Naphthalimide-thiazoles as novel photonucleases: Molecular design, synthesis, and evaluation

Article abstract of DOI:10.1016/j.tetlet.2003.11.145

A new family of photonucleases, naphthalimide-thiazoles was synthesized and evaluated. These compounds intercalated into DNA efficiently and damaged DNA photochemically at concentrations as low as 5μM. Mechanistic experiment suggests that a novel naphthalimide-thiazole radical produced via an excited triple state might be involved in the DNA photodamage. Different activity may arise from the impact of substituents at 2-phenyl ring of thiazole on the electron population of excited triple state according to AM1 semi-empirical calculation.

Full text of DOI:10.1016/j.tetlet.2003.11.145

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1247–1251
Naphthalimide–thiazoles as novel photonucleases: molecular design,
synthesis, and evaluation
Yonggang Li,a,c Yufang Xu,a,c Xuhong Qianb,* and Baoyuan Qua,c
aEast China University of Science and Technology, Shanghai 200237, China
bState Key Lab. Fine Chemicals, Dalian University of Technology, Dalian 116012, China
cShanghai Key Lab. Chem. Biology, Shanghai 200237, China
Received 2 May 2003; revised 22 November 2003; accepted 27 November 2003
Abstract—A new family of photonucleases, naphthalimide–thiazoles was synthesized and evaluated. These compounds intercalated
into DNA efficiently and damaged DNA photochemically at concentrations as low as 5 lM. Mechanistic experiment suggests that a
novel naphthalimide–thiazole radical produced via an excited triple state might be involved in the DNA photodamage. Different
activity may arise from the impact of substituents at 2-phenyl ring of thiazole on the electron population of excited triple state
according to AM1 semi-empirical calculation.
ꢀ 2003 Elsevier Ltd. All rights reserved.
The design of novel photonucleases is of great signifi-
cance from the standpoints of chemistry, biology, and
medicine. Activated by the ultra-violet or visible light,
these photocleavers can cause DNA scission via radi-
cals, active oxygen species or electron transfer mecha-
nisms.1 As for radicals generators, it is of interest to
incorporate new functional groups into the design of
new types of photonucleases. HechtÕs group has
reported that halogen and carbon-centered thiazole
radicals are produced via photohomolysis of carbon–
halogen bonds in halo-bithiazole compounds and that
halogen radicals play a major role in the DNA damage
event.2 Other forms of thiazole radicals and their pro-
duction of DNA damage have not been reported yet.
However, the conjugated C@N bond in aromatic het-
erocycles was reported to generate the photoexcited3
(n ꢀ pꢁ) state, which would have radical character and
could be able to cleave DNA photochemically.3
Continuing our research that is focused on the DNA
photodamage induced by oxygen-centered radicals,4 a
new family of photonucleases, which might produce a
novel naphthalimide–thiazole radical as the photo-
cleaving group via an excited triple state, is designed and
evaluated herein.
Thiazole or polythiazole is known as the sequence
recognition moiety, which appears in several photo-
nucleases and anti-cancer bleomycin antibiotics.2b;5 We
expected that conjugated thiazole itself might be a novel
DNA photocleaving group based on relevant refer-
ences.3 Inspired by these reports, a series of novel
photonucleases containing a 2-phenyl (or substituted
phenyl) thiazole and a naphthalimide group the A1–A6
were designed (Fig. 1) in our study. Here, thiazole was
introduced as photocleaving group and a conjugated
naphthalimide as a potent intercalation moiety, because
it was reported that 2+1 unfused tri-cyclic aromatic
systems were Ôminimal intercalatorsÕ.6 Furthermore, a
N,N-dimethylaminoethyl group was incorporated for
enhanced DNA affinity, because it commonly appears in
clinically useful anti-cancer drugs that interact with
DNA, such as amonafide and mitonafide.7
N
R= H
R= p
A1
A2
A3
A4
A5
O
CH3
OCH3
Cl
OH
NO2
N
S
p
R
R=
N
R= o
o
R=
O
A6 R= m
* Corresponding author. Tel.: +86-411-3673466; fax: +86-411-3673-
488; e-mail addresses: xhqian@dlut.edu.cn; xhqian@ecust.edu.cn
Figure 1. A new family of photonucleases A1–A6.
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.145

1248
Y. Li et al. / Tetrahedron Letters 45 (2004) 1247–1251
O
O
O
N
NH
2
b
O
O
O
SH
O
N
O
a
c
NO
2
O
O
O
d
Br
N
S
N
S
Scheme 1. Synthesis of thiazole–naphthalimide. (a) Na2S2, H2O, 8 h; (b) HCl; (c) benzaldehyde, HOAc, Ar, reflux, 4 h, 61% yield; (d) N,N-
dimethylethylenediamine, ethanol, reflux, 2.5 h, 83% yield.
These compounds were synthesized from 4-bromo-3-
nitro-1, 8-naphthalic anhydride3c as shown in Scheme 1
(with compound A1 as an example):8 4-bromo-3-nitro-1,
8-naphthalic anhydride was reacted with sodium disul-
fide, by refluxing for 8 h in water. Since it was difficult to
acidify the reaction mixture to form 4-mercapto-3-
aminonaphthalic anhydride, due to its instability in air,
was dropped in situ into glacial acetic acid containing
benzaldehyde, and then refluxed for 4 h. This Ôone potÕ
synthesis gave the 2-phenyl thiazole conjugated naph-
thalic anhydride. The obtained anhydride was con-
densed with N,N-dimethylethylenediamine in ethanol to
form the designed product. Structures were identified by
fluorescence quantum yields are very low, which might
be caused by excitation energy being transferred from
the singlet excited state to the triplet excited state, or
dissipated as heat through the internal conversion sys-
tem.
Using A2 as an example, the Scatchard binding con-
stant10 between it and CT-DNA (in 30 mM Tris–HCl
buffer, pH 7.5) was determined to be 1.19 · 105 Mꢀ1
indicating that efficient DNA binding.
,
The photoinduced relaxation of plasmid DNA by
compounds A1–A6 was assayed with supercoiled
pBR322DNA with a transluminator (366 nm) at a dis-
tance of 20 cm at 0 ꢁC for 3 h and analyzed on a 1%
agarose gel. The photocleavage efficiency was defined by
the degree of the relaxation of supercoiled DNA to the
relaxed circular form (form II, single-strand cleavage). It
was apparent from Figure 2 that the photocleaving
activity of A1, without a substituent (R@H) on phenyl
moiety, was stronger than those of analogues A2–A6,
1
IR, H NMR, MS, and element analysis.9
The UV–vis and fluorescence data for A1–A6 are shown
in Table 1. The maximal absorptions of A2, A3, and A5,
with electron-donating groups on 2-phenyl ring, are
around 386 nm, and the others around 376 nm. The
maximal emission wavelengths were obviously different
from each other (from 412 to 491 nm) by comparison of
their absorptions. The red-shift tendency in fluorescence
for A2, A3, and A5 is the same as that in absorption,
which is caused by that the presence of electron-donat-
ing groups on the 2-phenyl ring that enhance the elec-
tronic pushing–pulling effects for this ICT molecule. The
great changes in fluorescence wavelength implies that
there are great differences in the photophysical proper-
ties of their excited states due to the different pushing–
pulling effects of the substituents. In addition, their
a;b
Table 1. UV–vis and fluorescence data of A1–A6
Compound
UVkmax/nm (lge)
FLkmax/nm (U)
A1
A2
A3
A4
A5
A6
376 (3.85)
384 (3.78)
386 (3.76)
376 (4.13)
387 (3.85)
376 (3.90)
425 (0.006)
447 (0.009)
491 (0.017)
417 (0.003)
436 (<0.001)
412 (0.002)
Figure 2. Photocleavage of closed supercoiled DNA in 10% aceto-
nitrile in Tris–HCl buffer. (a) Photoirradiation: 3 h; lane 1: DNA alone
(no hm); lane 2: DNA alone; lanes 3–8: DNA and compound A1–A6 at
concentration of 100 lM, respectively. (b) Lane 1: DNA alone (no hm);
lane 2: DNA alone (hm, 3 h); lanes 3–8: DNA and A1 at concentration
of 2, 5, 10, 20, 50, 100 lM, respectively.
a In absolute ethanol.
b With quinine sulfate in sulfuric acid as quantum yield standard.

Y. Li et al. / Tetrahedron Letters 45 (2004) 1247–1251
1249
with a strong electron-donating or electron-withdrawing
group. A1 caused the obvious single-strand cleavage at
concentration as low as 5 lM and led to total single-
strand cleavage at a concentration of 100 lM (Fig. 2). It
was more active than its parent compound, 1,8-naph-
thalimide, which only caused 27% of single-strand
cleavage of pUC19 plasmid DNA under irradiation at a
concentration of 50 lM.11 Further experiments showed
that the photocleaving activity of A1 was sensitive to
pH. With the elongation of irradiation time, it photo-
nicked DNA more intensely. However, no DNA dam-
age was observed in the absence of light.
photoirradiation, which might damage DNA by
hydrogen abstraction.
As seen in Figure 2, the photocleaving activities were
in the following order: A1(H) > A4(o-Cl) > A2(p-
Me) > A6(m-NO2) > A3(p-OMe) > A5(o-OH). A1, with-
out a substituent on phenyl moiety, was the most
effective photocleaver. This contradicts the idea that a
strong electron-donating group would improve the sta-
bility of a radical and the Ôheavy atom effectÕ, which
would be favorable to the presence of the triplet-excited
state in a chemical system.
Mechanistic experiments were also performed with the
addition of histidine (singlet oxygen quencher), dithio-
threitol (DTT, superoxide radical scavenger), super-
oxide dismutase (SOD, superoxide radical killer), and
dimethyl sulfoxide (radical scavenger), respectively
(Fig. 3). It is clear that the DNA-cleaving activity of A1
decreases greatly in the presence of dimethyl sulfoxide
(lane 7 and 8) and that a radical is involved in the
photodamage of pBR322DNA. Organic triple states
have been demonstrated to react with DNA and indi-
vidual nucleotides via electron transfer or hydrogen
abstraction pathways.12 The excited triple state of
naphthalimide or thioxo-naphthalimide (without sub-
stituents on the naphthalene ring), which can damage
DNA only via electron transfer, have also been reported
by Saito, Kelly, and our group.11;13 However, in our
case, the DNA cleavage ability mainly comes from the
formation of naphthalimide–thiazole radical under
We did not find any steric effects on photocleaving
abilities of substituents on 2-phenyl ring by molecular
modeling (Pcmodel 6.0). With AM1 semi-empirical
quantum calculations (Hyperchem 5.5), no obvious
relationship was observed between the electron densities
in the ground state or excited singlet state of those
substituents and their photocleaving abilities. However,
it was found from AM1 calculations that the electron
clouds in the triplet state of these compounds (except
A6) were mainly concentrated on the thiazole ring, and
the electron clouds density on C@N bond of A1 was
higher than those of A2–A5 (with A1 and A3 as examples
in Figure 4). In addition, only A1 has obvious electron
density on the nitrogen atom of thiazole ring. The other
compounds have almost ÔnakedÕ nitrogen atoms. It was
inferred that concentrated electronic clouds on the thi-
azole ring and the C@N bond in the triplet state possibly
granted it high reactivity. A6 was an exception, the
electron clouds were populated mostly on the nitro
group in the triple state. Thus, the reactivity of A6
possibly arose from the nitro group in the triple state,14
although we cannot exclude the participation of thiazole
ring.
In conclusion, the present work demonstrates the design
and evaluation of novel photonucleases, thiazole–
naphthalimides A1–A6, using conjugated thiazole ring as
a novel photocleaving group. These compounds possibly
cleave circular supercoiled pBR322 DNA efficiently via
non-diffusible radical mechanism under the irradiation
of long-wavelength UV light (366 nm). Unsubstituented
A1 showed stronger DNA photocleaving ability than
A2–A6, with electron-withdrawing or electron-pushing
substituents on the phenyl ring. These compounds may
have anti-cancer activities and cytotoxicity studies are in
progress.
Figure 3. Mechanistic experiments of A1 on the photocleavage of
DNA. Photoirradiation: 3 h; lane 1: DNA alone (no hm); lane 2: DNA
alone; lane 3: DNA and compound A1 (30 lM); lane 4: DNA and A1
(30 lM) in the presence of histidine (6 mM); lane 5: DNA and A1
(30 lM) in the presence of dithiothreitol (DTT, 30 mM); lane 6: DNA
and A1 (30 lM) in the presence of superoxide dismutase (SOD, 100 lg/
mL). Photoirradiation: 2 h; lane 7: DNA and compound A1 at con-
centration of 100 lM in 10% DMSO in Tris–HCl buffer, respectively;
lane 8: DNA and A1 at concentration of 100 lM in 10% acetonitrile in
Tris–HCl buffer.
Figure 4. Electron clouds population of A1 and A3 simulated with AM1 semi-empirical calculation.

1250
Y. Li et al. / Tetrahedron Letters 45 (2004) 1247–1251
J ¼ 4:54 Hz, 3H, 30-H, 40-H, 50-H), 8.03 (t, J1 ¼ 7:79,
Acknowledgements
J2 ¼ 7:57, 1H, 2-H), 8.17–8.25 (m, 2H, 20-H, 60-H), 8.56 (d,
J ¼ 6:97, 1H, 1-H), 8.67 (d, J ¼ 49, 1H, 3-H), 8.95 (s, 1H,
7-H). HR-MS: C23H19N3O2S calculated: 401.1198; Found:
401.1186; m=z (%) 401 (Mþ) (5.46), 343 (5.73), 313 (8.58),
285 (9.97), 157 (7.56), 71 (41.4), 58 (100). IR (KBr): 2960,
2800, 1700, 1660, 1320, 780 cmꢀ1. Elemental analysis:
C23H19N3O2S: Calcd: C 68.81, H 4.77, N 10.47; Found: C
68.54, H 4.89, N 10.51.
The National Natural Science Foundation of China,
The Ministry of Education of china and the Shanghai
Foundation of Science and Technology supported this
study financially.
1
References and notes
A2: mp 202–203 ꢁC. H NMR (d6-DMSO) d (ppm): 2.31
(s, 6H, NCH3), 2.43 (s, 5H, NCH2, 40-CH3), 4.22 (s, 2H,
CONCH2), 7.46 (d, J ¼ 7:91 Hz, 2H, 30-H, 50-H), 8.03 (t,
J1 ¼ 7:81, J2 ¼ 7:83, 1H, 2-H), 8.10 (d, J ¼ 7:85 Hz, 2H,
20-H, 40-H), 8.57 (d, J ¼ 7:19, 1H, 1-H), 8.66 (d, J ¼ 8:11,
1H, 3-H), 8.94 (s, 1H, 7-H). EIMS: m=z (%) 415 (Mþ)
(15.48), 371 (3.51), 327 (5.66), 299 (6.45), 157 (6.50), 71
(71.0), 58 (100). IR (KBr): 2960, 2820, 1700, 1660, 1325,
790 cmꢀ1. Elemental analysis: C24H21N3O2S: Calcd: C
69.38, H 5.09, N 10.11; Found: C 69.30, H 4.71, N 10.25.
1. (a) Burrows, C. J.; Muller, J. G. Chem. Rev. 1998, 98,
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1
A3: mp 216–217 ꢁC. H NMR (d6-DMSO) d (ppm): 2.27
(s, 6H, CH3), 2.61 (s, 2H, NCH2), 3.89 (s, 3H, 40-OCH3),
4.21 (t, 2H, J1 ¼ 6:56, J2 ¼ 6:64, CONCH2), 7.19 (d,
J ¼ 8:66 Hz, 2H, 30-H, 50-H), 8.01 (t, J1 ¼ 7:77, J2 ¼ 7:77,
1H, 2-H), 8.15 (d, J ¼ 8:50 Hz, 2H, 20-H, 40-H), 8.55 (d,
J ¼ 7:28, 1H, 1-H), 8.63 (d, J ¼ 8:18, 1H, 3-H), 8.91 (s,
1H, 7-H). HRMS; C24H21N3O3S: Calcd: 431.1304; Found:
431.1311; m=z (%) 431(Mþ) (3.39), 386 (2.49), 343 (1.70),
246 (1.69), 157 (1.75), 71 (73.67), 58 (100). IR (KBr): 2970,
2810, 1700, 1665, 1330, 780 cmꢀ1. Elemental analysis:
C24H21N3O3S: Calcd: C 66.80, H 4.91, N 9.74; Found: C
66.94, H 4.73, N 10.03.
1
A4: mp 235–237 ꢁC. H NMR (d6-DMSO) d (ppm): 2.28
(s, 6H, CH3), 2.62 (d, 2H, J ¼ 1:44, NCH2), 4.19 (t, 2H,
J1 ¼ 6:78, J2 ¼ 6:81, CONCH2), 7.59–7.67 (m, 2H, 30-H,
50-H), 7.74–7.78 (m, 1H, 40-H), 7.99 (t, J1 ¼ 7:74,
J2 ¼ 7:75, 1H, 2-H), 8.38 (dd, J1 ¼ 1:78, J2 ¼ 7:50, 1H,
60-H), 8.54 (d, J ¼ 7:32, 1H, 1-H), 8.70 (d, J ¼ 8:17, 1H,
3-H), 8.94 (s, 1H, 7-H). HRMS: C23H18ClN3O2S Calcd:
435.0808; Found: 435.0792; m=z (%) 435 (Mþ) (5.06), 377
(2.45), 347 (4.14), 319 (4.03), 259 (1.14), 157 (7.16), 71
(67.76), 58 (100). IR (KBr): 2980, 2800, 1700, 1660, 1340,
780 cmꢀ1. Elemental analysis: C23H18ClN3O2S: Calcd: C
63.37, H 4.16, N 9.64; Found: C 63.42, H 4.43, N 9.35.
A5: mp 240–241 ꢁC. 1H NMR(d6-DMSO) d (ppm): 2.27 (s,
6H, CH3), 2.60 (s, 2H, NCH2), 4.21 (t, 2H, J1 ¼ 6:88,
J2 ¼ 6:95, CONCH2), 7.07 (t, 1H, J1 ¼ 7:39, J2 ¼ 7:32,
50-H), 7.15 (d, 1H, J ¼ 8:21, 30-H), 7.44–7.48 (m, 1H, 40-H),
7.99 (t, J1 ¼ 7:76, J2 ¼ 7:81, 1H, 2-H), 8.30 (dd, J1 ¼ 1:46,
J2 ¼ 8:11, 1H, 60-H), 8.53 (d, J ¼ 7:25, 1H, 1-H), 8.71 (d,
J ¼ 8:10, 1H, 3-H), 8.94 (s, 1H, 7-H). HRMS;
C23H19N3O3S Calcd: 417.1147; Found: 417.0342; m=z
(%) 417 (Mþ) (6.20), 372 (2.65), 358 (3.38), 300 (4.03),
259 (4.62), 156 (8.19), 71 (100), 58 (88.55). IR (KBr): 2980,
2800, 2500 (Br), 1700, 1660, 1330, 780 cmꢀ1. Elemental
analysis C23H19N3O3S: Calcd: C 66.17, H 4.59, N 10.07;
Found: C 66.34, H 4.78, N 9.89.
A6: mp 229–230 ꢁC. 1H NMR (d6-DMSO) d (ppm): 2.27 (s,
6H, CH3), 2.59 (s, 2H, NCH2), 4.21 (s, 2H, CONCH2), 7.91
(d, 1H, J ¼ 5:55, 50-H), 7.96–8.05 (m, 1H, 40-H), 8.39–8.47
(m, 1H, 60-H), 8.49–8.53 (m, 2H, 2-H, 20-H), 8.54–8.70 (m,
1H, 1-H), 8.76–8.84 (m, 1H, 3-H), 8.85–8.95 (m, 1H, 7-H).
EI-MS; m=z (%) 446 (Mþ) (1.47), 388 (1.05), 358.0 (1.79),
342 (1.10), 258 (1.62), 157 (1.98), 71 (41.03), 58 (100). IR
(KBr): 2970, 2800, 2750, 1700, 1660, 1525, 1340, 780 cmꢀ1
.
Elemental analysis C23H18N4O4S: Calcd: C 61.87, H 4.06,
N 12.55; Found: C 62.03, H 4.31, N 12.79.
10. Gupta, M.; Ali, R. J. Biochem. 1984, 95, 1253–1257.
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61–65.
9. A1: mp 220–221 ꢁC. H NMR (d6-DMSO) d (ppm): 2.25
(s, 8H, NCH2, CH3), 4.20 (s, 2H, CONCH2), 7.66 (d,
1

Y. Li et al. / Tetrahedron Letters 45 (2004) 1247–1251
1251
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