Carbazole-based bis-ureas and thioureas as electroneutral anion transporters

Article abstract of DOI:10.1080/10610278.2021.1946539

We report a series of easily accessible carbazole-based bis-ureas and thioureas as effective anion receptors and transporters. The compounds exhibit moderate Cl^? binding affinity in wet DMSO and Cl^? transport capabilities in phospholipid membranes predominantly through an electroneutral H⁺/Cl^? and anion exchange mechanisms.

Full text of DOI:10.1080/10610278.2021.1946539

Supramolecular Chemistry
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Carbazole-based bis-ureas and thioureas as
electroneutral anion transporters
Patrick Wang, Xin Wu & Philip A. Gale
To cite this article: Patrick Wang, Xin Wu & Philip A. Gale (2021): Carbazole-based bis-
ureas and thioureas as electroneutral anion transporters, Supramolecular Chemistry, DOI:
10.1080/10610278.2021.1946539
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SUPRAMOLECULAR CHEMISTRY
https://doi.org/10.1080/10610278.2021.1946539
Carbazole-based bis-ureas and thioureas as electroneutral anion transporters
Patrick Wanga, Xin Wua and Philip A. Galeb,a
aSchool of Chemistry, The University of Sydney, NSW, Australia; bThe University of Sydney Nano Institute (SydneyNano), The University of
Sydney, NSW, Australia
ABSTRACT
ARTICLE HISTORY
Received 15 May 2021
Accepted 17 June 2021
We report a series of easily accessible carbazole-based bis-ureas and thioureas as effective anion
receptors and transporters. The compounds exhibit moderate Cl− binding affinity in wet DMSO and
Cl− transport capabilities in phospholipid membranes predominantly through an electroneutral
H+/Cl− and anion exchange mechanisms.
KEYWORDS
Supramolecular chemistry;
anion transport; hydrogen
bonding; carbazole
Introduction
Hydrogen-bond-based discrete molecular anion
receptors have proven to be highly effective at facil-
itating the transport of a range of anions across both
synthetic and biological lipid bilayer membranes [1]
and are of interest due to their potential applications
in the treatment of diseases such as cystic fibrosis
[2,3] and cancer [4–7]. Some of the most effective
transporters reported to date are bis-ureas and
thioureas which may be constructed from simple or
more complex diamines [8], including ortho-
phenylenediamines [9–11], 1,8-diaminoanthracene
[12], diaminodecalins [13], and steroid-based scaffolds
[14]. The carbazole group has been shown to be an
effective anion-binding motif in a variety of receptors
to achieve high-affinity anion binding [15].
Chmielewski and co-workers have recently shown
that carbazole bis-amides and bis-thioamides derived
from 1,8-diaminocarbazole can function as anion
transporters [16,17]. In contrast, although analogous
carbazole bis-urea compounds were previously shown
to be effective carboxylate receptors [18], membrane
transport applications of these receptors have not
been explored. We anticipate that compared with
analogous anthracene or ortho-phenylene-based
receptors, the carbazole bis(thio)urea would offer an
additional hydrogen bond donor to the bound anion.
This provides an additional opportunity to tune the
anion-binding affinity, anion selectivity, and receptor-
phospholipid headgroup interactions, which are
important considerations for designing customised
anion receptors to target a specific therapeutic appli-
cation, such as cystic fibrosis or cancer [2,5]. We
therefore decided to investigate the anion complexa-
tion and membrane transport properties of a series of
CONTACT Philip A. Gale
chemistry.supramolecular@sydney.edu.au
Supplemental data for this article can be accessed here.
School of Chemistry, The University of Sydney, NSW 2006, Australia
© 2021 Informa UK Limited, trading as Taylor & Francis Group

2
P. WANG ET AL.
Figure 1. Structures of the carbazole compounds investigated in this work.
Scheme 1. Synthesis of carbazole compounds 1–4 and 6–9 from the starting carbazole diamine.
Scheme 2. Synthesis of carbazole transporters 5 and 10. Reagents and conditions: i) triphosgene, toluene, pentane, TEA, 70 °C, 2 h; ii)
thiophosgene, DCM, NaHCO3, RT, 12 h.

SUPRAMOLECULAR CHEMISTRY
3
carbazole-based bis(thio)urea containing anion trans-
porters (Figure 1).
(Table 1). In distinction to these results, the thioureas
showed much weaker Cl− binding affinities than the
analogous ureas, with K11 binding constants in the
range of 60–120 M−1. Despite the presence of an addi-
tional NH hydrogen bond donor, the Cl− affinities of the
carbazole bis-ureas are similar to the analogous ortho-
phenylenediamine-based bis-ureas while being substan-
tially lower than those of the anthracene and decalin-
based bis-ureas. This may be due to the relatively large
central binding cavity of the 1,8-diaminocarbazole scaf-
fold not being optimal for chloride binding. The lower
binding constants for the thioureas were attributed to
the larger sulfur atom distorting the planarity of the
compound, thus incurring an energy cost in order to
bind chloride in a favourable geometry. For all the com-
pounds, it was observed that the nitro- and bis-CF3
derivatives possessed the highest binding constants,
consistent with the electron-withdrawing nature of
these groups leading to the strongest enhancement of
the (thio)urea NH proton acidity.
Interestingly, while all (thio)urea NH protons shifted
downfield with increasing chloride concentrations initi-
ally, the carbazole NH proton stopped its downfield shift
at approximately 60 mM of TBA-Cl, before shifting
slightly upfield with further additions. Since this reversal
in the direction of shift was not observed with the (thio)
urea protons, we propose that at higher host/guest
ratios, the 1:1 receptor/chloride complex transformed
to a 1:2 complex which involves a conformational
change with the (thio)urea NH groups directed exo to
the 1:1 binding site (Figure 2).
Results and discussion
1,8-Diaminocarbazole was prepared according to the
literature methods [19]. Compounds 1–4 and 6–9 were
prepared from their respective iso(thio)cyanates and the
starting diamine in either acetonitrile or DMSO
(Scheme 1). Compounds 5 and 10 were prepared with
a variant of pre-existing literature methods [20], and the
iso(thio)cyanate intermediates were used without
further purification to obtain the para-SF5 compounds
(Scheme 2). Full synthetic details and characterisation
data are available in the ESI.
The chloride-binding properties of 1–10 were inves-
tigated using 1H NMR titration techniques in DMSO-d6
/0.5% H2O. Tetra-n-butylammonium chloride (TBA-Cl)
was titrated against the compounds, resulting in chemi-
cal shift changes of both (thio)urea NH protons and the
carbazole NH proton, indicative of chloride binding. The
change in the chemical shift of the NH peaks was fol-
lowed over the addition of 300 mM of TBA-Cl, and fitted
to a 1:1 and 1:2 model using BindFit v0.5 [21,22]. For all
receptors, both 1:1 and 1:2 models could be fitted to the
data; however, a 1:2 model was determined to be the
correct model (see Table S1 in the ESI). The receptors
show moderate binding to Cl−, with K11 binding con-
stants in the range of 100–300 M−1 for the urea receptors
Table 1. K11 and K12 binding constants (M−1) at 298 K of
receptors 1–10 with Cl− (added as TBA-Cl) in DMSO-d6/0.5%
H2O. BindFit errors are <5%. The data were fitted to a 1:2 model
as determined by the covariance of fit analysis (Table S1) and
also indicated by a reversal of shift direction for the carbazole
NH peak.
Anion transport properties of the compounds were
assessed using two assays: the Cl−/NO3− exchange assay
and the 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium
salt (HPTS) assay. The Cl−/NO3 assay was performed
−
using the chloride ion-selective electrode (ISE) method
[23]. Synthetic vesicles were prepared using POPC lipids
and loaded with a 487 mM NaCl solution, suspended in
a 487 mM solution of NaNO3, both buffered to pH 7.20 in
5 mM sodium phosphate salts. Chloride efflux induced
by the addition of a transporter, in DMSO, was recorded
over 300 s. EC50 values were calculated using the Hill
Cl− association constants
Compound
K11
K12
Compound
K11
K12
1
2
3
4
5
122
233
133
222
180
6
11
11
12
12
6
7
8
9
67
102
83
119
66
5
6
5
8
4
10
Figure 2. Proposed binding structures of the carbazole receptor to Cl− in a 1:1 fashion (left, low Cl− concentrations) or 1:2 fashion
(right, high Cl− concentrations). Hydrogen bonds are shown as dashed lines.

4
P. WANG ET AL.
Table 2. EC50 values and Hill coefficients (n) for compounds 1–
equivalent urea transporters [12]. In addition, the EWGs
also facilitated delocalisation of the charge of the bound
chloride anion, thus improving the overall lipophilicity of
the bound complex [24].
−
10 in the Cl−/NO3 assay. EC50 values were calculated using
a modified Hill equation to analyse incomplete Cl− efflux.
ISE NaCl/NaNO3 EC50 (mol%) and Hill coefficient (n)
Compound
EC50
n
Compound
EC50
n
The mechanism of anion transport was investigated
using a modified ISE assay involving valinomycin (VLN)
and monensin. POPC vesicles were loaded with 300 mM
KCl and suspended in a 300 mM solution of either
potassium gluconate or KNO3, buffered to pH 7.20 in
potassium dihydrogen phosphate. Gluconate cannot be
transported across the bilayer because it is large and
polar; thus, compound-mediated Cl− transport is depen-
dent on the coupling to either VLN or monensin. Both
cationophores transport K+ across the bilayer via differ-
ent mechanisms and indicate different modes of Cl−
transport.
1
2
3
4
5
14.7 4.9
1.02
6
7
8
9
2.56 0.30
0.81
0.108 0.012 0.91
0.208 0.036 1.15
0.94 0.19 0.78
0.0352 0.0026 2.11
0.03800 0.00073 2.20
0.0984 0.0088 1.92
0.0864 0.0041 1.81
0.357 0.059 0.74 10
VLN strictly uniports K+, thus coupling to VLN indi-
cates electrogenic transport of Cl− facilitated by the
tested transporter. Only compounds 1 and 6 showed
substantial activity in the presence of VLN. The chloride
uniport transport process required for coupling to VLN
(Figure 4) involves a step where the free transporter
diffuses across the lipid bilayer. This diffusion process is
hindered by the transporter binding to the phospholipid
head groups [25]. This uniport inhibition mechanism is
less likely for compounds 1 and 6 than for the remaining
compounds in the library that contain EWGs. To investi-
gate the transporter-phospholipid head group interac-
tions, a titration was performed on compounds 1 and 3
with POPC. This was performed in a 75% CDCl3/24.5%
DMSO-d6/0.5% H2O solvent system, following
Busschaert’s method [26]. Unfortunately, the data
Figure 3. Volume-dependent transport activity of compound 1
in the Cl−/NO3 assay at a fixed concentration of 2 mol%.
−
equation and a modified Hill equation (Equation S1 in
ESI), representing the concentration (as a mol % of the
total lipid concentration) of compound required to
obtain 50% efflux.
could not be fitted to
a simple binding model
(Figure 5). A qualitative analysis indicates that both
compounds show interactions with POPC; however, it
was not possible to determine which compound exhib-
ited stronger binding. Nevertheless, this evidence pro-
vides support for phospholipid head group interactions
with the transporters. Based on the chloride-binding
constants, we hypothesise that compounds 2–5 and 7–
10 will form stronger complexes with the phospholipid
head groups due to their higher acidity, leading to inhi-
bition of chloride uniport activity and hence the failure
to couple to VLN.
Compounds 1 and 6 had significantly lower transport
activities compared to the other compounds, with EC50
values more than 10 times higher than their respective
analogues (Table 2). This was partly due to solubility
issues with the receptor at concentrations >1 mol%.
The assay was modified by increasing the volume ratio
of DMSO (as the transport delivery medium) to 2% to
address the observed low solubility (Figure 3).
Furthermore, the electron-withdrawing groups (EWGs)
in compounds 2–5 and 7–10 improve their solubility in
the aqueous phase, improving the compounds’ ability to
solubilise between the hydrophobic and hydrophilic
environments. The improved aqueous solubility was
reflected in the EC50 values of compounds with EWGs
compared to the parent phenyl group. This relationship
was also observed with the thiourea compounds 7–10,
which exhibit lower EC50 values than the urea analogues.
This result was rationalised through the lipophilic nature
of the sulfur atom in the thiourea group, which is known
to increase overall transport activity when compared to
In contrast to VLN, monensin exchanges K+ and H+
across the phospholipid bilayer; thus, coupling to mon-
ensin is indicative of the electroneutral symport of Cl−/
H+ out of the vesicle facilitated by the anion transporter.
Proton efflux may be facilitated by the deprotonation of
the transporter, with the deprotonated form then diffus-
ing back across the bilayer before repeating the trans-
port cycle (Figure 4). All the compounds showed
coupling to monensin, indicating electroneutral H+/Cl−

SUPRAMOLECULAR CHEMISTRY
5
Figure 4. Modes of Cl− transport facilitated by coupling to monensin (left) and valinomycin (right). The transporter must be able to
freely diffuse back across the bilayer in electrogenic transport, which can be hindered by phospholipid head group interactions, but
not in electroneutral transport.
As all the compounds exhibited electroneutral H+/Cl−
co-transport, this mode of transport was further investi-
gated using the HPTS assay. In this assay, POPC vesicles
were loaded with a solution of 1 mM HPTS in 100 mM
KCl, buffered to pH 7.00 with 5 mM HEPES, and sus-
pended in an identical external solution without HPTS.
Anion transport was induced by the addition of an ali-
quot of NaOH, followed by the compound. Like the ISE
assay, the thiourea series exhibited lower EC50 values
than the urea analogues (Table 3), which could be attrib-
uted again to increased acidity of the thiourea NH pro-
tons. Compounds 2 and 7 showed the lowest EC50
values of 0.02 and 0.0008 mol%, respectively, highlight-
ing the propensity of the nitro-derivatives to be potent
Figure 5. Chemical shifts (ppm) of the carbazole NH and both
urea peaks in compounds 1 and 3 when titrated against up to
300 equivalents of POPC in 75% CDCl3/24.5% DMSO-d6/0.5% H2
O at 298 K. Peaks were referenced against CDCl3 (7.24 ppm).
anion transporters.
To minimise the impact of fatty acid flip-flop contri-
buting to the symport of H+/Cl−, the HPTS assay was
repeated at EC50 concentrations in the presence of
bovine serum albumin (BSA) [27]. Contrary to previous
studies [28], none of the compounds showed a decrease
in transport activity, while compounds 2–5 and 8–10
showed increased activity. This was unexpected as the
removal of fatty acids would typically decrease transport
activity as the fatty acid flip-flop mechanism of proton
transport is removed. Furthermore, increased activity
after fatty acid sequestration suggests that the com-
pounds bind to fatty acid carboxylate groups, which
compete with the chloride transport process. The rate-
limiting step in the H+/Cl− symport process can also be
probed by adding an ionophore, either the K+ ionophore
Table 3. EC50 values for compounds 1–10 in the HPTS assay.
EC50 values were calculated using the Hill equation.
HPTS EC50 (mol%)
Compound
EC50
Compound
EC50
1
2
3
4
5
0.112 0.019
0.02160 0.00066
0.057 0.013
0.22 0.12
6
7
8
9
0.118 0.010
0.000840 0.000043
0.00378 0.00051
0.008 0.014
0.068 0.019
10
0.0105 0.0014
symport as a viable pathway. It is unlikely that the trans-
porter directly co-transports H+/Cl− as HCl as the carba-
zole NH is not a likely protonation site, in addition to the
EWGs which would further enhance the acidity of the
overall compound.
VLN
or
the
H+
ionophore
carbonyl
cyanide m-chlorophenyl hydrazone (CCCP), where
enhanced activity in the presence of VLN and CCCP
indicates H+ > Cl− and Cl− > H+ selectivity, respectively.

6
P. WANG ET AL.
It should also be noted that for an anion transporter to
couple to either VLN or CCCP, the transporter needs to
be capable of facilitating H+ or Cl− uniport. A dramatic
acceleration of pH gradient dissipation by VLN was
found for compound 6, the unsubstituted thiourea, indi-
cating its high H+ > Cl− selectivity. For the analogous
urea, compound 1, the VLN-induced acceleration was
less pronounced, suggesting lower H+/Cl− selectivity,
which is rationalised based on its weaker H+ transport
activity due to the lower acidity of the urea group com-
pared to the thiourea group. For the remaining anion
transporters, VLN and CCCP did not significantly accel-
erate the pH dissipation and in some cases, decreased
activities were observed. As discussed previously, these
anion transporters are ineffective uniporters due to
transporter-phospholipid head group interactions,
which accounts for the failure of VLN and CCCP to accel-
erate the pH dissipation.
transport is required, such as in pH gradient disruption in
putative anti-cancer treatments.
Acknowledgments
P.W., X.W., and P.A.G. acknowledge and pay respect to the
Gadigal people of the Eora Nation, the traditional owners of
the land on which we research, teach and collaborate at the
University of Sydney. P.A.G. thanks the University of Sydney
and the Australian Research Council (DP200100453) for
funding.
Disclosure statement
The authors declare no competing interests.
Funding
To investigate the anion selectivity of the com-
pounds, a modified HPTS assay was carried out based
on our recently reported method [29]. POPC vesicles
were loaded with a solution of 1 mM HPTS in 100 mM
NaCl, buffered to pH 7.00 with 10 mM HEPES, and
suspended in different external solutions with an iso-
This work was supported by the Australian Research Council
[DP200100453].
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