Bismuth-rhodamine: A new red light-excitable photosensitizer

Article abstract of DOI:10.1039/c7dt03194g

Bismuth-rhodamine (BiR) was developed as a new photosensitizer scaffold, and its photophysical properties were evaluated. BiR showed significant red-shifted absorption and emission compared with other xanthene-based photosensitizers, together with an efficient quantum yield for the generation of ¹O₂. BiR showed efficient cell-permeability as well as photo-triggered generation of ¹O₂ in cells.

Full text of DOI:10.1039/c7dt03194g

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Bismuth-rhodamine: a new red light-excitable photosensitizer
Tasuku Hirayama,a Akari Mukaimine,a Kenta Nishigaki,a Hitomi Tsuboi,a Shusaku Hirosawa,a Kensuke
Okuda,a,b Masahiro Ebihara,c and Hideko Nagasawaa
aLaboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, 1ꢀ25ꢀ4,
Daigakuꢀnishi, Gifu, 501ꢀ1196, Japan.
b
Current address: Laboratory of Bioorganic & Natural Products Chemistry, Kobe Pharmaceutical
University, 4ꢀ19ꢀ1, Motoyamakitaꢀmachi, Higashinadaꢀku, Kobe, Hyogo, 658ꢀ8558, Japan.
c
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido,
Gifu, 501ꢀ1193, Japan
Footnotes: Electronic Supplementary Information (ESI) available: Experimental details, pH titration of absorption
and fluorescence spectra, fluorescence imaging data for EC50 measurements, NMR and mass data of the newly
synthesized compounds. CCDC 1530802. For ESI and cyrystallographic data in CIF or other electronic format see
DOI:xxxx.
Abstract
Bismuthꢀrhodamine (BiR) was developed as a new photosensitizer scaffold, and its photophysical properties were
evaluated. BiR showed significant redꢀshifted absorption and emission compared with other xantheneꢀbased
photosensitizers together with an efficient quantum yield for generation of 1O2. BiR showed easy
cellꢀpermeability as well as photoꢀtriggered generation of 1O2 in cells.
Bismuth (209Bi) is the heaviest stable typical element. Unlike the other sixth row elements such as thallium, lead,
and polonium, bismuth is known as a minimally toxic heavy element.1 This factor enables the clinical use of
bismuth compounds for antiflatulent such as bismuth subgallate (known as Dermatol® and Devrom®) and bismuth
subsalicilate2–9 for use in the treatment of gastrointestinal disorders. Organobismuth compounds have recently
attracted attention as unique structural building blocks,10 chemical reagents,11–15 and phosphorescent materials.16
Bismuth has the combination of low toxicity together with the characteristics of being a heavy atom. In this study,
both these factors are explored with a view for the development of a new pharmaceutical organobismuth
compound.
Both fluoresceins and rhodamines are categorized as xanthene fluorophores and have found wide application in
various types of fluorescent probes.17–19 Recently, several groups have reported that photophysical characteristics
including excitation/emission wavelength could be tuned to the long wavelength region by a replacement of the
oxygen atom within the xanthene core to the third row typical elements such as Si20,21 and P.22,23 Siꢀrhodamines
show significantly redꢀshifted (~80 nm) absorption and emission compared to conventional rhodamines such as
rhodamine B and have been widely utilized as redꢀemissive fluorophores.24–27 Very recently, Pꢀfluorescein22 and

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Siꢀrhodamines23 have successively emerged as deepꢀred and nearꢀinfrared emissive fluorophores. Incorporation of
the fourth or lower row chalcogen elements such as Se and Te into the xanthene ring by a replacement of the
oxygen atom results in a relatively small redꢀshift (30–40 nm) of the excitation/emission together with efficient
generation of an excited triplet state and subsequent singlet oxygen (1O2). This effect is a direct result of the
1
elements with heavy atoms.28–30 Chromophores that can generate O2 upon irradiation of appropriate light have
been utilized as photosensitizer of photodynamic therapy (PDT) of cancers.31,32 An ideal photosensitizer should
have a high absorption peak between 600 and 800 nm because the red to deep red absorption enable efficient
tissue penetration of excitation light.33 Additionally, no dark toxicity, water solubility, and high quantum yield for
1O2 generation are also required for photosensitizes of PDT.33 Conventional clinically used photosensitizers are
composed of conjugated tetrapyrrole scaffolds such as porphyrin and chlorine but their synthetic difficulty,
complexed structure, and large molecular sizes often hamper chemical modifications to improve their low water
solubility, cellular uptake, and cancer selectivity.31,33 Although photosensitizers consisting of fluoresceins and
rhodamines chromophores could potentially be a good candidate as PDT agents due to the compatibility with
chemical modifications and relatively high water solubility compared to the tetrapyrroles, the majority of them
show absorption at less than 610 nm, which needs further effort to achieve efficient excitation under the tissue.28–
30,34
It has been reported by Oshita et al. that a 2,2'ꢀbithiophene derivative bridged with phenylbismuth at 3 and
3'ꢀposition exhibited redꢀshifted absorption and emission compared to the corresponding carbonꢀbridged
2,2'ꢀbithiophene, and the redꢀshift effect was compatible to its siliconꢀbridged counterpart.16 These results
prompted the investigation performed in this work, namely, to develop a bismuthꢀrhodamine (BiR) because dual
effects of Biꢀincorporation on excitation/emission wavelength and photosensitizing properties were expected. This
investigation describes the preparation, structure, photophysical properties, and biological applications of BiR as a
new scaffold for red lightꢀexcitable photosensitizers.
BiR was synthesized from bis(4ꢀdimethylaminoꢀ2ꢀbromophenyl)ꢀ2ꢀtolylꢀmethane 1 via lithiation with secꢀBuLi
followed by treatment with PhBiCl2 and oxidation with pꢀchloranil (Scheme 1). BiR was obtained in 4% yield
from 1 as hexafluorophosphate salt after purification by recrystallization. The structure of BiR was characterized
by 1HꢀNMR, 13CꢀNMR, and mass spectrometry, elemental analysis, and single crystal Xꢀray diffraction analysis.

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Scheme 1. Structures of BiR and TMR and synthetic procedure of BiR
N2
C13
Bi1
C25
C2
C12
C11
C8
C9
C1
C6
C10
C3
N1
C7
C4
C5
Fig. 1 ORTEP image of the structure of BiR (atomic displacement parameters: 50% probability, only selected
−
atoms are labeled; hydrogen atoms, solvent (acetonitrile), and counter anion (PF6 ) molecules are omitted for
clarity. Gray: carbon. Blue: nitrogen. Purple: bismuth. Selected bond lengths (Å): Bi1–C1 = 2.226(5), Bi1–C8 =
2.236(5), Bi1–C25 = 2.283(7), C1–C2 = 1.389(6), C1–C6 = 1.426(7), C2–C3 = 1.412(6), C3–C4 = 1.407(8), C3–
N1 = 1.349(6), C4–C5 = 1.361(7), C5–C6 = 1.405(7), C6–C7 = 1.432(6), C7–C9 = 1.418(6), C7–C18 = 1.508(7),
C8–C9 = 1.428(7), C8–C13 = 1.361(6), C9–C10 = 1.449(7), C10–C11 = 1.331(7), C11–C12 = 1.411(8), C12–C13
= 1.421(7), C12–N2 = 1.335(6). Selected angles (°) C1–Bi1–C8 = 89.8(2), C1–Bi1–C25 = 92.4(2), C8–Bi1–C25
= 89.6(2), Bi1–C1–C2 = 116.1(4), Bi1–C1–C6 = 123.6(4), C2–C1–C6 = 120.2(5), C1–C2–C3 = 122.7(5), C2–
C3–C4 = 116.4(5), C2–C3–N1 = 122.3(5), C4–C3–N1 = 121.2(5), C3–C4–C5 = 120.8(6), C4–C5–C6 = 124.1(6),
C1–C6–C5 = 115.6(5), C1–C6–C7 = 126.2(5), C5–C6–C7 = 118.1(5), C6–C7–C9 = 129.3(5), C6–C7–C18 =
115.1(5), Bi1–C8–C9 =122.3(4), Bi1–C8–C13 = 115.0(4), C9–C8–C13 = 122.2(5), C7–C9–C8 = 127.3(5), C7–
C9–C10 = 119.0(5), C8–C9–C10 = 113.7(5).
The structure of BiR obtained is shown in Fig. 1. The bismuth atom is fused into the xanthene plane by bridging
the two phenyl rings with a bond angle of 89.8° (C1–Bi1–C8). Although two diastereomers may arise from the
orientations of the pendant phenyl group on Bi and the methyl substituent of the oꢀtolyl group, BiR was isolated
as a single isomer with the phenyl and methyl groups on the same side of the Biꢀxanthene plane. The pendant
phenyl ring bound to Bi1 is oriented perpendicularly to the Biꢀxanthene ring (C1–Bi1–C25: 92.4°, C8–Bi1–C25:
89.6°). This right angle trigonal pyramidal geometry is a characteristic for organobismuth(III) compounds because
the 6p orbital of the Bi atom participates in the C–Bi bonds without hybridization with the 6s orbital.11,15,35,36 The
Biꢀfused sixꢀmembered ring Bi1–C1–C6–C7–C9–C8 has an extruded hexagonal planer geometry. Endocyclic
bond angles at C1, C6, C7, C8, and C9 are much larger than 120° because of the extremely long Bi–C bonds
(Bi1–C1 = 2.226, Bi1–C8 = 2.236 Å) and the small bond angle around the Bi atom (C1–Bi1–C8: 89.8°). The
similar bond lengths of C3–N1 (1.349 Å) and C12–N2 (1.335 Å) are shorter than the typical single bond length as
well as good planarity of the Biꢀxanthene including methyl groups on N1 and N2 atoms suggest sp2 property of
N1 and N2 atoms, efficient deꢀlocalization of positive charge, and πꢀconjugation ranging from N1 to N2.

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Fig.2 (a) Absorption spectrum of 5 µM BiR in 50 mM HEPES buffer (pH 7.4, 0.5% DMSO as a coꢀsolvent) (b)
Fluorescence spectrum of 2 µM BiR in 50 mM HEPES buffer (pH 7.4, 0.2% DMSO as a coꢀsolvent). Excitation
was provided at 630 nm.
Table 1. Photophysical properties of BiR and comparison with other xantheneꢀbased fluorophores and
photosensitizers
heteroatom
λabs (nm) ε (M−1 cm−1)
λem (nm)
658
Φfl
Φ(1O2)
0.66
BiR
Bi
O
635
549
646
666
660
581
597
7.76 × 104
5.24 × 104
11.0 × 104
16.5 × 104
5.08 × 104
4.4 × 104
8.1 × 104
0.039
0.35
0.31
0.38
n.d.g
0.009
n.d.g
TMR
SiR650a
569
n.d.g
n.d. g
n.d. g
0.52f
0.87
Si
P
660
b
NR666
685
MBc
N
n.d. g
n.d. g
n.d. g
TMRꢀSed
TMRꢀTee
Se
Te
0.43
a Ref 25. bRef 23 cMB = methylene blue. dRef 29 (in methanol) eRef 37 (in methanol). fRef 38 (in acetonitrile).
gNot determined.
The photophysical properties of BiR were evaluated in aqueous buffer (50 mM HEPES, pH 7.4, 0.2% or 0.5%
DMSO as a coꢀsolvent). BiR exhibited maximum absorption at 635 nm (ε
= 77,600 M−1 cm−1) and maximum
emission at 658 nm (Figure 2), and these values are 86 nm and 91 nm redꢀshifted compared to
tetramethylrosamine (TMR, Scheme 1) that has an oxygenꢀbridged xanthene scaffold (Table 1). Similar redꢀshifts
have been observed in Siꢀrhodamine (SiR, λabs = 646 nm)25 and Pꢀrhodamine (NR666, λabs = 666 nm)23. Such a
large redꢀshift was not observed in the case for the heavy chalcogen atomꢀsubstituted rhodamines such as
Seꢀrhodamine (TMRꢀSe, λabs = 581 nm)29 and Teꢀrhodamine (TMRꢀTe, λabs = 597 nm).28 The fluorescence
quantum yield (ΦFL) of BiR was determined to be 0.039, which is much lower than both SiR and NR666. Both
absorption and fluorescence are found to be insensitive to pH change (Fig. S1).
In order to fully understand the redꢀshifted photoproperties of BiR, electrochemical analysis and density
functional theory (DFT) calculations were performed. Cyclic voltammograms of BiR and TMR are shown in Fig.
3a. Consideration of Fig. 3a indicates that BiR shows reversible peaks, thereby giving oxidation and reduction

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potentials of 0.64 V and −0.99 V, respectively, while TMR provided potentials at 0.80 V and −1.20 V. The
oxidation potential for BiR is 0.16 V lower than that for TMR. The reduction potential for BiR is 0.21 V higher
than that for TMR, which suggests a smaller HOMOꢀLUMO gap of BiR than that of TMR. DFT calculations gave
distinctly higher HOMO energy level for BiR than for TMR, while LUMO levels are not significantly different
between these two compounds (Fg. 3b). No obvious participation of the Bi atom into HOMO nor LUMO were
observed.
(a)
(b)
–0.99 V
BiR
0.64 V
−5.65
−5.64
10 ꢀA
TMR
–1.20 V
LUMO
LUMO
0.80 V
HOMO
HOMO
−8.14
−8.44
1.0
0.5
0
–0.5 –1.0
–1.5
Potential (V, vs Fc/Fc+)
BiR
TMR
Fig. 3 (a) Cyclic voltammograms of BiR and TMR in acetonitrile (0.1 M tetrabutylammonium perchlorate as an
electrolyte). The data were acquired with a glassy carbon electrode. The sample concentrations were 1 mM. The
scan speed was 0.2 V s−1. (b) Energy diagrams and HOMO/LUMOs for BiR and TMR calculated by using
B3LYP/LANL2DZ set.
Because bismuth is the heaviest stable element, the heavy atom effect of Bi was expected to induce
1
photoꢀgeneration of singlet oxygen (1O2) with BiR. The photoꢀgeneration of O2 was evaluated by absorption
1
spectroscopic analysis with a colorimetric O2 scavenger, 1,3ꢀdiphenylisobenzofuran (DPBF, λabs = 410 nm) and
methylene blue (MB) as a standard photosensitizer (Φ(1O2) = 0.52 in acetonitrile)38,39. Fig. 4 depicts the spectral
changes of DPBF in the presence of BiR (Fig. 4a) and MB (Fig. 4b) upon irradiation with red LED light (λex
=
625 nm, 1.2 mW cm−2). Upon irradiation by red light, a significant decrease in absorption of DPBF at 410 nm was
observed for BiR over a period of 500 s (kobs = −1.87×104 s−1), while a relatively slow decrease was seen for MB
(kobs = −1.47×104 s−1) (Fig. 4d). No apparent change was found in the absence of irradiation (Fig. 4c,d). The
Φ(1O2) of BiR was calculated to be 0.66 on the basis of initial consumption rates of DPBF. Integrated with the
high molar absorption (ε635 = 77,600 M−1 cm−1), BiR is found to be two times more efficient than MB (ε660
=
50,800 M−1 cm−1). Under the same irradiation condition, the photoꢀinduced degradation of BiR was 15% over 1 h,
and MB showed 10% degradation (Figure S2), indicating that the photostability of BiR is comparable to that of
MB. Taking the above observations into account suggests that BiR could act as a new red lightꢀexcitable
photosensitizer.

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Fig. 4 Absorption spectral changes of DPBF upon irradiation of red light (625 nm, 1.2 mW cm−2) in the presence
of BiR (a) and MB (b). The concentration of the photosensitizers and DPBF were set to show absorption of 0.2 at
625 nm and 0.8 at 410 nm, respectively. (c) Absorption spectral change of DPBF without irradiation in the
presence of BiR. (d) Plot of absorption at 410 nm measured in (a), (b), and (c) against time. The data was
collected every 60 s.
The photosensitizing ability of BiR under subcellular conditions was also evaluated. Two cancer cell lines were
selected, namely, hepatocellular carcinoma cells (HepG2) and human lung adenocarcinoma cells (A549) as well
as nonꢀcancerous cell lines, human embryonic kidney cells (HEK293) and normal human diploid cells (TIGꢀ3).
The cell viability after irradiation with red light (608–648 nm, 9.0 J cm−2) was assayed by measuring the
population of cells stained with propidium iodide (PI). The typical images used for the viability analysis of HepG2
cells are shown in Fig. 5a. Fluorescence microscopic studies revealed that BiR can easily permeate cell
membranes and brightly stain the perinuclear region that was determined as endoplasmic reticulum (Fig. S3). No
obvious cell death occurred without irradiation in the presence of BiR (Fig. 5a, middle column), indicating that
the negligible acute toxicity of BiR (Figure S8). Redꢀlight irradiation caused a significant increase in the
population of dead cells (Fig. 5a, right column), while irradiation in the absence of BiR resulted in no cell death
(Fig. 5a, left column). The dead cells increased in a doseꢀdependent manner with BiR under the irradiated
conditions (Fig. 5b, Fig. S8), and the EC50 value, which is defined as the concentrations for 50% cell death under
irradiation, was determined to be 375 nM for HepG2 cells (Fig 5c). EC50 values for the other cells were also
determined as follows: A549 (11 nM), HEK293 (40 nM), and TIGꢀ3 (20 nM). BiR showed moderate toxicity for
the cells used in this study (IC50 = 0.53 µM (HepG2), 0.62 µM (A549), 2.26 µM (HEK293), and 0.96 µM
(TIGꢀ3)) when the cells were treated with BiR for 24 h in dark conditions (Figure 5c and S9). In this study,
tumorꢀselectivity of BiR itself could not be observed, but its efficient ability to produce 1O2 even under subcellular
conditions indicates that it is a promising candidate to be used as an alternative to present photosensitizers.
In summary, we successfully synthesized a bismuthꢀcontaining analogue of rhodamine, BiR. Incorporation of
bismuth into a rhodamine scaffold provided the chromophore with dual functionalities, namely, redꢀshift and

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1
photoꢀgeneration of O2. This result shows that BiR can act as a new red lightꢀexcitable photosensitizer. The
absorption and emission of BiR was redꢀshifted compared to its corresponding tetramethylrhodamine and
xantheneꢀbased photosensitizers with heavy chalcogen atoms (Se and Te). Furthermore, it was shown that BiR can
generate 1O2 upon redꢀlight irradiation more efficiently than a known conventional redꢀlightꢀexcitable
photosensitizer, methylene blue (MB). This is due to the large molar absorption as well as high quantum yield
Φ(1O2) of BiR. Photosensitization of BiR was demonstrated in live cells and that the EC50 for the cells were
nanoꢀmolar in range. Red light has a great penetration properties and is therefore effective for the treatment of
deep targets in the body by photodynamic therapy (PDT). Preliminary application of BiR to photodynamic
treatment of a mouse xenograft model was performed, and unfortunately unexpected results were obtained.
Although fluorescence signal of BiR was observed stably in the xenograft tumor through the whole mouse in vivo
imaging, degradation of BiR unexpectedly proceeded upon irradiation (data not shown). Since BiR is stable
against either of irradiation (Figure S2) or subcellular condition, we speculate that decomposition of BiR would be
accelerated especially upon photoꢀirradiation in the presence of biological chemical species and that excited state
of BiR would be susceptible to intravital environments. Therefore, BiR could be an attractive pharmaceutical
1
scaffold for a new photosensitizer for PDT because of its redꢀlight excitation and O2ꢀgeneration properties.
Further studies on structural modifications of this compound with a view to targeting cancer as well as an
improvement in its in vivo photoꢀstability are currently in progress and will be the subject of future published
research.
We thank Prof. Shinae Kondoh and Dr. Takahiro Kuchimaru (Tokyo Institute of Technology) for their help for
preliminary mice xenograft experiments. We also thank Prof. Yukio Yamamoto, Dr. Masayasu Taki, and Ms.
Naoko Sakai (Kyoto University) for their help for Xꢀray diffraction analysis and Ms. Emi Inaba for her technical
assistance. This work was financially supported by JSPS KAKENHI (no. 15K14981 for T.H.).

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Fig.5 (a) Representative fluorescence images of HepG2 cells stained with BiR followed by PI/Hoechst. Left
column: Images of the irradiated cells without BiR staining. Middle column: Images of the nonꢀirradiated cells
stained with BiR. Right column: Images of the irradiated cells stained with BiR. All the cells were treated with a
mixture of PI and Hoechst 33342 after irradiation. The irradiation was done with Scale bars indicate 100 µm. (b)
Plot of the population of PIꢀpositive cells against BiR concentration with irradiation (filled circles) and without
irradiation (open circles). (c) Table of the calculated EC50 and IC50 of various cells. EC50 was defined as the
concentrations at which 50% cell death were observed under irradiation condition. IC50 was defined as the
concentration at which 50% cell death were observed after treatment for 24 h.
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DOI: 10.1039/C7DT03194G
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DOI: 10.1039/C7DT03194G
A new red-light excitable photosensitizer, Bi-rhodamine, was developed.