Thio-bisnaphthalimides as Heavy-Atom-Free Photosensitizers with Efficient Singlet Oxygen Generation and Large Stokes Shifts: Synthesis and Properties

Article abstract of DOI:10.1021/acs.orglett.6b02902

By structure transformation of benzo[k,l]thioxanthene-naphthalimide derivatives (ND-S), a novel series of nonplanar thio-heterocyclic bisnaphthalimide derivatives are designed and synthesized. They display high molar absorptivity and large Stokes shifts. They are also heavy-atom-free photosensitizers with high singlet oxygen quantum yields of 0.75 and 0.82. Thus, these new structures based on the naphthalimide skeleton have great potential for singlet oxygen applications.

Full text of DOI:10.1021/acs.orglett.6b02902

Letter
pubs.acs.org/OrgLett
Thio-bisnaphthalimides as Heavy-Atom-Free Photosensitizers with
Efficient Singlet Oxygen Generation and Large Stokes Shifts:
Synthesis and Properties
†
†
,†
†
†
‡
†
Lei Zhang, Zhisong Huang, Dongdong Dai, Yansheng Xiao, Kecheng Lei, Shaoying Tan,
†
,‡
,†
Jiagao Cheng, Yufang Xu,* Jianwen Liu,* and Xuhong Qian*
†State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China
University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
‡
State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China
University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
*
S Supporting Information
ABSTRACT: By structure transformation of benzo[k,l]-
thioxanthene-naphthalimide derivatives (ND-S), a novel series
of nonplanar thio-heterocyclic bisnaphthalimide derivatives are
designed and synthesized. They display high molar absorptivity
and large Stokes shifts. They are also heavy-atom-free
photosensitizers with high singlet oxygen quantum yields of
0
.75 and 0.82. Thus, these new structures based on the
naphthalimide skeleton have great potential for singlet oxygen
applications.
inglet oxygen sensitizers are versatile molecules and have1
research, a large number of naphthalimide and heterocyclic
S
been widely applied in photodynamic therapy (PDT).
fused naphthalimide derivatives have been reported as efficient
11
Upon photoexcitation, the photosensitizer enters a triplet
DNA photocleavers, while the mechanisms of photocleavage
are the induced generation of a hydroxyl radical, superoxide
excited state (T ) via intersystem crossing (ISC) and reacts
1
1
2
12
with triplet molecular oxygen to produce singlet oxygen ( O ).
anion, and singlet oxygen after DNA intercalating. Moreover,
2
One of the most common approaches to facilitate the ISC
process is to introduce heavy atom effects, i.e. transition metal
complexes with Ru(II), Ir(III), and Pt(II) or iodo-/bromo-
naphthalimide-based metal complexes have been reported with
a long-lived T
transfer (MLCT) at the excited state.
state because of the metal-to-ligand energy
1
11d,13
However, further
2b,3
containing compounds.
However, such photosensitizers
applications of naphthalimide derivatives as singlet oxygen
sensitizers are seldom reported. Inspired by the previous studies
containing heavy atoms have often been reported to exhibit
4
7,8
strong dark cytotoxicity. Also, it is not always easy to modify a
of heavy-atom-free photosensitizers, we consider developing
5
chromophore with heavy atoms. Thus, intense efforts have
some new singlet oxygen sensitizers based on the naphthali-
mide skeleton.
been devoted to the development of efficient heavy-atom-free
Our group has reported the synthesis of a series of benzo-
heterocycle substituted naphthalimides and evaluated their
photosensitizers for singlet oxygen applications.
Developing heavy-atom-free photosensitizers is challenging.
Some effective examples are listed as follows: Akkaya et al.
6
14
7
abilities as effective DNA photocleavers. According to their
synthetic methods, we anticipated that using naphthalimide
instead of a benzene ring might afford some novel nonplanar
bisnaphthalimide derivatives (Scheme 1) to simulate the
twisted cores of bay-substituted PDIs, which have been
reported the orthogonal boron-dipyrromethene (BODIPY)
dimers as heavy-atom-free photosensitizers which displayed
8
singlet oxygen quantum yields of 0.46−0.51. Fu et al. designed
several diperylene diimide (di-PDI) derivatives with high ISC
rates for singlet oxygen generation, harnessing enhanced spin−
orbital coupling of twisted di-PDI cores. Besides, the
substituted perylene diimide (PDI) derivatives at core positions
were also identified as efficient heavy-atom-free photosensi-
9
reported with efficient singlet oxygen productions. Based on
the above considerations, we designed and synthesized some
novel thio-heterocyclic bisnaphthalime derivatives and eval-
uated their photophysical characteristics. Finally, we found that
these thio-bisnaphthalimide derivatives demonstrated brilliant
singlet oxygen generation along with heavy-atom-free proper-
ties.
9
tizers. Nevertheless, these structures still show some limits in
synthesis and structural derivation.
As is well-known, Naphthalimide is a facile chromophoric
scaffold, exhibiting considerable molar absorptivity, low toxicity,
and high photostability, and has been routinely employed in
Received: September 27, 2016
10
developing fluorescent probes and anticancer drugs. In recent
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02902
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Design Concept from ND-S and PDI to Thio-
bisnaphthalimide
Figure 1. UV−vis absorption (A) spectra and fluorescent emission (B)
spectra of 6a, 6b−s, 6c, and ND-S in DMSO. Excitation wavelength:
4
60 nm, slit (6a, 6b−s, and 6c): (10, 10); slit (ND-S): (5, 2.5). The
final concentrations of all compounds: 5 μM.
Scheme 2 summarizes the synthetic routes of thio-
bisnaphthalimide compounds 6a−6c. Naphthalic anhydride
and Table 1 were mainly obtained in DMSO (the data obtained
in ethanol were shown in Figure S2 and Table S1). All of the
Scheme 2. Synthesis of Thio-bisnaphthalimide Derivatives
Table 1. Optical Properties of 6a, 6b−s, 6c, and ND-S
compd
6a
6b−s
6c
ND-S
b
λabs (nm)
371, 459
600
371, 460
601
371, 457
585
460
b
λem (nm)
520
,
ab
Stokes shift (nm)
141
141
128
57
ε (M cm−1
−
1
)
b
23200
0.012
0.75
16600
0.011
0.82
10800
0.013
18600
0.81
0.05
c
ΦF
d
ΦΔ
−
b
a
Stokes shifts were listed in units of nanometers. The spectroscopic
properties were measured in DMSO. Yields were calculated with N-
c
butyl-4-butylamino-naphthalimide as standard (0.81 in ethanol), and
d
the above data were obtained in DMSO. Yields were calculated with
Methylene blue as the standard (0.52 in acetonitrile).
thio-naphthalimide derivatives showed two separated absorp-
tion peaks at around 370 and 460 nm, while the benzo[k,l]-
thioxanthene-naphthalimide derivative (ND-S) had only one
peak at 460 nm (Table 1). The molar extinction coefficients of
−
1
−1
6
a and 6b−s in DMSO were 23 200 and 16 600 M cm ,
respectively. It suggested that they exhibited comparatively high
absorptive abilities in the visible region, while 6c displayed a
weaker absorptive ability (ε = 10 800 M− cm ). Besides, the
derivatives displayed broad emission spectra and the emission
maxima of 6a and 6b−s were around 600 nm (red shift about
1
−1
7
0 nm related to ND-S). Hence, the Stokes shifts were as large
16
as 141 nm, which minimized self-quenching via homo-FRET.
In addition, the UV−vis absorption and fluorescent emission
spectra of 6a and 6b−s upon variation of concentrations were
evaluated in ethanol (Figure S3). Almost no shift was observed
during the tests, which claimed that the molecular aggregation
had a negligible effect on large Stokes shifts. For fluorescence,
by comparison of ND-S, all of the thio-bisnaphthalimide
derivatives were weakly emissive while the fluorescence
quantum yields of 6a and 6b−s were determined to be around
0.01 in both ethanol and DMSO. We consequently supposed
that efficient ISC processes might have happened in these
compounds upon light irradiation.
derivatives 1 and 2 were reacted in ethylene glycol monomethyl
ether to produce additional product 3, which was then reduced
in HCl-SnCl to generate 4. Subsequently, substitution of 4
2
with different primary amines in ethanol obtained the key
intermediates 5a−5c. At last, the thio-bisnaphthalimide
precursors 5a−5c were diazotized in the presence of sodium
nitrite and then cyclized by a copper-catalyzed reaction to
afford 6a−6c through a one-pot synthesis (yields: 40−
1
4b,15
5
2%).
Moreover, to improve the solubility of the
morpholine-substituted derivative, 6b was treated with HCl in
ethanol solution (1 mol/L) to prepare 6b−s, which displayed
The singlet oxygen generation of these thio-bisnaphthalimide
derivatives were examined in air saturated acetonitrile with 1,3-
−1
1
characteristic peaks at the 2200−2700 cm region in infrared
spectroscopy (Figure. S1). Compared to the poor solubility of
compound 6c, 6a and 6b−s were soluble in multiple organic
solvents including CH Cl , CH OH, DMSO, DMF, etc.
diphenyl-isobenzofuran (DPBF) as the O scavenger and
2
methylene blue (MB) as the reference photosensitizer. Because
the light irradiation at 460 nm could cause photobleaching of
DPBF, we chose 470 nm as the experimental excitation
wavelength for activating 6a and 6b−s. Figures 2 and S4
showed the absorbance values of DPBF at 410 nm decreased
upon different irradiation times. There was no obvious change
2
2
3
The UV−vis absorption and fluorescence emission spectra of
6
a, 6b−s, and 6c were acquired in DMSO and ethanol. Due to
the low solubility of 6c in ethanol, the data listed in Figure 1
B
DOI: 10.1021/acs.orglett.6b02902
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
oxygen sensitizers in PDT research. However, we also noted
that photosensitive abilities were influenced by the relatively
low water solubility of novel compounds. Further studies on
improving these properties are under investigation.
To rationalize the abnormal ISC processes and spectral
behaviors of 6a and 6b−s, theoretical computational studies of
ground states and excited states were performed and optimized
by time-dependent density functional theory (TD-DFT)
calculations at the B3LYP/6-31G(d) level (Figures S7 and
S8). The optimized ground state geometries demonstrated that
6
a and 6b−s displayed slightly twisted planars with the addition
of a sulfur atom, which might decrease the self-aggregation of
these thio-bisnaphthalimide derivatives. Table 2 listed the
8b
Figure 2. Absorbance values (at 410 nm) of DPBF (100 μM) in air
saturated acetonitrile decreased upon time. The compounds’
concentration: 3 μM.
Table 2. Lowest Vertical Singlet and Triplet Electronic
Energies and Oscillator Strengths (f) of 6a and 6b−s at the
TD-B3LYP/6-31G(d) Level of Theory
in DPBF alone solution (no added compounds). When 6a and
compd
state
E (eV)
f
ΔE (S −T , eV)
n m
6b−s were added to the DPBF solution, the absorbance
6
a
S1
2.14
2.70
1.42
1.94
2.63
2.04
2.68
1.51
1.87
2.66
0.029
0.482
−
−
−
0.055
0.530
−
−
−
−
−
decreased dramatically upon light irradiation (470 nm), which
suggested that singlet oxygen had been produced in abundance.
However, only a slight decrease was detected with the addition
of ND-S. The relative singlet oxygen quantum yields were
determined by comparison to methylene blue (whose yield was
S3
T1
T2
T3
S1
0.72 (S →T )
1 1
0.20 (S →T )
1 2
0.07 (S →T )
3 3
2
b
6
b−s
−
−
0
.52 in acetonitrile ). Both two thio-bisnaphthalimide
derivatives exhibited noteworthy yields of 0.75 (6a) and 0.82
6b−s), respectively (much higher than ND-S of 0.05, showing
S2
T1
T2
T3
0.53 (S →T )
1 1
(
0.17 (S →T )
1 2
in Table 1). These results were in accordance with the
proposed efficient ISC processes from the singlet excited state
to the triplet excited state. Besides, when fixing the wavelength
and density of excitation light, the decreased absorbance of
DPBF had a linear relationship with respect to the duration of
irradiation. As a control, to verify the key role of oxygen in the
decrease of DPBF’s absorbance, 6a and 6b−s were further
treated in deoxygenated solutions (Figures S5 and S6). The
changes of absorbance value at 410 nm reduced significantly
relative to the results in air saturated situations. It indicated that
singlet oxygen generations were suppressed when removing the
oxygen of solutions. The above results confirmed that these
new thio-bisnaphthalimide compounds were highly efficient
and stable singlet oxygen sensitizers.
Subsequently, the photocytotoxic effects of these thio-
bisnaphthalimide derivatives were studied on human gastric
carcinoma cells (MKN45) for PDT evaluation. After 20 min of
treatment, both 6a and 6b−s displayed valid cytotoxic activities
with IC50 values of 13.2 and 31.4 μM, respectively, while the
control group without laser irradiation showed negligible cell
death above 50 μM (Figure 3). These data proved that 6a and
0.02 (S →T )
2 3
TD-B3LYP/6-31G(d) vertical excitation energies for the singlet
and triplet excited states of 6a and 6b−s based on their
optimized geometries of ground states. The calculations
predicted notable transitions from S to S (for 6a) and from
0
3
S to S (for 6b−s) according to the oscillator strengths. The
0
2
transition energies in Table 2 were consistent with the
determined data from absorption spectra (2.71 eV for 6a and
17
2
.70 eV for 6b−s). However, the calculated transition
energies between S1 and S0 were much lower than the
excitation energies. These results might lead to the large Stokes
shifts of thio-bisnaphthalimide derivatives. More importantly,
ISC processes of 6a and 6b−s were characterized by the low
energy gaps between singlet excited states and triplet excited
states (Table 2), which indicated that the S −T ISC channels
n
m
were energetically accessible for 6a (i.e., S → T , S → T , and
1
1
1
2
S → T ) and 6b−s (i.e., S → T , S → T , and S → T ), in
3
3
1
1
1
2
2
3
accordance with the previous experimental observations of high
18
singlet oxygen quantum yields.
6b−s might be utilized in potential applications as singlet
In summary, we have designed and synthesized a novel series
of nonplanar thio-heterocyclic thio-bisnaphthalimide derivatives
from single naphthalimide structures by a facile synthetic route.
These outstanding structures (6a and 6b−s) displayed high
singlet oxygen quantum yields of 0.75 and 0.82 without heavy
atoms, demonstrating that they were efficient singlet oxygen
sensitizers. MTT assays also proved their possible application in
PDT research. Furthermore, the photophysical properties of 6a
and 6b−s demonstrated that they both had brilliant light
absorptive abilities and large Stokes shifts. Additionally,
theoretical calculations illustrated the slightly twisted planars
of the thio-bisnaphthalimide cores for decreasing the self-
aggregations and demonstrated that the efficient ISC processes
were due to the low singlet−triplet energy gaps of 6a and 6b−s.
We believe that these thio-bisnaphthalimide structures would
Figure 3. MTT assays of 6a and 6b−s exposed with laser irradiation of
2
0
and 28.8 J/cm in MKN45 cells. All the data above are presented as
mean ± SD (n = 3 per group). Significant differences are considered as
p < 0.05; **p < 0.01; ***p < 0.001.
*
C
DOI: 10.1021/acs.orglett.6b02902
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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* Supporting Information
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02902.
Experimental procedures and characterization data
(
PDF)
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Corresponding Authors
*E-mail: yfxu@ecust.edu.cn.
*E-mail: liujian@ecust.edu.cn.
*E-mail: xhqian@ecust.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is financially supported by the National Natural
Science Foundation of China (Grants 21236002), the National
High Technology Research and Development Program of
China (863 Program 2011AA10A207), and the Fundamental
Research Funds for the Central Universities.
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