Silyl-naphthalene endoperoxides as switchable sources of singlet oxygen for bactericidal activity

Article abstract of DOI:10.1039/d1ra02933a

Singlet oxygen is a short half-life cytotoxic agent which can be generated by chemical and photochemical methods. In order to make use of its antibacterial action at a selected location, it is desirable to have singlet oxygen in a relatively stable, “caged” structure, in the form of an endoperoxide. Here, the trimethylsilyl (TMS) group supplies the steric bulk, inhibiting the cycloreversion reaction to produce very little singlet oxygen under ambient conditions. However, when fluoride ions are added as tetrabutylammonium fluoride, very rapid removal of the TMS group takes place, followed by the unhindered cycloreversion, releasing singlet oxygen much faster. The bactericidal action on surfaces was demonstrated usingE. coli, and imaged under fluorescence microscopy. Considering the issues related to emergence of antibiotic resistant bacterial strains, “on demand singlet oxygen” appears to be an exciting alternative.

Full text of DOI:10.1039/d1ra02933a

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Silyl-naphthalene endoperoxides as switchable
sources of singlet oxygen for bactericidal activity†
Cite this: RSC Adv., 2021, 11, 19083
Min Qu, Nan Wu, Wanqing Jiang, Lei Wang,* Mahinur S. Akkaya*c
ab
c
c
ab
ab
and Engin U. Akkaya
*
Singlet oxygen is a short half-life cytotoxic agent which can be generated by chemical and photochemical
methods. In order to make use of its antibacterial action at a selected location, it is desirable to have singlet
oxygen in a relatively stable, “caged” structure, in the form of an endoperoxide. Here, the trimethylsilyl (TMS)
group supplies the steric bulk, inhibiting the cycloreversion reaction to produce very little singlet oxygen
under ambient conditions. However, when fluoride ions are added as tetrabutylammonium fluoride, very
rapid removal of the TMS group takes place, followed by the unhindered cycloreversion, releasing singlet
oxygen much faster. The bactericidal action on surfaces was demonstrated using E. coli, and imaged
under fluorescence microscopy. Considering the issues related to emergence of antibiotic resistant
bacterial strains, “on demand singlet oxygen” appears to be an exciting alternative.
Received 15th April 2021
Accepted 20th May 2021
DOI: 10.1039/d1ra02933a
rsc.li/rsc-advances
oxygen release rate is signicantly slowed down. If this block
can be removed by the modulators mentioned above in a fast
Introduction
Among the reactive oxygen species (ROS), singlet oxygen is the most process (chemical or photochemical) singlet oxygen release
1
reactive and short-lived. In aqueous solutions, the half-life of singlet could be effectively controlled in both space and time.
2
oxygen is about 3.5 microseconds. As a result of its reactivity, it can
react with lipids, amino acids, nucleic acids and most of the cellular
3
components. Non-specic reactivity demands a tight spatiotem- Experimental
poral control of its generation, if this reactivity is to be harnessed in
Materials and instrumentation
a cytotoxic or antibacterial agent. In the last few decades, photody-
All commercial chemicals were used as supplied unless other-
wise indicated. Anhydrous solvents were obtained from
a Solvent Purication System. Column chromatography was
4
namic antibacterial activity has attracted attention, since the
bactericidal effect of singlet oxygen, is not subject to limitations of
ordinary anti-bacterial agents, such as bacterial antibiotic resistance.
1
13
performed using silica gel (200–300 mesh). H and C NMR
spectra were recorded on Bruker Avance II 400 MHz or Bruker
Avance III 500 MHz. Signal splitting patterns were described as
singlet (s), doublet (d), triplet (t), quartet (q) and multiplet (m)
with coupling constants (J) in hertz (Hz). High resolution mass
spectra (HRMS) were recorded with an Agilent mass spectrom-
eter. Reactions were monitored by thin-layer chromatography
using Merck TLC Silica gel 60 F254.
It is also important to note that, ROS and specically singlet oxygen
is believed to be ultimate cause of bactericidal action of most anti-
5
biotics, if not all. We propose that the chemical (non-photonic)
generation of singlet oxygen could extend the applicability of
singlet oxygen as an effective antibacterial agent.
In recent years, we have provided evidence that singlet
oxygen release reaction rate can be controlled by exogenic and
6
endogenic (biological) modulators. Various naphthalene
Synthesis of compound 2. 2-(2-Bromophenyl)-N-methoxy-N-
methylacetamide: a mixture of 2-bromophenylacetic acid (1)
7
endoperoxide cycloreversion rates which were studied in more
8
6b,c
detail than other endoperoxide reactions, were shown by us
(6.45 g, 30 mmol), EDC$HCl (6.9 g, 36 mmol), DMAP (0.37 g, 3
9
and others to be highly sensitive to steric crowding near the
endoperoxide bridge. When sterically crowded, the singlet
mmol), DIPEA (6.27 mL, 36 mmol), and N,O-dimethylhydroxyl-
amine hydrochloride (3.51 g, 36 mmol) in dichloromethane
(
150 mL) was stirred at room temperature for 12 h. The reaction
a
State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong mixture was concentrated under vacuum, and the residue was
Road, 116024, Dalian, China. E-mail: eua@dlut.edu.cn
b
diluted with ethyl acetate (200 mL). The organic layer was
washed with saturated NaHCO
Department of Pharmaceutical Sciences, Dalian University of Technology, 2 Linggong
3
(50 mL ꢀ 2) and brine (50 mL
Road, 116024, Dalian, China. E-mail: leiwang@dlut.edu.cn
ꢀ
2), dried over Na SO , and concentrated under vacuum. The
c
2
4
School of Bioengineering, Dalian University of Technology, 2 Linggong Road, 116024,
crude product was puried by column chromatography (15%,
EtOAc in n-hexane) to afford 2-(2-bromophenyl)-N-methoxy-N-
Dalian, China. E-mail: msa@dlut.edu.cn
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/d1ra02933a
1
1
methylacetamide (2) as a colorless oil. Yield: 7.4 g (95%). H
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NMR (400 MHz, chloroform-d) d 7.56 (d, J ¼ 7.8 Hz, 1H), 7.31– 5-Bromo-1,4-dimethylnaphthalene (5) (0.71 g, 3 mmol) was
7
3
1
.22 (m, 2H), 7.16–7.08 (m, 1H), 3.93 (s, 2H), 3.70 (s, 3H), 3.22 (s, added to the reaction mixture in ice-bath. Then, TMS-Cl (0.38 g, 3.6
1
3
H); C NMR (100 MHz, CDCl ) d 171.2, 135.1, 132.6, 131.5, mmol) was dissolved in 3.0 mL THF and was added to the reaction
3
28.6, 127.5, 125.1, 61.3, 39.6, 32.3.
mixture dropwise. The reaction mixture was allowed to stir at room
Synthesis of compound 3. 2-(2-Bromophenyl)-N-methoxy-N- temperature for 18 hours. Then, the mixture was extracted with
methylpropanamide: to a solution of 2-(2-bromophenyl)-N- water and DCM for three times. Aer removal of the solvent by
methoxy-N-methylacetamide (2) (5.16 g, 20 mmol) in anhydrous rotary evaporator, the crude product was puried by silica gel
THF (50 mL) was added NaHMDS (1.0 M in hexane, 30 mL, 30 column chromatography with hexane : EtOAc (95 : 5, v/v) as the
ꢂ
mmol) at ꢁ78 C via syringe under Ar atmosphere. Aer stirring eluent to afford (5,8-dimethylnaphthalen-1-yl)trimethylsilane (6) as
1
for 30 min, MeI (4.3 g, 60 mmol) was added at the same a colorless oil. Yield: 0.3 g (44%). H NMR (400 MHz, chloroform-d)
ꢂ
temperature. The reaction mixture was stirred at ꢁ78 C for 1 h d 7.95 (dd, J ¼ 8.4, 1.1 Hz, 1H), 7.81 (dd, J ¼ 6.9, 1.0 Hz, 1H), 7.36–
ꢂ
and 0 C for additional 1 h. The reaction mixture was quenched 7.31 (m, 1H), 7.22–7.06 (m, 2H), 2.75 (s, 3H), 2.58 (s, 3H), 0.38 (s,
1
3
with saturated NH
). The organic layer was washed with brine, dried over MgSO
and concentrated under vacuum. The residue was puried by
4
Cl and extracted with ethyl acetate (50 mL ꢀ 9H); C NMR (100 MHz, CDCl
3
) d 136.9, 136.1, 134.6, 132.58,
3
4
,
132.5, 132.0, 127.4, 125.5, 125.1, 122.7, 23.5, 19.1, 2.5.
Synthesis of compound 7. (5,8-dimethylnaphthalen-1-yl)
column chromatography (10–15%, EtOAc in n-hexane) to afford trimethylsilane (6) (0.3 g, 1.32 mmol) was dissolved in 10 mL
ꢂ
2
-(2-bromophenyl)-N-methoxy-N-methylpropanamide (3) as DCM. The reaction mixture was cooled to 0 C in the ice bath.
1
a colorless oil. Yield: 4.95 g (90%). H NMR (400 MHz, Methylene blue (0.04 g, 0.14 mmol) was added into the solution
chloroform-d) d 7.56 (dd, J ¼ 8.0, 1.3 Hz, 1H), 7.33 (dd, J ¼ 7.8, and mixture was stirred for 5 hours under oxygen atmosphere.
1
1
7
1
.8 Hz, 1H), 7.26 (td, J ¼ 7.6, 1.3 Hz, 1H), 7.08 (td, J ¼ 7.8, 1.6 Hz, During the reaction, 18 W, 630 nm red light was used. Aer
H), 4.65–4.49 (m, 1H), 3.41 (s, 3H), 3.16 (s, 3H), 1.38 (d, J ¼ removal of the solvent by rotary evaporator, the crude product
1
3
.0 Hz, 3H); C NMR (100 MHz, CDCl
27.2, 127.1, 126.9, 123.0, 60.0, 40.6, 31.4, 17.2.
Synthesis of compound 4. To a solution of 2-(2-bromo- tained in colorless oil. Yield: 0.33 g (98%). H NMR (400 MHz,
3
) d 173.9, 140.4, 131.8, was puried by silica gel column chromatography with hex-
ane : EtOAc (95 : 5, v/v) as the eluent. The product 7 was ob-
1
phenyl)-N-methoxy-N-methylpropanamide (3) (4.9 g, 18 mmol) in chloroform-d) d 7.44 (dd, J ¼ 7.8, 1.2 Hz, 1H), 7.29 (dd, J ¼ 7.4,
dichloromethane (50 mL) was added a solution of DIBAL-H (1.0 M 1.2 Hz, 1H), 7.19–7.11 (m, 1H), 6.61 (s, 2H), 1.96 (s, 3H), 1.78 (s,
ꢂ
13
in cyclohexane, 27 mL, 27 mmol) at 78 C via syringe under Ar 3H), 0.35 (s, 9H) ; C NMR (100 MHz, CDCl ) d 147.1, 140.0,
3
ꢂ
atmosphere. The reaction solution was stirred at 78 C for 1 h and 139.2, 138.6, 133.2, 131.5, 124.6, 120.7, 80.4, 77.0, 18.5, 15.7, 1.9.
quenched with 1.0 N HCl. The organic layer was washed with
4
brine, dried over MgSO , and concentrated under vacuum. The
Results and discussion
residue was puried by column chromatography (5% EtOAc in n-
hexane) to afford 2-(2-bromophenyl)propanal (4) as a colorless oil.
Based on the reported effects of 5-methyl substitution (Fig. 1) on
1
Yield: 3.07 g (81%). H NMR (400 MHz, chloroform-d) d 9.74 (s,
the cycloreversion rate of 1,4-dimethylnaphthalene endoper-
1
H), 7.64 (dd, J ¼ 8.0, 1.3 Hz, 1H), 7.33 (td, J ¼ 7.6, 1.3 Hz, 1H), 7.18
10
oxide (1,4), we targeted the compound 7 for synthesis. Previ-
ously, we synthesized its structural isomer where the steric
hindrance is on C-2, but steric block on the other side of the
bridgehead substitution, may offer additional advantages in
deprotection rates and/or stability of the initial endoperoxide.
The synthesis (Fig. 2) of compound 7 makes use of an effective
(
7
td, J ¼ 7.8, 1.7 Hz, 1H), 7.12 (dd, J ¼ 7.7, 1.7 Hz, 1H), 4.17 (q, J ¼
1
3
.1 Hz, 1H), 1.43 (d, J ¼ 7.1 Hz, 3H); C NMR (100 MHz, CDCl )
3
d 199.1, 136.8, 132.3, 128.2, 128.0, 127.1, 124.1, 50.9, 13.0.
Synthesis of compound 5. Propyne (0.52 g, 13 mmol) was
placed in a dry argon-ushed, 200 mL round-bottomed ask
equipped with a stirring bar and dissolved in dry CH
mL). Titanium tetrachloride (10 mmol, 10 mL of a 1.0 M CH
solution) was added via a syringe at room temperature. Then, 2-
2-bromophenyl)propanal (4) (2.13 g, 10 mmol) was added via
2
Cl
2
(60
10
methodology which allows the preparation of substituted
naphthalenes, starting from substituted phenylacetaldehyde (4,
in this case) and the appropriate alkyne. Aldehyde itself can be
obtained from the commercially available materials in just two
steps. Once the naphthalene core 5 is constructed, the bulky
trimethylsilyl (TMS) group is substituted via a Grignard reac-
tion. Irradiation of compound 6 under oxygen atmosphere with
methylene blue (MB) as a photosensitizer, and a red LED array
2
Cl
2
(
a syringe at room temperature. The reaction mixture was
allowed to stir for 4 h and then was hydrolyzed with water. The
mixture was extracted into hexanes, and the organic layer
4
separated, dried over anhydrous MgSO , concentrated under
reduced pressure, and puried by ash column chromatog-
raphy to afford 5-bromo-1,4-dimethylnaphthalene (5) as
1
a colorless liquid. Yield: 1.1 g (47%). H NMR (400 MHz,
chloroform-d) d 7.88 (d, J ¼ 8.4 Hz, 1H), 7.76 (d, J ¼ 7.4 Hz, 1H),
7
3
1
.15–7.19 (m, 2H), 7.12 (d, J ¼ 7.2 Hz, 1H), 3.00 (s, 3H), 2.54 (s,
13
3
H); C NMR (100 MHz, CDCl ) d 135.6, 133.5, 133.3, 133.2,
31.5, 130.6, 127.1, 125.4, 124.9, 120.7, 26.4, 20.4.
Synthesis of compound 6. Magnesium turnings (0.17 g, 7
mmol) was activated with catalytic amount of iodine in 5 mL of
Fig. 1 Bulky substituents near the endoperoxide bridge is known to
THF for 15 minutes with vigorous stirring under Ar atmosphere. inhibit cycloreversion reaction rate.
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1
Fig. 2 The synthesis of 5-TMS-1,4-dimethylnaphthalene 6 and its Fig. 4 Temporal evolution of H NMR spectra of the endoperoxide 7 in
ꢂ
corresponding endoperoxide 7.
DMSO-d following the addition of TBAF after t ¼ 0 at 37 C in DMSO-
6
6
d as the solvent. 0 h, 5 min, 1.5 h, 3.5 h, 5 h. The conversion of 7 to 9 is
complete in 5 minutes under these conditions.
emitting at 630 nm, gives the endoperoxide compound in high
yields. Endoperoxide 7 can be separated from the reactant and
any unreacted material from the previous step (compound 5) by
silica gel column chromatography.
unsubstituted 1,4-dimethylnaphthalene endoperoxide 11, the
cycloreversion reaction rate is 25 times slower.
1
We then wanted to demonstrate that the addition of uoride
indeed results in a fast removal of the TMS-steric inhibitor
group, which is followed by an accelerated cycloreversion. The
We studied cycloreversion rate of the compound 7 by H
NMR (Fig. 3). As expected, the TMS substituent at the 5 position
slowed down the cycloreversion reaction. We were able to
1
ꢂ
H NMR data shown in Fig. 4 clearly show these changes. The
determine the half-life (ESI) as 125 h at 25 C. Compared to the

rst (t ¼ 0) NMR shows the typical protons of the endoperoxide
7
in the 8.4–6.2 ppm region. Immediately aer the addition of
TBAF in THF, TMS is removed completely within 5 min (spec-
1
trum 2). H NMR data conrm the fact that removal of the TMS
group is much faster than the cycloreversion reaction of the
endoperoxide 7. Then the transformation of 9 to 11 takes place
at a much faster rate. In order to conrm the identity and rate of
the other product of cycloreversion, a solution of the endoper-
oxide 7 was prepared in DMSO, and the singlet oxygen probe
1,3-diphenyl-iso-benzofuran (DPBF) was added. As the reaction
proceeds, cycloaddition of singlet oxygen initiates degradation
of the benzofuran structure, and the absorbance peak at 414 nm
due the benzofuran decreases (Fig. 5) as the singlet oxygen is
1
1
Fig. 3 Temporal evolution of H NMR spectra of the endoperoxide 7 in Fig. 5 “Off–On” switching of O
2
release: when fluoride (6 mM) in the
ꢂ
CDCl
3
at 37 C. Top downfield region, bottom: upfield region of the form of TBAF in THF was added, the trap (DPBF, 27 mM) absorbance in
spectra. From bottom to top: 0 h, 0.5 h, 1.5 h, 2.5 h, 5.5 h, 8 h, 10 h, 12 h, DMSO at 414 nm starts to decrease sharply in a pseudo-first order
2
4 h, 33 h, 52 h, 73 h.
reaction, coupled to the cycloreversion of endoperoxide 7 (200 mM).
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Fig. 6 Steric inhibition of cycloreversion as illustrated with compound
6
7
and selected endoperoxide derivatives from literature. The cyclo-
reversion rates of 1,4-dimethylnaphthalene endoperoxides were
ꢂ
determined at 25 C. Steric bulk at positions 2 and 5 seem to be
a significant stabilizing factor for the endoperoxide. The other product
1
formed in all of the cycloreversion reactions is singlet oxygen ( O
2
).
produced. The reaction is highly specic to singlet oxygen.
Clearly, uoride addition causes a much accelerated release of
singlet oxygen, which is due to the rapid “uncaging” of the
endoperoxide. The general scheme of TMS-removal coupled
acceleration of singlet oxygen release is presented in Fig. 6.
Finally, we wanted to demonstrate the antibacterial action of
singlet oxygen generated by uoride addition. For bacterial
overnight culture, a single colony of E. coli (Dh5a) used to
ꢂ
inoculate 2.0 mL LB for 18 h at 37 C for constant shaking at
2
00 rpm. These cells were aliquoted into fresh tubes for endo-
ꢁ
peroxide/F and mock treatments. Varying concentrations (40
mM) of endoperoxides 7 or 8 in DMSO and TBAF (100 mM) in
DMSO were mixed at 1 : 1 (5 mM/5 mM) ratio, incubated for
30 min at RT for activation. Then 10 mL of the reaction mixture
was added directly into fresh tubes, onto which the cells in 90
Fig. 7 Dead/live assay picture matrix of the action of endoperoxides 7
mL were added, and incubated for 30 minutes. The treated and or 8 activated by TBAF on E. coli. Red emission intensity to green
emission intensity ratios are indicated in each picture at the bottom
left. These are the resulting after 30 minutes incubation followed by
mock treated cells were collected by spinning and washed with
200 mL phosphate-buffered saline (PBS) for two times. The cells
washing and staining. (a) control, (b) 10% v/v DMSO, (c) 10% v/v DMSO,
mM TBAF; (d) 10% v/v DMSO, 2 mM endoperoxide 8; (e) 10% v/v
DMSO, 2 mM endoperoxide 7; (f) 10% v/v DMSO, 2 mM endoperoxide
were suspended and incubated in 20 mL acridine orange/
ethidium bromide staining solution (prepared according to
5
the manufacturer's instructions; BBI Life Sciences, Shanghai, 8, 5 mM TBAF; (g) 10% v/v DMSO, 2 mM endoperoxide 7, 5 mM TBAF.
Column 1 from left: bright field images, Column 2: FITC filter, Column
PRC) in dark. The cells were collected by spinning and washed
3: TxRED filter, Column 4: merged. The numbers on the bottom left
and suspended in 20 mL 1ꢀ buffer of the staining kit. The
are total intensity in that filter range, except for the final column where
it is the red to green ratio.
samples were investigated under bright eld, FTIC, and TxRED

lters using uorescent microscope. The pictures were taken
with exposures of 100 milliseconds for brighteld and 500
milliseconds exposures with FITC and TxRED lters at 100ꢀ
magnication. We compared the bactericidal activity of the
isomeric endoperoxides 7 and 8 at 2.0 mM concentration.
The ratio of the red channel total intensity (corresponding to
dead cells) and the green channel total intensity (corresponding
to live cells) is provided on the microscopy images (Fig. 7.). The
microscopy data show that singlet oxygen generated by the
action of uoride on endoperoxide 7 has a demonstrable
bactericidal effect, which signicantly larger than endoperoxide
7
alone, and endoperoxide 8 + uoride. The latter difference
may be due to rate of TMS displacement.
Conclusions
In summary, we present a proof of principle for the use of caged
singlet oxygen compounds as potential bactericidal agents
activated by uoride ions. The current work, while presenting
a novel and interesting synthesis of a 5-TMS-substituted
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naphthalene endoperoxide, it also demonstrates the generality
of steric hindrance via silyl functionalization. We provide
a stable endoperoxide which could be transformed into an
effective antibacterial agent on exposure to uoride for 5
minutes. These properties of the endoperoxide compounds
could make them potentially useful especially in dental anti-
bacterial applications. Work in that direction is currently in
progress in our laboratories.
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Conflicts of interest
5
6
There are no conicts to declare.
(a) W. Fudickar and T. Linker, Angew. Chem., Int. Ed., 2018,
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7, 12971–12975; (b) E. Ucar, D. Xi, O. Seven, C. Kaya,
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Acknowledgements
The authors acknowledge support from LiaoNing (China)
Revitalization Talents Program XLYC1902001 (E. U. A),
XLYC1907021 (L. W.), and the Fundamental Research Funds for
the Central Universities DUT19RC(3)009 (L. W.), DUT18RC(3)
5
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©
2021 The Author(s). Published by the Royal Society of Chemistry
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