Improved synthetic method of Benzo[a]pheno-selenazinium phototherapeutic agents

Article abstract of DOI:10.1016/j.dyepig.2021.109154

Benzo[a]phenoselenazinium dyes are excellent photodynamic therapeutic agents that have a red absorption (660 nm), high singlet oxygen quantum yield (>0.8), and good water-solubility and liposolubility. Bis-(3-diethylaminophenyl) diselenide, the most impor

Full text of DOI:10.1016/j.dyepig.2021.109154

Dyes and Pigments 188 (2021) 109154
Contents lists available at ScienceDirect
Dyes and Pigments
journal homepage: http://www.elsevier.com/locate/dyepig
Improved synthetic method of Benzo[a]pheno-selenazinium
phototherapeutic agents
a
a
b
a,
c,
*
d
Xiuxiu Yue , Jing Xu , Xiaozhong Liu , Xiangzhi Song
, James W. Foley
a
College of Chemistry & Chemical Engineering, Central South University, Changsha, 410083, Hunan Province, China
b
c
Medoncare Pharmaceutical Company Ltd. Changsha, 410205, Hunan Province, China
Key Laboratory of Hunan Province for Water Environment and Agriculture Product Safety, Changsha, 410083, Hunan Province, China
Rowland Institute at Harvard, Harvard University, Cambridge 02142, Massachusetts, USA
d
A R T I C L E I N F O
A B S T R A C T
Keywords:
Benzo[a]phenoselenazinium dyes are excellent photodynamic therapeutic agents that have a red absorption
Photodynamic therapeutic agents
Benzo[a]phenoselenazinium dye
CuO nanopowder
(
660 nm), high singlet oxygen quantum yield (>0.8), and good water-solubility and liposolubility. Bis-(3-
diethylaminophenyl) diselenide, the most important intermediate for the synthesis of benzo[a]phenoselenazi-
nium dyes, is previously prepared in one pot through 3 steps, during which special care is needed for the
preparation of Grinard reagent and toxic selenium vapor. In this work, we employed CuO nanopowder to directly
couple haloaniline with selenium to obtain pure bis-(3-diethylaminophenyl) diselenide (one step) under a mild
condition with a high reaction yield without the need of column chromatography. Four benzo[a]phenoselena-
zinium dyes, 5a-d, were easily prepared using the improved synthesis method; and their phototoxicity in living
cells were investigated. The improved method could be employed in large-scale synthesis of benzo[a]phenose-
lenazinium dyes, thereby may stimulate the photodynamic study of this type of photosensitizer.
Singlet oxygen
Improved synthesis
1
. Introduction
As a treatment that has low toxicity, low cost and minimal inva-
are highly suitable for photodynamic therapy in vivo because they have a
red absorption in the optical window (600–900 nm), a high single ox-
ygen quantum yield, good water-solubility and liposolubility, and
excellent photo-stability [29–32].
siveness, but high effectiveness and dual selectivity, photodynamic
therapy (PDT) is a promising alternative therapy for ophthalmologic,
dermatologic, and cancerous oral lesions, head and neck cancers,
bladder carcinoma, and a variety of intraperitoneal carcinomatosis and
sarcomatous transformation [1–11]. In PDT, photosensitizers (PSs) are
the key components which can be excited by absorbing photons so that
they can subsequently react with oxygen to generate reactive oxygen
We have previously synthesized benzo[a]phenoselenazinium dyes in
six steps [25], as illustrated in Scheme 1. First, iodoaniline is converted
into the Grignard reagent (3-diethylamino) phenylmagnesium iodide
that subsequently reacts with selenium powder, is oxidized with air, and
is finally nitrosated to produce bis-(3-diethylamino-6-nitrosophenyl)
diselenide. Bis-(3-diethylamino-6-nitrosophenyl) diselenide is then
condensed with 1-naphthylamine derivatives to afford dye EtNBSe.
Although it was a successful approach, the synthesis of the key inter-
mediate bis-(3-diethylaminophenyl) diselenide requires harsh condi-
tions during the following two steps: i) the preparation and handling of
the Grignard reagent (3-diethylamino) phenylmagnesium iodide re-
quires a very dry environment; and ii) during the air oxidation process,
toxic selenium vapor is produced, and aqueous sodium hypochlorite is
needed to trap and bleach the vapor. In order to prepare more EtNBSe
analogue dyes at a larger scale for use in intensive medical studies, there
is a high demand for the neat synthesis under mild reaction conditions.
In this work, we improved the preparative process of bis-(3-
species (ROS) such as singlet oxygen, superoxide anion radicals, hy-
1
droxyl radicals, and so on. Singlet oxygen ( O
2
) is the main ROS that can
kill cancer cells through multifactorial mechanisms, such as stimulation
of the inflammatory and immune responses [12–21]; therefore, photo-
sensitizers with high singlet oxygen quantum yield are desirable. We
first developed a new photodynamic therapeutic agent, benzo[a]phe-
noselenazinium dye EtNBSe, an effective photosensitizer that treats
cutaneous leishmaniasis, tuberculosis and Mycobacterium bovis by
oxidative damage [22–25]. Following the development, more studies on
the derivative of EtNBSe have also been conducted [26–28]. All these
studies have shown that benzo[a]phenoselenazinium photosensitizers
*
Corresponding author. College of Chemistry & Chemical Engineering, Central South University, Changsha, 410083, Hunan Province, China.
E-mail address: xzsong@csu.edu.cn (X. Song).
https://doi.org/10.1016/j.dyepig.2021.109154
Received 14 November 2020; Received in revised form 13 January 2021; Accepted 13 January 2021
Available online 18 January 2021
0
143-7208/© 2021 Elsevier Ltd. All rights reserved.

X. Yue et al.
Dyes and Pigments 188 (2021) 109154
diethylaminophenyl) diselenide with an aim to increase the level of the
2 4
brine. After being dried over anhydrous Na SO , the solvent was
synthesis of EtNBSe derivatives to a larger scale (Scheme 2).
distilled in vacuo to obtain a crude solid, which was recrystallized in
isopropanol to afford an orange powder (16.35 g, 71%).
2
. Experimental
2
.5. Synthesis of 1-naphthylamine derivatives (4a-d)
2
.1. Instruments and materials
The synthetic method for compounds 4a-d have been described in
1H NMR and 13C NMR spectra were on a Bruker 400 spectrometer;
the literature [33].
the chemical shifts were reported in ppm in relative to those of TMS
tetramethyl silicane), an internal standard. Mass spectra were acquired
(
2
.6. General procedure for the synthesis of benzo[a] phenoselenazinium
using a Bruker Daltonics micrOTOF-Q II mass spectrometer. Absorption
and emission spectra were recorded on Hitachi F-7000 fluorometer and
Shimadzu UV-2450 spectrophotometer, respectively. Unless otherwise
stated, all reagents were used as received. Twice-distilled water was
used in all experiments.
dyes 5a-d
Benzo[a]phenoselenazinium dyes 5a-d were synthesized from bis-
3-diethylamino-6-nitrosophenyl) diselenide and the corresponding 1-
(
naphthylamine derivatives (4a-d). Compound 3 (4.62 g, 9.0 mmol)
was mixed with the corresponding 1-naphthylamine derivatives 4a-
d (26.0 mmol) in 60.0 mL of trifluoroethanol, and the mixture was
refluxed for 30 min. The solvent was then removed in vacuo to obtain a
blue residue, which was subsequently washed with 60.0 mL of ethyl
ether. The resultant residue was dissolved in 300.0 mL of a mixture
containing 1.0 M aqueous sodium hydroxide solution and dichloro-
methane (1:1, v/v). The organic phase was washed twice with brine;
after that, concentrated hydrochloric acid (0.1 mL) was added to the
solution, which caused the solution color to change from magenta to
dark blue. The solvent was removed in vacuo to obtain a blue residue,
which was then purified by flash silica gel column using a solvent
gradient of methanol/dichloromethane (0:100, 1:50, 1:30, 1:20, and
2
.2. Synthesis of CuO nanopowder
4
Fifty milliliters of aqueous CuSO solution (0.5 M) was mixed by
stirring with 50.0 mL of aqueous NaOH solution (1.0 M) in a beaker;
immediately after mixing, blue flocculent precipitate was formed. Next,
add 130.0 mL of sodium carbonate aqueous solution (0.5 M) to the
mixture, and continue to stir for 30 min. Collect the precipitate by
ꢀ
filtration and then wash with distilled H
detected by BaCl
2
O until SO2
4
was no longer
◦
2
. The obtained solid was dried in an oven at 90 C for 3
h and was then ground into powder. Finally, the powder was calcined at
◦
3
50 C for 4 h from which black CuO nanopowder was obtained.
1
:10, v/v) to yield the product.
2
.3. Synthesis of bis-(3-diethylaminophenyl) diselenide (2)
5a. Blue solid, yield: 41%. HRMS (ESI) m/z: calcd for C22H24N Se
3
+
1
[
M] , 410.1130; found, 410.1123. H NMR (400 MHz, DMSO‑d
6
) δ
Under argon atmosphere and while being stirred, powdered Se metal
10.48 (s, 1H), 8.73 (d, J = 5.2 Hz, 1H), 8.62 (s, 1H), 7.89–7.76 (m, 1H),
7.65 (d, J = 4.5 Hz, 2H), 7.19 (d, J = 8.3 Hz, 1H), 7.13 (s, 1H), 7.01 (s,
(
(
9.53 g, 120.0 mmol), CuO nanoparticles (0.46 g, 6.0 mmol) and KOH
6.74 g, 120.0 mmol) were added to a solution of 3-iodo-N, N-dieth-
1
3
1H), 3.70 (s, 6H), 1.48 (d, J = 5.8 Hz, 2H), 1.42–1.30 (m, 6H). C NMR
ylaniline (1) (16.5 g, 60.0 mmol) in dry DMSO (60.0 mL). The mixture
(100 MHz, CDCl ) δ 152.9, 150.3, 143.5, 138.7, 134.4, 133.7, 132.7,
3
◦
was then heated to 110 C overnight. After cooling down to room
131.96, 130.8, 129.4, 125.3, 124.4, 123.8, 115.8, 107.6, 105.9, 45.7,
temperature, 10.0 mL of water was added. After that, the reaction
mixture was extracted three times with ethyl acetate (3 x 40.0 mL). The
organic phase was washed twice with brine and thereafter dried over
39.3, 14.1, 12.7.
5b. Blue solid, yield: 40%. HRMS (ESI) m/z: calcd for C23H26N O SSe
3 3
+
1
[M] , 504.0855; found, 504.0354. H NMR (400 MHz, DMSO‑d ) δ
6
anhydrous Na
2
SO
4
overnight. After ethyl acetate was removed under a
10.20 (s, 1H), 8.99 (dd, J = 8.2, 1.1 Hz, 1H), 8.62 (d, J = 8.1 Hz, 1H),
reduced pressure, light red oil (20.35 g, 74%) was obtained.
8.02 (d, J = 9.4 Hz, 1H), 7.95 (s, 1H), 7.91 (t, J = 7.6 Hz, 1H), 7.85–7.79
(
m, 1H), 7.73 (d, J = 2.7 Hz, 1H), 7.31 (dd, J = 9.5, 2.7 Hz, 1H), 3.73
2
.4. Synthesis of bis-(3-diethylamino-6-nitrosophenyl) diselenide (3)
(dd, J = 14.3, 7.1 Hz, 2H), 3.64 (q, J = 6.9 Hz, 4H), 1.37 (t, J = 7.2 Hz,
13
4
H), 1.24 (t, J = 7.0 Hz, 6H). C NMR (100 MHz, CDCl ) δ 153.2 150.9,
3
In an ice-water bath, a solution of NaNO
2
(6.20 g, 98.2 mmol) in
144.0, 139.3, 134.9, 133.9, 132.6, 131.2, 129.7, 125. 8, 124.7, 123.3,
116.5, 108.0, 106.0, 46.0, 39.6, 29.9, 14.1, 12.9.
8
0.0 mL water was added dropwise to a solution of bis-(3-dieth-
ylaminophenyl) diselenide (2) (20.35 g, 44.8 mmol) in 100.0 mL of 1.0
M HCl for 10 min. After another 10 min stirring, extract with
dichloromethane (4 x 75.0 mL) and wash the organic phase twice with
5c. Blue solid, yield: 38%. HRMS (ESI) m/z: calcd for C23
H
24
N
3
O
2
Se
) δ 8.63
(d, J = 7.7 Hz, 1H), 8.34 (d, J = 7.3 Hz, 1H), 7.62 (dd, J = 17.0, 7.3 Hz,
+
1
[M] , 454.1028; found, 454.1020. H NMR (400 MHz, DMSO‑d
6
Scheme 1. Schematic diagram showing the previous synthetic route of photosensitizer EtNBSe (5a).
2

X. Yue et al.
Dyes and Pigments 188 (2021) 109154
Scheme 2. The improved synthetic route of the photosensitizers 5a-d presented in this work.
4
3
H), 7.11 (s, 1H), 6.85 (d, J = 8.3 Hz, 1H), 3.80 (t, J = 6.6 Hz, 2H),
3. Results and discussion
1
3
.53–3.44 (m, 4H), 2.70 (t, J = 6.5 Hz, 2H), 1.16 (t, J = 6.9 Hz, 6H).
) δ 175.0, 156.2, 151.0, 145.2, 139.1, 134.6,
32.2, 132.1, 129.7, 125.9, 124.2, 124.1, 117.0, 115.8, 111.1, 109.3,
07.9, 55.4, 45.6, 29.5, 22.6, 19.0, 13.2.
d. Blue solid, yield: 45%. HRMS (ESI) m/z: calcd for C22
C
NMR (100 MHz, DMSO‑d
6
3.1. Chemistry of the synthesis
1
1
In this study, bis-(3-diethylamino-6-nitrosophenyl) diselenide was
synthesized in one step using CuO nanopowder as a catalyst. This new
synthetic method had several advantages as follows: (i) the special care
needed for the Grignard reaction was avoided; (ii) the toxic selenium
vapor was not generated because air bubbles were omitted; and (iii) the
reaction procedure was simple (as it could be accomplished in only one
step), and the product yield was improved from 56% to 74.5% without
the need of column chromatography. Thus, this new synthetic method
was able to readily prepare four pure benzo[a]phenoselenazinium dyes
5
H
24
N
3
OSe
) δ
0.08 (s, 1H), 9.00 (d, J = 8.0 Hz, 1H), 8.60 (d, J = 8.1 Hz, 1H),
.08–7.98 (m, 2H), 7.91 (t, J = 7.6 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.71
+
1
[
M] , 426.1079; found, 426.1072. H NMR (400 MHz, DMSO‑d
6
1
8
(
s, 1H), 7.30 (d, J = 9.3 Hz, 1H), 5.14 (s, 1H), 3.79 (d, J = 2.4 Hz, 4H),
1
3
3
.64 (q, J = 6.9 Hz, 4H), 1.24 (t, J = 7.0 Hz, 6H). C NMR (100 MHz,
) δ 157.3, 154.6, 147.5, 142.9, 138.5, 137.7, 137.4, 136.4, 134.7,
33.1, 129.3, 128.2, 126. 5, 120.3, 111.7, 110.2, 63.6, 50.5, 49.6, 16.3.
CDCl
3
1
5
a-d with high yields.
2
Δ
.7. Measurement of singlet oxygen quantum yield (Φ )
3
.2. Optical properties of photosensitizers
The 1
O
quantum yields (Φ
) of the photosensitizers were deter-
= 0.5 in methanol)
2
Δ
mined with methylene blue (MB) as a reference (Φ
34]. 1,3-Diphenylisobenzofuran (DPBF) in air-saturated dichloro-
Δ
We determined the optical spectra of the four photosensitizers 5a-
[
d in methanol and H
charge and are soluble in methanol and H
intensive absorption band within the optical window (λmax ≈ 660 nm;
Fig. 1). In H O, the dyes exhibited an absorption band at about 627 nm,
2
O. All the dyes contain a delocalized positive
1
methane with an optical density (OD) at 1.0 was used to scavenge O
The concentration of the photosensitizer was adjusted to an OD between
.2 and 0.3. The cuvette was irradiated for 10 s with monochromatic
2
.
2
O. The four dyes exhibited an
0
2
light at the maximum absorption wavelength of photosensitizers, and
the absorbance was measured several times after each irradiation. The
slope of the plot between the absorbance of DPBF at 411 nm versus time
for each photosensitizer was calculated. Singlet oxygen quantum yield
which might be caused by H-aggregation of the photosensitizers [25]. As
expected, the dyes also exhibited weak fluorescence due to the effect of
the heavy metal Se [35,36] (Fig. 1).
bod
ref
(
Φ
Δ
) was calculated according to a modified equation: Φ
Δ
= Φ
Δ
*
3.3. Singlet oxygen quantum yield
(
k
bod/kref)*(Fref/Fbod), where bod and ref refer to the photosensitizers
and MB, respectively, k is the slope of the plot between the absorbance of
DPBF (411 nm) versus irradiation time, and F is the absorption correc-
The singlet oxygen quantum yields of the photosensitizers 5a-d in
1
2
methanol were measured using the O trapping reagent 1,3-diphenyli-
ꢀ O.D.
tion factor (which was calculated by F = 1-10
, where O.D. is the
sobenzofuran (DPBF). As shown in Fig. 2 and S2, illuminating the so-
optical density of the solution at the irradiation wavelength).
lutions of the photosensitizers 5a-d in DPBF with 660 nm LED light
caused their absorption intensity at 411 nm to decrease due to the
1
irreversible 1,4-cycloaddition reaction between DPBF and
2
O . More-
2
.8. In vitro toxicity assay
over, with increasing illumination time, the decrease was intensified.
The singlet oxygen yields of the photosensitizers 5a-d were determined
to be over 0.8 (Table 1).
MTT assay was used to assess the toxicity to cancer cells of the
photosensitizers [32]. HepG2 cells (100.0
μL; density = 5000 cells/mL)
in the logarithmic phase were added to 96-well plates and incubated at
◦
3
7
C in 5% CO
2
for 24 h. After that, 100.0
μL of each of the photo-
3.4. In vitro photodynamic therapy and imaging
sensitizers 5a-d in DMSO solution was added to each well, and cells were
further incubated for 1 h. After being illuminated with 660 nm LED light
HepG2 cells were cultured with photosensitizers 5a-d for 30 min;
2
◦
2
(
20 mW/cm ), cells were incubated for 24 h at 37 C in 5% CO
2
atmo-
after that, they were irradiated under a 660 nm light (20 mW/cm ) for 0,
sphere. Subsequently, the medium in each well was replaced with 100.0
1, 5, and 10 min, respectively; non-irradiated samples were also pre-
pared for comparison. As shown in Fig. 3, the non-irradiated photo-
sensitizers 5a-d were non-toxic, suggesting they have good
biocompatibility in vitro. In contrast, as expected, the light-irradiated
photosensitizers 5a-d were highly cytotoxic, and the cytotoxicity
increased with increasing the dose of photosensitizer as well as with the
irradiation time. Interestingly, photosensitizers 5a, 5b and 5d at a low
μ
L of fresh medium, and 20.0
μ
L of MTT solution was added thereafter.
◦
After the culture plates were then incubated at 37 C in 5% CO
2
for 4 h,
the culture medium was discarded, and 100.0 L of DMSO was added.
μ
The absorbance at 570 nm of the samples was measured using a
microplate reader. Cells incubated with photosensitizers without light
irradiation were used as a control.
3

X. Yue et al.
Dyes and Pigments 188 (2021) 109154
2
Fig. 1. Absorption (top row) and fluorescence (bottom row) spectra of photosensitizers 5a-d in methanol (a, c) and in H O (b, d).
Table 1
Photophysical properties of photosensitizers 5a-d in methanol.
1
Compounds
λ
abs/nm
λ
em/nm
Δ 2
Φ ( O )
5
5
5
5
a
b
c
660
660
660
660
707
707
708
708
0.80
0.83
0.86
0.86
d
4
. Conclusion
In conclusion, CuO nanopowder was used as the catalyst to optimize
the synthesis of the key intermediate of benzo[a]phenoselenazinium
PDT agents, bis-(3-diethylaminophenyl) diselenide. This new synthetic
method required a mild reaction condition, but resulted in the product
with high purity without the need of purification by column chroma-
tography; it also had a simple and straightforward operation procedure.
This work presents the synthesis method for benzo[a]phenoselenazi-
nium PDT agents that can be potentially up-scaled. With this method,
the clinical studies and practical applications of the agents can poten-
tially be boosted.
Fig. 2. The decay curves of the absorbance at 411 nm of DPBF in methanol as a
function of irradiation time without and with photosensitizers 5a-d and
2
methylene blue (MB). Light source 660 nm LED (20 mW/cm ).
concentration of 0.04
ation time was 10 min; however, this is not the case for photosensitizer
c. As shown in Fig. S4, these four dyes all exhibited bright red fluo-
μM displayed high cytotoxicity when the irradi-
5
rescence in HepG2 cells. These results indicate that photosensitizers 5a-
d had good photodynamic therapeutic effect and could also be applied
for cell imaging.
4

X. Yue et al.
Dyes and Pigments 188 (2021) 109154
2
Fig. 3. Cytotoxicity against HepG2 cells of photosensitizers 5a-d at various concentrations under a 660 nm light (20 mW/cm ) irradiation for (a) 0 min, (b) 1 min, (c)
min, and (d) 10 min.
5
Credit author statement
Appendix A. Supplementary data
Xiuxiu Yue prepared the photosensitizers 5a-d, performed the mea-
surements, analyzed the data, and wrote the paper. Jing Xu prepared the
performed the experiments. Xiangzhi Song processed the data and
writing-review & editing supervision with Xiaozhong Liu and James W.
Foley. All authors have given approval to the final version of the paper.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.dyepig.2021.109154.
References
[
[
[
1] Zhang Y, Shen W, Zhang P, Chen L, Xiao C. GSH-triggered release of sulfur dioxide
gas to regulate redox balance for enhanced photodynamic therapy. Chem Commun
Funding sources
2
020;56:5645–8.
2] Ferraz RC, Fontana CR, Ribeiro AP, Trindade FZ, Bartoloni FH, Baader JW, Lins EC,
Bagnato VS, Kurachi C. Chemiluminescence as a PDT light source for microbial
control. J Photochem Photobiol, B 2011;103:87–92.
This work was supported by the Natural Science Foundation of
Hunan Province, China (No. 2019JJ40360), National Natural Science
Foundation of China (No. 21907110) and Basic Research Foundation of
3] Hu W, He T, Zhao H, Tao H, Chen R, Jin L, Li J, Fan Q, Huang W, Baev A,
Prasad PN. Stimuli-responsive reversible switching of intersystem crossing in pure
organic material for smart photodynamic therapy. Angew Chem Int Ed 2019;58:
Shenzhen
Science
and
Technology
Innovation
(No.
1
1105–11.
JCYJ20190806144605441).
[
[
4] Demir Duman F, Sebek M, Thanh NTK, Loizidou M, Shakib K, MacRobert AJ.
Enhanced photodynamic therapy and fluorescence imaging using gold nanorods
for porphyrin delivery in a novel in vitro squamous cell carcinoma 3D model.
J Mater Chem B 2020;8:5131–42.
Declaration of competing interest
5] Rizvi I, Anbil S, Alagic N, Celli J, Zheng LZ, Palanisami A, Glidden MD, Pogue BW,
Hasan T. PDT dose parameters impact tumoricidal durability and cell death
pathways in a 3D ovarian cancer model. Photochem Photobiol 2013;89:942–52.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
5

X. Yue et al.
Dyes and Pigments 188 (2021) 109154
[
[
6] Famularo G, De Simone C. HIV infection of CD8 lymphocytes: a critical step for the
disease? Nat Rev Canc 1998;13:65–6.
[23] Wagner SJ, Skripchenko A, Robinette D, Foley JW, Cincotta L. Factors affecting
virus photoinactivation by a series of phenothiazine dyes. Photochem Photobiol
1998;67:343–9.
7] Bachor R, Shea CR, Gillies R, Hasan T. Photosensitized destruction of human
bladder carcinoma cells treated with chlorin e6-conjugated microspheres. Proc
Natl Acad Sci USA 1991;88:1580.
[24] Akilov OE, Kosaka S, O’Riordan K, Song X, Sherwood M, Flotte TJ, Foley JW,
Hasan T. The role of photosensitizer molecular charge and structure on the efficacy
of photodynamic therapy against Leishmania parasites. Chem Biol 2006;13:
839–47.
[
[
8] Celli JP, Spring BQ, Rizvi I, Evans CL, Samkoe KS, Verma S, Pogue BW, Hasan T.
Imaging and photodynamic therapy: mechanisms, monitoring, and optimization.
Chem Rev 2010;110:2795–838.
[25] Foley JW, Song X, Demidova TN, Jilal F, Hamblin MR. Synthesis and properties of
benzo[a]phenoxazinium chalcogen analogues as novel broad-spectrum
antimicrobial photosensitizers. J Med Chem 2006;49:5291–9.
9] Lovell JF, Liu TWB, Chen J, Zheng G. Activatable photosensitizers for imaging and
therapy. Chem Rev 2010;110:2839–57.
[
[
10] Li M, Xia J, Tian R, Wang J, Fan J, Du J, Long S, Song X, Foley JW, Peng X. Near-
infrared light-initiated molecular superoxide radical generator: rejuvenating
photodynamic therapy against hypoxic tumors. J Am Chem Soc 2018;140:
[26] Vecchio D, Bhayana B, Huang L, Carrasco E, Evans CL, Hamblin MR. Structure-
function relationships of Nile blue (EtNBS) derivatives as antimicrobial
photosensitizers. Eur J Med Chem 2014;75:479–91.
1
4851–9.
[27] Liu A, Zhang W, Chen Y, Zhou D, Wang Z, Kang J, Wei L. EtNBSe-PDT inhibited
proliferation and induced autophagy of HNE-1 cells via downregulating the Wnt/
beta-catenin signaling pathway. Photodiagnosis Photodyn Ther 2019;26:65–72.
[28] Chen J, Huang J-H, Wang Z, Song X, Chen Z, Zeng Q, Zhou X, Zuo Z, Zhao S,
Chen X, Kang J. Endoplasmic reticulum stress-mediated autophagy contributes to
5-ethylamino-9-diethylaminobenzo[a]phenoselenazinium-mediated
11] Li M, Xiong T, Du J, Tian R, Xiao M, Guo L, Long S, Fan J, Sun W, Shao K, Song X,
Foley JW, Peng X. Superoxide radical photogenerator with amplification effect:
surmounting the achilles’ heels of photodynamic oncotherapy. J Am Chem Soc
2
019;141:2695–702.
[
[
12] Jiang Y, Li J, Zeng Z, Xie C, Lyu Y, Pu K. Organic photodynamic nanoinhibitor for
synergistic cancer therapy. Angew Chem Int Ed 2019;58:8161–5.
photodynamic therapy via the PERK-eIF2 pathway. OncoTargets Ther 2018;11:
α
13] Chen H, Li S, Wu M, Kenry, Huang Z, Lee CS, Liu B. Membrane-anchoring
photosensitizer with aggregation-induced emission characteristics for combating
multidrug-resistant bacteria. Angew Chem Int Ed 2020;59:632–6.
4315–25.
[29] Kelland LR, Abel G, McKeage MJ, Jones M, Goddard PM, Valenti M, Murrer BA,
Harrap KR. Preclinical antitumor evaluation of bis-acetato-ammine-dichloro-
cyclohexylamine platinum(IV): an orally active platinum drug. Canc Res 1993;53:
2581–6.
[
14] Cui D, Huang J, Zhen X, Li J, Jiang Y, Pu K. A semiconducting polymer nano-
prodrug for hypoxia-activated photodynamic cancer therapy. Angew Chem Int Ed
2
019;58:5920–4.
[30] Akilov OE, Kosaka S, O’Riordan K, Hasan T. Photodynamic therapy for cutaneous
leishmaniasis: the effectiveness of topical phenothiaziniums in parasite eradication
and Th1 immune response stimulation. Photochem Photobiol Sci 2007;6:1067–75.
[31] Cincotta L, Szeto D, Lampros E, Hasan T, Cincotta AH. Benzophenothiazine and
benzoporphyrin derivative combination phototherapy effectively eradicates large
murine sarcomas. Photochem Photobiol 1996;63:229–37.
[
[
15] Viola G, Dall’Acqua F. Photosensitization of biomolecules by phenothiazine
derivatives. Curr Drug Targets 2006;7:1135–54.
16] Azizi B, Budimir A, Bago I, Mehmeti B, Jakovljevi ´c S, Kelmendi J, Stanko AP,
Gabri ´c D. Antimicrobial efficacy of photodynamic therapy and light-activated
disinfection on contaminated zirconia implants: an in vitro study. Photodiagnosis
Photodyn Ther 2018;21:328–33.
[32] Cincotta L, Foley JW, Cincotta AH. Novel red absorbing benzo[a]phenoxazinium
and benzo[a]phenothiazinium photosensitizers: in vitro evaluation. Photochem
Photobiol 1987;46:751–8.
[
[
[
[
17] Castano AP, Mroz P, Hamblin MR. Photodynamic therapy and anti-tumour
immunity. Nat Rev Canc 2006;6:535–45.
18] Shen Y, Shuhendler AJ, Ye D, Xu JJ, Chen HY. Two-photon excitation
nanoparticles for photodynamic therapy. Chem Soc Rev 2016;45:6725–41.
19] Castano AP, Mroz P, Hamblin MR. Photodynamic therapy and anti-tumour
immunity. Nat Rev Canc 2006;6:535–45.
[33] Frade VHJ, Barros SA, Moura JCVP, Coutinho PJG, Gonçalves MST. Synthesis of
short and long-wavelength functionalised probes: amino acids’ labelling and
photophysical studies. Tetrahedron 2007;63:12405–18.
[34] Detty MR, Merkel PB. Chalcogenapyrylium dyes as potential
photochemotherapeutic agents. Solution studies of heavy atom effects on triplet
yields, quantum efficiencies of singlet oxygen generation, rates of reaction with
singlet oxygen, and emission quantum yields. J Am Chem Soc 1990;112:3845–55.
[35] Ohulchanskyy TY, Donnelly DJ, Detty MR, Prasad PN. Heteroatom substitution
induced changes in excited-state photophysics and singlet oxygen generation in
chalcogenoxanthylium dyes: effect of sulfur and selenium substitutions. J Phys
Chem B 2004;108:8668–72.
20] Castano AP, Demidova TN, Hamblin MR. Mechanisms in photodynamic therapy:
part two-cellular signaling, cell metabolism and modes of cell death.
Photodiagnosis Photodyn Ther 2005;2:1–23.
[
[
21] Zheng X, Sallum UW, Verma S, Athar H, Evans CL, Hasan T. Exploiting a bacterial
drug-resistance mechanism: a light-activated construct for the destruction of
MRSA. Angew Chem Int Ed 2009;48:2148–51.
22] O’Riordan K, Akilov OE, Chang SK, Foley JW, Hasan T. Real-time fluorescence
monitoring of phenothiazinium photosensitizers and their anti-mycobacterial
photodynamic activity against Mycobacterium bovis BCG in in vitro and in vivo
models of localized infection. Photochem Photobiol Sci 2007;6:1117–23.
[36] Piao W, Hanaoka K, Fujisawa T, Takeuchi S, Komatsu T, Ueno T, Terai T, Tahara T,
Nagano T, Urano Y. Development of an azo-based photosensitizer activated under
mild hypoxia for photodynamic therapy. J Am Chem Soc 2017;139:13713–9.
6