A water soluble light activated hydrogen sulfide donor induced by an excited state meta effect

Article abstract of DOI:10.1039/c9ob01502g

We have utilized an m-amino benzyl based photoremovable protecting group (PRPG) to develop a new water soluble H₂S donor. It efficiently releases H₂S on demand in a spatio-temporally controlled fashion by an excited state "meta effect" with good chemical and photochemical quantum yield in an aqueous environment. The efficient photorelease of H₂S under physiological conditions was also demonstrated by in vitro studies.

Full text of DOI:10.1039/c9ob01502g

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
A water soluble light activated hydrogen sulfide
donor induced by an excited state meta effect†
Cite this: Org. Biomol. Chem., 2019,
7, 9059
1
a
b
a
a
b
Manoranjan Bera, Somnath Maji, Amrita Paul, Souvik Ray, Tapas Kumar Maiti and
a
N. D. Pradeep Singh
*
We have utilized an m-amino benzyl based photoremovable protecting group (PRPG) to develop a new
water soluble H S donor. It efficiently releases H S on demand in a spatio-temporally controlled fashion
Received 5th July 2019,
Accepted 27th September 2019
2
2
by an excited state “meta effect” with good chemical and photochemical quantum yield in an aqueous
DOI: 10.1039/c9ob01502g
2
environment. The efficient photorelease of H S under physiological conditions was also demonstrated by
rsc.li/obc
in vitro studies.
donor with efficient release ability and good solubility under
physiological conditions.
Introduction
Hydrogen sulfide (H
2
S), first discovered in 1777 by Carl
Recently, Wang and co-workers reported an m-amino benzyl
1
Wilhelm Scheele, has been traditionally known as a toxic air based photoremovable protecting group (PRPG) for the unca-
pollutant with the characteristic odour of rotten eggs. ging of carboxylic acids and alcohols.
1
5–21
The photorelease of
However, this gaseous molecule has been recently recognized alcohols and carboxylic acids results from selective electron
as a member of the gasotransmitter family along with nitric transmission from an electron-donating group to the meta
2
–6
oxide (NO) and carbon monoxide (CO).
Hydrogen sulfide
(H
2
S) is well known for mediating many physiological pro-
cesses. H S gas is highly diffusive in nature and can target
2
multiple sites within a cell. Therefore, cell signalling by H S is
2
mostly complex and is dependent on its local concentration.
This indicates the need for controlled generation of H S gas
2
under physiological conditions. Now-a-days light activated H2S
donors are receiving much attention because of their spatio-
7
–12
temporal control over H S release.
2
Chakrapani and co-workers reported the photorelease of
carbonyl sulfide (COS) from a BODIPY-caged thiocarbamate
1
3
upon visible light irradiation. The released COS subsequently
gets hydrolysed in the presence of carbonic anhydrase to yield
2
H S (Fig. 1a). The limitation of this system is its requirement
of carbonic anhydrase (external agent) for H S release.
2
Recently, our group developed p-hydroxyl phenacyl based
2
ESIPT molecules for direct release of H S gas upon visible
1
4
light irradiation with real time monitoring (Fig. 1b). However
the abovementioned light activated H S donors have poor solu-
2
bility under physiological conditions. Keeping this in mind,
we were interested in designing a new light activated H2S
a
Department of Chemistry, Indian Institute of Technology Kharagpur,
7
21302 Kharagpur, West Bengal, India. E-mail: ndpradeep@chem.iitkgp.ernet.in
b
Department of Biotechnology, Indian Institute of Technology Kharagpur,
Fig. 1 Selected visible light-triggered H
vated COS/H S donor; (b) an ESIPT based visible light activated H
donor with real-time monitoring; and (c) a newly developed water
2
S donors: (a) a visible light acti-
7
21302 Kharagpur, West Bengal, India
2
2
S
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob01502g
soluble light activated H
2
S donor.
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem., 2019, 17, 9059–9064 | 9059

View Article Online
Paper
Organic & Biomolecular Chemistry
sites on an aromatic ring in its first excited singlet state. Upon
irradiation the molecule gets excited to the singlet excited
state and undergoes heterolytic cleavage of the benzylic bond
to produce an ion pair, which eventually abstracts a proton
from the solvent to release the corresponding alcohol. They
also developed a water soluble m-amino benzyl based PRPG by
2
2
protecting the amine group with butanoic acid.
Inspired by this strategy, we designed a water soluble H2S
donor using an m-amino benzyl photoremovable protecting
group on the basis of the excited state meta effect (Fig. 1c).
This effect facilitates photochemical cleavage of the benzylic
Fig. 2 (a) UV-Vis absorption spectra and (b) emission spectra of 4 (1 ×
−4
10
M) in water.
C–S bond to release the H
S donors are (i) a simple synthetic procedure, (ii) fast and
clean release with high quantum yield and (iii) good solubility buffer (pH ∼ 7.4). We performed the photolysis of 4 under a
2
S molecule. The advantages of our
H
2
under physiological conditions.
nitrogen atmosphere under a medium-pressure mercury lamp
1
7
(
125 W, incident intensity (I
source of light (λ ≥ 365 nm) using 1 M CuSO
cut-off filter with continuous stirring for 30 min. We analysed
the photodecomposition of H S donor 4 and formation of the
photoproduct by reversed-phase HPLC. As shown in Fig. 3a,
= 6.15 min corres-
Scheme 1. Compound 2 was prepared by chlorinating the ponding to 4 indicates gradual photodecomposition of the H
0
) = 1.55 × 10 quanta per s) as the
4
solution as a UV
Results and discussion
2
Synthesis of the H S donor
2
Light activated H
2
S donor 4 was synthesized as shown in the gradual disappearance of a peak at t
R
2
S
3
-nitro benzyl alcohol 1 to its corresponding benzyl chloride donor with the increase in the irradiation time. On the other
using SOCl
2
in dry DCM followed by condensation reaction hand, the appearance and the gradual increase in the intensity
= 3.83 min indicate the formation of the
pound 2 was reduced with iron and acetic acid in ethanol by photoproduct, 6. The newly formed peak at t = 3.83 was
sonicating for 2 h at room temperature. Finally, protection of assigned to the photoproduct (6) by co-injection of authentic
the amine group of compound 3 in the presence of K CO
synthesized compound 6 and further confirmed by isolation
with Na S for 4 h in an acetone–water mixture. Then com- of the new peak at t
R
2
R
2
3
1
13
using 4-bromobutyric acid produced H
2
S donor 4. The product and characterization by H & C NMR spectroscopy (see Fig. S4,
obtained in each step was characterized by H NMR and
1
13
C
ESI†). The photodecomposition of donor 4 was also confirmed
by UV-Vis and fluorescence spectroscopy (Fig. 4).
NMR spectroscopy (see Fig. S1–S3 in the ESI†).
Furthermore, we observed about 95% of photorelease, cal-
culated from the increase in the HPLC peak area of the photo-
Photophysical properties of H S donor 4
2
2
product formed from 4 due to the release of H S after 30 min
of irradiation (Fig. 3b).
The photochemical quantum yield (ϕ ) of the photorelease
p
2
of H S from 4 was determined to be 0.14 ± 0.05 using potassium
The photophysical properties of H S donor 4 was investigated.
2
2
The UV-Vis spectrum of H S donor 4 (Fig. 2a) shows a strong
−1
−1
absorption band at λmax = 314 nm (ε = 4960 M cm ) in
water. The donor 4 also exhibited an emission maximum (exci-
tation wavelength = 314 nm) at λmax = 370 nm (Fig. 2b).
ferrioxalate as an actinometer (see the ESI† for further details).
H S detection using fluorescent probe N,N-dimethylaniline–
hemicyanine dye
2
2
Photochemical properties of H S donor 4
We studied the photochemical properties of our water soluble
H S donor using 1 × 10 M solution of H S donor 4 in PBS
2 2
2
To detect H S generation from 4, we used the N,N-dimethyl-
aniline–hemicyanine dye (D1) as a photostable (see Fig. S9,
−
4
ESI†) and H S-sensitive probe. The N,N-dimethylaniline–hemi-
2
2
cyanine dye reacts with H S to form P1 (Scheme 2). It shows an
intense red colour visible to the naked eye and bright red
fluorescence.
The dye (10 μM) was irradiated with UV-Vis light (λ ≥
3
65 nm) in the presence of H
2
S donor 4 (100 μM) in PBS buffer
(
10 mM) (pH ∼ 7.4) with continuous stirring. The UV-Vis
absorption spectrum of the D1 dye displayed an absorption
maximum at 521 nm. With the increase in the irradiation time
from 0 min to 30 min, we observed that the intensity of the
absorption peak at 521 nm decreased with a concomitant
increase in the new absorption maximum at around 431 nm
(Fig. 4a). This hypsochromic shift in the absorption spectra in
Scheme 1 Synthesis procedure of the water soluble light activated H
donor. Reagents and conditions: (i) SOCl , dry DCM, 4 h; (ii) Na
acetone–H O, rt, 4 h (70%); (iii) iron powder, acetic acid, ethanol, rt, 2 h
70%); and (iv) 4-bromobutyric acid, K CO , acetone, reflux, 24 h (55%).
2
S
2
2
S,
2
(
2
3
9060 | Org. Biomol. Chem., 2019, 17, 9059–9064
This journal is © The Royal Society of Chemistry 2019

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 2
H
2
S detection from 4 by using H
2
S-sensitive fluorescent
probe dye D1.
2
We further investigated the release of H S from 4 in
aqueous buffer by fluorescence spectroscopy using the same
H S sensitive fluorescent probe D1. The dye D1 exhibited red
2
fluorescence (excitation wavelength = 521 nm) at 595 nm in
the absence of H S. With the increase in the irradiation time
2
from 0 to 30 min, H S was gradually released and it reacted
2
with the probe (D1) leading to its decomposition, and as a
result a decrease in the fluorescence intensity was observed
(
Fig. 4b). The accurate determination of H S from 4 was not
2
possible. However, the changes in the absorption spectra and
the decrease in the fluorescence intensity indicated the gene-
ration of H S from 4. No detectable fluorescence change was
2
observed when the donor (4) and probe (D1) were incubated
under similar conditions in the absence of light.
2
To quantify the amount of H S released from 4, we used the
standard methylene blue assay (see Fig. S6, ESI†). In this
study, a 100 μM solution of 4 in pH 7.4 PBS buffer was pre-
pared and mixed with the methylene blue cocktail. Upon
irradiation of light (λ ≥ 365 nm), the solution exhibited an
increase in absorption at 663 nm at different time intervals
corresponding to the formation of methylene blue, confirming
2
the ability of 4 to produce H S (Fig. 5). We found that the con-
centrations of released H S from 4 reached a maximum of
2
∼45 μM in about 30 min.
2
To show the precise control over H S release by light, we
Fig. 3 (a) Overlay of HPLC chromatograms of 4 at regular time intervals monitored the release of H S by periodically switching the
2
(
0–30 min) of irradiation with light (λ ≥ 365 nm). (b) % of photorelease
with respect to the increase in the HPLC peak area of the photoproduct
formed from 4 due to the release of H S at different time intervals.
light source on and off. Fig. 6 clearly indicates that whenever
the light source was switched off, H S release stopped; this
clearly indicates that only an external stimulus light induces
S release.
2
2
H
2
2
Fig. 4 Detection of released H S from 4 using (a) UV-vis and (b) fluor-
escence spectra with the probe D1.
the presence of H S was due to the loss in conjugation of D1
2
2
when H S reacted with it to form P1 (Scheme 2).
We also showed that the photoproduct had no influence in the
Fig. 5 Spectra of methylene blue assay. Black line: Na
2
S (50 μM). Other
quenching of the fluorescence of the dye (D1) (see Fig. S8, ESI†).
lines: H S release from 4 upon irradiation at different times.
2
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem., 2019, 17, 9059–9064 | 9061

View Article Online
Paper
Organic & Biomolecular Chemistry
Cellular internalization and cell viability study
The roles of H S in cancer development and progression are
still controversial. A clear relationship between the H S level
and cancer progression remains to be understood. Still a
deeper understanding of whether and how H S plays a role in
2
2
2
2
3,24
cancer etiology and progression is needed.
Hence, we
thought that our H S donor can be used in the future to under-
2
2
stand the role of H S in cancer biology. Because of this reason,
we used HeLa cells for our studies.
The H S releasing ability of 4 was studied in live cells using
2
H
2
S-sensitive probe D1 by confocal microscopy imaging.
Cervical cancer cells (HeLa) were incubated with 4 and D1 for
h followed by irradiation with light (λ ≥ 365 nm) for 30 min.
6
2
Fig. 6 Progress of the photodegradation of H S donor 4 under light
Initially the cells emitted bright red fluorescence (excitation
wavelength = 540 nm) from the incubated dye (D1) (Fig. 7a).
With the increase in the irradiation time from 0 to 30 min a
gradual decrease in the fluorescence intensity of the cells was
observed, indicating a steady time dependent release of H2S
from 4 (Fig. 7a–c). The cells did not show any significant
decrease in fluorescence in the absence of either light or the
and dark conditions calculated from the HPLC peak area (ON indicates
the start of light irradiation and OFF indicates the end of light
irradiation).
2
Furthermore, the spatiotemporal control ability of our H S
donor was also investigated (see Fig. S7, ESI†).
H S donor 4 (see Fig. S10, ESI†). Furthermore, we also calcu-
2
The hydrolytic stability of the H S donor 4 was examined
2
lated the changes in the fluorescence intensities at different
irradiation times from the confocal microscopy images (see
Fig. S11, ESI†).
individually in PBS buffer (pH ∼ 7.4) by keeping them under
darkness for a period of 20 days. The fate of the H
2
S donor 4
was studied using H NMR. We observed only 4% decompo-
sition of the H S donor 4. The aqueous solubility of the H
donor 4 is found to be 22.5 g per 100 mL at 25 °C.
1
For our H S donor 4 to be useful as a H S releasing biologi-
2
2
2
2
S
cal tool, it should be biocompatible. Therefore, we evaluated
the cytotoxicity of 4 using the MTT (3-(4,5-dimethylthiazol-2-
yl)-2,5-diphenyltetrazolium bromide) assay on HeLa cells
before and after photolysis (Fig. 8a and b). Briefly, HeLa cells
Mechanism of H
2
S release from 4
S from 4 was investigated. Based on the
The photorelease of H
2
literature studies, we proposed the mechanism of the release
of H S from 4 as shown in Scheme 3. H S donor 4, upon
2
2
irradiation, initially gets excited to the singlet excited state
4*). At this excited sate, the benzylic C–O bond undergoes het-
(
erolytic cleavage due to electron transmission from the amine
group (meta effect) to produce ion pairs. These ion pairs in the
presence of water result in the release of H S and the corres-
2
ponding benzylic alcohol (6) as the photoproduct.
Fig. 7 Confocal microscopy images of H
release of H S from 4 was monitored using an H
probe (D1) at different time intervals during irradiation with light (λ ≥
65 nm), (a) 0 min; (b) 15 min; and (c) 30 min.
2
S release from 4. Gradual
2
2
S sensitive fluorescent
3
Fig. 8 Cell viability assay of 4 on the HeLa cell line (72 h MTT assay): (a)
before and (b) after photolysis for 30 min. Values are presented as mean
± standard deviation from three independent experiments.
2
Scheme 3 Proposed mechanism of H S release from 4.
9062 | Org. Biomol. Chem., 2019, 17, 9059–9064
This journal is © The Royal Society of Chemistry 2019

View Article Online
Organic & Biomolecular Chemistry
Paper
were incubated with 20 μM, 10 μM and 5 μM concentrations of General procedure for the preparation of the H
2
S donor
4
for 6 h and subjected to photolysis under λ ≥ 365 nm light
for 30 min. After 72 h of incubation, MTT was added to the
Synthesis of bis(3-nitrobenzyl)sulfane (2). 3-Nitrobenzyl
cells at 0.4 mg mL− and incubated for another 4 h. From the alcohol (612 mg, 4 mmol) was dissolved in dry CH
Cl (20 mL)
1
2
2
results, we observed that there is no evidence of the inhibition with Et N (1.1 mL) into a round bottom flask. Then SOCl2
3
of proliferation of HeLa cells by 4 before (Fig. 8a) and after (0.5 ml, 4 mmol) was slowly added with stirring over 10 min.
(
Fig. 8b) photolysis, suggesting that H
2
S donor 4 is not cyto- After 4 h, the solvent was removed by rotary evaporation at
45 °C and subjecting to high vacuum, respectively. Then the
toxic at the studied concentrations.
residue was dissolved in 10 ml acetone and add to a stirred
and ice-cooled solution of sodium sulfide nonahydrate
(
Na S·9H O) (600 mg, 2.5 mmol) in water (20 ml). After com-
2 2
Conclusions
pletion of the addition, the mixture was warmed to room
In conclusion, we have developed a water soluble H S donor temperature for an hour. The completion of the reaction was
2
that generates H S under UV-Vis light (λ ≥ 365 nm) irradiation, monitored by TLC and the mixture was extracted with EtOAc
2
with the release of a bio-compatible photoproduct. The meta and washed with water. The collected organic layer was dried
effect of the N,N-dibutyl acid amine group helped in efficient over Na SO and the solvent was removed by rotary evaporation
2
4
uncaging of H S with high quantum yield. In vitro studies under reduced pressure. The crude product was purified by
2
revealed that our H S donor exhibited good biocompatibility column chromatography using 10% EtOAc in petroleum ether
2
1
and cellular internalisation. Furthermore, the H S release to give the product as a yellow solid (0.345 g, 70%). H NMR
2
ability of our donor at the cellular level was also demonstrated. (600 MHz, CDCl ) δ 8.10 (d, J = 8.0 Hz, 4H), 7.59 (d, J = 7.6 Hz,
3
1
3
Thus, our newly developed H S donor played a dual role: (i) 2H), 7.50 (t, J = 7.7 Hz, 2H), 3.71 (s, 4H). C NMR (151 MHz,
2
controlled release of H S under UV-Vis light (λ ≥ 365 nm) CDCl ) δ 148.38 (s), 139.81 (s), 134.98 (s), 129.63 (s), 123.75 (s),
2
3
without the aid of any additional reagent and (ii) being soluble 122.38 (s), 35.36 (s).
under physiological conditions.
Synthesis of 3,3′-(thiobis(methylene))dianiline (3). To a sus-
pension of bis(3-nitrobenzyl)sulfane (2) (600 mg, 2 mmol) in a
mixture of glacial acetic acid (5 mL), ethanol (5 mL) and water
(1 mL) was added reduced iron powder (560 mg, 10 mmol).
The resulting suspension was stirred for 1 h at room tempera-
ture with TLC analysis monitoring for the completion of the
reaction. The reaction mixture was filtered to remove the iron
residue which was washed with ethyl acetate (30 mL). The fil-
trate was partitioned with 2 M KOH and the basic layer was
further extracted with ethyl acetate (3 × 25 mL). The combined
organic extracts were washed with brine (2 × 25 mL) and water
Experimental section
Chemicals and starting materials
All reagents were purchased from Sigma-Aldrich and were
used without further purification. Dichloromethane was dis-
tilled from CaH before use. All anhydrous reactions were per-
2
formed under a dry nitrogen atmosphere.
Methods and techniques
1
(
3 × 50 mL), dried over Na SO and concentrated under
2 4
H NMR spectra were recorded on a Bruker-AC 600 MHz reduced pressure. The crude residue was then subjected to
spectrophotometer. The chemical shifts were reported in ppm flash silica gel column chromatography (40% ethyl acetate in
1
from tetramethylsilane with the solvent resonance as the hexane) yielding 3 (89%). H NMR (400 MHz, CDCl ) δ 7.09 (t,
3
internal standard (deuterochloroform: 7.26 ppm,
.79 ppm). The data were reported as follows: chemical shifts, Hz, 2H), 3.53 (s, 4H). C NMR (101 MHz, CDCl
multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet), 139.42 (s), 129.30 (s), 119.44 (s), 115.72 (s), 113.93 (s), 35.72 (s).
2
D O: J = 8 Hz, 2H), 6.68 (d, J = 8 Hz, 2H), 6.64 (s, 2H), 6.57 (d, J = 8
1
3
4
3
) δ 146.50 (s),
1
3
and coupling constant (Hz). The C NMR (150 MHz) spectra
Synthesis of bis(4,4′-(phenylazanediyl)dibutanoic acid)
were recorded on a Bruker-AC 600 MHz spectrometer with sulfane (4). Compound 3 (2.5 g, 10 mmol) was dissolved in
complete proton decoupling. The chemical shifts were 30 mL of dry DMF in an ice-bath and then Na HPO (5.5 g,
2
4
reported in ppm from tetramethylsilane with the solvent reso- 40 mmol) was added. To this mixture 4-bromobutyric acid
nance as the internal standard (deuterochloroform: 77.0 ppm). (4.1 ml, 40 mmol) was added dropwise. Finally, the mixture
UV/Vis absorption spectra were recorded on a Shimadzu was refluxed overnight until all the starting material was con-
UV-2450 UV/Vis spectrophotometer; the fluorescence emission sumed. The reaction mixture was then cooled to room temp-
3
spectra were recorded on a Hitachi F-7000 fluorescence erature, neutralized by dropwise addition of NaHCO solution
spectrophotometer. The photolysis of the caged compounds and extracted with EtOAc. The combined organic extracts were
was carried out using a 125 W medium-pressure Hg lamp sup- washed with saturated brine. Next, purification was done by
plied by SAIC (India). Chromatographic purification was done column chromatography (methanol : DCM = 1 : 5) to afford the
with 60–120-mesh silica gel (Merck). For reaction monitoring, pure product as a pale yellow gel (2.3 g, yield 40%).
1
precoated silica gel 60 F254 TLC sheets (Merck) were used.
2 3
H NMR (600 MHz, D O–CD OD) δ 7.05 (s, 2H), 6.81–6.35
RP-HPLC was performed using acetonitrile as the mobile (m, 6H), 3.61 (s, 4H), 3.12–3.05 (m, 8H), 2.06–1.95 (m, 8H),
−
1
13
phase, at a flow rate of 1 mL min
.
1.64–1.57 (m, 8H). C NMR (151 MHz, D O) δ 182.94 (s),
2
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem., 2019, 17, 9059–9064 | 9063

View Article Online
Paper
Organic & Biomolecular Chemistry
1
48.21 (s), 139.23 (s), 129.92 (s), 117.61 (s), 114.03 (s), 112.61
4 J. M. Fukuto, S. J. Carrington, D. J. Tantillo, J. G. Harrison,
L. J. Ignarro, B. A. Freeman, A. Chen and D. A. Wink, Chem.
Res. Toxicol., 2012, 25, 769–793.
5 K. R. Olson, J. A. Donald, R. A. Dombkowski and S. F. Perry,
Respir. Physiol. Neurobiol., 2012, 184, 117–129.
6 Y. Zhao and M. D. Pluth, Angew. Chem., Int. Ed., 2016, 55,
14638–14642.
7 N. O. Devarie-baez, P. E. Bagdon, B. Peng, Y. Zhao, C. Park
and M. Xian, Org. Lett., 2013, 15, 2786–2789.
8 Y. Zhao, S. G. Bolton and M. D. Pluth, Org. Lett., 2017, 19,
2278–2281.
9 W. Chen, M. Chen, Q. Zang, L. Wang, F. Tang, Y. Han,
C. Yang, L. Deng and Y.-N. Liu, Chem. Commun., 2015, 51,
9193–9196.
(s), 50.64 (s), 35.37 (s), 34.93 (s), 23.10 (s). HRMS (ESI+) calcd
+
for C30
40 2 8
H N O S [M + H] , 588.2505; found: 588.2586.
−
4
Photolysis of H
2
S donor 4. A solution of 10 M H
2
S donor 4
was prepared in PBS buffer. Half of the solution was kept in
the dark and to the remaining half, nitrogen was passed
through and it was irradiated under UV light (≥365 nm), using
a 125 W medium pressure Hg lamp filtered by using suitable
filters with continuous stirring. At regular intervals of time,
2
0 μl of the aliquot was taken and analyzed by absorption spec-
troscopy, fluorescence spectroscopy and RP-HPLC using aceto-
nitrile as the mobile phase, at a flow rate of 1 ml min− (detec-
tion: UV 254 nm). Peak areas were determined by RP-HPLC
with an average of three runs, which indicated a gradual
1
decrease of H
until the consumption of H
initial content. Based on the HPLC data for each compound,
2
S donor 4 with time. The reaction was followed 10 N. Fukushima, N. Ieda, K. Sasakura, T. Nagano,
2
S donor 4 was less than 5% of the
K. Hanaoka, T. Suzuki, N. Miyata and H. Nakagawa, Chem.
Commun., 2014, 50, 587–589.
we plotted normalized [A] (HPLC peak area) versus irradiation 11 N. Fukushima, N. Ieda, M. Kawaguchi, K. Sasakura,
time.
Characterisation of photoproduct (6). H NMR (600 MHz,
T. Nagano, K. Hanaoka, N. Miyata and H. Nakagawa,
Bioorg. Med. Chem. Lett., 2015, 25, 175–178.
1
2
D O) δ 7.19 (t, J = 6.7 Hz, 1H), 6.80–6.70 (m, 2H), 6.65 (d, J = 12 Z. Xiao, T. Bonnard, A. Shakouri-Motlagh, R. A. L. Wylie,
6
1
1
4
.5 Hz, 1H), 4.47 (s, 2H), 3.19 (s, 4H), 2.09 (d, J = 6.0 Hz, 4H),
J. Collins, J. White, D. E. Heath, C. E. Hagemeyer and
L. A. Connal, Chem. – Eur. J., 2017, 23, 11294–11300.
1
3
.69 (s, 4H). C NMR (151 MHz, D O) δ 182.98 (s), 148.46 (s),
2
41.73 (s), 129.89 (s), 115.78 (s), 113.00 (s), 112.54 (s), 64.19 (s), 13 A. K. Sharma, M. Nair, P. Chauhan, K. Gupta, D. K. Saini
8.74 (s), 34.89 (s), 23.09 (s).
and H. Chakrapani, Org. Lett., 2017, 19, 4822–4825.
4 Y. Venkatesh, J. Das, A. Chaudhuri, A. Karmakar,
T. K. Maiti and N. D. Pradeep Singh, Chem. Commun., 2018,
1
1
54, 3106–3109.
Conflicts of interest
5 X. Ding and P. Wang, J. Org. Chem., 2017, 82, 7309–7316.
There are no conflicts to declare.
16 P. Wang, J. Photochem. Photobiol., A, 2017, 335, 300–310.
17 P. Wang, D. Devalankar, Q. Dai, P. Zhang and S. Michalek,
J. Org. Chem., 2016, 81, 9560–9566.
1
8 X. Ding, D. Devalankar and P. Wang, Org. Lett., 2016, 18,
Acknowledgements
5396–5399.
We thank DST SERB (Grant No. DIA/2018/000019) for financial 19 P. Wang, D. Devalankar and W. Lu, J. Org. Chem., 2016, 81,
support and DST-FIST for 600 and 400 MHz NMR. M. Bera is
thankful to the IIT Kharagpur for the fellowship.
6195–6200.
20 P. Wang, W. Lu, D. A. Devalankar and Z. Ding, Org. Lett.,
2
015, 17, 2114–2117.
1 P. Wang, W. Lu, D. Devalankar and Z. Ding, Org. Lett.,
015, 17, 170–172.
2 X. Ding and P. Wang, J. Org. Chem., 2018, 83, 7459–7466.
2
2
Notes and references
2
1
M. S. Vandiver and S. H. Snyder, J. Mol. Med., 2012, 90, 23 D. Wu, W. Si, M. Wang, S. Lv, A. Ji and Y. Li, Nitric Oxide,
55–263. 2015, 50, 38–45.
2
2
3
R. Wang, Physiol. Rev., 2012, 92, 791–896.
C. Szabó, Nat. Rev. Drug Discovery, 2007, 6, 917–935.
24 M. R. Filipovic, J. Zivanovic, B. Alvarez and R. Banerjee,
Chem. Rev., 2018, 118, 1253–1337.
9064 | Org. Biomol. Chem., 2019, 17, 9059–9064
This journal is © The Royal Society of Chemistry 2019