Intramolecular Electrophilic Cyclization Approach to 6-Substituted Naphtho[2,1- b]benzofurans: Novel Dual-State Emissive Fluorophores with Blue Emission

Article abstract of DOI:10.1021/acscombsci.9b00006

A regiospecific synthesis of naphtho[2,1-b]benzofurans with a substituent at the C6 position was achieved via intramolecular 6-endo-dig electrophilic cyclization under acidic conditions to construct the central aromatic C ring. Screening of the synthesize

Full text of DOI:10.1021/acscombsci.9b00006

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Article
Intramolecular Electrophilic Cyclization Approach to 6-
Substituted Naphtho[2,1-b]benzofurans: Novel Dual-
State Emissive Fluorophores with Blue Emission
Dileep Kumar Singh, Kyungkuk Jang, Jinhwang Kim, Jeeyeon Lee, and Ikyon Kim
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.9b00006 • Publication Date (Web): 29 Mar 2019
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Intramolecular Electrophilic Cyclization Approach to 6-Substituted
Naphtho[2,1-b]benzofurans: Novel Dual-State Emissive Fluorophores with
Blue Emission
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a,
b
a
,b
,a
‡
‡
Dileep Kumar Singh, Kyungkuk Jang, Jinhwang Kim, Jeeyeon Lee,* and Ikyon Kim*
a College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University
85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea
b College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National
University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
‡ These authors contributed equally.
* Corresponding authors.
Tel.: +82 32 749 4515; fax: +82 32 749 4105; e-mail: ikyonkim@yonsei.ac.kr
Tel.: +82 2 880 2471; fax: +82 2 884 8334; e-mail: jyleeut@snu.ac.kr
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Table of Contents
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Abstract:
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A regiospecific synthesis of naphtho[2,1-b]benzofurans with a substituent at the C6 position
has been achieved via intramolecular 6-endo-dig electrophilic cyclization under acidic
conditions to construct the central aromatic C ring. Screening of the synthesized compounds
using a high-content imaging system enabled us to discover novel dual state emissive
compounds 2{1,6}, 2{1,8}, and 2{4,3}, which are highly emissive with blue emission in their
solid states as well as in solution states in most solvents. In addition, the compounds 2{4,3},
2{4,12}, and 2{5,13} were found to be the most cell permeable in HeLa cells for live cell
imaging with negligible phototoxicity.
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Keywords: Naphtho[2,1-b]benzofuran; Sonogashira coupling; Intramolecular reaction;
Electrophilic reaction; Polycycles; Heteroaromatics; Fluorescence.
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Introduction
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Polycyclic heteroaromatic compounds represent an important class of organic functional
materials with aromaticity exhibiting various biological, electrochemical, and photochemical
properties.1-7 Among the various applications of heteroaromatic scaffolds, the development of
novel fluorescent probes is immensely powerful in biomedical research, particularly for
bioimaging applications.8-10 Desirable features of fluorescent probes for bioimaging are better
photostability and higher contrast of fluorescence. Aggregation-caused quenching (ACQ)
effects of conventional fluorophores, such as pyrene, perylene, and naphthalene diimide (NDI),
are detrimental to practical applications in bioimaging, optoelectronic materials, and sensors.11-
13 Aggregation-induced emission (AIE) or Aggregation-induced emission enhancement (AIEE)
molecules have shown great potential as a new modality because they are not quenched at high
concentrations.14-18 Nonradiative deactivation pathways observed in solutions can be
suppressed by restricted intramolecular rotation (RIR) in highly concentrated solutions or in
solid states, leading to a better contrast in fluorescence imaging. To date, a variety of AIE
luminogens with their quantum yields (QY) close to unity have been developed, but there still
remains a solubility issue in most systems for bioimaging applications, thus requiring
nanoparticle fabrication processes for enhanced cellular uptake.19
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Novel fluorophores with high fluorescence in solution as well as in solid states are highly
demanded for bioimaging and biosensors, but such probes are still limited.20-25 In particular,
blue fluorescent materials functioning in solution and solid states are still rare and in high
demand for high performance blue OLEDs.26-28 In addition, dual state emission (DSE)
molecules that are emissive in all types of solvents are rarely encountered.29-31 To overcome
the practical limits of conventional fluorophores, extensive synthetic efforts have been
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dedicated to identify new polycyclic heteroaromatic scaffolds. The development of novel
emissive scaffolds can be more efficiently implemented in combinatorial approaches along
with a high content imaging system, since cell permeability, photostability, and cytotoxicity
are not predictable from the rational design of biosensors in the context of the cellular system.4,
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As part of our continued efforts toward benzofurans,33-39 we recently became interested in
regiospecific construction of benzofuran-containing polycyclic structures.40-41
Scheme 1. Synthetic plans
(a) via intramolecular alkyne carbonyl metathesis
R
R
O
O
5
6
5
6
or
O
O
5- and 6-acylnaphtho[1,2-b]benzofurans
O
5
R
6
O
G
5-acylnaphtho[2,1-b]benzofurans
(b) via intramolecular electrophilic ring closure
Sonogashira
coupling
1.
2.
D
5
I
C
electrophilic
cyclization
A
B
O
6
R
O
1
G
G
this work
2
In particular, employing intramolecular alkyne carbonyl metathesis enabled us to install an acyl
moiety to naphtho[1,2-b]benzofurans or naphtho[2,1-b]benzofurans in a regiospecific manner
in the course of the central aromatic ring formation (Scheme 1(a)). During this study, we
expected that sequential Sonogashira coupling42-45 and 6-endo-dig electrophilic cyclization46-
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of 3-(2-iodophenyl)benzofurans (1) would lead to naphtho[2,1-b]benzofurans with a
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9
substituent at the C6 position (Scheme 1(b)).50 Despite the importance of this core skeleton in
the area of organic electronic devices,51-54 only a limited number of synthetic approaches in
which expensive metal catalysts and/or harsh reaction conditions were used have appeared in
the literature.55-60 These shortcomings as well as a great interest in furan-fused polycyclic
systems for optoelectronic applications61 encouraged us to evaluate our route to this polycyclic
heteroaromatic scaffold, which is the focus of this study.
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Results and discussion
For reaction optimization, we used 3-arylbenzofuran 1{1} which was prepared by following
the previous procedure.40, 62 Sonogashira coupling of 1{1} with phenylacetylene 3{1} in the
presence of (Ph3P)2PdCl2 (0.1 equiv) and CuI (0.1 equiv) in Et3N at 80 °C afforded 4{1,1}.
Scheme 2. Synthesis of 2{1}
TFA
3
DCE
Ph {1}
5
I
cat. (Ph3P)2PdCl2
cat. CuI
80 °C
93%
Ph
6
Ph
O
O
O
MeO
MeO
MeO
Et3N, 80 °C
88%
1
4
2
{1,1}
{1}
{1,1}
After screening of the several reaction conditions, we found that exposure of 4{1,1} to catalytic
amount of InCl3 (0.05 equiv) at 80 °C for 12 h gave the tetracyclic product 2{1,1} in 85% yield.
However, full conversion was not observed in some substrates where other alkynes were
attached although the reason is not clear. It turned out that PtCl2, Bi(OTf)3, or AgOTf was
ineffective in this transformation. Finally, it was discovered that heating of 4{1,1} in TFA/1,2-
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dichloroethane (DCE) (=1/2) at 80 °C for 0.5 h cleanly provided the desired 2{1,1} in excellent
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yield.
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Having established the optimal conditions, reaction scope was first examined with substrates
4{1,2-9} with different R groups (Table 1). Benzofurans 1{1-6} and terminal alkynes 3{1-13}
for Sonogashira coupling are listed in Figures 1 and 2. Not only electron-rich aryl groups but
also electron-poor aryl moiety were well tolerated under these conditions to afford the
corresponding 6-arylnaphtho[2,1-b]benzofurans in good to excellent yields (entries 1-6). A
naphtho[2,1-b]benzofuran-bearing heterocycle such as thiophene was also produced in 63%
yield (entry 7). However, only a trace amount of the product was obtained with alkyl-
substituted benzofuran 4{1,9} (entry 8). Next, this sequence was applied to the other
benzofurans 1{2-6}63 with different alkynes to further demonstrate a wide substrate scope
(entries 9-19). Overall, the desired tetracyclic skeletons were established in good overall yields
without side products.
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Figure 1. Benzofurans 1{1-6}
I
I
I
O
O
O
MeO
1{1}
1{2}
1{3}
OMe
OMe
1{5}
7
I
I
I
MeO
MeO
O
MeO
O
O
MeO
CHO
1{4}
1{6}
Figure 2. Terminal Alkynes 3{1-13}
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OMe
OMe
7
8
9
3{1}
3{2}
3{3}
Me
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OMe
Me
3{4}
3{7}
3{5}
3{6}
3{9}
S
Cl
3{8}
OMe
CF3
OMe
F
3{10}
3{13}
3{11}
3{12}
Table 1. Synthesis of Diverse 6-Substituted Naphtho[2,1-b]benzofuransa
3
TFA/DCE
80 °C
R
I
cat. (Ph3P)2PdCl2
cat. CuI, Et3N
80 °C
R
R
O
O
O
G
G
G
2
4
1
entry
1
alkyne
4b
2b
4{1,2}
2{1,2}
(88)
1
1{1}
3{2}
(85)
O
MeO
OMe
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4{1,3}
2{1,3}
(90)
2
3
4
1{1}
1{1}
1{1}
3{3}
3{4}
3{5}
(83)
O
MeO
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OMe
4{1,4}
2{1,4}
(78)
(90)
O
MeO
Me
4{1,5}
2{1,5}
(86)
(91)
O
MeO
Me
4{1,6}
2{1,6}
(76)
5
6
1{1}
1{1}
3{6}
3{7}
O
(78)
MeO
OMe
4{1,7}
(80)
2{1,7}
(74)
O
MeO
Cl
4{1,8}
(83)
2{1,8}
(63)
7
8
1{1}
1{1}
3{8}
3{9}
O
MeO
S
4{1,9}
(98)
trace
2{1,9}
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4{2,1}
(92)
2{2,1}
(77)
9
1{2}
1{2}
3{1}
3{7}
O
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4{2,7}
(66)
2{2,7}
(89)
10
O
Cl
4{3,10}
(62)
2{3,10}
11
12
1{3}
1{3}
3{10}
3{4}
(95)
O
OMe
MeO
4{3,4}
(79)
2{3,4}
(88)
O
Me
4{4,3}
(81)
2{4,3}
(92)
MeO
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14
1{4}
1{4}
3{3}
O
MeO
OMe
4{4,11}
(93)
2{4,11}
MeO
MeO
3{11}
(78)
O
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MeO
4{4,12}
(81)
2{4,12}
15
1{4}
3{12}
(86)
O
MeO
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CF3
OMe
4{5,1}
(94)
2{5,1}
(84)
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17
18
1{5}
1{5}
1{6}
3{1}
3{13}
3{1}
O
MeO
OMe
4{5,13}c
2{5,13}
(69)
(65)
O
MeO
F
OMe
4{6,1} c
(62)
2{6,1}
(77)
O
MeO
CHO
OMe
4{6,2}c
(65)
2{6,2}
(76)
19
1{6}
3{2}
O
MeO
CHO
OMe
a A mixture of 1, terminal alkyne (1.1 equiv), (Ph3P)2PdCl2 (0.1 equiv), CuI (0.1 equiv) in Et3N
was stirred at 80 °C. A solution of 4 in TFA/DCE (1/2) was heated at 80 °C for 1 h. b Isolated
yield (%). c DIPEA/DMF (1/2) was used instead of Et3N.
With the synthesized compounds in hand, we investigated the optical properties of the
naphtho[2,1-b]benzofurans series and summarized the absorption and emission maxima along
with the quantum yields in Table 2. Figure 3 depicts the UV/Vis absorption and emission
spectra of representative compounds. The absorption maxima of the compounds were observed
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at approximately 300−350 nm, whereas emission maxima were observed at approximately 380
−450 nm in DMSO. The observed large Stokes shift up to 100 nm that avoids reabsorption of
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emitted photons is a critical parameter for bioimaging applications. Structure-property
relationship analysis based on the optical properties revealed that electron-donating -OCH3
groups attached to the A ring increased the redshifts of emission spectra, whereas the electron-
withdrawing groups (-Cl and -CF3) in the E ring resulted in a redshift of emission maxima
(Figure S1).
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Figure 3. Absorption (a) and emission (b) spectra of 2{1,2}, 2{1,6}, 2{1,8}, 2{2,1}, 2{4,3},
2{4,11}, and 2{4,12} measured in DMSO.
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λem (nm)
εmax (M-1cm-1)
λabs (nm)
ΦF (Solution)
Compound
DW
EtOH
DMSO
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2{1,1}
2{1,2}
2{1,3}
2{1,4}
2{1,5}
2{1,6}
2{1,7}
2{1,8}
2{2,1}
2{2,7}
2{3,10}
2{3,4}
2{4,3}
2{4,11}
2{4,12}
2{5,1}
2{5,13}
2{6,1}
2{6,2}
329
331
328
328
329
308
328
332
321
322
325
324
342
350
355
322
322
354
311
420.5
412.5
413.5
431.5
411.5
425.5
430.5
412.5
380
389.5
384.5
390.5
388
400.5
393.5
401.5
397.5
399.5
406
18600
23200
18600
18800
18800
32800
17900
20100
19300
21700
14400
21800
22800
20700
18400
15900
14900
15400
22100
0.60
0.74
0.67
0.62
0.57
0.78
0.63
0.63
0.38
0.45
0.39
0.51
0.66
0.70
0.72
0.52
0.58
0.06
0.03
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389
393.5
393.5
385.5
379.5
383.5
382.5
379.5
404.5
402
408.5
394
384.5
388.5
387
386
392
406
383.5
425
435.5
426.5
447.5
444.5
452
423
424.5
398.5
405.5
478
449
412
423
-
-
473.5
487
424.5
Table 2. Optical properties of 6-substituted naphtho[2,1-b]benzofurans.
By using a high-content imaging system, we also screened the synthesized compounds for live
cell imaging in HeLa cells and the compounds 2{4,3}, 2{4,12}, and 2{5,13} were found to be
the most cell permeable, located in the cytosol of HeLa cell (Figure S2 and Figure S3).
Meanwhile, 2{1,6} and 2{1,8} exhibited high fluorescence via aggregation induced emission
properties. The phototoxicities of these compounds were found to be negligible (Figure S4).
Figure 4 depicts DSE properties of 2{1,6}, 2{1,8}, and 2{4,3}. The increase of water contents
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resulted in fluorescence enhancement up to 70% of water in THF, but fluorescence decrease
was observed at > 70% of water contents. These compounds possessed high QYs in ethanol
solution and in solid states (Figure 5 and Table 3). DLS analysis showed that the particle sizes
of 2{1,6}, 2{1,8}, 2{4,3}, and 2{4,12} are 211 nm, 208 nm, 167 nm, and 200 nm, respectively
(Figure S5). In addition, they exhibited high fluorescence in most solvents, except water
(Figure S6).
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Figure 4. Photographs of 10 μM 2{1,6} (a), 2{1,8} (b), and 2{4,3} (c) in THF/water mixture
(0-99%) under natural light (up) and UV light (down, λex = 312 nm). Fluorescence spectra of
10 μM 2{1,6} (d), 2{1,8} (e), and 2{4,3} (f) in THF/water mixture (0-99%) with excitation at
308 nm (d), at 332 nm (e), and at 342 nm (f); inset: plots of fluorescence intensity of 2{1,6} at
396 nm (d), 2{1,8} at 388 nm (e), and 2{4,3} at 405 nm (f).
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Figure 5. Fluorescence spectra of 2{1,6} (a), 2{1,8} (b), 2{4,3} (c), and 2{4,12} (d) in EtOH
(0.5 μM, dashed line) and solid states (solid line); inset: photographs of 2{1,6} (a), 2{1,8} (b),
2{4,3} (c), and 2{4,12} (d) in the solid state under visible light (left) and UV light (right, λex =
365 nm).
EtOH
Solid
Compound
λabs (nm) λem (nm) ΦF (Solution) λabs (nm) λem (nm) ΦF (Solid, %)
2{1,6}
2{1,8}
2{4,3}
2{4,12}
308
332
342
355
393.5
385.5
404.5
424.5
0.78
0.63
0.66
0.72
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408
422
434
437
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22.15
16.33
1.54
Table 3. Optical properties of 2{1,6}, 2{1,8}, 2{4,3}, and 2{4,12} in ethanol and in the solid
state.
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To understand the interactions that contributed to solid state emission, we also investigated the
intermolecular interactions of 2{1,8} by analyzing the geometry and packing arrangements in
crystal states (Figure 6). One of the featured interactions in 2{1,8} packing is slip-stacks,64 in
which the intermolecular distance between 6-arylnaphtho[2,1-b]benzofuran rings from each
centroid was 5.729 Å with a pitch angle of 54.711°, much deviated from conventional π-π
stacking interactions that cause fluorescence decreases. Through the slip-stacks, each 2{1,8}
compound is arranged to have a short distance between S atoms of the thienyl group. The
intermolecular S…S interaction (3.769 Å) along with nonclassical hydrogen bonds (CH…O
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bond: 2.524 Å; CH…S bond: 3.156 Å) comprise the intermolecular networks, rigidifying the
molecular packing of 2{1,8} as depicted in Figure 6. These intermolecular hydrogen bonds in
addition to the well-aligned O and S atoms had significant influence on the molecular packing
mode, resulting in high emission in solid states.65 These nonbonding interactions are found to
extend electronic communication, leading to a radiative pathway.66
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Figure 6. (a) Crystal structure of 2{1,8} with the intramolecular CH…O interaction (2.249 Å)
shown in yellow line. (b) Slip-stacked 2{1,8} molecules from a side view. (c) Packing structure
of 2{1,8} via intermolecular S…S bond (3.769 Å) shown in red line. (d) Packing structure of
2{1,8} via intermolecular interactions; red: intermolecular S…S bond (3.769 Å); green:
intermolecular CH…S bond (3.156 Å); blue: intermolecular CH…O bond (2.524 Å).
In conclusion, we have developed a modular approach to a wide range of 6-substituted
naphtho[2,1-b]benzofurans by way of sequential Sonogashira cross-coupling and 6-endo-dig
electrophilic cyclization. The synthesized compounds were tested for their optical and imaging
properties. By using a high-content imaging system, 2{4,3}, 2{4,12}, and 2{5,13} were found
to be the most cell permeable, whereas 2{1,6} and 2{1,8} exhibited high fluorescence via
aggregation-induced emission properties. Interestingly, 2{1,6}, 2{1,8}, and 2{4,3} are solid-
state emissive and highly fluorescent in most solvents in solution, exhibiting dual state
emission (DSE) properties that are highly valuable for broad applications including bioimaging.
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The compounds we developed in this work would serve as a novel fluorescent scaffold with a
variety of biomedical and optoelectronic applications.
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Experimental procedures
General Methods
Unless specified, all reagents and starting materials were purchased from commercial sources
and used as received without purification. “Concentrated” refers to the removal of volatile
solvents via distillation using a rotary evaporator. “Dried” refers to pouring onto, or passing
through, anhydrous magnesium sulfate followed by filtration. Flash chromatography was
performed using silica gel (230−400 mesh) with hexanes, ethyl acetate, and dichloromethane
as the eluents. All reactions were monitored by thin-layer chromatography on 0.25 mm silica
plates (F-254) visualizing with UV light. Melting points were measured using a capillary
1
melting point apparatus. H and 13C NMR spectra were recorded on 400 MHz NMR
spectrometer and were described as chemical shifts, multiplicity (s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet), coupling constant in hertz (Hz), and number of protons. HRMS was
measured with electrospray ionization (ESI) and Q-TOF mass analyzer.
Synthesis of 6-methoxy-3-(2-(phenylethynyl)phenyl)benzofuran (4{1,1})
In
a
vial
charged
with
3-(2-iodophenyl)-6-
methoxybenzofuran (1{1}) (50 mg, 0.14 mmol) in Et3N (2
mL) were added phenylacetylene (3{1})(17 µL, 0.154 mmol),
(Ph3P)2PdCl2 (9.8 mg, 0.014 mmol), and CuI (2.7 mg, 0.014
O
MeO
mmol). After being stirred at 80 °C for 12 h, the reaction mixture was concentrated in vacuo to
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yield the crude product. Purification by flash chromatography on silica gel (hexanes:EtOAc,
6
7
1
49:1) afforded 4{1,1} as a yellow gum (40.6 mg, 88%). H NMR (400 MHz, CDCl3) δ 7.99
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9
(s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.61-7.64 (m, 2H), 7.44 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 7.2
Hz, 1H), 7.29 (s, 5H), 7.11 (s, 1H), 6.94 (dd, J = 2.0, 8.8 Hz, 1H), 3.89 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 158.2, 156.3, 142.8, 134.0, 133.4, 131.5, 129.4, 128.7, 128.4, 128.4, 127.3,
123.3, 122.2, 121.3, 120.5, 120.4, 112.1, 96.2, 93.1, 89.4, 55.9; HRMS (ESI-QTOF) m/z
[M+H]+ calcd for C23H17O2 325.1223, found 325.1225.
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Synthesis of 9-methoxy-6-phenylnaphtho[2,1-b]benzofuran (2{1,1})
A solution of 4{1,1} (25 mg, 0.08 mmol) in a mixture of DCE
(2.0 mL) and TFA (1.0 mL) in a vial was stirred at 80 °C for
30 min. After being cooled down to rt, the reaction mixture
O
MeO
was concentrated in vacuo to afford the crude product which
was purified by flash chromatography on silica gel
(hexanes:EtOAc, 49:1) to give 2{1,1} as a pale yellow solid, (23.2 mg, 93%); mp: 93.7-95.2 °C;
1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.05 (d, J =
8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.95 (s, 1H), 7.69 (t, J = 6.8 Hz, 1H), 7.53-7.61 (m, 3H),
7.48 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.10 (dd, J = 2.0, 8.8 Hz, 1H), 3.93 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 159.2, 157.4, 152.1, 136.7, 131.0, 129.4, 129.2, 128.8, 128.2,
128.1, 126.9, 126.9, 126.2, 124.8, 123.4, 122.4, 118.4, 118.4, 112.0, 96.8, 55.9; HRMS (ESI-
QTOF) m/z [M+H]+ calcd for C23H17O2 325.1223, found 325.1226.
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Optical characterization
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The UV-Vis absorption spectra of the synthesized compounds were measured at ambient
temperature using a Lambda25 UV/Vis spectrometer (PerkinElmer, Waltham, MA, USA).
Fluorescence emission spectra were obtained with an FP-6500 spectrofluorometer (JASCO,
Tokyo, Japan) with slit widths of 3 nm for excitation and 5 nm for emission. The solid state
fluorescence emission spectra were measured at room temperature using a Fluoromax-4
spectrofluorometer (Horiba Jobin Yvon, Kyoto, Japan) with a slit width of 0.5 nm for both
excitation and emission. Fluorescence quantum yields of the compounds in solution were
determined using anthracene (Φ = 0.27 in EtOH) as a standard and the absolute fluorescence
quantum yields of solids were measured using a Horiba FluoroMax-4 spectrofluorometer with
an integrating sphere assembly. Dynamic light scattering was employed to analyze the particle
size distribution using ELSZ-2000 (Otsuka, Chiyoda, Japan).
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Image-based cell screening
HeLa (human cervical cancer cell line) cells were seeded at 20,000 cells per well in a
Cellcarrier-96 black plate (PerkinElmer, Waltham, MA, USA) and incubated for 24 h at 37 °C
in 5% CO2. For live cell imaging, the cells were treated with the compounds for 1 h and cell
screening images were acquired via the Operetta High-Content imaging system (PerkinElmer,
Waltham, MA, USA) at 410-480 nm with blue fluorescence upon excitation at 360-400 nm
with a 20x objective lens. Image analysis was performed using Harmony software
(PerkinElmer, Waltham, MA, USA).
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Confocal microscopy
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For live cell imaging, HeLa cells were seeded on a confocal dish for 24 h under 37 °C in 5%
CO2. After incubation, the same samples were incubated with 10 μM NP compounds for 1 h at
37 °C under 5% CO2, followed by staining with 150 nM MitoTracker Red (Molecular probes,
Eugene, OR, USA) for 20 min or with 75 nM LysoTracker Red (Molecular probes, Eugene,
OR, USA) for 30 min. After staining, the samples were washed twice with Dulbecco's
phosphate-buffered saline (DPBS) and live cell imaging was carried out using a TCS-SP8
confocal laser scanning microscope (Leica, Wetzlar, Germany). Cell images of NP-treated cells
were acquired at 410-560 nm with blue fluorescence upon excitation at 405 nm, whereas
LysoTracker Red and MitoTracker Red were excited at 561 nm and detected at >566 nm with
red fluorescence.
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Cytotoxicity test
The phototoxicity of the compounds was evaluated using the MTT assay. MCF7 (human breast
cancer cell line) cells were seeded in 96-well cell culture plates (SPL Life Science Co.,
Gyeonggi-do, Republic of Korea) at a density of 10,000 cells per well. After incubation for 24
h, the cells were treated with different concentrations (0.5, 1, 2, 5, and 10 μM) of compounds
in cell culture media for 1 h at 37 °C in the dark. The cell medium was replaced with fresh
medium and cells were then irradiated by a blue LED light (800 lm/m2) for 0, 5, and 10 min.
After illumination, the cells were incubated at 37 °C under 5% CO2 in the dark for 24 h. After
medium replacement, 20 μM 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) (5 mg/mL) was added to each well and incubated for another 3 h. At the end, the
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medium was removed and the formazan product was dissolved in DMSO (100 μL per well).
Cell viability was evaluated by measuring the absorbance at 570 nm using a Mithras2 plate
reader (Berthold Technologies, Bad Wildbad, Germany).
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Single Crystal X-ray Diffraction Studies
Single crystals of 2{1,8} with a dimension of 0.427 × 0.22 × 0.104 mm3 were grown by the
vapor diffusion method using CH2Cl2 and cyclopentane. The suitable crystal was mounted on
SuperNova, Dual, Cu at home/near, and a AtlasS2 diffractometer (Agilent, Santa Clara, CA,
USA). The data collection of 2{1,8} was performed using a SuperNova dual source
diffractometer operating with Cu-Kα radiation (λ = 1.542 mm-1) at 294.4 K. Using Olex2,67 the
structure was solved by direct methods with ShelXT software68 and refined by the least squares
minimization method using ShelXL software.69 Supplementary crystallographic data of 2{1,8}
in this paper can be obtained from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. The deposition number of 2{1,8} is CCDC 1884862.
All copies of the data can be downloaded upon request to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK.
Author information
Corresponding authors
* I. Kim: e-mail: ikyonkim@yonsei.ac.kr; fax: +82 32 749 4105
* J. Lee: e-mail: jyleeut@snu.ac.kr; fax: +82 2 884 8334
The authors declare no competing financial interest.
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Acknowledgements
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This work was supported by the National Research Foundation of Korea (NRF) grant funded
by the Korea government (MSIP) (NRF-2017R1A2A2A05069364 and NRF-
2018R1A6A1A03023718) to I. K.; the National Research Foundation of Korea (NRF) grants
funded by the Korean government (MSIP) (NRF-2018R1A2B2005535 and
2018R1A4A1021703) to J. L.
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Abbreviations
ACQ: aggregation-caused quenching
AIE: aggregation-induced emission
AIEE: aggregation-induced emission enhancement
DSE: dual state emission
DPBS: Dulbecco's phosphate-buffered saline
MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
NP: naphtho[2,1-b]benzofuran
QY: quantum yields
RIR: restricted intramolecular rotation
Supporting Information
1H and 13C NMR spectra of synthesized compounds, compound synthesis and characterization
data, supporting figures, and crystal structure determination of 2{1,8}.
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References
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