Family of BODIPY Photocages Cleaved by Single Photons of Visible/Near-Infrared Light

Article abstract of DOI:10.1021/jacs.8b04040

Photocages are light-sensitive chemical protecting groups that provide external control over when, where, and how much of a biological substrate is activated in cells using targeted light irradiation. Regrettably, most popular photocages (e.g., o-nitrobenzyl groups) absorb cell-damaging ultraviolet wavelengths. A challenge with achieving longer wavelength bond-breaking photochemistry is that long-wavelength-absorbing chromophores have shorter excited-state lifetimes and diminished excited-state energies. However, here we report the synthesis of a family of BODIPY-derived photocages with tunable absorptions across the visible/near-infrared that release chemical cargo under irradiation. Derivatives with appended styryl groups feature absorptions above 700 nm, yielding photocages cleaved with the highest known wavelengths of light via a direct single-photon-release mechanism. Photorelease with red light is demonstrated in living HeLa cells, Drosophila S2 cells, and bovine GM07373 cells upon ～5 min irradiation. No cytotoxicity is observed at 20 μM photocage concentration using the trypan blue exclusion assay. Improved B-alkylated derivatives feature improved quantum efficiencies of photorelease ～20-fold larger, on par with the popular o-nitrobenzyl photocages (?φ = 50-100 M^-1 cm^-1), but absorbing red/near-IR light in the biological window instead of UV light.

Full text of DOI:10.1021/jacs.8b04040

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Article
A Family of BODIPY Photocages Cleaved
by Single Photons of Visible/Near-IR Light
Julie A. Peterson, Chamari Wijesooriya, Elizabeth J. Gehrmann, Kaitlyn M Mahoney, Pratik P.
Goswami, Toshia R Albright, Aleem Syed, Andrew S. Dutton, Emily A Smith, and Arthur H. Winter
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b04040 • Publication Date (Web): 18 May 2018
Downloaded from http://pubs.acs.org on May 18, 2018
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A Family of BODIPY Photocages Cleaved by Single Photons of Visi-
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Julie A. Peterson, Chamari Wijesooriya, Elizabeth J. Gehrmann, Kaitlyn M. Mahoney, Pratik P. Gosꢀ
wami, Toshia R. Albright, Aleem Syed, Andrew S. Dutton, Emily A. Smith*, Arthur H. Winter*
Department of Chemistry, Iowa State University, Ames, IA, 50014 (USA)
Eꢀmail: winter@iastate.edu, esmith1@iastate.edu
Supporting Information Placeholder
1000 nm, where tissues have maximal light transmittance. At
these far red/nearꢀIR wavelengths, light achieves maximal tissue
penetration while minimizing phototoxicity.28 Photorelease using
these wavelengths holds promise for studies in living animals or
as targeted photoactivated therapeutics.
ABSTRACT: Photocages are lightꢀsensitive chemical protecting
groups that provide external control over when, where, and how
much of a biological substrate is activated in cells using targeted
light irradiation. Regrettably, most popular photocages (e.g. oꢀ
nitrobenzyl groups) absorb cellꢀdamaging ultraviolet wavelengths.
A challenge with achieving longer wavelength bondꢀbreaking
photochemistry is that longꢀwavelengthꢀabsorbing chromophores
have shorter excited state lifetimes and diminished excited state
energies. However, here we report the synthesis of a family of
BODIPYꢀderived photocages with tunable absorptions across the
visible/nearꢀIR that release chemical cargo under irradiation. Deꢀ
rivatives with appended styryl groups feature absorptions above
700 nm, yielding photocages cleaved with the highest known
wavelengths of light via a direct singleꢀphoton release mechaꢀ
nism. Photorelease with red light is demonstrated in living HeLa
cells, Drosophila S2 cells, and bovine GM07373 cells in ~ 5 min
irradiation. No cytotoxicity is observed at 20 ꢁM photocage conꢀ
centration using the trypan blue exclusion assay. Improved Bꢀ
alkylated derivatives feature improved quantum efficiencies of
photorelease ~20ꢀfold larger, on par with the popular oꢀ
nitrobenzyl photocages (εФ = 50 – 100 Mꢀ1cmꢀ1), but absorbing
red/nearꢀIR light in the biological window instead of UV light.
The drawbacks of using UV light as a biological initiator has
led to a number of different approaches to permit photorelease of
biologicallyꢀactive substrates using visible light. The de facto
method for releasing target molecules with visible light is to exꢀ
ploit multiphoton absorption methods, wherein a UVꢀabsorbing
photocage is excited with two or more visible light photons.29ꢀ31
Other methods to achieve photorelease using visible light include
photorelease initiated via photoinduced electron transfer,32ꢀ34 via
metalꢀligand photocleavage,35 or by using photosensitizers that
generate reactive singlet oxygen that can initiate reaction cascades
leading to substrate release.36ꢀ38
Cargo
Cargo
O
O
O
Bn
O
N
OR3
N
OH
OAc
N
O
N
h
N
N
N
N
R3OH
B
B
B
B
2
R2
R2
R2
R2
R1 R1
R1R1
max = 512-693 nm
F
F
1
OAc
OAc
OAc
N
OAc
N
INTRODUCTION. Photocages are lightꢀsensitive moieties that
are prized for giving investigators spatial and temporal control
over the release of covalentlyꢀlinked substrates.1ꢀ4 When a photoꢀ
cage blocks a critical functional group on the substrate (e.g. a
carboxylic acid), the substrate is rendered biologically inert.
Lightꢀinduced cleavage of the photocageꢀsubstrate bond restores
the reactivity or function of the substrate. Photocages have been
used to activate proteins,5, 6 nucleotides,7, 8 ions,9ꢀ11 neurotransmitꢀ
ters,12, 13 pharmaceuticals,14, 15 and fluorescent dyes using light.16ꢀ
N
N
B
F
N
N
N
N
B
B
B
F
F
F
F
F
F
F
3
4
5
6
OMe
Bn
NMe2
MeO
OMe
O
O
Bn
O
OBn
O
N
O
N
O
N
18
The vast majority of photocaging studies used in biological
studies exploit the oꢀnitrobenzyl photocages19, 20 and their derivaꢀ
B
7
B
8
B
9
N
N
N
tives, but others include those based on the phenacyl,21, 22 acriꢀ
25
dinyl,23 benzoinyl,24,
structures.
coumarinyl,26 and oꢀhydroxynaphthyl27
MeO
OMe Me2N
NMe2
Me2N
NMe2
A major limitation of these popular photocages is that their
chromophores absorb mostly in the ultraviolet region of the optiꢀ
cal spectrum. Ultraviolet light has limited tissue penetration,
restricting photocaging studies to cells and tissue slices. In addiꢀ
tion, exposure of cells or tissues to intense UV light results in
phototoxic cell damage or death. The ideal wavelength range to be
used in animal tissues, known as the biological window, is ~600ꢀ
Figure 1. Substrates described in this study. Substrates 1 and 2
from our prior work39, 40 while 3ꢀ9 are from this work.
However, it is advantageous to achieve photorelease with simꢀ
ple biologically benign organic structures that directly release
substrates with single photons of visible light. Recently, a new
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class of photoremovable protecting groups derived from mesoꢀ
lation mechanism that liberates CO2 as a byproduct. For compariꢀ
son, the most popular photocages, the oꢀnitrobenzyl photocages,
1
2
3
4
5
6
7
8
substituted BODIPY dyes was reported by us and Weinstain.39, 41
For these photocages (1 and 2 Figure 1), cleavage occurs using
green wavelengths ~520 nm. In related recent work, Klan and
coworkers have also demonstrated the photorelease of carbon
monoxide from irradiation of BODIPYꢀ42 and xantheneꢀ43
substituted carboxylic acids. Also of relevance, aminoquinones
are reported to undergo neighboring H atom abstraction with
longꢀwavelength light that can lead to hydroquinones that release
have εФ of ~ 100 Mꢀ1cmꢀ1 at λirr = 350 nm, and much less at λirr
>
400 nm. [1a] Thus, the quantum efficiencies of 8 and 9 are on the
same order of magnitude as nitrobenzyl photocages, but absorb
light in the biological window ~700 nm instead of UV light. An
interesting observation is that while the mono styryl 4 bearing a
dimethylamino group has a smaller quantum yield than 3 bearing
a methoxy, bis(styryl) compound 8 bearing the two dimethylaꢀ
mino groups has a larger quantum yield than 7 bearing the two
methoxy groups. This change cannot be explained in a simple
way, as a calculation of the LUMO p orbital coefficients at the
meso carbon of these compounds did not reveal a trend that exꢀ
plained the difference in quantum yields (Scheme S2). Probably,
more subtle effects such as the rates of competitive pathways are
needed to explain this difference.
appended leaving groups via
a
selfꢀimmolative release
pathway.)44
A
recent structureꢀactivity relationship varying
9
substituents and leaving groups om BODIPY photocages was
conducted in collaborative work between us, Weinstain, and
Klan.40 Sitkowska, Feringa, and Szymanski have recently demonꢀ
strated amineꢀreleasing BODIPY derivatives by irradiation of
BODIPY carbamates.45
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Table 1. Optical and Photochemical Properties of 1-9
λmax
λem
ε
Ф
(%)
εФ
(nm) (nm) (x104 Mꢀ1 cmꢀ1)
(Mꢀ1cmꢀ1)
1[b] 515
2[b] 512
526
550
7.1
6.9
0.099
5.5
70
3800
3
4
5
6
586
633
640
661
607
650
656
684
6.1
6.0
6.5
6.5
0.0098
0.0069
0.0045
0.0041
6.0
4.1
2.9
2.7
7
8
9
647
689
693
660
728
745
4.9
7.8
5.2
0.084
0.11
0.14
41
86
73
[a] Quantum yields (Ф) determined by ferrioxalate actinometry
in MeOH with a 532 nm ND:YAG laser source and release folꢀ
b
lowed using quantitative LCꢀUV (average of 3 runs). [b] Values
from reference39, 40
.
RESULTS AND DISCUSSION. We synthesized compounds
3-9 that have extended conjugation and a redꢀshifted λmax values
between 580ꢀ690 nm (λem between 600ꢀ750 nm) (Figure 2).
Compounds 3-9 are thermally stable, showing no change by NMR
when refluxed in the dark for 1 hour (Figure S11), yet release
carboxylates when irradiated with visible light (Figure S1). The
quantum yields of the release of the leaving groups (ϕ) of 3-9
were determined by ferrioxalate actinometry (SI) and are reported
as the average value of three trials. The extinction coefficient (ε)
at the λmax was determined by UVꢀvis spectroscopy (Table 1).
These photocages feature high extinction coefficients typical of
BODIPY dyes (~50,000ꢀ120,000 Mꢀ1cmꢀ1 at λmax). In general, the
quantum yields (ϕ) for photorelease of acetic acid for the longest
wavelength absorbing photocages 3-6 are an order of magnitude
lower than those of the unconjugated substrates (1 or 2).
Figure 2. Absorbance and emission spectra of select BODIPY
photocages. Data for all photocages can be found in the SI.
Compound 10 was synthesized to test the usefulness of these
photocages in live cell imaging. 4ꢀnitrobenzoic acid was used as
the leaving group, since nitrobenzoic acids are known fluoresꢀ
cence quenchers of BODIPY dyes. A short ethylene glycol chain
was appended to the styryl groups to aid with water solubility.
Compound 10 does not exhibit detectable fluorescence when kept
in the dark at room temperature. We anticipated that upon irradiaꢀ
tion and release of 4ꢀnitrobenzoic acid, a fluorescent photoproduct
would be formed with a λem at ~685 nm. However, we found that
when 10 is irradiated in MeOH or cell culture buffer under air we
instead observe growth in fluorescence at 610 nm. Similarly,
when 6 is irradiated in methanol we see a peak grow in at 610 nm,
as the peak at 685 nm decreases (See Fig. 3 and S6). This new
blueꢀshifted fluorescent peak is similar to the emission waveꢀ
However, boronꢀalkylation leads to a large increase in the
quantum yield of release, while not significantly perturbing the
λmax of the chromophore. For example, the boronꢀalkylated 7 has
a quantum yield ~20ꢀfold larger than 6, which is boronꢀ
fluorinated. Because many biologically interesting compounds
have alcohols, we also synthesized compound 9 to demonstrate
release of benzyl alcohol. This compound releases benzyl alcohol
with a similar quantum yield as the carboxylates via a decarboxyꢀ
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length of 3. H NMR studies of the photolysis of 10 confirm that
the quencher is released upon irradiation (Figure S10). Photoꢀ
product studies of 6 and 10 under air show that in addition to aceꢀ
tic acid, pꢀanisaldehyde is a minor photoproduct for 6 and the
tri(ethylene) glycolꢀsubstituted anisaldehyde for 10 (Figures S2,
S3). Formation of the benzaldehyde and a λem at a similar waveꢀ
length to 3 indicates that photocage byproducts have either
cleaved or broken the conjugation of a styryl group (further inꢀ
formation on product studies of 6 can be found in Supplementary
Information), explaining the wavelength shift.
1
2
3
4
5
6
7
8
t ~ 0 min
t ~ 2 min
t ~ 4 min
t ~ 6 min
A
E
B
F
C
D
H
G
9
We considered two possible mechanisms for this cleavage and
aldehyde formation. First, the photocage could sensitize singlet
oxygen, which could then oxidatively cleave the olefin. This
process would be independent of photorelease. Alternatively,
oxidative cleavage could arise from oxygen trapping a cation
intermediate (possibly in its triplet state), a mechanism that is
correlated with the photorelease process.
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I
J
1.6
1.2
0.8
0.4
0
0 min
20 min
60 min
100 min
120 min
The simplest release mechanism to consider is a photoheterolyꢀ
sis mechanism, either from the singlet or triplet excited state. The
putative carbocation formed by heterolysis of 6 is computed to be
a triplet ground state carbocation by ca. 3 kcal/mol using density
functional theory (UB3LYP/6ꢀ31G(d), including correction for
singlet spin contamination; see SI). Photolysis occurring through
the triplet excited state would be expected to yield the triplet carꢀ
bocation to conserve spin. Indeed, we selected mesoꢀsubstituted
BODIPY dyes as potential photocages based on these ions having
lowꢀlying diradical states, which we had previously suggested
might be critical for providing a surface crossing (conical interꢀ
section) between the excited state surface and the ground state ion
pair surface.46 Inspection of the computed SOMOs of the triplet
carbocation indicates that the radicals are located on the styryl
groups. Little is known about triplet carbocation reactivity,47 but
triplet diradicals are known to react with oxygen, which could
lead to a pathway involving oxidative cleavage at one of the styryl
groups. A similar styryl BODIPY compound has been demonꢀ
strated to be reactive to radicals in the ground state, breaking the
conjugation of the olefin and causing a similar wavelength shift to
what we observe.48
575 625 675 725
Wavelength (nm)
Figure 3. Fluorescence images of HeLa cells incubated with 20
ꢁM compound 10 irradiated with 635 nm light (AꢀD) and cells
incubated with compound 10 with no irradiation (EꢀH) as a funcꢀ
tion of time. Average fluorescence intensity v. time of 10 incubatꢀ
ed in HeLa cells (n = 10) with (i) and without (ii) 635 nm irradiaꢀ
tion (I). Increase in fluorescence of compound 7 in H2O with 5%
BSA when irradiated.
As a proof of principle demonstration that photorelease could
be performed in cells, 20 ꢁM compound 10 was incubated with
HeLa cells at 36±2 ºC. The cells were irradiated with 635 ±15 nm
light. Fluorescence emission was measured at 605 nm. Control
experiments were performed without irradiation. An increase in
fluorescence was observed at 605 nm when irradiated (Figure 3
AꢀD). In control studies, no increase in fluorescence was obꢀ
served in the dark (Fig. 3 EꢀH). Similar imaging studies were
performed in bovine GM07373 cells and Drosophila S2 cells
(Figure S13ꢀS14), yielding similar results. Cytotoxicity studies
showed no decrease in cell viability (trypan blue exclusion assay)
with treatment of 10 (90±3% for HeLa cells with no treatment,
92±5% for HeLa cells with 10, 95±2% for S2 cells without treatꢀ
ment, 93±2% for S2 cells with 10, 90±1% for GM07373 cells
without treatment, and 92±5% for GM07373 cells with 10).
To corroborate that this fluorescence blue shift was correlated
with release of the carboxylic acid, a derivative of compound 6
with no leaving group was synthesized as a control and showed no
fluorescence blueshift upon photolysis (Scheme S1, Figure S7).
Irradiation of this compound simply led to a slow fluorescence
bleaching at long irradiation times. If oxidative cleavage were
independent of the photorelease process, this compound, which is
identical except for the absence of the leaving group, would be
expected to have a similar fluorescence blueshift. That it does not
supports the mechanism involving trapping of a reactive intermeꢀ
diate following the photorelease.
CONCLUSIONS. In conclusion, a family of BODIPYꢀderived
photocages have been synthesized that release chemical cargos at
a range of wavelengths in the visible absorptions range from
~450ꢀ700 nm. The longestꢀwavelength absorbing derivatives (8,
9) represent photocages that can release substrates with the highꢀ
est known wavelengths of light via a singleꢀphoton direct photoreꢀ
lease pathway. The wide range of wavelengths of absorbance
allows photorelease to be achieved using essentially any color of
visible light. This work opens up the possibility of the targeted
and controlled release of pharmaceuticals or other biomolecules
using irradiation with red light in the biological window. It is
remarkable that a net photoheterolysis reaction can be achieved
using red light given the much diminished photon energies associꢀ
ated with these wavelengths (~40 kcal/mol for 700 nm vs ~100
kcal/mol for a UV photon), and it will be interesting to test the
maximum wavelengths of photorelease possible, as increasing
wavelengths correspond to increasingly diminished photon enerꢀ
gies.
This blueꢀshifted fluorescence provides a convenient assay by
which to follow the photorelease process using fluorescence miꢀ
croscopy, since the photocaged acid 6 does not absorb at 605 nm,
the wavelength the blueshifted byproduct absorbs. NMR studies
showed that there is mass balance between compound 6 and acetic
acid
over
3
hr
of
irradiation
(Figure
S5).
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Blake, J. A.; Bareiss, B.; Jimenez, L.; Griffith, M.; Scaiano, J.
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