 (d, J = 8.6 Hz, 2 H, Ar-
H), 6.46 (s, 1 H, CH), 5.72 (s, 1 H, N–H), 7.2–3.9 (4 H, OCH2-
silica gel (CHCl3/MeOH, from 150:1 to 40:1) to afford 11 as a pale
yellow solid (4.2 g, 95%). H NMR (400 MHz, CD3OD): δ = 7.99
1
CH2O), 3.89 (s, 3 H, OCH3), 1.37 [s, 9 H, C(CH3)3] ppm. 13C NMR (d, J = 9.7 Hz, 1 H, Ar-H), 7.77 (d, J = 8.4 Hz, 1 H, Ar-H), 7.34
(600 MHz, CDCl3): δ = 166.8, 153.4, 148.7, 146.8, 130.7, 130.5, (d, J = 8.4 Hz, 1 H, Ar-H), 6.73 (d, J = 9.7 Hz, 1 H, Ar-H), 2.66
127.9, 125.6, 120.1, 116.5, 112.8, 103.8, 83.2, 65.3, 52.1, 28.1 ppm.
HRMS (ESIMS, positive-ion mode, MeOH): calcd. for
C22H26N2NaO6 [M + Na]+ 437.1689; found 437.1691.
(s, 3 H, CH3) ppm. 13C NMR (100 MHz, CD3OD): δ = 164.1,
151.1, 143.3, 140.6, 128.6, 124.6, 120.4, 116.7, 17.9 ppm. HRMS
(ESIMS, positive-ion mode, MeOH): calcd for C9H8N2NaO2 [M +
Na]+ 199.0484; found 199.0483.
Methyl 4-{[4-(1,3-Dioxolan-2-yl)phenyl]diazenyl}benzoate (8): N-
Bromosuccinimide (NBS; 789 mg, 4.5 mmol) was added to a solu-
tion of 7 (1.17 g, 2.82 mmol) in CH2Cl2 (16 mL). Immediately after
the addition of NBS, the color of the mixture changed to orange.
After the mixture had been stirred at ambient temperature for 2 h,
it was washed with saturated aqueous NaHCO3 and brine. The
organic layer was dried with anhydrous MgSO4 and filtered, and
the solvent was removed in vacuo. The residue was purified by flash
chromatography on silica gel (AcOEt/hexane, 1:8) to give 8 as an
orange solid (538.2 mg, 1.72 mmol). 1H NMR (400 MHz, CDCl3):
7-(Hydroxymethyl)-1,8-naphthyridin-2(1H)-one (12): Trifluoroacetic
anhydride (2 mL) was carefully added at 0 °C to a solution of 11
(62 mg, 0.35 mmol) in CHCl3 (1 mL), and the mixture was heated
at reflux for 15 min. The resulting solution was concentrated in
vacuo. The residue was dissolved in MeOH (3 mL). K2CO3
(155 mg, 1.12 mmol) was then added to the mixture, which was
stirred at 55 °C for 1 h. The resulting mixture was directly concen-
trated in vacuo. The residue was purified by flash chromatography
on silica gel (CHCl3/MeOH, from 100:1 to 20:1) to afford 12
1
δ = 8.20 (d, J = 8.5 Hz, 2 H, Ar-H), 7.97–7.94 (4 H, Ar-H), 7.65 (60.8 mg, 98%) as a white solid. H NMR (400 MHz, CD3OD): δ
(d, J = 8.1 Hz, 2 H, Ar-H), 5.90 (s, 1 H, 3-H), 4.18–4.06 (m, 4 H,
OCH2CH2O), 3.96 (s, 3 H, 1-H) ppm. 13C NMR (100 MHz, H), 7.41 (d, J = 8.0 Hz, 1 H, Ar-H), 6.62 (d, J = 9.5 Hz, 1 H, Ar-
CDCl3): δ = 166.5, 155.1, 153.0 141.3, 131.9, 130.6, 127.3, 123.1,
H), 4.74 (s, 2 H, CH2) ppm. 13C NMR (100 MHz, CD3OD): δ =
= 8.08 (d, J = 8.1 Hz, 1 H, Ar-H), 7.94 (d, J = 9.5 Hz, 1 H, Ar-
122.7, 103.1, 65.4, 52.3 ppm. HRMS (ESIMS, positive-ion mode, 166.1, 165.0, 150.1, 141.3, 138.3, 122.6, 116.8, 115.0, 65.8 ppm.
MeOH): calcd. for C17H16N2O4 [M + H]+ 313.1188; found
313.1183.
HRMS (ESIMS, positive-ion mode, MeOH): calcd. for
C9H8N2NaO2 [M + Na]+ 199.0484; found 199.0480.
(4-{[4-(1,3-Dioxolan-2-yl)phenyl]diazenyl}phenyl)methanol (1): DIBAL-
H (1  in CH2Cl2, 480 µL, 0.48 mmol) was added dropwise at 5 °C
to a solution of 8 (45 mg, 0.14 mmol) in THF (3 mL), and the
mixture was stirred at 5 °C for 1 h. The resulting mixture was care-
fully poured into an aqueous solution of sodium potassium tartrate
(1 , 3 mL) and stirred for 30 min. The mixture was extracted with
AcOEt, and the combined organic fractions were washed with
brine and dried with MgSO4, and the solvent was evaporated in
vacuo. The residue was purified by flash chromatography on silica
gel (AcOEt/hexane, 3:1) to afford 1 as an orange solid (39.1 mg,
7-(Chloromethyl)-1,8-naphthyridin-2(1H)-one (13): A mixture of 12
(23 mg, 0.13 mmol) and SOCl2 (500 µL) was stirred at 0 °C for sev-
eral minutes and then heated at reflux for 2 h. After cooling to
room temperature, the mixture was concentrated in vacuo. The resi-
due was diluted with CHCl3, washed with saturated aqueous
NaHCO3 solution, and dried with anhydrous MgSO4. After fil-
tration, the organic phase was concentrated to dryness. The residue
was purified by flash chromatography on silica gel (AcOEt/hexane,
3:1) to afford 13 (24 mg, 94%) as pale yellow needles. 1H NMR
(600 MHz, CD3OD): δ = 8.12 (d, J = 8.0 Hz, 1 H, Ar-H), 7.97 (d,
J = 9.5 Hz, 1 H, Ar-H), 7.44 (d, J = 7.7 Hz, 1 H, Ar-H), 6.67 (d,
J = 9.5 Hz, 1 H, Ar-H), 4.74 (s, 2 H, CH2) ppm. 13C NMR
(151 MHz, CD3OD): δ = 166.0, 160.0, 150.3, 140.9, 138.8, 123.6,
1
96%). H NMR (600 MHz, CDCl3): δ = 7.93 (d, J = 6.2 Hz, 2 H,
Ar-H), 7.92 (d, J = 5.9 Hz, 2 H, Ar-H), 7.63 (d, J = 8.4 Hz, 2 H,
Ar-H), 7.05 (d, J = 8.5 Hz, 2 H, Ar-H), 5.89 (s, 1 H, CH), 4.78 (s,
2 H, CH2), 4.2–4.0 (m, 4 H, OCH2CH2O), 1.87 (br, 1 H, OH) ppm. 119.3, 115.7, 47.1 ppm. HRMS (ESIMS, positive-ion mode,
13C NMR (150 MHz, CDCl3): δ = 153.2, 152.2, 144.2, 140.7, 127.5, MeOH): calcd. for C9H7ClN2NaO [M + Na]+ 217.0145; found
127.4, 123.3, 123.0, 103.4, 65.5, 65.0 ppm. HRMS (ESIMS, posi- 217.0147.
tive-ion mode, MeOH): calcd. for C16H17N2O3 [M + H]+ 285.1239;
7-(Iodomethyl)-1,8-naphthyridin-2(1H)-one (14): NaI (2.3 g,
found 285.1236.
15.4 mmol) was added to a stirred solution of 13 (1.0 g, 5.1 mmol)
4-{[4-(1,3-Dioxolan-2-yl)phenyl]diazenyl}benzaldehyde (9): Dess– in dry acetone (33 mL), and the resulting mixture was heated at
Martin periodinane (70 mg, 0.17 mmol) was added to a stirred
solution of 1 (47 mg, 0.17 mmol) in CH2Cl2 (5 mL). The solution
was stirred at room temperature for 1 h. The organic layer was
washed with water and dried with MgSO4. After removal of the
solvent, the mixture was purified by flash chromatography on silica
gel (AcOEt/hexane, 3:1) to give 9 as an orange solid (46 mg, 96%).
1H NMR (400 MHz, CDCl3): δ = 10.11 (s, 1 H, CHO), 8.05 (s, 4
H, Ar-H), 7.98 (d, J = 8.3 Hz, 2 H, Ar-H), 7.66 (d, J = 8.5 Hz, 2
reflux under argon for 2 h. The solvent was removed under reduced
pressure, and the residue was dissolved in CHCl3. The organic layer
was washed with water and dried with MgSO4. After filtration, the
organic phase was concentrated to dryness in vacuo to afford 14
1
(1.35 g, 92%) as a brown solid. H NMR (400 MHz, CD3OD) δ =
8.02 (d, J = 8.0 Hz, 1 H, Ar-H), 7.93 (d, J = 9.5 Hz, 1 H, Ar-H),
7.37 (d, J = 7.8 Hz, 1 H, Ar-H), 6.63 (d, J = 9.3 Hz, 1 H, Ar-H),
4.61 (s, 2 H, CH2) ppm. 13C NMR (150 MHz, CDCl3): δ = 163.3,
H, Ar-H), 5.91 (s, 1 H, CH), 4.2–4.0 (m, 4 H, OCH2CH2O) ppm. 160.2, 149.0, 138.6, 137.2, 123.6, 118.4, 114.1, 5.19 ppm. HRMS
13C NMR (150 MHz, CDCl3): δ = 191.8, 155.9, 153.1, 141.8, 137.6, (ESIMS, positive-ion mode, MeOH): calcd. for C9H8IN2O [M +
130.8, 127.5, 123.5, 123.4, 103.2, 103.2, 65.6 ppm. HRMS (ESIMS,
positive-ion mode, MeOH): calcd. for C16H15N2O3 [M + H]+
283.1083; found 283.1084.
Na]+ 308.9501; found 308.9493.
3-Amino-N-[(7-oxo-7,8-dihydro-1,8-naphthyridin-2-yl)methyl]pro-
panamide (3): Compound 14 (0.58 g, 2.4 mmol) was dissolved in
7-Methyl-1,8-naphthyridin-2(1H)-one 8-Oxide (11): mCPBA (70%, liquid ammonia (20 mL) at –78 °C, and the solution was stirred for
7.5 g, 14.8 mmol) in CHCl3 (30 mL) was slowly added to a stirred
solution of 10 (4.0 g, 25.0 mmol) in CHCl3 (30 mL), and the re-
3 h. The liquid ammonia was evaporated by removing the cooling
bath, and the reaction mixture was allowed to warm to room tem-
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perature to afford 15 quantitatively as a pale yellow solid. Com-
pound 16 (785 mg, 2.21 mmol) and diisopropyl(ethyl)amine (DI-
PEA, 850 µL, 4.9 mmol) were added to a stirred solution of 15
raphy on silica gel (AcOEt/hexane, 3:1) to give 18 (200 mg, 91%).
NMR analysis showed that 18 consists of 92% of the trans isomer
and of 8% of the cis isomer. NMR signals of the cis isomer are
(300 mg, 1.70 mmol) in DMF (15 mL). The resulting mixture was denoted by “cis”. 1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J =
stirred at 40 °C for 19 h. The solvent was evaporated in vacuo, and
the residue was diluted with CHCl3. The organic layer was washed
with saturated aqueous NaHCO3, and the mixture was dried with
MgSO4. After removal of the solvent under reduced pressure, the
resulting crude products were purified by flash chromatography on
silica gel (CHCl3/MeOH, 50:1) to afford Boc-protected 3 as a white
8.6 Hz, 1 H, Ar-H), 8.04–7.90 (2 H, Ar-H), 7.86 (d, J = 8.3 Hz, 1
H, Ar-H), 7.82–7.78 (4 H, Ar-H, NH), 7.65–7.58 (4 H, Ar-H), 7.54
(d, J = 8.6 Hz, 2 H, Ar-H), 7.41 (d, J = 8.3 Hz, 2 H, Ar-H), 7.32
(d, J = 8.3 Hz, cis), 7.16 (d, J = 8.3 Hz, 1 H, Ar-H), 6.77 (d, J =
8.5 Hz, cis), 6.74 (d, J = 8.0 Hz, cis), 5.82 (s, 1 H, CH), 5.66 (s,
cis), 4.57 (s, 2 H, ArCH2), 4.42 (s, cis), 4.1–3.9 (6 H, OCH2
+
1
solid (449 mg, 76%, 2 steps). H NMR (600 MHz, CD3OD): δ =
OCH2CH2O), 3.37 (t, J = 7.6 Hz, 2 H, CH2NH), 3.29 (t, J =
7.3 Hz, cis), 2.39 (s, 3 H, CH3), 1.80 (quint, J = 6.8 Hz, 2 H,
CH2CH2CH2), 1.67 (quint, J = 6.8 Hz, cis) ppm. 13C NMR
(400 MHz, CDCl3): δ = 163.0, 154.4, 152.8, 152.7, 152.4, 152.0,
147.8, 140.6, 138.8, 138.4, 136.2, 133.7, 132.8, 131.7, 130.8, 128.8,
128.5, 127.0, 126.9, 124.2, 123.2, 122.7, 121.2, 120.7, 120.1, 117.8,
112.3, 103.0, 102.7, 65.2, 62.5, 51.3, 44.3, 27.1, 25.4 ppm. HRMS
(ESIMS, positive-ion mode, MeOH): calcd. for C35H34N7O8S [M
+ H]+ 712.2190; found 712.2192.
8.03 (d, J = 7.9 Hz, 1 H, Ar-H), 7.93 (d, J = 9.5 Hz, 1 H, Ar-H),
7.23 (d, J = 7.9 Hz, 1 H, Ar-H), 6.62 (d, J = 9.5 Hz, 1 H, Ar-H),
4.54 (s, 2 H, CH2), 3.35 (t, J = 6.5 Hz, 2 H, tBocNHCH2), 2.48 (t,
J = 6.6 Hz, 2 H, COCH2), 1.41 [s, 9 H, C(CH3)3] ppm. 13C NMR
(100 MHz, CD3OD): δ = 174.2, 166.1, 161.7, 158.4, 150.3, 141.2,
138.4, 122.8, 117.8, 115.0, 80.2, 45.7, 38.0, 37.3, 28.8 ppm. HRMS
(ESIMS, positive-ion mode, MeOH): calcd. for C17H22N4NaO4 [M
+ Na]+ 369.1539; found 369.1539. Hydrogen chloride in AcOEt
(4 , 2 mL) was added to a solution of Boc-protected 3 (30.6 mg,
88.4 mmol) in CHCl3 (2 mL), and the mixture was stirred for 1 h.
The reaction mixture was concentrated to afford 3. 1H NMR
(600 MHz, D2O): δ = 7.83 (d, J = 8.0 Hz, 1 H, Ar-H), 7.83 (d, J
= 9.5 Hz, 1 H, Ar-H), 7.21 (d, J = 8.1 Hz, 1 H, Ar-H), 6.54 (d, J
= 9.5 Hz, 1 H, Ar-H), 4.51 (s, 2 H, CH2), 3.27 (t, J = 6.2 Hz, 2
H, NH2CH2), 2.78 (t, J = 6.6 Hz, 2 H, COCH2) ppm. 13C NMR
(150 MHz, D2O): δ = 173.3, 166.1, 159.9, 148.2, 141.7, 139.2, 121.3,
118.0, 115.0, 44.9, 36.3, 32.5 ppm. HRMS (ESIMS, positive-ion
mode, MeOH): calcd. for C12H15N4O2 [M + H]+ 247.1195; found
247.1199.
3-[(4-{[4-(1,3-Dioxolan-2-yl)phenyl]diazenyl}benzyl)amino]propyl (7-
Methyl-1,8-naphthyridin-2-yl)carbamate (19): 2-Mercaptoethanol
(33 mL, 0.48 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU;
72 mL, 0.48 mmol) were added to a stirred solution of 18 (200 mg,
0.28 mmol) in acetonitrile (4 mL). The resulting solution was
stirred at room temperature for 1 h. The solvent was evaporated
under reduced pressure. The crude mixture was purified by flash
chromatography on silica gel (CHCl3/MeOH, 50:1) to give 19 as a
pale yellow powder (141 mg, 96%). NMR analysis showed that 19
consists of 92% of the trans isomer and of 8% of the cis isomer.
NMR signals of the cis isomer are denoted by “cis”. 1H NMR
(400 MHz, CDCl3): δ = 8.21 (d, J = 8.8 Hz, 1 H, Ar-H), 8.07 (d,
J = 8.8 Hz, 1 H, Ar-H), 7.93 (d, J = 8.3 Hz, 1 H, Ar-H), 7.9–7.8
(4 H, Ar-H + NH), 7.59 (d, J = 8.3 Hz, 2 H, Ar-H), 7.47 (d, J =
8.3 Hz, 2 H, Ar-H), 7.2 (d, J = 8.3 Hz, 1 H, Ar-H), 6.83 (d, J =
8.6 Hz, cis), 6.79 (d, J = 8.3 Hz, cis), 5.87 (s, 1 H, CH), 5.70 (s,
cis), 4.32 (t, J = 6.3 Hz, 2 H, OCH2), 4.2–4.0 (4 H, OCH2CH2O),
3.89 (s, 2 H, ArCH2), 3.73 (s, cis), 2.79 (t, J = 6.6 Hz, 2 H,
CH2NH), 2.71 (s, 3 H, 1-H), 1.92 (quint, J = 6.8 Hz, 2 H,
CH2CH2CH2), 1.22 (s, 1 H, NH) ppm. 13C NMR (150 MHz,
CDCl3): δ = 163.2, 154.7, 153.5, 153.3, 153.2, 151.8, 140.5, 139.1,
136.5, 128.9, 127.3, 123.1, 122.9, 121.4, 120.9, 120.4, 118.0, 112.7,
103.3, 103.3, 65.5, 64.0, 53.6, 45.7, 29.2, 25.7, 25.7 ppm. HRMS
(ESIMS, positive-ion mode, MeOH): calcd. for C29H31N6O4 [M +
3-{[(2-Nitrophenyl)sulfonyl]amino}propyl (7-Methyl-1,8-naphthyr-
idin-2-yl)carbamate (2): Triethylamine (34 mL, 0.25 mmol) and 2-
nitrobenzene-1-sulfonyl chloride (46 mg, 0.21 mmol) were added at
0 °C to a stirred solution of 3-aminopropyl N-(7-methyl-1,8-
naphthyridin-2-yl)carbamate[6] (50 mg, 0.19 mmol) in CH2Cl2
(2 mL), and the mixture was stirred for 3.5 h. The organic layer
was washed with saturated aqueous NaHCO3 and brine. The or-
ganic phase was dried with anhydrous MgSO4. After filtration, the
solvent was removed under reduced pressure. The residue was puri-
fied by flash chromatography on silica gel (CHCl3/MeOH, 50:1) to
1
give 2 as a pale yellow powder (78 mg, 92%). H NMR (600 MHz,
CDCl3): δ = 8.22 (d, J = 8.8 Hz, 1 H, Ar-H), 8.16 (m, 1 H, Ar-H),
8.13 (d, J = 8.8 Hz, 1 H, Ar-H), 8.01 (d, J = 8.3 Hz, 1 H, Ar-H),
7.86 (m, 1 H, Ar-H), 7.8–7.6 (2 H, Ar-H), 7.67 (br, 1 H, NH), 7.28 H]+ 527.2407; found 527.2408.
(d, J = 8.3 Hz, 1 H, Ar-H), 5.78 (t, J = 6.2 Hz, 1 H, Ar-H), 4.31
3-[(tert-Butoxycarbonyl)(4-{[4-(1,3-dioxolan-2-yl)phenyl]diazenyl}-
(t, J = 5.9 Hz, 2 H, OCH2), 3.27 (q, J = 6.6 Hz, 2 H, CH2NH),
2.76 (s, 3 H, CH3), 1.98 (quint, J = 6.2 Hz, 2 H, CH2CH2CH2),
1.24 (s, 1 H, NH) ppm. 13C NMR (150 MHz, CDCl3): δ = 163.5,
154.8, 153.2, 153.2, 148.2, 139.3, 136.6, 133.8, 133.8, 133.0, 131.1,
125.6, 121.7, 118.2, 112.7, 62.6, 40.6, 29.5, 25.8 ppm. HRMS (ES-
IMS, positive-ion mode, MeOH): calcd. for C19H19N5NaO6S [M +
Na]+ 468.0954; found 468.0954.
benzyl)amino]propyl (7-Methyl-1,8-naphthyridin-2-yl)carbamate
(20): Compound 19 (141 mg, 0.27 mmol) and di-tert-butyl dicar-
bonate (118 mg, 0.54 mmol) were dissolved in CHCl3 (5 mL), and
the mixture was stirred at room temperature for 1.5 h. The resulting
mixture was concentrated in vacuo. The residue was purified by
flash chromatography on silica gel (CHCl3/MeOH, 50:1) to give 20
as an orange powder (172 mg, 100%). NMR analysis showed that
3-{(4-{[4-(1,3-Dioxolan-2-yl)phenyl]diazenyl}benzyl)[(2-nitrophenyl)- 20 consists of 89% of the trans isomer and of 11% of the cis isomer.
sulfonyl]amino}propyl (7-Methyl-1,8-naphthyridin-2-yl)carbamate
(18): Compound 1 (105 mg, 0.37 mmol) and PPh3 (123 mg,
0.47 mmol) in THF/CH2Cl2 (1:1, 4 mL), together with diethyl azo-
dicarboxylate (DEAD) in toluene (40 % solution, 229 mL,
0.47 mmol), were added at 0 °C under argon to a stirred solution
of 2 (137 mg, 0.31 mmol), and the mixture was stirred at room
temperature for 10 h. The organic layer was washed with saturated
aqueous NaHCO3 and brine. The organic phase was dried with
anhydrous MgSO4. After filtration, the solvent was removed under
reduced pressure. The residue was purified by flash chromatog-
NMR signals of the cis isomer are denoted by “cis”. 1H NMR
(600 MHz, CDCl3, 45 °C): δ = 8.21 (d, J = 8.8 Hz, 1 H, Ar-H),
8.11 (d, J = 8.8 Hz, cis), 8.06 (d, J = 8.8 Hz, 1 H, Ar-H), 7.98 (d,
J = 8.0 Hz, cis), 7.95 (d, J = 8.0 Hz, 1 H, Ar-H), 7.89–7.85 (4 H,
Ar-H + NH), 7.66 (br., 1 H, Ar-H), 7.60 (d, J = 8.4 Hz, 2 H, Ar-
H), 7.38 (br. d, J = 6.6 Hz, 2 H, Ar-H), 7.36 (d, J = 8.5 Hz, cis),
7.24 (d, J = 8.4 Hz, 1 H, Ar-H), 7.11 (br. d, J = 6.6 Hz, cis), 6.85–
6.80 (cis), 5.88 (s, 1 H, CH), 5.71 (s, cis), 4.53 (br., 2 H, CH2), 4.37
(br., cis), 4.22 (br., 2 H, CH2), 4.16–3.95 (4 H, OCH2CH2O), 3.36
(br., 2 H, CH2 NH), 2.75 (s, 3 H, CH3 ), 1.95 (br., 2 H,
4056
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4051–4058

Photoswitchable Unsymmetrical Ligand for DNA Hetero-Mismatches
CH2CH2CH2), 1.49 [br., 9 H, C(CH3)3] ppm. 13C NMR (150 MHz, CH2NH), 2.79 (t, J = 7.0 Hz, 2 H, CH2NH), 2.72 (s, 3 H, CH3),
CDCl3): δ = 163.3, 156.0, 155.7, 154.4, 154.1, 153.5, 153.2, 153.1,
152.3, 152.0, 146.8, 141.9, 141.7, 140.6, 139.2, 137.0, 128.6, 128.1,
127.9, 127.4, 127.3, 123.3, 123.0, 121.5, 121.1, 120.5, 118.1, 112.8,
103.4, 103.3, 103.2, 85.3, 80.3, 65.5, 63.6, 51.1, 50.2, 44.3, 43.9,
28.5, 27.9, 27.5, 25.5, 1.3, 1.1 ppm. HRMS (ESIMS, positive-ion
mode, MeOH): calcd. for C34H39N6O6 [M + H]+ 627.2931; found
627.2923.
2.51 (t, J = 6.2 Hz, 2 H, CH2CO), 1.94 (quint, J = 6.6 Hz, 2 H,
CH2CH2CH2) ppm. 13C NMR (150 MHz, CDCl3): δ = 172.8,
164.0, 163.3, 160.3, 154.8, 153.6, 153.4, 151.8, 151.8, 149.3, 143.5,
143.0, 139.1, 139.1, 137.3, 136.5, 128.9, 128.9, 123.1, 123.0, 122.9,
121.5, 118.1, 117.9, 113.8, 112.8, 64.1, 53.7, 53.3, 45.8, 45.1, 44.7,
35.9, 29.4, 25.7 ppm. HRMS (ESIMS, positive-ion mode, MeOH):
calcd. for C39H40N10NaO4 [M + Na]+ 735.3132; found 735.3138.
3-[(tert-Butoxycarbonyl){4-[(4-formylphenyl)diazenyl]benzyl}-
amino]propyl (7-Methyl-1,8-naphthyridin-2-yl)carbamate (21):
Compound 20 (171 mg, 0.27 mmol) and p-toluenesulfonic acid
(PTSA, 77 mg, 0.41 mmol) were dissolved in water/THF (1:25,
5 mL). The mixture was stirred at 50 °C for 1 h. The mixture was
extracted with CHCl3 and dried with anhydrous MgSO4. After fil-
tration, the organic layer was concentrated in vacuo. The residue
was purified by flash chromatography on silica gel (CHCl3/MeOH,
50:1) to give an orange powder (147 mg, 94 %). NMR analysis
showed that 21 consists of 92% of the trans isomer and of 8% of
the cis isomer. NMR signals of the cis isomer are denoted by “cis”.
1H NMR (600 MHz, CDCl3, 45 °C): δ = 10.10 (s, 1 H), 9.92 (s,
cis), 8.22 (d, J = 8.5 Hz, 1 H), 8.08 (d, J = 8.8 Hz, 1 H), 8.05–7.98
(4 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.92 (d, J = 8.1 Hz, 2 H), 7.78 (d,
J = 7.3 Hz, cis), 7.60 (br., 1 H), 7.42 (br., 2 H), 7.25 (d, J = 11.7 Hz,
1 H), 7.12 (br., cis), 6.94 (d, J = 8.0 Hz, cis), 6.83 (d, J = 7.7 Hz,
cis), 4.55 (br., 2 H, CH2), 4.23 (br., 2 H, CH2), 3.35 (br., 2 H,
CH2NH), 2.75 (s, 3 H, CH3), 1.96 (br., 2 H, CH2CH2CH2), 1.50
[br., 9 H, C(CH3)3] ppm. 13C NMR (150 MHz, CDCl3): δ = 163.4,
156.0, 154.8, 153.3, 153.1, 152.0, 142.9, 142.7, 139.1, 137.5, 136.5,
130.8, 128.6, 128.0, 123.7, 123.4, 121.5, 120.4, 118.1, 112.6, 80.4,
63.7, 63.6, 51.1, 50.3, 44.3, 44.0, 29.8, 28.5, 27.6, 27.5, 25.7 ppm.
HRMS (ESIMS, positive-ion mode, MeOH): calcd. for
C32H34N6NaO5 [M + Na]+ 605.2488; found 605.2480.
Measurements of UV/Vis Spectra: NCAA (30 µ) was dissolved in
a sodium cacodylate buffer (10 m, pH = 7.0) containing NaCl
(100 m). UV/Vis absorption spectra were recorded with
a
Beckman Coulter DU® 800 spectrometer in a 1 cm pathlength cell
at ambient temperature before and after photoirradiation at
360 nm for the indicated time period.
HPLC Analysis: A solution (total volume 100 µL) containing
NCAA (40 µ) in sodium cacodylate buffer (10 m, pH = 7.0) and
aqueous NaCl (100 m) was exposed to 360 and 430 nm light for
5 min. After the photoirradiation, the sample solution was ana-
lyzed by reversed-phase HPLC on a Cosmosil packed column (Na-
calai tesque, 4.6ϫ150 mm) fitted with a photodiode array detector
(Jasco, MD-2010); elution was carreid out with a solvent mixture
of 0.1% trifluoroacetic acid/water and 0.1% trifluoroacetic acid/
acetonitrile (5–30% for 25 min) at a flow rate of 1.0 mLmin–1. The
cis/trans ratios were determined by the HPLC peak areas deter-
mined at the isosbestic point (277 nm).
Circular Dichroism (CD) Measurements: CD experiments were per-
formed with a J-725 CD spectrometer (Jasco). CD spectra of DNA
[2.3 µ, 5Ј-d(CTAA CAG AA TG)-3Ј/5Ј-d(CATT CAG TTAG)-3Ј]
in sodium cacodylate buffer (10 m, pH = 7.0), NaCl (100 m)
and Tween 20 (0.1%) were measured in the presence of different
concentration of NCAA at 25 °C. For the titration with cis-NCAA,
pre-photoirradiated NCAA (360 nm irradiation for 5 min, 67% of
cis isomer) was used instead of the dark equilibrated NCAA (91%
of trans isomer).
({3-[4-({4-[(3-Oxo-3-{[(7-oxo-7,8-dihydro-1,8-naphthyridin-2-yl)-
methyl]amino}propyl)amino]methyl}phenyl)diazenyl]benzyl}amino)-
propyl (7-Methyl-1,8-naphthyridin-2-yl)carbamate (NCAA): Com-
pounds 21 (147 mg, 0.25 mmol) and 3 (77 mg, 0.31 mmol) were
dissolved in CHCl3/methanol (2:1, 15 mL), and the pH of the mix-
ture was adjusted to 5–6 by addition of acetic acid. The mixture
was stirred at room temperature for 30 min. Sodium cyanoborohyd-
ride (19.5 mg, 0.31 mmol) in MeOH (1 mL) was then added to the
stirred solution. The mixture was stirred at room temperature for
10 h. The resulting mixture was washed with saturated aqueous
NaHCO3 and brine, and dried with MgSO4. After concentration,
the mixture was purified by flash chromatography on silica gel
(CHCl3/MeOH, 50:1) to give 22 (114 mg, 56%). Hydrogen chloride
in ethyl acetate (4 , 5 mL) was added to a solution of 22 (114 mg,
141 mmol) in CHCl3 (5 mL), and the mixture was stirred for 1 h.
The reaction mixture was concentrated to afford NCAA as a hydro-
chloride salt (101.6 mg). For NMR analysis NCAA was neutralized
with saturated aqueous NaHCO3. The solution was extracted sev-
eral times with CHCl3, and the combined organic layers were dried
with anhydrous MgSO4. After filtration, the solvent was removed
under reduced pressure. NMR spectra of this residue were mea-
sured without further purification. 1H NMR (600 MHz, CDCl3): δ
= 10.84 (br., 1 H, NH), 8.54 (br., J = 5.8 Hz, 1 H, NH), 8.24 (d, J
= 8.8 Hz, 1 H, Ar-H), 8.09 (d, J = 8.8 Hz, 1 H, Ar-H), 7.96 (d, J
= 8.0 Hz, 1 H, Ar-H), 7.82 (d, J = 8.4 Hz, 2 H, Ar-H), 7.78 (d, J
= 8.1 Hz, 1 H, Ar-H), 7.74 (d, J = 8.4 Hz, 2 H, Ar-H), 7.62 (d, J
= 9.5 Hz, 1 H, Ar-H), 7.46 (d, J = 8.1 Hz, 2 H, Ar-H), 7.37 (d, J
= 8.4 Hz, 2 H, Ar-H), 7.23 (d, J = 8.0 Hz, 1 H, Ar-H), 7.21 (d, J
= 7.7 Hz, 1 H, Ar-H), 6.60 (d, J = 9.5 Hz, 1 H, Ar-H), 4.64 (d, J
= 5.9 Hz, 2 H, ArCH2), 4.33 (t, J = 6.2 Hz, 2 H, OCH2), 3.89 (s,
2 H, ArCH2), 3.86 (s, 2 H, ArCH2), 2.97 (t, J = 6.2 Hz, 2 H,
Supporting Information (see footnote on the first page of this arti-
cle): CD spectra with different DNAs and synthetic details of NAA.
Acknowledgments
This work was supported by a Grant in Aid for Scientific Research
(S) from the Japan Society for the Promotion of Science (18105006)
to K. N.
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Received: March 25, 2009
Published Online: July 2, 2009
4058
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Eur. J. Org. Chem. 2009, 4051–4058