Indolizines Enabling Rapid Uncaging of Alcohols and Carboxylic Acids by Red Light-Induced Photooxidation

Article abstract of DOI:10.1021/acs.orglett.0c01799

The irradiation of red light-emitting-diode light (λ = 660 nm) to 3-acyl-2-methoxyindolizines in the presence of a catalytic amount of methylene blue triggered the photooxidation of the indolizine ring, resulting in a nearly quantitative release of alcohols or carboxylic acids within a few minutes. The method was applicable for photouncaging various functional molecules such as a carboxylic anticancer drug and a phenolic fluorescent dye from the corresponding indolizine conjugates, including an insulin-indolizine-dye conjugate.

Full text of DOI:10.1021/acs.orglett.0c01799

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Letter
Indolizines Enabling Rapid Uncaging of Alcohols and Carboxylic
Acids by Red Light-Induced Photooxidation
Kenji Watanabe,* Nodoka Terao, Isao Kii, Reiko Nakagawa, Takashi Niwa, and Takamitsu Hosoya*
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ABSTRACT: The irradiation of red light-emitting-diode light (λ = 660 nm) to 3-acyl-2-
methoxyindolizines in the presence of a catalytic amount of methylene blue triggered the
photooxidation of the indolizine ring, resulting in a nearly quantitative release of alcohols
or carboxylic acids within a few minutes. The method was applicable for photouncaging
various functional molecules such as a carboxylic anticancer drug and a phenolic
fluorescent dye from the corresponding indolizine conjugates, including an insulin−
indolizine−dye conjugate.
aged compounds, which are deactivated (bio)functional
1C).20−22 These systems were successfully applied to the in
vivo photouncaging of functional molecules in model mice,
demonstrating the utility of this approach. Nevertheless, these
methods require long irradiation times (>30 min) to achieve
the cleavage of C−C double bonds with high efficiency. To
develop more advanced systems, such as phototherapy in deep
tissues where only weak light is reachable, improvement in the
photoreactivity of caged compounds is required. In principle,
increasing the electron density of the alkene moiety accelerates
the photooxidative reaction. However, introducing electron-
donating groups often makes alkene moieties significantly
unstable, particularly under acidic conditions, thus under-
mining the practical utility of the method. Herein, we report
that designer indolizine derivatives serve as efficient caged
compounds for the alcohols and carboxylic acids released by
short irradiation of red light in the presence of suitable PS.
First, we focused on the C−C double bond in electron-rich
heterocycles as a covalent bond reactive with 1O2. In particular,
we paid attention to indolizines,23−26 as it was reported by Xu
1
Cmolecules protected by photodegradable groups,
are
widely used in molecular biology and drug discovery
research.2,3 Photoirradiation of caged compounds triggers the
release of active molecules, thus enabling the restoration of the
original (bio)functions in the desired spatiotemporal field.
Thus, caged compounds have been effectively used as
molecular tools for mechanistic investigation of biological
phenomena. Typically, ultraviolet light has been used to
photodegrade the protecting groups of caged compounds.
However, the low tissue permeability of ultraviolet light has
impeded the application of this technique to in vivo
experiments. To overcome this problem, the use of light
with a longer wavelength (λ = 650−900 nm) with higher tissue
permeability has been recommended.4,5 However, the energy
of such light is insufficient to achieve deprotection via the
cleavage of covalent bonds. Indeed, there are only a few
examples of molecules that undergo cleavage of covalent bonds
under the irradiation of long-wavelength light.6−12
The use of singlet oxygen (1O2) is another potential strategy
for addressing this issue, as 1O2 can be easily generated by the
irradiation of long-wavelength light to a suitable photo-
1
et al. that O2 underwent electrophilic addition to the C3
carbon in indolizine by photoirradiation with a xenon lamp
(500 W) in the presence of PSs, affording pyridinyl acrylates
(Figure 1D).27,28 When an acyl group was attached at the C3
position, it could be expected that it would be released as a
carboxylic acid after intramolecular rearrangement, though the
sensitizer (PS).13 The reactivity of O2 is also sufficiently
1
high to cleave covalent bonds, as exhibited in the oxidative
cleavage of carbon−carbon (C−C) double bonds (Figure
1A).14−17 This strategy has previously been applied to uncage
bioactive molecules. For instance, You et al. developed PS-
conjugated aminoacrylates to release an anticancer drug via
oxidation with 1O2 generated by the irradiation of long-
wavelength light (λ = 690 nm; Figure 1B).18,19 Schnermann et
al. also developed cyanine-based photocaged compounds in
which the alkene moiety was photooxidized to release
hydrolyzable precursors of aromatic alcohols or amines (Figure
Received: May 28, 2020
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Figure 2. Photooxidation experiments. (A) Photooxidation of
indolizine 1. (B) Oxidation of 1 with 1O2 generated from
endoperoxide 2. (C) Comparison of the apparent rate constants
(kobs) for the photooxidation of 1 and 3.
2, a reagent known to generate 1O2,29 and phenol was obtained
1
almost quantitatively (Figure 2B). The photoinduced O2-
dependent rapid uncaging of 1 was also supported by
treatment with an excess amount of hydrogen peroxide (100
equiv) at room temperature, resulting in sluggish conversion to
afford phenol only in 13% yield after 5 h (Figure S2).
The apparent rate constant (kobs) for the release of phenol
from 1 was determined to be 0.149 s−1 by quantifying the
amount of phenol produced as a function of the photo-
irradiation time and analyzing the data using a pseudo-first-
order rate eq (Figure 2C; Figure S3). For comparison, the kobs
of the photooxidation of aminoacrylate 3 was determined to be
0.0138 s−1 under the same conditions (Figure S4),
demonstrating the faster photooxidation of 2-methoxyindoli-
zine 1 compared with that of 3.
Figure 1. Photouncaging methods by singlet oxygen (1O2). (A)
1
Cleavage of a C−C double bond with O2. (B) Photooxidation of a
PS-conjugated aminoacrylate. (C) Photooxidation of a cyanine-based
cage compound. (D) Xu’s proposed mechanism for photooxidation of
3-acylindolizines.
behavior of this group has not been previously confirmed. On
the basis of this proposed mechanism, we designed 3-acyl-2-
alkoxyindolizines as a photocaged compound of carboxylic
acids. The introduction of a 2-alkoxy group in addition to a
nitrogen atom attached directly to the C2−C3 double bond of
indolizine was assumed to increase its electron density,
whereas the π-conjugation could contribute to maintaining
the chemical stability.
Next, to examine the substrate scope of this method, we
prepared various 3-acylindolizines (Figure 3). Friedel−Crafts
On the basis of this concept, we first attempted the
photooxidation of 2-methoxy-3-(phenyloxycarbonyl)indolizine
(1) under irradiation with 660 nm light-emitting-diode (LED)
light in the presence of various PSs in deuterated methanol
under air atmosphere. An extensive screening study revealed
that methylene blue (1 mol %) served as an effective PS,
quantitatively liberating phenol within 30 s (Figure 2A; see
Table S1 and Figure S1 for full screening results). The phenol
could be formed via photooxidation with 1O2 to afford
monophenyl carbonate followed by spontaneous decarbox-
ylation. Indeed, the reaction did not proceed under argon
atmosphere, whereas a comparable result was obtained under
1% oxygen atmosphere. This result demonstrated the high
reactivity of 1 and the potential applicability of the present
system to low-oxygen regions, such as tumor tissues. To
further confirm the involvement of 1O2 in this event, indolizine
1 was treated under argon with 1.2 equiv of dioxynaphthalene
Figure 3. Synthesis of various 3-acyl-2-methoxyindolizines.
B
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acylation of indolizines is known to occur more easily in
electron-rich C3 carbon compared with C1 carbon.30 Indeed,
the acylation of 2-methoxyindolizine, which was prepared by
extensively modifying the reported method (Table S2),31 with
various chloroformates (Figure 3A) and acyl chlorides (Figure
3B) proceeded smoothly to afford C3-acylated 2-methox-
yindolidines 1 and 4−8. These included a derivative of
bexarotene, an anticancer drug, in high yields (Figure 3B).
These substrates were bench-stable, and the benzoyl derivative
6 showed particularly high tolerance to strong acid and base
(Figure S2). In addition, an ester exchange reaction of p-
nitrophenyl carbonate 5 with alcohols was also feasible under
basic conditions (Figure 3A). For example, 4-methylumbelli-
fenone (4-MU) ester derivative 9 was prepared using this
method. These methods allowed for the effortless protection of
carboxylic acids and alcohols by the 2-methoxyindolizines.
Having obtained various 3-acylindolizines, we next examined
their uncaging reactions by irradiation of 660 nm LED light to
the substrates in the presence of methylene blue (1 mol %) for
1 min at room temperature in aqueous acetonitrile under air
atmosphere (Table 1). The importance of the electron-
donating substituent at the C2 position was demonstrated in
the reactions of 3-(phenoxycarbonyl)indolizines 1, 10, and 11
bearing 2-methoxy, 2-methyl, and 2-ethoxycarbonyl groups,
respectively (entries 1−3). The release of phenol from C2−
methoxy substrate 1 was the fastest, whereas the photo-
uncaging reaction of indolizine 11 with the C2 electron-
withdrawing group was considerably slower than that of the
others. In addition to phenol, aliphatic alcohol was efficiently
uncaged, as demonstrated in the photooxidation of benzyl ester
4 (entry 4). It is noteworthy that aromatic and aliphatic
carboxylic acids could be uncaged with excellent efficiency
under the same conditions, thus significantly expanding the
scope of the method (entries 5 and 6). The photooxidation of
12 with a clickable terminal alkyne moiety proceeded without
difficulty to afford phenol (entry 7). The release of bexarotene
from caged compound 8 also proceeded smoothly without
affecting the olefinic moiety, which is potentially susceptible to
oxygenation (entry 8). Moreover, restoration of the strong
fluorescence of 4-MU was achieved by the photoirradiation of
fluorescent caged compound 9. Using this caged dye, a time
course analysis in serum as a biological crowding media was
conducted. Photoirradiation of 9 in dimethyl sulfoxide
containing 20 v/v% serum with methylene blue (10 mol %)
was completed within 5 min to afford 4-MU almost
quantitatively (Table 1, entry 9; Figure S5). We also confirmed
the stability of 9 in this medium by observing that only 17% of
4-MU was released after 10 days in darkness (Figure S2).
These results indicate the applicability of the photoinduced
uncaging reaction of indolizine-caged compounds in a complex
biological mixture.
Table 1. Scope of Indolizines for Photooxidative Uncaging
Finally, the applicability of this uncaging system to a larger
biomolecule was examined. We designed insulin derivative 13
conjugated with three indolizine−4-MU as a model molecule.
This molecule was prepared by copper-catalyzed cycloaddition
reaction of the known triazidoinsulin derivative 1432 and 4-
MU-caged alkyne 15 (Scheme 1). The photoirradiation of
conjugate 13 in dimethyl sulfoxide/H2O (4/1) containing
methylene blue (10 mol %) for 1 min resulted in the
quantitative release of 4-MU, as determined by fluorescence
measurement (Scheme 1). The complete consumption of 13
and generation of the counterpart peptide 16 was also
confirmed by deconvoluted electrospray ionization-mass
a
Yields of released molecules determined by HPLC analysis.
Methylene blue (10 mol %), DMSO/serum (4/1), 660 nm LED,
b
5 min. Yield determined by fluorescence measurements shown in
parentheses.
spectrometry analysis (Scheme 1; Figure S7). This result
demonstrates the applicability of the indolizines to the
photoinduced release of functional molecules from biomacro-
molecules, such as peptides.33
C
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acylindolizines, this system has great advantage over the
conventional methods. A number of further studies are
currently underway, including the expansion of the method
to the uncaging of molecules with other functional groups
(such as amino groups), synthesis of an indolizine platform
bearing an intramolecular PS moiety, and application of the
method to molecular cell biology research and development of
antibody−drug conjugates bearing photocleavable indolizine
linkers.
Scheme 1. Preparation and Uncaging of 4-MU by
Photooxidation of Insulin−Indolizine−4-MU Conjugate 13
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01799.
Experimental procedures for synthesis of substrates,
photoreactions, kinetic studies, and characterization for
1
new compounds including H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Kenji Watanabe − Laboratory for Chemical Biology, RIKEN
Center for Biosystems Dynamics Research (BDR), Kobe 650-
0047, Japan; Email: kenji.watanabe.vs@riken.jp
Takamitsu Hosoya − Laboratory for Chemical Biology, RIKEN
Center for Biosystems Dynamics Research (BDR), Kobe 650-
0047, Japan; Laboratory of Chemical Bioscience, Institute of
Biomaterials and Bioengineering, Tokyo Medical and Dental
University (TMDU), Chiyoda-ku, Tokyo 101-0062, Japan;
orcid.org/0000-0002-7270-351X; Email: thosoya.cb@
tmd.ac.jp
Authors
Nodoka Terao − Laboratory for Chemical Biology, RIKEN
Center for Biosystems Dynamics Research (BDR), Kobe 650-
0047, Japan
Isao Kii − Laboratory for Chemical Biology, RIKEN Center for
Biosystems Dynamics Research (BDR), Kobe 650-0047, Japan;
RIKEN, Cluster for Science, Technology and Innovation Hub,
Kobe 650-0047, Japan; Laboratory for Drug Target Research,
Integrated Bioscience Division, Institute of Agriculture, Shinshu
University, Nagano 399-4598, Japan
Reiko Nakagawa − Laboratory for Phyloinformatics, RIKEN
Center for Biosystems Dynamics Research (BDR), Kobe 650-
0047, Japan
Takashi Niwa − Laboratory for Chemical Biology, RIKEN
Center for Biosystems Dynamics Research (BDR), Kobe 650-
0047, Japan; orcid.org/0000-0002-6209-5362
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01799
a
Yield determined by fluorescence measurement.
In summary, we developed an efficient method for the
uncaging of functional alcohols and carboxylic acids via the
photooxidation of 3-acyl-2-methoxyindolizines. The reactions
were promoted by irradiation with red LED light along with
the assistance of PS. In our experiments, the high oxidative
susceptibility of the designed indolizines allowed for the rapid
and nearly quantitative release of various alcohols and
carboxylic acids, including functional molecules. Because the
uncaging is triggered by highly biopermeable red light and
because a wide variety of functional alcohols and carboxylic
acids can be easily derived to the corresponding caged 3-
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Hidefumi Mukai and Ms. Chizuru Kiyota
(RIKEN BDR) for their kind support for the LC/MS
measurement. This research was supported by Japan Agency
for Medical Research and Development (AMED) under Grant
Nos. JP19am0401021 (Science and Technology Platform
Program for Advanced Biological Medicine) and
D
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