Organelle-Targeted BODIPY Photocages: Visible-Light-Mediated Subcellular Photorelease

Article abstract of DOI:10.1002/anie.201900850

Photocaging facilitates non-invasive and precise spatio-temporal control over the release of biologically relevant small- and macro-molecules using light. However, sub-cellular organelles are dispersed in cells in a manner that renders selective light-irradiation of a complete organelle impractical. Organelle-specific photocages could provide a powerful method for releasing bioactive molecules in sub-cellular locations. Herein, we report a general post-synthetic method for the chemical functionalization and further conjugation of meso-methyl BODIPY photocages and the synthesis of endoplasmic reticulum (ER)-, lysosome-, and mitochondria-targeted derivatives. We also demonstrate that 2,4-dinitrophenol, a mitochondrial uncoupler, and puromycin, a protein biosynthesis inhibitor, can be selectively photoreleased in mitochondria and ER, respectively, in live cells by using visible light. Additionally, photocaging is shown to lead to higher efficacy of the released molecules, probably owing to a localized and abrupt release.

Full text of DOI:10.1002/anie.201900850

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
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Accepted Article
Title: Organelles Targeted BODIPY Photocages: Visible-Light
Mediated Sub-Cellular Photorelease
Authors: Dnyaneshwar Kand, Lorena Pizarro, Inbar Angel, Adi Avni,
Dinorah Friedmann-Morvinski, and Roy Weinstain
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900850
Angew. Chem. 10.1002/ange.201900850
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Organelles Targeted BODIPY Photocages: Visible-Light Mediated
Sub-Cellular Photorelease
[a]
[a]
[b]
[a]
[b]
Dnyaneshwar Kand , Lorena Pizarro , Inbar Angel , Adi Avni , Dinorah Friedmann-Morvinski , and
[a]
Roy Weinstain *
Abstract: Photocaging facilitates non-invasive and precise spatio-
temporal user control over the release of biologically relevant small-
and macro-molecules using light. Yet, sub-cellular organelles are
scattered or dispersed in cells in a manner that renders selective light
irradiation of a complete organelle impractical. Organelle-specific
photocages could provide a powerful method to release bioactive
molecules in sub-cellular locations. Herein, we report a general post-
synthetic method for chemical functionalization and further
conjugation of meso–methyl BODIPY photocages and its utilization
for synthesizing endoplasmic reticulum (ER)-, lysosome- and
mitochondria-targeted derivatives. We further demonstrate that 2, 4-
dinitrophenol, a mitochondrial uncoupler, and puromycin, a protein
biosynthesis inhibitor, can be selectively photoreleased in
mitochondria and ER, respectively, by visible-light-mediated
excitation in live cells. We find that not only that photocaging
introduces exquisite spatio-temporal specificity to organelle targeting,
it additionally leads to higher efficacy of the released bioactive
molecule, most probably due to a localized and abrupt release.
compartments due to their chemical and/or physical properties
(e.g. pH, charge, hydrophobicity, etc.). Such motifs include, for
example, triphenylphosphonium[ (TPP), phenyl sulfonamide[6]
and tertiary/secondary amines[ that tend to accumulate in
5]
7]
mitochondria,
endoplasmic
reticulum
(ER)
and
lysosomes/endosomes, respectively. Their coupling to small- and
even macro-molecules was found to effectively impart sub-
cellular specificity to the entire conjugate.
The combination of sub-cellular targeting with photocaging,
providing a mean to preserve the advantages of the two strategies
while overcoming their distinct limitations, has been effectively
[
8]
demonstrated using 2-nitrobenzyl derivatives caging groups .
However, the use of UV excitable photocages often lead to
inherent hurdles, including sample overheating and phototoxicity.
More recent work has effectively improved the utility of targeted
photocages by using the ~400 nm excitable coumarins as caging
[
9]
groups .
Here, we establish a range of organelle-targeted photocages
based on the recently introduced, visible-light excitable (> 500
nm) meso-methyl BODIPY photocage[ (Figure 1). To this end,
10]
The interior of cells is a highly organized environment. Cellular
tasks such as energy production, protein synthesis and many
others, are functionally compartmentalized in organelles, along
with most of the biomolecules required for their execution.
Studying localized process, including those taking place inside
organelles, often makes use of small-molecules to manipulate
we also developed
functionalization method of BODIPYs that streamlines their
synthesis.
a
straightforward, post-synthetic
[
1]
their progress . Unfortunately, most small-molecules lack an
innate specificity to cellular locations; they tend to disperse
randomly in cells, not necessarily arriving at the desired place due
to unfitting physical-chemical properties or conversely, ending up
acting in too many locations in an unspecific manner.
Photocaging[2] is an effective light-mediated controlled-release
strategy that enables activation of small- or macro-bioactive
[
3]
molecules with high spatio-temporal resolution . This strategy is
widely utilized to achieve localized control over the activation of
[
4]
bioactive molecules in vitro and in vivo . However, organelles are
scattered or dispersed in cells in a manner that renders selective
irradiation of a complete organelle (e.g. mitochondria, golgi
apparatus, etc.) impractical, undermining the utility of the strategy
in this context. Over the years, several chemical motifs have been
identified to passively accumulate in specific sub-cellular
Figure 1. Schematic illustration of ER, lysosome and mitochondria targeted
BODIPY photocages.
The photoreaction efficiency in BODIPY photocages[10d], as well
as in many other photocaging groups[ , is highly sensitive to
changes in electronic and steric properties of the core. We
therefore first sought to establish a robust synthetic approach for
chemical functionalization of BODIPY photocages without
affecting their photorelease ability.
The synthetic procedure is outlined in Figure 2A. Using a one-pot,
two-steps protocol i.e. bromination with NBS followed by
nucleophilic substitution, compounds 1-5 were synthesized. This
11]
[
a]
b]
Dr. D. Kand, Dr. L. Pizarro, Prof. Dr. Adi Avni and Dr. Roy
Weinstain, School of Plant Sciences and Food Security, Life
Sciences Faculty, Tel-Aviv University, Tel-Aviv 6997801, Israel.
E-mail: royweinstain@tauex.tau.ac.il
I. Angel and Dr. D. Friedmann-Morvinski
School of Neurobiology, Biochemistry and Biophysics, Life Sciences
Faculty, Tel-Aviv University, Tel-Aviv 6997801, Israel.
[
Supporting information for this article is given via a link at the end of
the document.
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coupling of compound 4 with different amine-bearing organelle-
directing groups such as phenyl sulfonamide (ER targeting),
morpholine (lysosome targeting) and triphenylphosphonium
(mitochondria targeting), afforded targeted BODIPY photocages
11-13, respectively (Figure 2B). Compounds 11-13 are stable in
the absence of light and show controlled release of PNA upon
irradiation with visible-light (Table S1 and Figure S3). Their
cellular uptake and sub-cellular localization were evaluated in
HeLa cells by live-cell imaging using commercial stains for ER,
lysosomes and mitochondria (Figures 3, S9 and S10). All three
compounds demonstrated efficient localization to their target
organelles as determined by Pearson’s sample correlation
coefficients (r = 0.95, 0.73 and 0.75 for 11-13, respectively) with
the respective organelles stains (ER-tracker Blue, LysoTracker
deep-red and MitoTracker deep-red).
Figure 2. (A) Synthetic scheme of compounds 1-5. (B) Synthetic scheme of
organelle targeting compounds 11-13.
is a modified approach to an earlier report[12], which leverages the
nucleophilic character of BODIPY α-methyls to introduce bromine
as a leaving group. Here, the superior nucleophilicty of thiols is
employed to introduce less necluophilic yet reactive functional
groups via appropriate bifunctional molecules. Thus, various
unprotected functional groups including amine, thiol, chloro,
carboxylic acid and azide, all key building blocks in construction
of more elaborate molecules, could be simply and directly
introduced. We verified that the reactive functionalities installed
can be further conjugated in the context of BODIPY photocages
by reacting each of them in a compatible manner (i.e. amidation,
Michael addition to N-ethyl maleimide, copper-mediated click
reaction, etc.) (compounds 6-10, Figure S1).
The photophysical and photoreaction properties of all synthesized
compounds are summarized in Tables S1. Compared to
previously reported BODIPY photocages[10a, 10b, 10d], all new
derivatives (1-10) present a 5-7 nm red-shift in both absorbance
and fluorescence λmax, with molar extinction coefficient values in
Figure 3. Cellular distribution and co-localization of compounds 11-13. Confocal
fluorescence images of live HeLa cells incubated with (a-c) ER-Tracker Blue (2
µM) and 11 (10 µM, 30 min), (d-f) LysoTracker deep-red (2 µM) and 12 (10 µM,
30 min), (g-i) MitoTracker deep-red (2 µM), and 13 (10 µM, 30 min). Co-
localization appears as yellow/orange (c, f, i).
-1
-1
the typical BODIPY range (~35,000-70,000
M
cm ).
Photoreaction properties were determined by UV-vis
spectroscopy, monitoring p-nitroaniline (PNA) release (see
Supporting Information). Compounds 5-8 and 10 are stable in the
absence of light but release PNA in response to irradiation with
To evaluate the utility of organelle-targeted BODIPY photocages,
we synthesized and tested a caged version of the protonophore
2,4-dinitrophenol (DNP). DNP is an uncoupler of mitochondrial
2
oxidative phosphorylation, dissipating proton gradient across the
membrane thus decreasing mitochondrial membrane potential[
visible-light (545/30 nm, 42 mW/cm ), presenting comparable
13]
photoreaction properties (quantum yield (Φ
and chemical yield) to previously reported BODIPY photocages
Table S1, Figure S2). These results confirm that the above post-
r
), half-life time (t1/2)
m
(Δψ ). Compound 14 was synthesized by ipso-substitution of 1-
fluoro-2,4-dinitrobenzene with meso-methyl BODIPY and
functionalized by employing the above protocol using thioglycolic
acid as a nucleophile. A TPP motif was subsequently coupled to
obtain the mitochondria-targeted BODIPY-DNP 16 (Figures 4A
and S4). Quantum yields, half-life times (t1/2) and chemical yields
for photorelease of DNP were determined by UV-vis spectroscopy
and confirmed by HPLC-MS. Compounds 14 and 16 are stable in
(
synthetic methodology can be straightforwardly applied to
conjugate BODIPY photocages through diverse chemical
functionalities while retaining their spectroscopic and
photoreaction properties.
We next applied the synthetic approach to generate a panel of
organelle-targeted BODIPY photocages. A direct HBTU-mediated
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Figure 4. (A) Structures of compounds 14 and 16. (B) Light-mediated release of DNP from 14 and 16 (10 µM, ACN/water 7/3) following light irradiation (545/30 nm,
2
4
2 mW/cm ) for the indicated times. Absorbance at 367 nm (representing free DNP) Vs time was plotted. (C) Distribution and co-localization of 14 and 16. Confocal
images of live HeLa cells treated with Hoechst 33342 (17 µM), MitoTracker deep-red (2 µM) and 14 (upper) or 16 (lower) (10 µM, 30 min). Areas of co-localization
appear in yellow/orange in Merged. (D) Photorelease of DNP in live cells leads to decrease in mitochondrial membrane potential. Confocal images of live HeLa
cells stained with Hoechst 33342 (17 µM), Rhod123 (26 µM, 15 min) and: (a,e) before and after treatment with: 200 µM DNP; (b,f) compound 16 (25 µM) with and
2
without light (545/25 nm, 1.4 mW/cm , 15 seconds); (c,g) before and after treatment with light, (d and h) compound 14 (25 µM) with and without light (545/25 nm,
2
1
.4 mW/cm , 15 seconds). (E) Graph presents fold-decrease in cells fluorescence intensity, where F
0
is fluorescence intensity before either light or DNP treatment
and F is fluorescence intensity after either light or DNP treatment. Localized photoactivation of DNP in live cells. HeLa cells were incubated with Rho123 (26 µM),
2
1
6 (25 µM) and Hoechst 33342 (17 µM) for 15 minutes before (F) and after (G) light irradiation (545/25 nm, 1.4 mW/cm , 15 seconds) of a selected region. (H) Fold-
decrease in fluorescence intensity of cells in irradiated and non-irradiated regions, where F
0
and F are defined as in E. ⃰ Statistical significance (one-way ANOVA
with Tukey correction, p < 0.05) from control (E) or non-irradiated cells (H). Error bars represent standard error measurement (SE).
the dark and release DNP when irradiated with visible-light
Figures 4B, S5 and S6), compound 16 presenting the highest
photorelease efficiency (Φ = 43) within this series of compounds
Table S1). Although BODIPY photocages were previously
demonstrated to release halides, acids, carbon monoxide, thiols,
and xanthates[10], this is first example of direct uncaging of
phenols, expanding the palette of functional groups and bioactive
molecules amenable for caging by BODIPYs.
m
itself does not disrupt Δψ . However, upon irradiation of the cells
2
(
(545/25 nm, 1.4 mW/cm , 15 seconds), a 6-fold decrease in
Rho123 mitochondrial fluorescence was observed. Importantly,
photoactivation of the non-targeted 14 under similar conditions
did not have any effect on Rho123 fluorescence. Cells treated
with Rho123 alone and exposed to similar irradiation conditions
did not show any change in mitochondrial fluorescence, ruling out
r
(
m
direct light effect on Δψ . In addition, in the absence of light, 16
Cellular uptake and mitochondrial localization of 16 was
examined and compared to the non-targeted 14 by live-cell
imaging of HeLa cells (Figures 4C, S9 and S11). Low Pearson's
sample correlation coefficients (r = 0.13) confirmed poor targeting
of 14 to the mitochondria while 16 showed efficient and specific
mitochondrial accumulation (r = 0.84).
did not show any sign of toxicity at the applied concentration
(Figure S14).
Finally, we tested light-mediated selective activation of 16 in
specific cells. Thus, HeLa cells were treated with Roh123, 16 and
the DNA stain Hoechst 33342 and confocal images were acquired
at three channels (Figure 4F and S13a). Cells were then irradiated
2
Next, intracellular photoactivation of 16 was investigated.
for 15 seconds (545/25 nm, 1.4 mW/cm ) in a selected region
Alterations in Δψ
m
were assessed using the Δψ
m
sensitive
(marked by a yellow rectangle) and re-imaged after 5 minutes
(Figure 4G and S13b). Results show a significant (~13-fold)
decrease in fluorescence signal only in cells within the light-
exposed region while cells outside of it remains unaffected.
Quantification of the averaged fluorescence intensities of cells
within the irradiated area vs. those outside of it, before and after
light exposure, are summarized in Figure 4H.
To demonstrate the general applicability of BODIPY photocages
targeting, we synthesized an ER-targeted caged version of the
protein synthesis inhibitor puromycin[15] (19, Figure S15).
Compound 19 showed efficient light-dependent release of
lipophilic cationic dye, Rhodamine 123 (Rho123). In intact cells,
Rho123 accumulates in mitochondria, leading to a strong
localized fluorescence signal[14]. Conversely, reduction in Δψ
leads to redistribution of the dye to the cytoplasm, resulting in its
dilution and a decrease in fluorescence signal. In HeLa cells
treated with Rho123, strong mitochondrial fluorescence could be
detected, which was significantly reduced (~3-fold) by further
treatment with 200 µM DNP (Figure 4D and S12). When similar
cells were treated with Rho123 and 16 (25 µM), a mitochondria
localized fluorescence signal was observed, indicating that 16 by
m
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puromycin in vitro and in HeLa cells (Figure S15B) and
Keywords: BODIPY • photocages • organelles • photo-release •
colocalized efficiently with ER-tracker blue (r = 0.95, Figure S16C).
mitochondria
Following photoactivation of 19 in live cells (20 µM, 545/305 nm,
2
4
2 mW/cm ), released puromycin could be detected specifically
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functional groups onto BODIPY α -methyl in one synthetic step
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compartments.
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mitochondria-targeted
BODIPY
was
demonstrated to release the protonophore DNP in live cells with
exquisite spatio-temporal control, achieving a much higher effect
compared to non-targeted DNP. Thus, not only that photocaging
introduces spatio-temporal specificity to organelle targeting, it
additionally leads to higher efficacy of the bioactive molecule,
most probably due to localized and abrupt release. Finally, we
expect that our approach could be extended to selective delivery
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Acknowledgements
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4844; dJ. Kohl-Landgraf, F. Buhr, D. Lefrancois, J. M. Mewes, H.
WR would like to thank the United States-Israel Binational
Science Foundation (Grant No. 2016060), the Germany-Israel
Foundation (Grant No. I-2387-302.5/2015) and the ERC (Grant
No. 679189), and D. F. M. to the Israeli Science Foundation
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(1310/15), for funding this research. D.K. thanks the Planning and
Budgeting Committee (PBC) of the Israeli Council for Higher
Education for a postdoctoral fellowship. We would like to thank
Prof. Evan W. Miller (UC Berkeley) for helpful discussions.
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
[
a]
[a]
Organelle specific
Dnyaneshwar Kand , Lorena Pizarro , Inbar
[
b]
[b]
BODIPY photocages: A
general synthetic platform
for synthesis of BODIPY
photocages suitable for
visible-light-mediated
release of bioactive
Angel, , Dinorah Friedmann-Morvinski, , and Roy
[
a]
Weinstain *
1 – 6
Organelles Targeted BODIPY Photocages:
Visible-Light Mediated Sub-Cellular Photorelease
molecules in specific, pre-
designated organelles
[
a]
Title(s), Initial(s), Surname(s) of Author(s) including Corresponding
Author(s)
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Department