Azobenzene-based chloride transporters with light-controllable activities

Article abstract of DOI:10.1039/c4cc07560a

Synthetic chloride transporters containing two urea groups linked through a diazobenzene spacer have been prepared and the trans-to-cis isomerization by light stimulation results in dramatic changes in the chloride transport activities across lipid and ce

Full text of DOI:10.1039/c4cc07560a

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ARTICLE TYPE
Azobenzene-based chloride transporters with light-controllable
activities†
Ye Rin Choi,a‡ Gyu Chan Kim, a‡ Hae-Geun Jeon,a Jinhong Park,b Wan Namkungb and
Kyu-Sung Jeonga*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
in 10% (v/v) DMSOꢀd6/CDCl3 saturated with water (<0.1%).7
Synthetic chloride transporters containing two urea groups
linked through a diazobenzene spacer have been prepared
and the trans-to-cis isomerization by light stimulation results
10 in dramatic changes in the chloride transport activities across
lipid and cell membranes.
50 The association constants were calculated by nonlinear squares
fitting8 of the titration curves plotting the downfield shifts of two
urea NH signals against the concentration of added
tetrabutylammonium chloride (Fig. S10ꢀ23†). The results are
summarized in Table 1. Trends are apparent. First, the cis isomers
55 show larger association constants than the corresponding trans
isomers by approximately one order of magnitude. This is
anticipated because four convergent NH protons in the cis
isomers can participate in the hydrogen bonding with a chloride
ion in a chelative manner but such a binding mode is not possible
60 in the trans isomers. According to Job’s plots, the cis isomers
formed 1:1 complexes with chloride ion (Fig. S10ꢀ23†).9 Second,
electronꢀwithdrawing substituents (CN, CF3, CO2R) at the para
positions of terminal phenyl rings increase the binding affinities
as anticipated based on the enhanced hydrogen bond donor ability
65 of the aromatic urea NH proton. In addition, the association
constant of thiourea 7 was slightly larger than that of the
corresponding urea 6. Third, relative affinities of some anions
were revealed using cisꢀ2 as a representative compound and the
association constants (Ka’s) were determined to increase in the
A variety of synthetic molecules that facilitate chloride transport
across lipid membranes by carrier or channel mechanism have
been reported in recent years.1,2 In particular, small carrier
15 molecules are attractive due to the therapeutic advantages in the
treatment of diseases related to defective chloride transport.3 A
unique feature of natural ion channels or transporters is that their
action can be precisely controlled by biological stimuli. However,
synthetic anion transporters that show stimuliꢀresponsive
20 transport activities are extremely rare.4,5 Herein, we describe for
the first time synthetic transporters that exhibit the
photoresponsive activities of transporting chloride ions across
lipid and plasma membranes. The transporters consist of two urea
binding sites linked through a diazobenzene spacer that can adopt
25 either trans or cis conformation in response to light stimulation.
The cis isomers are proven to be active mobile carriers for
chloride ions while the trans isomers are all ineffective.
–
70 order of HSO4– (410 Mꢀ1) > Cl– (310 Mꢀ1) > Br– (170 Mꢀ1) > NO3
(76 Mꢀ1) > I– (40 Mꢀ1) (Fig. S24†).
As a lightꢀresponsible unit, diazobenzene scaffold6 is chosen
because the transꢀtoꢀcis isomerization gives rise to dramatic
30 changes in the binding site and molecular shape of the
transporters. For this study, a series of diazobenzeneꢀbased diurea
compounds 1ꢀ7 have been first prepared and synthetic details are
described in the Supporting Information. Under ambient
conditions, all of the azo compounds prepared here existed in the
35 thermally stable trans isomers (> 98%) in the dark. Irradiation
with ultraviolet light (365 nm, 5 min) led to the corresponding cis
1
isomers as major components (90ꢀ96%) based on the H NMR
(400 MHz) integrations in DMSOꢀd6 (Table S1). Upon transꢀtoꢀ
cis isomerization, 1H NMR signals for CH protons on the internal
40 diazophenyl ring were characteristically shifted upfield (ꢀδ =
0.60 ~ 0.72) due to the ring current of adjacent diazophenyl rings
while the CH signals on the terminal phenyl rings remain nearly
constant (Fig. S1ꢀ9†). In addition, upon UV irradiation (30 sec)
of azo compounds, a πꢀπ* absorption band around 340 nm was
45 reduced significantly but an nꢀπ* band around 440 nm increased
(Fig. S1ꢀ9†) as a result of the transꢀtoꢀcis isomerization.
The association constants (Ka’s) between azo compounds and
Scheme 1. Molecular structures of compounds 1ꢀ7.
[journal], [year], [vol], 00–00 | 1
1
chloride ion were determined by H NMR titrations at 24 ± 1 oC
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DOI: 10.1039/C4CC07560A
Table 1. Association constants (Ka’s, M–1)a between compounds 1ꢀ
9 and tetrabutylammonium chloride, EC50 values (mol% to lipid)b
at 300 sec and Hill coefficients (n, mol% to lipid)b for compounds
1ꢀ9.
100
80
60
40
20
0
(a)
trans
Ka
cis
Compound
Ka
EC50
5.34
n
c
c
1
–
–
1.59
d
d
2
34
310
–
–
trans-1~9
& no carrier
c
c
3
–
–
4.62
1.24
d
d
0
100
200
Time (sec)
300
400
4
140
260
410
610
570
820
1000
1300
2800
5900
8400
> 104
–
–
5
2.35
1.13
0.19
0.38
0.15
1.08
1.07
1.48
0.90
1.22
100
80
60
40
20
0
(b)
cis-7, 9
cis-8
6
7
cis-6
cis-5
8
9
cis-3
cis-1
Association constants Ka (M–1) were measured in 10% (v/v)
DMSOꢀd6/CDCl3 saturated with water (< 0.1%) at 24 ± 1 C and
errors were within 15%. Determined using Origin 8.0 (Fig. S27ꢀ
33†). Not determined due to low solubility. Not determined due
to low activities.
a
o
b
cis-2, 4
c
d
no carrier
0
100
200
300
400
Time (sec)
The chloride transport activities of transꢀ and cisꢀazo
compounds 1ꢀ7 were measured using unilamellar 1ꢀpalmitoylꢀ2ꢀ
oleoylphosphatidylcholine (POPC) vesicles containing sodium
chloride (500 mM in 5 mM phosphate buffer at pH = 7.2). The
vesicles were suspended in an isotonic sodium nitrate solution
and the chloride efflux mediated by each compound (2 mol% to
lipid) was monitored using a chloride selective electrode. As
shown in Fig. 1a and 1b, the transport activities of trans isomers
are all negligible but the cis isomers exhibit moderate to high
10 activities of transporting chloride ions across a POPC membrane.
As mentioned, the cis isomers bind chloride ion more strongly
than the trans isomers, which is in part responsible for
differences in the transport activities between trans and cis
isomers. In addition, the trans isomer has a planar, extended
15 structure while the cis isomer adopts a nonplanar, concave
conformation with a relatively large dipole moment (~ 3D)
around the diazo bond.10 These structural features could affect the
partitioning and shuttling rate of the isomers, both of which are
important variables to determine the transport activity.
20 Furthermore, chloride ion can be entrapped in the middle of the
binding site surrounded by four phenyl planes in the cis isomer.
This may decrease the contact area of the bound chloride ion with
the lipid surface, which may speed up the shuttling movement of
the complex in the lipid bilayer. It was demonstrated by Davis
25 and Judd that a cholaphane with a more enclosed binding site
showed the increased activity of chloride transport across a lipid
membrane compared to acyclic analogues.11
100
80
60
40
20
0
(c)
irradiated
5
365 nm
for 20 sec
without
irradiation
no carrier
600
0
100
200
300
Time (sec)
400
500
Fig. 1 Plots of chloride efflux against time (sec) across a POPC
membrane. (a) Chloride effluxes facilitated by trans isomers 1ꢀ9 (2
mol% to lipid). (b) Chloride effluxes facilitated by cis isomers 1ꢀ9 (2
mol% to lipid). (c) The in situ activation of chloride efflux by UV
irradiation (365 nm, 20 sec) of transꢀ7 after 2 min transport.
Chloride effluxes from vesicles containing NaCl (500 mM in 5 mM
phosphate buffer at pH = 7.2) into a NaNO3 (500 mM in 5 mM
phosphate buffer at pH = 7.2) solution were measured using a
chloride selective electrode.
relative binding affinities towards chloride ion.12 On the other
hand, cisꢀ3 with methyl ester substituents has moderate transport
activity but cisꢀ4 with longer butyl esters is inactive despite the
40 same binding affinity (Fig. 1b). Lipophilic groups were in general
known to improve the transport activity of carriers13 but negative
effects were observed when the carriers became too lipophilic,14
possibly due to the poor deliverability of the carriers into the lipid
bilayer and/or the reduced shuttling rate in the membrane. It was
45 also suggested that the transport activity depends on the relative
position and balance of lipophilic appendages in the carriers.15
Using compound 7 with the highest chloride transport activity, it
was examined that the chloride transport could be switched on by
the in situ irradiation without pretreatment of the carrier into the
50 cis isomer (Fig. 1c). The transport activity of thermally stable
transꢀ7 was negligible prior to irradiation. When the solution was
The relative transport activities of cis isomers have been
quantitatively compared by Hill analyses based on the EC50
30 values that correspond to the concentrations needed to achieve
50% chloride transport in 300 sec. As summarized in Table 1, the
activities of the cis isomers strongly depend on the nature of
substituents at the para positions of the terminal phenyl rings. For
example, the EC50 values (mol% to lipid) decrease in the order of
35 R = H (5.34) > CO2CH3 (4.62) > CF3 (2.35) > ureaꢀCN (1.13) >
thioureaꢀCN (0.19), which nicely correlates to the trend of
2
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Scheme 2. Molecular structures of compounds 8 and 9.
irradiated for 20 sec by UV (365 nm) light during the transport
experiment in 120 sec, the chloride transport was suddenly
activated as a result of the in situ isomerization of transꢀ7 to cisꢀ7.
To improve further the chloride transport activity based on the
modeling studies, we prepared two more azo compounds 8 and 9
wherein the urea groups were located at the meta position to the
diazo unit. Compared with the corresponding paraꢀlinked
analogues 6 and 7, compounds 8 and 9 were determined to form
more stable complexes with chloride ion (Table 1). As a
5
10 consequence, cisꢀ8 and cisꢀ9 showed better transport activities
with the EC50 values of 0.38 and 0.15 mol% to lipid, respectively.
The activities of the trans isomers are however negligible.
Fig. 2 Fluorescence changes of YFP transfected in FRT cells. (a)
Time dependent fluorescence changes of YFP in FRT cells treated
cisꢀ9 (30 µM). ꢀI = It – I0 when I0 is initial fluorescence intensity
and It is fluorescence intensity at time. (b) Proportional fluorescence
changes of YFP after 2 h exposure to each isomer of 6ꢀ9. The
control (Ct) fluorescence intensities calibrated to 100%. (c) Pseudoꢀ
color images of YFP fluorescence at 0 and 2 h after addition of each
isomer of 8 and 9.
As a representative example, cisꢀ6 was chosen to reveal whether
azo compounds act as mobile carriers or channels. The transport
15 experiment was repeated in vesicles composed of 7:3
POPC/cholesterol molar ratio. Cholesterols with a rigid molecular
framework presumably decrease the fluidity of the membrane to
slow down the shuttling rate of a mobile carrier,16 which results
in reducing the transport activity. Indeed, the transport rate of cisꢀ
20 6 was slightly reduced in a 7:3 POPC/cholesterol membrane (Fig.
S25†), supporting the carrier mechanism. In addition, Hill
coefficients on the chloride transport of 1ꢀ9 were in the range of n
= 0.9 to 1.6 (Table 1), suggesting also that azo compounds
function as monomeric transporters.17
25 Next, the chloride efflux from vesicles to a sodium nitrate
solution may occur via Cl–/NO3– antiport and/or Cl–/Na+ symport.
To differentiate them, the transport experiment was carried out in
a sodium sulfate solution (166 mM in 5 mM phosphate buffer at
pH = 7.2). Here, possible Cl–/SO42– antiport is negligible because
30 sulfate ion is too hydrophilic to be transported by small carriers
although synthetic molecules capable of transporting the sulfate
ions were reported recently by Gale and coꢀworkers.18 The
chloride efflux mediated by cisꢀ6 was very efficient in a sodium
nitrate solution but was extremely sluggish in a sodium sulfate
35 solution (Fig. S26†), confirming that the chloride transport occurs
mostly via Cl–/NO3– antiport.
45 F46L/H148Q/I152L, a mutant EYFP.19 The FRT cells were
stably transfected with the halide sensor YFP and the effects of 6ꢀ
9 on the intracellular chloride concentration were monitored by
the fluorescence change of the YFP.20 First, the cells were
exposed to the most efficient transporter cisꢀ9 (30 ꢁM) and the
50 YFP fluorescence changes were monitored every 10 min. The
fluorescence intensity was gradually decreased and reached a
plateau in 90 min (Fig. 2a) as a result of the facilitated influx of
extracellular chloride ions into the FRT cells. Based on this
observation, cells were treated with each of trans and cis isomers
55 of compounds 6ꢀ9 (30 ꢁM), and the YFP fluorescence intensities
were measured and compared after 2 h (Fig. 2b, 2c and Fig.
S34†). The YFP fluorescence in FRT cells was greatly reduced
on exposure to cisꢀ8 or cisꢀ9 with respect to control (Ct), while no
change was observed with all the trans isomers, cisꢀ6 and cisꢀ7.
60 These results clearly indicate that cisꢀ8 and cisꢀ9 induce chloride
influx in living cells. An important difference was realised
between the chloride transport experiments on live cells and on
POPC vesicles. In vesicle experiments, paraꢀlinked analogues
cisꢀ6 and cisꢀ7 were very efficient in the chloride transport, but
65 no activity was observed in live cells. Only metaꢀlinked
analogues cisꢀ8 and cisꢀ9 showed chloride transport activities in
in vitro experiment regardless of functional groups, thiourea and
urea. This is possibly attributed to the intrinsic difference in the
permeability of these molecules between POPC and plasma
70 membranes. 21
To investigate whether effective POPC chloride transporters 6ꢀ9
are able to transport chloride ions across the plasma membrane of
mammalian cells, we examined changes in intracellular chloride
40 concentration in Fischer rat thyroid epithelial (FRT) cells. The
FRT cells were chosen because of their low basal halide transport
activity, rapid growth on uncoated plastic plates, and stable
expression of transfected cDNAs. The intracellular concentration
In conclusion, we have demonstrated for the first time that
of chloride was measured using
a halide sensor YFPꢀ
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5
For pHꢀresponsive ion carriers, see: (a) P. V. Santacroce, J. T. Davis,
M. E. Light, P. A. Gale, J. C. IglesiasꢀSánchez, P. Prados and R.
Quesada, J. Am. Chem. Soc., 2007, 129, 1886–1887. (b) O. A.
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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 and P. A. Gale,
Chem. Sci., 2014, 5, 3617–3626.
synthetic mobile carriers are able to exhibit the photoswitchable
activity of facilitating chloride transport across lipid and plasma
membranes. Thermally stable transꢀazo compounds are
practically inactive but their activities can be switched on by the
UV irradiation which results in isomerising them into the
corresponding cis compounds. This study provides us with an
opportunity to develop synthetic molecules that can transport
chloride ions to a specific target in living systems through
spatiotemporal control using light.
70
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6
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10 This study was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government (MEST)
o
7
8
9
During titrations for 1~2 h at 24 ± 1 C, isomerization between cis
(NRFꢀ2013R1A2A2A05005796).
G.C.K.
and
H.ꢀG.J.
and trans compounds is negligible and their ratios remain constant.
K.ꢀJ. Chang, Y.ꢀJ. An, H. Uh and K.ꢀS. Jeong, J. Org. Chem., 2004,
69, 6556–6563.
acknowledge the fellowship of the BK 21ꢀplus program and
Y.R.C. acknowledges the fellowship of the National Junior
15 Research (NRFꢀ2013H1A8A1003806).
According to Job’s plots, trans isomers also formed 1:1 complexes
1
with chloride ion. Owing to the low solubilities of trans isomers, H
NMR titrations and Job’s plots were conducted with diluted
concentrations (0.5ꢀ4 mM) in 10% (v/v) DMSOꢀd6/CDCl3 saturated
with water (<0.1%). Under these conditions, 1:1 complexes may be
predominant. However, it cannot be ruled out the formation of 1:2 or
Notes and references
a Department of Chemistry, Yonsei University, Seoul, 120ꢁ749, Korea.
Fax: (+)82ꢁ2ꢁ364ꢁ7050; Tel: (+)82ꢁ2ꢁ2123ꢁ2643 ; Eꢁmail:
ksjeong@yonsei.ac.kr
oligomeric n:n (trans/Cl–
) complexes in a more concentrated solution.
20 b College of Pharmacy, Yonsei International Campus, Incheon, 406ꢁ840,
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21 A referee suggests that another possibility for differences in the
cellular transport activities of analogous cisꢀ7 and cisꢁ9 is the
selective binding of the former to a protein in the cell membrane.
Alternatively, the decrease in YFP fluorescence is possibly due to
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