Design of a Multiuse Photoreactor To Enable Visible-Light Photocatalytic Chemical Transformations and Labeling in Live Cells

Article abstract of DOI:10.1002/cbic.202000392

Despite the growing use of visible-light photochemistry in both chemistry and biology, no general low-heat photoreactor for use across these different disciplines exists. Herein, we describe the design and use of a standardized photoreactor for visible-li

Full text of DOI:10.1002/cbic.202000392

Combining Chemistry and Biology
Accepted Article
Title: Design of a Multi-Use Photoreactor to Enable Visible Light
Photocatalytic Chemical Transformations and Labeling in Live
Cells
Authors: Noah Bissonette, Keun Ah Ryu, Tamara Reyes-Robles,
Sharon Wilhelm, Erik Hett, Lee Roberts, Daria Hazuda, M.
Jared Willis, Rob Oslund, and Olugbeminiyi Fadeyi
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemBioChem 10.1002/cbic.202000392
Link to VoR: https://doi.org/10.1002/cbic.202000392
01/2020

10.1002/cbic.202000392
ChemBioChem
Design of a Multi-Use Photoreactor to Enable Visible Light
Photocatalytic Chemical Transformations and Labeling in Live Cells
Noah B. Bissonnette1, Keun Ah Ryu1, Tamara Reyes-Robles1, Sharon Wilhelm1, Erik C. Hett1, Lee R.
Roberts1, Daria J. Hazuda1,2, M. Jared Willis3, Rob C. Oslund1*, and Olugbeminiyi O. Fadeyi1*
1 Exploratory Science Center, Merck & Co., Inc., Cambridge, Massachusetts, USA
2Infectious Diseases and Vaccine Research, Merck & Co., Inc., West Point, Pennsylvania, USA
3Efficieny Aggregators, Richmond, Texas, USA
*co-correspondence: rob.oslund@merck.com and olugbeminiyi.fadeyi@merck.com
ABSTRACT
Despite the growing utilization of visible light photochemistry in both chemistry and biology, a general
low-heat photoreactor for use across these different disciplines does not exist. Herein, we describe the
design and utilization of a standardized photoreactor for visible light driven activation and photocatalytic
chemical transformations. Using this single benchtop photoreactor, we perform photoredox reactions
across multiple visible light wavelengths, a high throughput photocatalytic cross coupling reaction, and in
vitro labeling of proteins and live cells. Given the success of this reactor in all tested applications, we
envision that this multi-use photoreactor will be widely used in biology, chemical biology, and medicinal
chemistry settings.
Keywords
Photoreactor, photochemistry, photoredox, multiplex capabilities, protein and live cell labeling
INTRODUCTION
Photochemistry has long been utilized by chemists to generate reactive species to achieve unique
transformations otherwise inaccessible through thermodynamic means. Molecules are electronically
excited (to singlet or triplet excited states) by light absorption, promoting the formation of species with
new reactivity patterns relative to the ground state.[1] Small molecule based, photoactivation chemistry
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has a rich history in organic synthesis particularly in driving complex small molecule rearrangements such
as isomerizations and cyclizations.[2,3] The true power of photoactivation chemistry is best illustrated in
Eschenmoser’s classic total synthesis of cobyric acid, the key organic component of vitamin B12, where
sunlight was utilized to catalyze a macrocyclization of the A and D rings.[4]
Photoactivation has also enabled the use of photoaffinity labeling within chemical biology. For
these applications, substrates including aryl azides, diazirines and benzophenones are activated by UV
light (~300 nm) for covalent cross linking to biomolecules.[5,6] Probes based on these substrates have
found applications in radiolabeling,[5] drug-antibody conjugation,[7] chemoproteomics,[8] target ID[9] and
protein cross linking.[10] In some cases, the reactive intermediate used for these applications forms from
the T1 excited state.[11] This state is formed in two steps: (I) direct excitation to S1 excited state using UV
light then (II) Intersystem crossing (ISC) to form the reactive T1 state. Many times, there is a significant
energy gap between the S1 and T1 energy states, therefore there is a large energy loss due to ISC.[12] If
direct excitation to the T1 state was possible, a significantly lower energy light source could be utilized.
However, quantum mechanics forbids direct excitation to the T1 state because spin is not conserved.
Recognizing this inefficient use of energy, as well as the constraints due to quantum mechanics, organic
chemists have made significant progress in utilizing photosensitization and photoredox chemistry to
access reactive intermediates, particularly free radicals, using lower energy excitation sources.[13] Over
the last decade, an unprecedented number of highly valuable synthetic transformations have been
developed utilizing photoredox chemistry.[14]
Photoredox catalysis reactions[15-18] have gone from obscure to commonplace in both industry and
academia. This upheaval can largely be attributed to the development of a uniform tool set used to
perform photoredox chemistry. This toolset includes both photocatalysts as well as a uniform photoredox
reactor with efficient cooling and modular light intensity.[19] Commercial reactors have standardized and
enabled the fine tuning of reaction conditions and more recently have become multiplex in design.
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Multiplex or high throughput synthesis (HTS) enables speedy reaction optimization through screening
multiple reaction conditions at once. Additionally, multiplex synthesis can empower medicinal chemists
to generate multiple analogs in parallel, allowing efficient collection of SAR (Structure-Activity
Relationship) data. Considering current reactor capabilities, chemists looking to utilize multiplex
photoredox synthesis must choose between buying multiple singleton reactors, which can be expensive,
or designing their own, which can introduce variabilities in light exposure and heating between devices.
While some HTS photoredox reactors have been developed, they are solely engineered for small molecule
transformations.[20] Thus, an ideal all-purpose photoreactor is currently lacking. Furthermore, safety
concerns may arise with DIY systems as strong blue LED light can be particularly harmful to the eye.[21]
Although tinted shields and glasses are available to block blue wavelengths, engineering a self-contained
system would aid in limiting exposure to potentially harmful wavelengths.
The boundaries of visible light photochemistry have been pushed into protein and live systems
by emerging methodologies for peptide and biomolecule functionalization,[22–25] bioconjugation,[26]
protein labeling,[27,28] and crosslinking.[29] Recently, we reported the development of a photocatalytic-
based proximity labeling platform for mapping protein microenvironments on live mammalian cell
surfaces.[30] The successful applications of photocatalysis within biological systems will continue to
increase the utility of this approach to explore biology. However, photocatalytic conditions can limit live-
cell applications leading to a need for suitable biocompatible tools and reagents. Surprisingly, a uniform
visible light photoreactor for probing biological systems is non-existent. Relative to small molecules,
proteins and living cells are significantly more sensitive to heat which can cause dramatic perturbations
to a protein structure or physiological environment within the cell. Therefore, an ideal device would have
efficient heat dissipation that can maintain samples at a low temperature. Furthermore, the optimal
device would be compatible with multiple samples in order to ensure uniformity across a data set or
multiple reactions. A final important feature of this new device would be the ability to function at
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different wavelengths. Although blue light is used in most photoredox methodologies, new
methodologies that utilize lower energy green[31] and red light[32,33] have emerged. In addition to the
chemical transformations achieved by these lower energy light sources, longer wavelengths have
significantly better penetration into living tissue.[34] As such, a uniform device integrating all of these
features would be widely employed within the medicinal chemistry, chemical biology, and biology
communities. Herein we describe the design and development of a multi-use, low heat photoreactor to
enable multiplex photoredox reactions, covalent labeling of biomolecules, and labeling within live cells
(Figure 1). We showcase a proof of concept framework for known light-driven chemical transformations
at different wavelengths, a model photoredox high throughput screen (HTS) Buchwald coupling on drug-
like scaffolds, protein biotinylation, and live cell labeling for confocal microscopy imaging analysis.
This Work—A standard photoreactor enables:
Figure 1: Features desired in an ideal photoreactor which would enable chemical synthesis,
bioconjugation, and cellular labeling reactions.
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RESULTS AND DISCUSSION
Photoreactor Design and Development
To develop a photoreactor that enables multifunctional application in biology and chemistry
settings, the reactor size needs to accommodate multiple reaction vials of different types and sizes (e.g.
dram vials, microcentrifuge tubes, cell culture plates) with even light distribution across the entire reactor
space. To achieve this goal, we designed an oven-styled photoreactor consisting of two chambers. The
outer chamber contains a pull-out lid for sample insertion onto interchangeable, translucent reaction
trays into a cylindrical inner chamber containing low heat light chips (Figure 2a). To maximize light
coverage, the inner chamber cylinder (Figure 2b) was designed using 6063 T5 aluminum polished to a
mirror finish to minimize light absorbance and optimize the light scattering effect (Figure 2c). Four LED-
based chips (455 nm, 555 nm, or 660 nm wavelengths) were arrayed in a staggered X position onto the
inner chamber to create a consistent light distribution across the horizontal midline of the inner chamber
and eliminate any shadowing effect from reaction samples (Figure 2b). To dissipate heat generated from
the LEDs, heat sinks were physically attached to each light chip that extend into the outer chamber of the
reactor (Figure 2d). This heat sink technology functions through absorbing heat away from the LED chips
into the heat sink core and fins located in the outer chamber. While the device relies primarily on passive
cooling within the heat sinks, two fans (80 mm, 2200 rpm at 100% output) were mounted to the inner
wall of the outer chamber on the top and bottom center of the device (Figure 2e). The fans pull air from
outside of the device to displace radiant heat within the inner and outer chambers and cool the heat sink
fins. In order to facilitate easy removal and replacement of the four LED chips, each LED/heat sink
assembly connects to the inner chamber via wireless magnetic contact to electrical contact pins. Finally,
the device was designed to be controlled wirelessly through a mobile app via a Bluetooth (BLE) antenna
connected inside of the outer chamber to control photoreactor light intensity (0-100%), light duration
(hr/min/s), and cooling fan percent output (0-100%).
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Figure 2: Biophotoreactor schematic diagrams. (A) Biophotoreactor with highlighted features. (B)
Cutaway view of inner chamber with external components marked. (C) Internal view highlighting the
reflective interior of inner chamber for efficient light distribution. (D) Internal view of inner and outer
chambers showing heat flow. Red and blue arrows indicate hot and cool air flow, respectively. (E) Internal
cutaway view showing inner and outer chamber with components marked.
Multiplex of Photocatalytic Chemical Transformations
Given the historical impact of photoredox catalysis in advancing the field of synthetic organic
chemistry, we explored the utility of the photoreactor by first investigating three photocatalytic synthetic
transformations at different visible light wavelengths. We began our photoreactor evaluation studies
utilizing the protocol for the elegant photoredox-mediated iridium (1)/nickel dual catalyzed C-N coupling
of trifluoromethyl bromobenzene (2) and morpholine (3) reported by Macmillan et al. [35] Using a 2-dram
vial that easily fits into a single spot of the 24-hole array tray of this new reactor, the reaction was
performed under blue light (455 nm) irradiation using nickel(II) bromide glyme and
{Ir[dF(CF3)ppy]2(dtbbpy)}PF6 (1) to successfully give the desired coupled product (4) in 68% yield (Figures
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3a and 3d).[35] When this same reaction was performed simultaneously across all 24 vial spots of the
reaction tray, similar reaction conversions were achieved (Figure S1). While this experiment does not
indicate the light intensity variability at different spots of the reactor, the similar conversions at each
reaction spot clearly shows the suitability of this device for photoredox-mediated library synthesis. To
highlight the readily interchangeable LED chips feature of the reactor, we next performed a photocatalytic
dehalogenation reaction reported by Zeitler et al. In the presence of organic photocatalyst Eosin Y (5),
under irradiation with lower energy green light in the photoreactor (555 nm), dehalogenation of an α-
bromoacetophenone (6) proceeded quantitatively (Figures 3b and 3d).[31] Inspired by the red light-based
photocatalytic fluoroalkylation of heteroarenes reported by Postigo et al.,[32] we set out to functionalize
capped-tryptophan (9) using a interchangeable red light (660 nm) LED chip. In the presence of
1,1,1,2,3,3,3-heptafluoro-2-iodopropane (10), tryptophan easily underwent C-H functionalization to give
excellent yield (80%) of the fluoroalkylated-tryptophan product using a red-light activated zinc
phthalocyanine photocatalyst (8) (Figures 3c and 3d). The efficient coupling yield of the tryptophan amino
acid under red light illumination showcases the potential opportunity to utilize this transformation in an
in vivo or tissue setting for tryptophan labeling. Finally, for all three wavelengths the internal heat
temperatures were measured and observed to not exceed ~30 °C when run at 100% light intensity over
time indicating the ability to maintain low temperature within the device (Figure 3e). The three model
reactions tested within the integrated photoreactor at multiple LED wavelengths and the low
temperatures maintained will permit the development and application of novel chemical transformations
for profiling biological environments, particularly where higher temperatures can have adverse effects on
protein stability or cell viability.
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Figure 3: Magnetically interchangeable LED lights allows for light irradiation at (A) blue (455 nm) (B) green
(555 nm) and (C) red (660 nm) wavelengths. (D) Photocatalysts used across the different wavelengths for
the indicated chemical transformations in panels A-C. (E) Recorded temperature over time for blue, green
and red LED lights run at 100% intensity.
High Throughput Screening (HTS) capabilities have served a vital role in medicinal chemistry
efforts to perform SAR studies for drug design. Therefore, the ease to quickly access various analogs of a
bioactive compound is critical for the cycle time of synthesis to biological testing. To explore the ability
of this new integrated photoreactor to enable parallel library synthesis (Figure 4a), we selected
photocatalytic Buchwald C-N coupling reactions, one of the most frequently utilized reactions in drug
discovery. Using an Iridium photocatalyst (1) (Figure 4b), the photoreactor enabled the concurrent
synthesis of functionalized bioactive molecules (Figure 4c). All the coupled monomers feature elements
commonly found in medicinal chemistry such as high fraction sp3 containing monomers, basic amines, and
highly functionalized heterocyclic cores. The ability to rapidly screen multiple photoredox-based
transformations involving different functional groups would be of large interest to medicinal chemistry
groups to quickly access useful compound targets for SAR studies using a benchtop reactor. These results
further highlight the utility of the photoreactor’s multiplex design for overcoming issues associated with
concurrent running of multiple photoredox reactions that currently rely on the use of multiple singleton
reactors, or the building of custom reactors using Kessil lamps or LED strips.
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Figure 4: Photocatalytic reaction multiplexing. (A) Photoreactor with reaction tray loaded with dram vials
for parallel synthesis. (B) Iridium catalysts used for library synthesis. (C) Parallel scope photoredox
Buchwald C-N coupling reaction.
Visible Light Induced Protein Labeling
Successful application of the photoreactor for small molecule reactions at or near room
temperature conditions (Figure 3e) led us to next explore protein labeling in vitro. A photocatalytic and
photoactivatable visible light induced protein labeling reaction were each selected to install biotin onto
carbonic anhydrase (CA) over time (Figure 5a). For the photocatalytic protein labeling system we turned
to Ru(bpy)32+ that is known to oxidize tyrosine residues to form tyrosyl radicals in the presence of blue
light and ammonium persulfate ((NH4)2S2O8).[36] This system has been utilized to develop protein cross
linking,[29] and ligand-directed protein labeling techniques.[27,28,37],[38] Inspired by these applications, we
utilized this ruthenium-based system to generate phenoxy radicals from biotin tyramide for protein
biotinylation (Figure 5a, protein labeling A). We observed CA protein biotinylation upon blue light
irradiation in the photoreactor that was dependent on the light exposure time (Figure 5b). The multiplex
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feature of the photoreactor (Figure 5c) enables the ability to irradiate multiple labeling conditions
simultaneously. Accordingly, altering the reaction conditions to remove the photocatalyst and/or visible
light did not lead to protein labeling (Figure 5b).
Azido phenol probes have recently been used for protein proximity labeling through a technique
called enzyme mediated activation of radical sources (EMARs) where a peroxidase is used to generate a
radical labeling species.[39] Since phenyl azides are known to undergo UV activated protein labeling,[5,7]
we wondered whether the presence of a hydroxy group on the ring system would make the probe
sensitive to visible light activation for protein labeling as the hydroxy group has been shown to induce a
bathochromic shift in absorption spectra when present on a benzene ring (Figure 5a, Protein labeling
B).[40] CA protein was mixed with the azido phenol biotin probe and irradiated with visible light to yield
time dependent protein labeling (Figure 5b). Additionally, a light on/off protein labeling experiment
shows that biotinylation using the azido phenol biotin probe only occurs upon addition of visible light,
highlighting the utility of the photoreactor to maintain exquisite control over the protein labeling reaction
(Figure 5d). As a final demonstration of the light box to facilitate protein labeling, visible light activation
of Eosin Y was used to induce protein oxidation that could be trapped by biotin hydroxyl amine (Figure
S2). Collectively, these results highlight the ability to achieve temporal control over protein labeling using
the photoreactor and open the possibility to explore other light controlled protein labeling reactions.
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Figure 5: Visible light-mediated protein labeling. (A) General reaction scheme for the photocatalytic and
photoactivatable biotinylation of carbonic anhydrase (CA). (B) Western blot analysis shows time
dependent biotinylation of (CA). (C) Biophotoreactor loaded with microcentrifuge tubes for reaction
multiplexing. (D) Biotin-azido-phenol on/off light experiment showcasing light dependency of the protein
labeling reaction (average of 3 independent experiments, error bars represent ± S.D.).
Live Cell Photochemical Labeling
To test the feasibility of using the photoreactor for labeling of live cells, we initially determined
viability of the A375 melanoma cell line upon extended exposure to full intensity visible light and observed
no reduction in viability (Figure S3). Encouraged by these results, we next investigated the ability to
induce protein labeling via photoredox on live A375 cells. Given the successful protein labeling results
2+
observed with the Ru(bpy)3 photocatalyst in Figure 5b, we selected this system for live cell labeling
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(Figure 6a). Cellular biotinylation was monitored by confocal imaging using streptavidin Alexa Fluor 488
(AF 488) conjugate dye that binds biotinylated cells after washing unreacted biotin tyramide (Figure 6a).
Gratifyingly, cellular biotinylation only occurred in the presence of Ru(bpy)32+, (NH4)2S2O8, and visible light
irradiation in the photoreactor (Figure 6b). In contrast, in the absence of visible light irradiation no cellular
labeling was detected (Figure 6b). Similarly, removing (NH4)2S2O8 or both (NH4)2S2O8 and Ru(bpy)32+ also
led to minimal cellular labeling (Figure 6b). These results clearly show that the photoreactor is also
capable of inducing labeling of live cells for downstream analysis and can allow for the screening of other
light-activated chemistry reactions in live cell systems. To our knowledge, this photoreactor represents
the first uniform reactor for protein or cellular labeling.
Figure 6: Live cell labeling in the multi-use photoreactor. (A) General reaction scheme for the biotinylation
of A375 cells using Ru(bpy)32+, (NH4)2S2O8, and biotin-tyramide. (B) Confocal microscopy images showing
nuclei (blue) and biotinylation (green). Scale bars indicate 10 µm. Duplicate images are shown below each
condition.
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CONCLUSION
The use of visible light as a reagent in photocatalysis to generate reactive species in a controlled
manner provides unique advantages for profiling biological environments due to the highly tunable
temporal and spatial precision of light. Thus, for photocatalysis to bridge the gap from chemistry centric
methods towards enabling biological investigation, a uniform photoreactor that is biocompatible and
permits the use of cell culture plates and microcentrifuge tubes with efficient light distribution and low
heat generation is a required piece of the photochemistry toolbox.
Herein, we disclosed the design and development of a multifunctional photoreactor that can be
broadly used for visible light driven activation and catalytic reactions for proteins and live cells. The
photoreactor LED was designed with heat dissipation sinks to reduce heat while efficiently and uniformly
illuminating light within the reflective reaction chamber. Photocatalytic reactions at multiple visible light
wavelengths (blue, green, and red) were easily achieved in the modular photoreactor through
interchangeable light chips. The multiplexing capability of the photoreactor enabled high throughput
library synthesis as shown through a relevant medicinal chemistry coupling reaction.
In addition to the demonstrated utility for chemical transformations, we showcased protein
labeling methods as well as photocatalytic biotinylation of live A375 cells for confocal microscopy imaging.
To our knowledge, this photoreactor represents the first uniform reactor for protein and live cell labeling
in biological environments that we anticipate will enable the transfer of light-mediated chemical
transformations, and the development of new ones, into cellular environments and tissues.
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SUPPLEMENTAL INFORMATION
All supplementary figures, experimental details, and synthesis information are included in Supporting
Information.
ACKNOWLEDGMENTS
We thank Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA for financial
support. N.B.B would like to acknowledge Northeastern University’s Co-Op Program. We are very grateful
to Chelsea Kae, Jake Tomlinson, and Kelly Crotty for useful discussions.
AUTHOR CONTRIBUTIONS
Project was conceived and initiated by R.C.O. and O.O.F. All experiments were designed by N.B.B., R.C.O
and O.O.F. and performed by N.B.B., K.A. R., T.R.R. The manuscript was written by N.B.B., R.C.O and O.O.F
and proofread by all authors.
DECLARATION OF INTERESTS
N.B.B., K.A.R., T.R.R., S. W., E.C.H., L.R.R., D.J.H., R.C.O., O.O.F. are employees of Merck Sharp & Dohme
Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. M.J.W. is an employee of Efficiency
Aggregators. A patent on the photoreactor has been filed by Efficiency Aggregators.
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