Phototriggered Release of a Transmembrane Chloride Carrier from an o-Nitrobenzyl-Linked Procarrier

Article abstract of DOI:10.1002/anie.201900869

While there have been many studies on synthetic chloride carriers and a recent application for apoptotic cell death, so far, the proposed huge potential of these systems in targeting cancer has not been realized due to their cytotoxicity to healthy cells. Herein, we describe the development of an indole-2-carboxamide receptor as an efficient membrane chloride carrier while the corresponding o-nitrobenzyl-linked derivative is a procarrier of the ion. Photoirradiation of the procarrier in liposomes results in release of the active carrier with up to 90 % transport efficiency. Such photorelease of the carrier also works within cancer cells, resulting in efficient cell killing. Such photocleavable procarriers have great potential as a photodynamic therapy to combat various types of cancers.

Full text of DOI:10.1002/anie.201900869

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Phototriggered release of transmembrane chloride carrier from an
o-nitrobenzyl-linked procarrier
Authors: Swati Bansi Salunke, Javid Ahmad Malla, and Pinaki Talukdar
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
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: Angew. Chem. Int. Ed. 10.1002/anie.201900869
Angew. Chem. 10.1002/ange.201900869
Link to VoR: http://dx.doi.org/10.1002/anie.201900869
http://dx.doi.org/10.1002/ange.201900869

10.1002/anie.201900869
Angewandte Chemie International Edition
COMMUNICATION
Phototriggered release of transmembrane chloride carrier from
an o-nitrobenzyl-linked procarrier
Swati Bansi Salunke,[a] Javid Ahmad Malla,[a] and Pinaki Talukdar*[a]
Abstract: While there have been tremendous studies about
synthetic chloride carriers and their recent application in the
apoptotic cell death, so far the proposed huge potential of these
systems in targeting cancer has not been materialized due to their
cytotoxicity to healthy cells as well. Herein, we describe the
development of an indole-2-carboxamide receptor as an efficient
membrane chloride carrier while the corresponding o-nitrobenzyl-
linked derivative is a procarrier of the ion. Photoirradiation of the
procarrier in liposomes results in the release of the active carrier
displaying up to 90% transport efficiency. Such photorelease of the
carrier also works within cancer cells resulting in efficient cell death.
All in all, such photocleavable procarriers have great potential as a
photodynamic therapy to combat various types of cancers.
used for releasing active ion carrier from a procarrier (i.e. the
inactive form of the carrier molecule).[14] Photoisomerization of
molecules, on the other hand, was used to activate or deactivate
channel/carrier mediated ion transport.[15]
Herein, we have introduced the “photocleavable prodrug”
concept in the domain of artificial ion transporters and developed
a procarrier that endows photo-controlled release of an active
carrier to induce chloride mediated cell death. Photocleavable
protecting groups are well-known in organic synthesis for
several decades,[16] and recently have had a rejuvenation in
recent years due to their extensive application in biology.[17] For
example, phototriggered removal of the o-nitrobenzyl (ONB)
group[18] was successfully applied for either delivery[19] or
activation[20] of anticancer drugs. Mo et. al. have illustrated the
photoactivation of an anticancer prodrug to release the 5-
fluorouracil (an anticancer drug to treat solid cancers, such as
colon, breast, rectal, and pancreatic cancers), and induce
cellular apoptosis.[20d] Photocleavable prodrugs have already
shown promises in the photodynamic anticancer therapy. Such
remarkable literature support provoked us designing an ONB-
linked N-aryl-1H-indole-2-carboxamide procarrier (Figure 1A).
In classical anticancer chemotherapy, the drugs target specific
genes or proteins/enzymes found in cancer cells to trigger
apoptosis induction and related cell death networks to eliminate
malignant cells.[1] However, the activation of different anti-
apoptotic pathways,[2] mutations in the drug targets that prevent
the binding of the drug,[3] and over-expression of proteins that
compensate for the loss of the drug target[4] are known to cause
tumor survival, therapeutic resistance, and recurrence of cancer.
The cellular apoptosis is also linked to the homeostasis of
several ions e.g., sodium, potassium, calcium, and chloride.[5] In
literature, several biomimetic synthetic systems have been
reported for transporting ions across the lipid membrane.[6]
Recently, natural and synthetic chloride transporters, e.g.,
In this design, the N-phenyl-1H-indole-2-carboxamides 1a-
1d were selected as carrier molecules (Figure 1B). The para-
substituent of the phenyl ring was changed among R = –CH3, –
C(CH3)3, –Br and –CF3 to vary the acidity of N–Hb proton (Table
S1). Theoretical estimation based on the calculator plugins of
MarvinSketch program[21] gave pKa = 14.31, 14.23, 13.89 and
13.86 for the N–Hb protons of 1a-1d, respectively, suggesting
the higher acidity of the proton when a stronger electron
withdrawing R group was used. The R groups also influenced
the acidity of N-Ha protons in the same way (i.e., pKa = 11.85,
11.85, 11.77 and 11.76 for 1a-1d, respectively). The program
prodigiosin,[7]
tambjamine,[8]
ureas/thioureas,[9]
calix[4]pyrroles,[10] squaramides,[11] and bis-sulfonamides[12]
causing apoptosis-mediated cancer cell death were also
reported. These molecules function in the lipid membrane, unlike
binding to any specific genes or proteins/enzymes, and perturb
the intracellular chloride ion concentration to kill the cells.
Therefore, in principle, synthetic chloride transporters can
overcome the resistance related to the mutations and over-
expression of genes and proteins. However, chloride transport-
mediated death was also observed for normal cells as an
undesired consequence. This toxicity is considered as
a
limitation for applying ion transporters in anticancer therapy.
Therefore, there is a need to develop stimuli-responsive systems,
which can be applied selectively for cancer cells. In this line, pH
was used primarily to activate the ion transports in specific pH-
ranges.[13] Recently, enzymes (esterase and glycosylase) were
[a]
S B Salunke, J A Malla, Dr. P Talukdar
Chemistry Department
Indian Institute of Science Education and Research Pune
Dr. Homi Bhabha Road, Pashan, Pune 411008, Maharashtra (India)
E-mail: ptalukdar@iiserpune.ac.in
Supporting information for this article is given via a link at the end of
the document.
Figure 1. Phototriggered release of an anion carrier from corresponding ONB
protected procarrier (A). Structures of carriers 1a-1d and a procarrier 2 (B).
This article is protected by copyright. All rights reserved.

10.1002/anie.201900869
Angewandte Chemie International Edition
COMMUNICATION
was further useful in predicting the membrane permeability of
these molecules, logP = 3.60, 4.63, 3.85 and 3.96 for 1a-1d,
respectively. Molecule 2 was designed as the procarrier form of
1d. Relatively higher pKa = 11.85 for N–Ha proton and the
absence of the N-Hb proton were considered as crucial
limitations of 2 to be an anion transporter although, its
amphiphilicity (i.e., logP = 5.49) was ideal for the membrane
permeation. Compounds 1a-1d were synthesized by the
coupling of indole-2-carboxylic acid 3 with para-substituted
aniline derivatives 4a-4d in the presence of EDC·HCl and HOBt
(Scheme S1). Prior to the synthesis of 2, compound 5 was
prepared by the reductive amination of o-nitrobenzaldehyde and
4d (Scheme S2). Subsequently, compound 3 was treated with
SOCl2 followed by the reaction with 5 in the presence of DMAP
to get 2 in 92% yield (Scheme S3).
Variation of external cations (i.e., M+ = Li, Na, K, Rb, and
Cs) in the aforementioned LUVs did not provide any noticeable
difference in the ion transport rate indicating no role of alkali
metal cations in the transport process (Figure S12). However,
the change of external anions (i.e., X = F Cl, Br, OAc, and
,

NO3 ) in the EYPC‒LUVsHPTS provided a significant variation
of ion transport activity (Figure 2B). To determine the operative
ion transport mechanism, transport activity of 1d was monitored
in the presence of either carbonyl cyanide-4-(trifluoromethoxy)
phenylhydrazone (FCCP, a proton transporter)[23] or valinomycin
(a K+ ion selective carrier).[24] Under the applied pH gradient
conditions (pHin = 7.0 and pHout = 7.8), 1d (280 nM) displayed
significantly enhanced transport activity in the presence of FCCP
(937.5 nM) compared to that observed in the absence of FCCP
(Figure S13). On the other hand, the transporting activity data of
1d (340 nM) in the absence and presence of valinomycin (15
pM) were comparable (Figure S14). The FCCP and valinomycin
coupled ion transport data corroborates to the OH/Cl antiport
as the main transport mechanism.[25]
At first, the Cl ion binding properties of 1a-1d were verified
by 1H NMR titration experiments in CD3CN. Upon addition of
tetrabutylammonium chloride (TBACl) to 1a-1d (5 mM),
downfield shifts of Ha, Hb, and Hc protons were observed
indicating the interactions of these protons with the Cl ion
(Figure S1–S4). The Job’s plot analysis based on the change in
N-Ha proton chemical shift of 1a-1d confirmed the 1:1
complexation of the receptor and Cl (Figure S7). The binding
constant, Ka = 599.43 ± 12.57 M1 was also calculated for 1d
using Bindfit program (Figure S4).[22] Cl ion binding constants
for 1a (Ka = 281.76 ± 3.47 M1), 1b (Ka = 505.73 ± 15.1 M1), and
1c (Ka = 656.14 ± 9.20 M1) were relatively poor (Figure S1–S3).
Subsequently, the Cl transport activity of 1d and procarrier
2 across EYPCLUVslucigenin were monitored at em = 535

nm (ex = 455 nm) by applying a gradient of intravesicular NO3
and extravesicular Cl.[12] At comparable conditions, the
compound 1d showed significant Cl influx activity while
compound 2 was inactive (Figure 2C). The concentration-
dependent Cl influx study of 1d across EYPCLUVslucigenin
provided EC50 = 1.251 µM and n = 2.047 (Figure S16). The Hill
1
The H NMR titration of 1d with Br showed 1:1 and 1:2 binding
stoichiometries with Ka(1:1) = 103.31 ± 2.45 M1 and Ka(1:2) = 9.83
± 1.04 M1, respectively (Figure S5). The binding constant of 1d
with I could not be calculated precisely due to the insufficient
shifts of the Ha, Hb, and Hc protons (Figure S6).
The ion transport properties of compounds 1a-1d and 2 were
examined across large unilamellar vesicles (LUVs), which were
prepared from egg-yolk phosphatidylcholine (EYPC) lipids by
entrapping 8-hydroxypyrene-1,3,6-trisulfonate (HPTS, 1 mM)
dye in the buffer containing 1 mM HPTS, 10 mM HEPES and
100 mM NaCl (see ESI).[12] The collapse of the applied pH
gradient (pHin = 7.0 and, pHout = 7.8) upon addition of each
compound was monitored by measuring the change in HPTS
fluorescence at em = 510 nm (ex = 450 nm) with time. The
comparative ion transport activity of 1a-1d at concentration c =
400 nM provided ion transport activity sequence: 1d >> 1c > 1b
~ 1a which suggests the roles of N-H proton acidity as well as
logP values in the transport activity (Figure 2A). Compound 2
was inactive at this concentration, suggesting that it is a
procarrier of ion as its ONB group acts as a barrier for efficient
ion binding. The concentration profile of 1d provided the
effective concentration at 50% activity, EC50 = 0.219 µM (i.e.,
compound/lipid ratio = 0.327 mol%). The Hill coefficient, n = 1.88
indicates the involvement of two molecules of 1d in the active
transporter formation (Figure S9). For 1c, the EC50 and n values
were 0.768 µM and 2.72, respectively (Figure S10). EC50 and n
values of 1a and 1b could not be determined due to the
precipitation of these compounds at high concentrations.
Figure 2. Comparison of ion transport activities of 1a-1d and 2 (400 nM each)
across EYPCLUVsHPTS (A). Anion selectivity of 1d (340 nM) measured by
varying the external anions of EYPCLUVsHPTS (B). Comparison of Cl−
influx activity of 1d and 2 (2 µM each) across EYPCLUVslucigenin (C).
Comparison of Cl− influx activity of 1d (1.25 µM) in the absence and in the
presence of valinomycin (1.25 µM) (D).
The most active N-aryl-1H-indole-2-carboxamide 1d was
then studied for its ion selectivity across EYPC‒LUVsHPTS.
This article is protected by copyright. All rights reserved.

10.1002/anie.201900869
Angewandte Chemie International Edition
COMMUNICATION
coefficient value further confirmed the involvement of two
molecules of 1d in the active transporter formation. The Cl
influx activity of 1d in the absence and presence of valinomycin
were comparable, which further confirmed the antiport of anions
as the main transport mechanism. (Figure 2D). The variation of
extravesicular cation salts MCl (M = Li, Na, K, Rb, Cs) did
not show any change in transport activity further confirmed the
anion antiport mechanism (Figure S17).
Finally, the procarrier 2 and Cl− carrier 1d were evaluated for
their cytotoxic effects in MCF 7 cell line. When the cells were
incubated with the compound 2 for 24 h, no significant
cytotoxicity was observed (Figure 3C). Surprisingly, compound
1d also showed poor cytotoxicity. Interestingly, when the cells in
the culture were analyzed under fluorescence microscope,
significant precipitation of 1d (10 µM) was observed in the
extracellular media (Figure S22). Such precipitation was not
observed for the compound 2. Therefore, the poor cytotoxicity of
1d was attributed to the low cell permeability of the
compound.[29] To check whether the procarrier can be subjected
to photorelease within cells, the cells were incubated with
compound 2 for 4 h and then irradiated with 365 nm light for 5
minutes. The cells were then kept in the incubator for 20 more h
and monitored by standard MTT assay. The photoirradiated cells,
incubated with compound 2, showed pronounced cell death.
However, photoirradiated control cells were completely viable
(Figure 3C). The viability of the MCF 7 cells in the presence of in
situ generated by-product (o-nitrosobenzaldehyde 8) was
evaluated independently and the compound showed negligible
cytotoxicity compared to the photoreleased carrier 1d (Figure
S21). This data successfully established our proposition of
inducing cell death by photoactivating Cl− transport in cancer
cells.
Based on the experimentally determined Hill coefficient
value of ~ 2, the geometry-optimized structure of the [(1d)2+Cl−]
complex was obtained first by generating the most probable
conformation by using CONFLEX 8 program (Figure S23),[26]
and subsequently optimizing the generated conformation by
Gaussian 09 program[27] using B3LYP functional and 6-
311G(d,p) basis set.[28] The geometry optimized structure of
[(1d)2+Cl−] complex indicated that two receptor molecules are
orthogonally oriented around the central Cl− ion (Figure S24A).
The structure confirmed that each receptor participates in the
anion recognition by Nindole−Ha···Cl− (Nindole···Cl− = 3.22 Å) as
well as Namide−Hb···Cl− (Namide···Cl− = 3.38 Å) interactions (Figure
S24B). In addition to these, the Cortho···Cl− distance = 3.75 Å and
Cortho−Hc···Cl− bond angle ≈ 144.8o confirmed the presence of
Cortho−Hc···Cl− interaction between a receptor and the ion.
The assessment of the photolytic conversion of procarrier 2
to the active transporter 1d was confirmed by 1H NMR. The
solution of procarrier 2 in DMSO-d6 (5 mg in 0.5 mL) was
irradiated by 365 nm wavelength LED lamps with 5 min interval
of time for 45 min. The Ha signal of 2 at δ 11.78 disappeared
ꞌ
upon photoirradiation with the appearance of a new signal at δ
11.81 that corresponds to the indole Ha, indicating the release of
1d (Figure 3A). Similarly, the appearance of amide Hb signal at δ
10.52 ppm confirmed the cleavage of the ONB moiety from the
indole-2-carboxamide. The disappearance of the Hc signal at δ
ꞌ
5.45 ppm and the appearance of the new Hc signal at δ 11.66
ppm confirmed the formation of o-nitrosobenzaldehyde 8 as the
photocleavage product.[18c]
The successful release of the indole carboxamide 1d upon
photoirradiation of corresponding ONB protected derivative 2
prompted us studying the photoactivated membrane ion
transport by 2. For this purpose, the ion transport activities were
monitored across EYPCLUVsHPTS under the pH gradient
conditions (pHin = 7.0 and pHout = 7.8) after photoirradiating the
samples of 2 (380 nM) for varied duration (i.e., irradiation time, tR
= 0, 1, 2, 3 and 5 min) in the presence of the LUVs (Figure
S18A). During the ion transport experiments, the activities of
these samples (i.e., relative fluorescence intensity) at 190 s after
NaOH addition were compared by setting the HPTS
fluorescence of blank sample to 0 and that of 1d (380 nM) to
100. The nonirradiated sample of as-synthesized 2 was inactive
(FR = 1.7) as expected (Figure 3B). Upon irradiating 2 for tR
=
1min, the percent transport efficiency, FR = 42.3 was recorded. It
is interesting to note that up to 90.5% transport efficiency was
achieved by irradiating the sample of 2 for just 3 min. A sample
of 1% DMSO, when photoirradiated for 5 min under comparable
conditions, gave only FR = 0.1, which confirms that DMSO does
not destroys the integrity of the lipid bilayer membrane.
Figure 3. Phototriggered release of indole carboxamide 1d from procarrier 2
monitored by 1H NMR in DMSO-d6 recorded at intervals of 5 min (A). Percent
transport efficiencies of photoirradiated the samples measured relative to the
activity of 1d (B). Cell viability obtained from MTT assay upon addition 1d and
2 for 24 h in MCF 7 cells. Mean cell viability was represented from three
independent experiments (C).
This article is protected by copyright. All rights reserved.

10.1002/anie.201900869
Angewandte Chemie International Edition
COMMUNICATION
Tomás, I. Marques, P. J. Costa, V. Félix, P. A. Gale, Chem. Sci. 2013,
4, 103‒117.
In conclusion, we developed an o-nitrobenzyl (ONB) protected
N-aryl-1H-indole-2-carboxamide procarrier that features efficient
activation of membrane transport by cleaving its photolabile
protecting group. The ONB protected procarrier with p-CF3-
phenyl as the aryl group was inactive while the free carboxamide
was an efficient carrier of ion giving EC50 = 0.219 µM and Hill
coefficient, n = 1.88 when studied using EYPC‒LUVsHPTS.
The carrier also exhibited Cl−/anion antiport across lipid bilayer
membranes. The geometry optimized structure of the 2:1 carrier-
Cl− complex showed multivalent hydrogen bond interactions
involved in the recognition of the anion. The mechanism of ONB
[10] S.-K. Ko, S. K. Kim, A. Share, V. M. Lynch, J. Park, W. Namkung, W.
Van Rossom, N. Busschaert, P. A. Gale, J. L. Sessler, I. Shin, Nat.
Chem. 2014, 6, 885‒892.
[11] N. Busschaert, S.-H. Park, K.-H. Baek, Y. P. Choi, J. Park, E. N. W.
Howe, J. R. Hiscock, L. E. Karagiannidis, I. Marques, V. Félix, W.
Namkung, J. L. Sessler, P. A. Gale, I. Shin, Nat. Chem. 2017, 9,
667‒675.
[12] T. Saha, M. S. Hossain, D. Saha, M. Lahiri, P. Talukdar, J. Am. Chem.
Soc. 2016, 138, 7558‒7567.
[13] a) E. N. W. Howe, N. Busschaert, X. Wu, S. N. Berry, J. Ho, M. E. Light,
D. D. Czech, H. A. Klein, J. A. Kitchen, P. A. Gale, J. Am. Chem. Soc.
2016, 138, 8301-8308; b) N. Busschaert, R. B. P. Elmes, D. D. Czech,
X. Wu, I. L. Kirby, E. M. Peck, K. D. Hendzel, S. K. Shaw, B. Chan, B.
D. Smith, K. A. Jolliffe, P. A. Gale, Chem. Sci. 2014, 5, 3617-3626; c) A.
Roy, O. Biswas, P. Talukdar, Chem. Comm 2017, 53, 3122-3125; d) S.
V. Shinde, P. Talukdar, Angew. Chem. Int. Ed. 2017, 56, 4238-4242.
[14] a) Y. R. Choi, B. Lee, J. Park, W. Namkung, K.-S. Jeong, J. Am. Chem.
Soc. 2016, 138, 15319-15322; b) E. B. Park, K.-S. Jeong, Chem.
Comm 2015, 51, 9197-9200.
1
photo-cleavage was also confirmed by the H NMR study. The
photocleavage of the ONB group facilitated up to 90.5%
transport efficiency within
3
minutes of radiation. The
photorelease of carrier 1d from procarrier 2 within cancer cells
and the resulting cell death were also confirmed by MTT assay.
This rewarding outcome, based on our simple and innovative
concept, can be extended in photodynamic therapy for surface
cancer treatment and can also be adapted for deep-seated
cancer therapy employing endoscopes or optical fibers.
[15] Y. R. Choi, G. C. Kim, H.-G. Jeon, J. Park, W. Namkung, K.-S. Jeong,
Chem. Comm 2014, 50, 15305-15308.
[16] a) J. A. Barltrop, P. Schofield, Tetrahedron Lett. 1962, 3, 697‒699; b) J.
A. Barltrop, P. J. Plant, P. Schofield, Chem. Comm. 1966, 822‒823.
[17] a) A. P. Pelliccioli, J. Wirz, Photochem. Photobiol. Sci. 2002, 1,
441‒458; b) P. Klán, T. Šolomek, C. G. Bochet, A. Blanc, R. Givens, M.
Rubina, V. Popik, A. Kostikov, J. Wirz, Chem. Rev. 2013, 113, 119‒191.
[18] a) I. R. Dunkin, J. Gębicki, M. Kiszka, D. Sanín-Leira, J. Chem. Soc.,
Perkin Trans. 2 2001, 1414‒1425; b) X. Bai, Z. Li, S. Jockusch, N. J.
Turro, J. Ju, Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 409‒413; c) Y. V.
Il'ichev, M. A. Schwörer, J. Wirz, J. Am. Chem. Soc. 2004, 126,
4581‒4595.
Acknowledgements
This work was supported in part by collaborative grants from
SERB, DST, Govt. of India (Grant No. EMR/2016/001897) and
DBT (BT/HRD/NBA/36/06/2018). S.B.S. thanks DST, India for
the Inspire Fellowship. We thank Sopan V. Shinde for valuable
discussion.
[19] a) N.-C. Fan, F.-Y. Cheng, J.-a. A. Ho, C.-S. Yeh, Angew. Chem., Int.
Ed. 2012, 51, 8806‒8810; b) J. Liu, W. Bu, L. Pan, J. Shi, Angew.
Chem., Int. Ed. 2013, 52, 4375‒4379; c) W. S. Shin, J. Han, R. Kumar,
G. G. Lee, J. L. Sessler, J.-H. Kim, J. S. Kim, Sci. Rep. 2016, 6, 29018;
d) Y. Yang, J. Mu, B. Xing, Wiley Interdiscip. Rev. Nanomed.
Nanobiotechnol. 2017, 9, e1408.
Keywords: procarrier • photoactivation • anion binding • chloride
selectivity • apoptosis
[1]
a) L. H. Pinto, G. R. Dieckmann, C. S. Gandhi, C. G. Papworth, J.
Braman, M. A. Shaughnessy, J. D. Lear, R. A. Lamb, W. F. DeGrado,
Proc. Natl. Acad. Sci. U. S. A. 1997, 94, 11301‒11306; b) F. Lang, M.
Föller, K. S. Lang, P. A. Lang, M. Ritter, E. Gulbins, A. Vereninov, S. M.
Huber, J. Membr. Biol. 2005, 205, 147‒157.
[20] a) R. Reinhard, B. F. Schmidt, J. Org. Chem. 1998, 63, 2434‒2441; b)
W. Lin, D. Peng, B. Wang, L. Long, C. Guo, J. Yuan, Eur. J. Org. Chem.
2008, 2008, 793‒796; c) S. K. Choi, M. Verma, J. Silpe, R. E. Moody, K.
Tang, J. J. Hanson, J. R. Baker, Bioorganic Med. Chem. 2012, 20,
1281‒1290; d) S. Mo, Y. Wen, F. Xue, H. Lan, Y. Mao, G. Lv, T. Yi, Sci.
Bull. 2016, 61, 459‒467.
[2]
[3]
W. R. Sellers, D. E. Fisher, J. Clin. Invest. 1999, 104, 1655‒1661.
a) J. M. Brown, L. D. Attardi, Nat. Rev. Cancer 2005, 5, 231‒237; b) L.
Portt, G. Norman, C. Clapp, M. Greenwood, M. T. Greenwood, Biochim.
Biophys. Acta 2011, 1813, 238‒259.
[21] Marvin 5.8.0, ChemAxon, 2012 (http://www.chemaxon.com)
[22] a) BindFit v0.5. http://app.supramolecular.org/bindfit/ (accessed July
2017); b) P. Thordarson, Chem. Soc. Rev. 2011, 40, 1305‒1323.
[23] R. Benz, S. McLaughlin, Biophys. J. 1983, 41, 381‒398.
[24] L. Rose, A. T. A. Jenkins, Bioelectrochemistry 2007, 70, 387‒393.
[25] T. Saha, S. Dasari, D. Tewari, A. Prathap, K. M. Sureshan, A. K. Bera,
A. Mukherjee, P. Talukdar, J. Am. Chem. Soc. 2014, 136,
14128‒14135.
[4]
[5]
[6]
R. S. Y. Wong, J. Exp. Clin. Cancer Res. 2011, 30, 87.
F. H. Igney, P. H. Krammer, Nat. Rev. Cancer 2002, 2, 277‒288.
a) S. Matile, A. Vargas Jentzsch, J. Montenegro, A. Fin, Chem. Soc.
Rev. 2011, 40, 2453-2474; b) T. M. Fyles, Chem. Soc. Rev. 2007, 36,
335-347; c) P. V. Santacroce, J. T. Davis, M. E. Light, P. A. Gale, J. C.
Iglesias-Sánchez, P. Prados, R. Quesada, J. Am. Chem. Soc. 2007,
129, 1886-1887; d) O. A. Okunola, J. L. Seganish, K. J. Salimian, P. Y.
Zavalij, J. T. Davis, Tetrahedron 2007, 63, 10743-10750.
[26] a) H. Goto, S. Obata, N. Nakayama, K. Ohta, CONFLEX 8, CONFLEX
Corporation, Tokyo, Japan, 2012; b) H. Goto, E. Osawa, J. Am. Chem.
Soc. 1989, 111, 8950‒8951.
[7]
[8]
R. Pérez-Tomás, B. Montaner, E. Llagostera, V. Soto-Cerrato, Biochem.
Pharmacol. 2003, 66, 1447‒1452.
[27] M. J. Frisch, et al., Gaussian 09, Revision B.01; Gaussian, Inc.:
Wallingford, CT, 2010.
P. Manuel-Manresa, L. Korrodi-Gregório, E. Hernando, A. Villanueva, D.
Martínez-García, A. M. Rodilla, R. Ramos, M. Fardilha, J. Moya, R.
Quesada, V. Soto-Cerrato, R. Perez-Tomas, Mol. Cancer Ther. 2017,
16, 1224‒1235.
[28] A. D. McLean, G. S. Chandler, J. Chem. Phys. 1980, 72, 5639‒5648.
[29] a) D. Jornada, G. dos Santos Fernandes, D. Chiba, T. de Melo, J. dos
Santos, M. Chung, Molecules 2016, 21, 42; b) S. V. Gupta, D. Gupta, J.
Sun, A. Dahan, Y. Tsume, J. Hilfinger, K.-D. Lee, G. L. Amidon, Mol.
Pharm. 2011, 8, 2358‒2367.
[9]
a) N. Busschaert, M. Wenzel, M. E. Light, P. Iglesias-Hernández, R.
Pérez-Tomás, P. A. Gale, J. Am. Chem. Soc. 2011, 133, 14136‒14148;
b) S. J. Moore, C. J. E. Haynes, J. González, J. L. Sutton, S. J. Brooks,
M. E. Light, J. Herniman, G. J. Langley, V. Soto-Cerrato, R. Pérez-
This article is protected by copyright. All rights reserved.

10.1002/anie.201900869
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Layout 1:
COMMUNICATION
A photocleavable procarrier is
reported to release a transmembrane
chloride carrier. Such photorelease of
the active carrier in cancer cells
resulted in a remarkable cell death.
Swati Bansi Salunke, Javid Ahmad
Malla, Dr. Pinaki Talukdar*
Page No. – Page No.
Phototriggered release of
transmembrane chloride carrier from
an o-nitrobenzyl-linked procarrier
This article is protected by copyright. All rights reserved.