Additive-Free Green Light-Induced Ligation Using BODIPY Triggers

Article abstract of DOI:10.1002/anie.201912555

Photochemical ligation is important in biomaterials engineering for spatiotemporal control of biochemical processes. Such reactions however generally require activation by high energy UV or short wavelength blue light, which can limit their use as a consequence of the potential of these high energy light sources to damage living cells. Herein, we present an additive-free, biocompatible, chemical ligation triggered by mild visible light. BODIPY dyes with a pendant thioether attached at the meso-position undergo photolysis of the [C?S] bond under green light (λ=530 nm) excitation, producing an ion pair intermediate that can react specifically with a propiolate group. The utility of this photochemical ligation in materials science is demonstrated by the fabrication of hydrogels with specific architectures, photo-immobilization of biomacromolecules, and live cell encapsulation within a hydrogel scaffold.

Full text of DOI:10.1002/anie.201912555

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Accepted Article
Title: Additive-Free Green Light-Induced Ligation Using BODIPY
Triggers
Authors: Ming Li, Andrew P. Dove, and Vinh Xuan Truong
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912555
Angew. Chem. 10.1002/ange.201912555
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Additive-Free Green Light-Induced Ligation Using BODIPY
Triggers
[c]
[b]
[a]
Ming Li, Andrew P. Dove and Vinh X. Truong*
Abstract: Photochemical ligation is important in biomaterials
engineering for spatiotemporal control of biochemical processes.
Such reactions however generally require activation by high energy
UV or short wavelength blue light, which can limit their use as a
consequence of the potential of these high energy light sources to
damage living cells. Herein, we present an additive-free,
biocompatible, chemical ligation triggered by mild visible light.
BODIPY dyes with a pendant thioether attached at the meso-position
undergo photolysis of the [C-S] bond under green light (λ = 530 nm)
excitation, producing an ion pair intermediate that can react
specifically with a propiolate group. The utility of this photochemical
ligation in materials science is demonstrated by the fabrication of
hydrogels with specific architectures, photo-immobilization of
biomacromolecules, and live cell encapsulation within a hydrogel
scaffold.
Kowollik and co-workers reported visible light triggered ligation of
polymers using 1,3-dipole 2H-azirine ligation (λmax = 405 nm),[
nitrile imine-mediated tetrazole-ene cycloaddition (λmax = 405
nm),[6] and photoreversible styrylpyrene dimerization (λmax = 420
nm).[7] The group of Zhu has extensively utilised coumarin
derivatives as photocaging groups for construction of hydrogels
via photo-uncaging of thiocarbamate (λ = 405-450 nm) followed
by thiol-maleimide addition,[8] while An et. al. have reported
several tetrazoles derivatives that can be activated by 405 nm
laser light to generate nitrile imine for 1,3 dipolar cycloaddition.[
More recently, Li et al. introduce a visible light-triggered [4+2]
cycloaddition based on 9,10-phenanthrenequinone functionality
that is activated at λ = 405-460 nm.[10] Our group has employed a
number of visible light triggered photo-reactions, including
photocycloaddition of anthracene[11] and styrylpyrene,[12] triggered
by irradiation at λmax = 420 nm, in the fabrication of dynamic
hydrogels as biomaterials. Nevertheless, the short wavelength (λ
5]
9]
Photochemical transformations were first performed using solar
energy as the natural light sources.[1] With the development of
lamp technology, chemists have had access to UV light with
wavelengths as low as 200 nm and photon energy that is greater
than that attained from sunlight.[2] This has allowed a wider range
of photochemical reactions to be accessed. Nevertheless,
reliance on UV light for activation of chemical processes
significantly hinders their application in biomaterials science as a
consequence of the high cost of equipment and energy usage,
large heat generation and harmful side effects from UV light
exposure.[ Thus, new photochemical reactions that can be
triggered by low energy, long wavelength visible light will
significantly expand the applications of photochemistry in organic
synthesis and materials engineering.[3] Furthermore, employment
of red-shifted photoreactive moieties that avoids the use of
damaging UV light and additives can further enable their utility in
sensitive biological environments.[4] Perhaps more importantly,
longer-wavelength absorption leads to deeper tissue penetration
thus enhancing the translatability of this method.
=
405-455 nm) at which all of these chemistries operate, despite
13
being non-harmful to living cells at low intensity, is limiting their
further application in biomaterials engineering due to the low
tissue penetration property.
Recent computational studies by Winter and co-workers
suggested that boron-dipyrromethene (BODIPY) moieties, in their
excited state, can effectively decay, with the scission of [C-O]
bond at the meso-position, to ground state ion pairs.[14] This
theoretical analysis was practically confirmed by the caging and
light-activated release of various groups including carboxylic
acids,[14] amines,[15] and chloride[14a] under green light (λmax = 520
nm) irradiation using BODIPY scaffolds. These advances inspired
us to examine the possibility of using BODIPY in photochemical
ligation by photo-induced scission of [C-S] bond to generate a
short-lived thiolate anion that can be captured by an appropriate
electrophile. Herein, we demonstrate that green light can be used
to induce a nucleophilic thiol-yne addition by utilizing BODIPY
scaffolds as the photo-trigger. BODIPY groups are used to directly
cage the thiol group via a thioether linkage. Under irradiation of
visible light at λmax = 530 nm, the excited BODIPY-thioether is
converted to an ion-pair intermediate which can participate in the
nucleophilic thiol-yne addition (Figure 1a). Compared to the
normal approach in which the caged-thiol is released from the
thiocarbonate group,[8] here we take advantage of the high
reactivity of the propiolate group towards the thiol anion. Critically,
the thioether group is stable under ambient light in the absence of
an electrophile, which is highly advantageous for storage and
processing of materials prior to green-light-activated ligation.
3]
Despite this need, reports that are focussed on catalyst free
photo-ligation still mostly rely on the activation by short
wavelength blue light (λ = 405-460 nm). In particular, Barner-
[
a]
Dr, V. X., Truong
Department of Materials Science and Engineering
Monash University
Clayton, VIC, Australia 3800
E-mail: vinh.truong@monash.edu
Prof Dr, A. P., Dove
School of Chemistry
University of Birmingham
[
b]
c]
Edgbaston, Birmingham, UK, B15 2TT
Prof. Dr, Ming Li
[
School of Materials Science and Engineering
Central South University
Changsha, Hunan 410083, China
Supporting information for this article is given via a link at the end
of the document.
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We next investigated the photochemical reactivity of the
synthesised chromophores with methyl propiolate in
water/acetonitrile (v/v = 1/4) under irradiation of green light at λ =
-2
1
5
30 nm and intensity of 30 mW cm . Inspection of the H NMR
spectra of the lyophilised products post-irradiation reveals the
formation of the alkenyl adducts (Figure 2 and S23) similar to
those observed from base-catalysed thiol-propiolate addition. The
reaction did not proceed in chloroform (Figure S16), hexane or
acetonitrile, even in the presence of the triethylamine which is a
good catalyst for the nucleophilic thiol-yne addition (Figure S17).
This suggests that polar protic solvents play a key role in this
photochemical addition, presumably through stabilization of the
ion-pair intermediate. Further analysis of the chemical shifts of the
photoderived-adducts from either 1 or 2 with methyl propiolate
reveals that the thio-alkene adduct is mostly cis isomer (88%).
The predominant cis isomer adduct is similar to what was
observed in the base-catalysed thiol-yne reaction in polar
solvents.[16] Our photo-induced thiol-yne reaction however does
not require a base catalyst, which presents a significant
advantage with regards to the versatility of this reaction in a range
of environments, including biological environments. Green light
irradiation of both 1 and 2 in the absence of methyl propiolate in
water/acetonitrile however, showed no reaction, which suggests
that the thioether BODIPY compounds are stable to photo-
induced hydrolysis.
Figure 1. a) Mechanism of visible light activation of nucleophilic thiol-yne; b)
UV-vis spectra of 1 and 2 in acetonitrile/water (v/v = 4/1).
The synthesis of BODIPY thioethers 1 and 2 was targeted
to create a versatile precursor for photoligation (Figure 1a). The
molecular design of these photocaged thiols was undertaken
such that the ester group imparts significant versatility with which
to attach a range of functional groups. Initially, we attempted to
synthesise 1 via nucleophilic thiol-bromo addition (Scheme S1),
however significant degradation of the BODIPY-Br was observed
under several reaction conditions, even in the presence of a mild
base such as triethylamine. Thus we re-examined the synthesis
and prepared BODIPY from an acyl precursor that contains a
thioether moiety (Scheme S2). This synthetic route resulted in the
desired compound 1 with moderate yield (ca. 24%). Compound 2
can be synthesised from reaction of 1 with iodine monochloride in
dichloromethane in good yield. As anticipated, UV-Vis spectra of
compounds
1 and 2 in acetonitrile/water mixture show
absorbance in the green light region (λ = 470-580 nm) with very
high molar extinction coefficients (values of 68 000 M-1 cm-1 and
5
7 000 M-1 cm-1 for 1 and 2 respectively, see Table 1).
Table 1. Optical properties of 1 and 2 and quantum efficiencies of the
conversion to alkene thioether.
1
Figure 2. H NMR spectra of compound 1 (1 eq.) and methyl propiolate (3 eq.).
in water/acetonitrile (v/v = 1/4) before (top) and after irradiation (bottom) with
green light (λ = 530 nm, I = 30 mW cm ) for 5 h. After irradiation, the solutions
were lyophilised, during which methyl propiolate was evaporated together with
3
the solvent, before being dissolved in CDCl for NMR analysis.
-2
Compound
λ
max
ε (x10 M-1
cm )
4
Φ[a] (x10-4)
εΦ
(M cm )
-
1
-1
-1
(nm)
1
2
510
543
6.8
5.7
7.2
31
49
177
As a consequence of the very low solubility of both 1 and 2
in both water and methanol, we were not able to monitor the
reaction using HPLC. Thus the conversion of the BODIPY
thioether to alkene thioether adduct was followed by 1H NMR
[
a] Quantum efficiency of the conversion of BODIPY thioether to alkene
thioether determined by ferrioxalate actinometry in water/acetonitrile at λ =
5
determined by H NMR.
-
2
30 using a LED light source (I = 30 mW cm ) and the conversion was
1
spectroscopy. After 2 h of green light irradiation, 43% of 1 was
consumed in the photo-induced reaction with methyl propiolate,
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while 81% of 2 was consumed under the same reaction conditions
suggestive of minimal interference from oxidation by singlet
oxygen generation.[17]
(
Figure S21). Clearly, the iodinated derivative 2 not only showed
a redshifted absorbance but also a higher chemical quantum
efficiency in the photo-triggered thiol-yne addition. This may be a
result of the intersystem crossing to a triplet state being enhanced
by the iodine atoms, which have a longer lifetime compared to the
singlet states under excitation,[14b] This consequently increases
the stabilization of the ion-pair intermediate for nucleophilic
conjugation.
To demonstrate the versatility of this approach, we also
examined the photochemical ligation of the thioether BODIPY
with common nucleophiles including acrylate ester and maleimide.
Irradiation of 1 or 2 and methyl acrylate in acetonitrile/water with
green light after 5 h did not result in any observable thiol-ene
addition product. This result indicates that the acrylate group is
not a strong enough electrophile for reacting with the ion pair
intermediate. Irradiation of 1 or 2 with N-ethylmaleimide led to a
number of by-products accompanied by photobleaching (Figure
S22). We were not able to identify the thiol-maleimide or alcohol
product (BODIPY-OH) when analysing the resultant solution by
HRMS. A reasonable explanation for this is that the maleimide
acts as an electron acceptor for the donor-excited photoinduced
electron transfer (d-PeT) effect, following the excitation of the
BODIPY moiety (Figure S23).[18] Consequently, the activated
maleimide underwent oxidation and hydrolysis in aqueous media,
resulting in an array of unidentified products.
In tracking the photochemical addition process, we were
able to isolate the alcohol by-products using preparative thin layer
chromatography (Figure S27-S30). The chemical structures of
1
the alcohol by-products were confirmed by H NMR spectroscopy
and high resolution mass spectrometry (HRMS), confirming the
mechanism of the photoligation shown in Figure 1. Furthermore,
performing the light-induced reactions in degassed solutions and
under argon protection showed no difference in the conversion
compared to untreated solvents and under ambient atmosphere,
Figure 3. a) Schematic of gelation via green light initiated crosslinking; b) kinetics of gelation followed by the change in storage modulus (G’) and loss modulus (G”)
upon irradiation of light (green dashed line) at λ = 530 nm; spatial control of hydrogels properties demonstrated by c) fabrication of hydrogels with built-in micro-
channels using a brightfield mask (scale bar = 400 µm) and d) patterned presentation of TRICT-labelled streptavidin via biotin attachment (the red fluorescence
belongs to TRITC-streptavidin while the background green fluorescence is due to thioether BODIPY within the gel, scale bar = 100 µm); e) reaction scheme of biotin
photo-immobilization.
To demonstrate the utility of our visible light induced
chemical ligation in biomaterial science, we synthesised 4-arm
poly(ethylene glycol)s (PEGs) with BODIPY thioether end-groups
with 4-arm PEG alkyne (5) in deionized water under green light
illumination (Figure 3a). Rheological data show that rapid
gelation occurred, as indicated by the evolution of storage
modulus, when the polymer-containing solutions were irradiated
(
3 and 4) via amide formation and investigated their crosslinking
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-2
with light at λ = 530 nm and I = 30 mW cm . Mixture of 3 and 5
displayed an initial rise of storage modulus and thereafter gradual
increase to ca. 1000 Pa after 60 min. Similar to the kinetics of
small molecule reactions, the gelation rate was faster for PEG
having thioether iodinated-BODIPY endgroup (4). The
crosslinking of 4 and 5 reached completion after 30 min of
irradiation, resulting a gel with a G’ of ca. 4200 Pa. Both 4-arm
PEGs with thioether BODIPY endgroups were found to have high
stability in cell culture conditions – incubation of 3 or 4 at 37 °C
for 24 h in PBS solution did not show any change in the UV-vis
absorption and NMR spectra. In our previous work on base-
catalysed thiol-yne crosslinking, the hydrogels degraded, via
hydrolysis of the alkenyl ester linkage, over a period of 1-15
days.[19] We expect that the photo-induced thiol-yne gels would
display similar degradation behavior, however the degradation
time can be tuned by varying the crosslinking density of the
polymer network.
affinity of biotin towards streptavidin allowed for conjugation of the
peptide specifically to the patterned region, and appeared as red
fluorescence stripes under a microscope.
Our studies on small molecules indicate the BODIPY-OH
side product can provide competitive absorption of the incident
light, which may affect the photochemical process. In general, this
effect is minimal at low concentrations or very thin sample,[20] as
being designed in small molecule study and rheology set up. To
account for light attenuation in a larger sample, we examined the
crosslinking of polymer solution (3+5) having a thickness of 1.2
cm. We found that a solid gel was formed across the thickness
investigated (Figure S34). In addition, light attenuation after
transmitting through the hydrogel sample of this thickness was
found to be 60%. In comparison, light at λmax = 470 nm showed
Figure 4. Live/dead staining of hMSC-laden gels 24 h post-encapsulation,
(Green = live cells; red = dead cells; scale bar = 100 µm; Z-stack height 300
µm).
100% attenuation after passing through the same hydrogel
sample. This result demonstrates the advantage of utilizing longer
wavelength light in materials science such as green light, which
provides better medium penetration compared to shorter
wavelength blue or UV light.
To highlight the spatiotemporal control over materials
properties, we attempted to fabricate a hydrogel with pre-
determined architectures using a photomask. Here, a solution of
Finally, we further tested the suitability of the green light-
triggered ligation for three-dimensional primary cell culture
studies using human mesenchymal stem cells (hMSCs). In this
study, hMSCs were homogenized with a solution containing
polymer 4 and 5 before green light-induced crosslinking to form
cell-laden hydrogel. The encapsulated hMSCs were then cultured
for 24 h and cell viability was assessed by live/dead staining. We
observed a very high cell viability (97.9% ± 0.8%), confirming that
the green-light induced crosslinking process is non-toxic to
hMSCs. Interestingly, although the porpiolate has been reported
to be toxic to hMSCs during gelation via base-catalysed thiol-yne
crosslinking, the high viability in the photo-induced thiol-yne
suggests that the photoligation process reduce the impact of the
3
and 5 was covered with a brightfield photomask before being
subjected to green light irradiation for 30 min, after which a
hydrogels with cross-shape or triple junction microchannels
(
Figure 3c) were formed having width and depth of ca. 200 µm
ca. 1.2 mm respectively (Figure S35). Hydrogels with embedded
microchannels are highly valuable for in vitro drug discovery
model[20] and organ on a chip platforms,[21] however fabrication of
well-defined microchannels on hydrogels often relies on printing
techniques using cytotoxic materials[22] or UV light-initiated
polymerization.[23] Here we demonstrate that hydrogels with built-
in microchannels can be formed by simply using an appropriate
photomask and a LED light source. Of note, our method may not
be able to fabricate channels with nanometer details and
resolution compared to soft lithography or direct photo-printing,[24]
mostly due to light diffraction during the photo-induced
crosslinking process.
The hydrogel network can be further photo-patterned with
bioactive molecules, such as biotin. In this demonstration, the
hydrogel was first formed using stoichiometric excess of 3 so that
the resultant gel contained pendent BODIPY thioether after
photo-crosslinking. The gel was then treated with a solution of
biotin-propiolate, covered with a chrome photomask (Figure 4d)
and subjected to green light irradiation for photo-patterned
immobilization of biotin (Figure 4e) . The gel was then exposed
to a solution containing TRITC-labeled streptavidin. The high
[23]
propiolate group on live hMSCs. Possibly, the low toxicity is due
to lower pH used in cell encapsualtion process, as the propiolate
is know to be reactive at pH >7.4.
In summary, we demonstrate that BODIPY can be
employed as a phototrigger for the thiol-propiolate addition by
incorporation to the thioether at meso-substitution. The long-
wavelenth absorption of the BODIPY moeities allows for
activation of the reaction under green light (λ = 530 nm) - by far
the longest wavelength employed for additive-free photochemical
ligation. As shown here, this new method of visible-light triggered
ligation is highly valuable for applications in material
manufactering and biomaterials engineering.
Acknowledgements
V.X.T. acknowledges funding support from the Department of
Materials Science and Engineering, Monash University. M. L.
thanks the financial support by National Natural Science
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Foundation of China (No. 51871246), Innovation-Driven Project
of Central South University (No. 2018CX002) and Hunan
Provincial Science & Technology Program (No. 2017XK2027).
Keywords: BODIPY • visible light • photochemistry • hydrogel •
bioconjugation • thiol-yne
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Entry for the Table of Contents
COMMUNICATION
Photochemical ligation between
BODIPY thioether and propiolate,
triggered by green light, enables
formation of hydrogel and photo-
patterning of bioactive molecules
Ming Li, Andrew P. Dove and Vinh X.
Truong*
Page No. – Page No.
Additive-Free Green Light-Induced
Ligation Using BODIPY Triggers
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