Anion Selective Ion Channel Constructed from a Self-Assembly of Bis(cholate)-Substituted Fumaramide

Article abstract of DOI:10.1021/acs.orglett.8b02115

The self-assembled ion channel constructed from bis(cholate)-substituted fumaramide is reported. Such ion channel formation was favored by intermolecular hydrogen bonding interactions among fumaramide moieties. Fluorescence kinetics experiments and planar bilayer conductance measurements confirmed the selective chloride transport through the channel. Theoretical calculations were done to confirm the hydrogen bonded self-assembly of fumaramides and chloride recognition within the cavity.

Full text of DOI:10.1021/acs.orglett.8b02115

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Anion Selective Ion Channel Constructed from a Self-Assembly of
Bis(cholate)-Substituted Fumaramide
†
Javid Ahmad Malla, Arundhati Roy, and Pinaki Talukdar*
Department of Chemistry, Indian Institute of Science Education and Research Pune, Pune, 411008, India
*
S Supporting Information
ABSTRACT: The self-assembled ion channel constructed from
bis(cholate)-substituted fumaramide is reported. Such ion channel
formation was favored by intermolecular hydrogen bonding
interactions among fumaramide moieties. Fluorescence kinetics
experiments and planar bilayer conductance measurements confirmed
the selective chloride transport through the channel. Theoretical
calculations were done to confirm the hydrogen bonded self-assembly
of fumaramides and chloride recognition within the cavity.
on transport proteins (channels, carriers, and pumps) play
due to the presence of terminal steric groups. Such orientation
of consecutive molecules allowed each molecule to form
hydrogen bonds with four neighboring molecules, and this
helped in the formation of a stable supramolecular ion channel
I
pivotal roles in facilitating the controlled movement of ions
1
across lipid membranes. The process ensures normal cellular
functions, e.g., cell proliferation, cell signaling, transepithelial
2
11
transport, signal transduction, etc. The natural ion channels
in the lipid bilayer membrane.
are very complex from their structural and functional aspects.
To solve these mysteries, chemists have developed diverse
synthetic molecules, which form either the transmembrane
It is obvious that if the steric crowding is moved away from
the fumaramide core, the flat-ribbon type of consecutive
molecules can be regained, and if the steric moiety can provide
distinct hydrophobic and hydrophilic faces, supramolecular
3
channels or mobile ion carriers and mimic both the structure
1
2
and functions of natural ion transport systems. Moreover,
barrel-stave ion channels can be formed. Herein, we
demonstrate the formation of anion selective barrel-stave ion
channel by a fumaramide system that is bis-functionalized with
a cholic acid-derived amine. The cholic acid backbone was
used as a side chain, because of its distinct hydrophobic β-face
for the van der Waals interactions with the membrane and a
hydrophilic α-face (three −OH groups are present on the α-
4
recent findings have suggested potential antibacterial and
5
anticancer activities of these systems. Such encouraging
outcomes have prompted a renewed interest in finding new
synthetic systems that can allow selective ion transport across
lipid bilayer membranes.
Fumaramide is a very captivating chemical moiety for self-
assembly, because of its specific conformation and directional
13
face) surface to provide the polar interior of the channel.
6
There are multiple reports about ion channel formation
utilizing adequately functionalized cholate moieties (with
intermolecular hydrogen bonding ability. The moiety offers
two hydrogen bond donors and two hydrogen bond acceptors
for efficient self-assembly. In contrast, its maleamide congener
is a poor self-assembling moiety, because of intramolecular
hydrogen bonding, which locks it in the folded conformation.
Therefore, photoisomerization of fumaramide to maleamide
1
3c−f
either methylated hydroxyl groups
or free hydroxyl
14
groups ); however, all these channels are reported to be
cation selective. We envisaged that the free hydroxyl groups of
each cholic acid part would help in the anion recognition,
through O−H···anion interactions. In addition, the alkene C
C of fumaramide moiety would participate in the anion
7
and the thermal isomerization of maleamide to fumaramide
were useful in constructing various types of molecular
1
1
8
9
10
recognition by anion−π interactions. The structure of the
designed fumaramide 1a is shown in Figure 1. The
corresponding maleamide 1b was also designed as a negative
control to appraise the importance of flat-ribbon self-assembly.
Syntheses of 1a and 1b were performed from cholic acid
involving the conversion of the terminal acid group to the
machines, drug delivery systems, peptide helicity control,
etc. However, the intermolecular hydrogen bonding ability of
fumaramide has received the least attention in the field of
transmembrane ion transport. We have very recently reported
1
4
that N ,N -dihexylfumaramide prefers the conventional flat-
ribbon-type hydrogen-bonded self-assembly in the solid
13g
1
1
amine by a reported protocol.
The cholic-acid-derived
state. In this assembly, each pair of consecutive molecules
is connected by two hydrogen bonds. However, the solid-state
amine was then coupled to fumaryl chloride 2a to give 1a in
1
4
structure of N ,N -dicyclohexylfumaramide reveal that each
pair of consecutive molecules are connected by a single
hydrogen bond, and these molecules are orthogonally oriented
Received: July 6, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02115
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
fluorescent dye, 8-hydroxy-1,3,6-pyrenetrisulfonate (HPTS)
and then applying a pH gradient of 0.8 unit (pH 7.0 and
in
15
pHout 7.8) with NaOH (see the SI). Under comparable
conditions, the activity of compound 1a (6 μM) was much
higher than that of 1b (6 μM) (see Figure 3A). The dose-
Figure 1. Structures and self-assembly processes of (A) fumaramide
1a and (B) maleamide 1b. (C) Description of the R group.
4
1% yield (see Scheme 1). The reaction of the same amine
with maleic acid 2b in the presence of EDC·HCl provided 1b
Figure 3. (A) Comparison of activities of 1a and 1b (6 μM
concentration) and photoisomerization of 1a to 1b (6 μM
concentration). (B) Anion selectivity of 1a 3 μM.
in 36% yield.
Scheme 1. Synthesis of Fumaramide 1a and Maleamide 1b
responsive ion transport activity of 1a and 1b provided the half
maximal activity (EC ) values of 3.1 μM, i.e., 4.6 mol %,
5
0
relative to lipid concentration (see Figure S3A in the SI) and
.8 μM, i.e., 14.6 mol %, relative to lipid concentration (see
9
Figure S3B in the SI), respectively. The fumaramide derivative
showed much better activity than the corresponding
maleamide derivative. The Hill coefficient n = 4 for 1a
indicated that the ion channel is formed by the self-assembly of
16
monomers in the lipid bilayer membrane. Furthermore, the
compound 1a was subjected to the photoisomerization of the
CC bond (see the SI) and ion transport activity was
checked. The activity of the resulting sample (6 μM) was
comparable to that of 1b (see Figure 3A). This information
further indicates that the trans conformation of the CC
bond provides efficient self-assembly to form the active ion
transport system. When the conformation of the CC bond
was changed to the cis form, the self-assembly was disturbed
because of the intramolecular hydrogen bonding of each
isomerized molecule.
At first, the morphological characterization of 1a was
performed using atomic force microscopy (AFM). The sample
of the compound, when prepared in THF (100 μM), showed
self-assembled fibril formation (see Figure 2A, as well as Figure
The ion transport activity of the fumaramide derivative
encouraged us to evaluate the ion selectivity and mechanism of
ion transport. To evaluate the preferential transport of cations
or anions through the channel, HPTS assay was used and the
transport activity was studied by varying the extravesicular
15,17
ions.
At first, ion transport of 1a was evaluated across
Figure 2. (A) Atomic force microscopy (AFM) image of 1a in THF
at 100 μM concentration. (B) Possible modes of self-assembly in
solution phase by 1a.
EYPC-LUVs with entrapped HPTS in the presence of
+
intravesicular NaCl and extravesicular isoosmolar MCl (M =
+
+
+
+
Li , K , Rb , and Cs ). In each case, the variation of external
cations did not show any significant differences in the transport
activity of 1a (see Figure S5 in the SI). This result rules out the
S1 in the Supporting Information (SI)). The observation can
be rationalized based on CO···H−N (among fumaramides)
and C−O···H−O (among hydroxyl groups present on the α-
face of cholates) hydrogen bond interactions, and van der
Waals interactions (among β-faces of cholates) resulting in the
fibrils (Figure 2B). These fibrils further self-assemble to form
hierarchical self-assembled structures. This interesting result
encouraged us to evaluate the ion transport activity of the
compound.
+
+
+
−
involvement of any cation (i.e., H /M antiport or M /OH
symport) in the ion transport process.
Next, the anion selectivity was checked by varying the
18
intravesicular as well as extravesicular anions, and changes in
the ion transport rate were examined when a pH gradient of
0.8 (pHin 7.0 and pHout 7.8) was applied. Considerable
changes in the ion transport rate were observed for different
−
−
−
−
−
−
NaX salts (X = Cl , Br , I , NO , and ClO ) (see Figure
3
4
The ion transport activities of 1a and 1b were evaluated
across egg-yolk phosphatidylcholine-based large unilamellar
vesicles (EYPC-LUVs), prepared by entrapping pH-sensitive
3B, as well as Figure S6 in the SI). The observed ion transport
activity sequence corroborated to the Cl ion selectivity of
compound 1a. The anion selectivity order seems to be
−
B
DOI: 10.1021/acs.orglett.8b02115
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
−
controlled by both the radius and hydration energy of anions
Cl ion (3.6 Å). The variation of current with voltage (I−V)
showed a linear relation in the range of −90 mV to +90 mV in
both symmetrical as well as unsymmetrical concentrations of
KCl (see Figure 4C), with the reversal potential to be −15 ± 2
mV. Thus, the channel shows ohmic behavior, which is
expected due to the non-dipolar nature of channel forming
molecules.
19
(
see Figure S7 in the SI). The ion selectivity studies
confirmed the participation of anions in the ion transport
mechanism. The hydrogen bonding interactions of an anion
with the hydroxyl groups of cholate and anion−π interactions
of the ion with the fumaramide moieties can be responsible for
its recognition within the lumen of the channel.
−
To confirm further the Cl ion selectivity of the fumaramide
These data encouraged us to construct a theoretical model
of the proposed channel. At first, the cholate moieties were
replaced with the propyl groups and an equivalent all-atom
model such a channel was constructed using four fumaramide
−
derivative 1a, the influx of Cl ions into vesicles was monitored
20
by lucigenin fluorescence assay following a reported protocol.
Ion transporter structure formed by compound 1a showed a
concentration-dependent quenching of lucigenin fluorescence,
16
molecules. The presumed structure was optimized using
−
23
24
confirming the Cl influx during transport (see Figure S8A in
MOPAC2012 software with the PM6-DH+ method. The
results indicate that fumaramide molecules are interlocked by
intermolecular CO···H−N hydrogen bonding interactions
the SI). To gain more insight into the mechanism of ion
transport, a modified method of the lucigenin assay was used.
The EYPC liposomes were prepared by entrapping NaCl (200
−
and recognition of Cl ion within the cavity is through
2
1
25
mM) and 1 mM of lucigenin dye. Then, isoosmolar Na SO
anion−π interactions (see Figure S11 in the SI). Sub-
2
4
−
was added to the extravesicular solution and Cl efflux was
sequently, a model of the full channel was constructed
−
monitored. A similar experiment was also performed with
involving four molecules of 1a and three Cl ions were placed
−
extravesicular isoosmolar NaNO . The results indicate that the
within the channel (one Cl near the fumaramide moieties and
3
2−
−
SO4 ion being highly hydrophilic is not transported easily by
a (see Figure S8B in the SI). However, the less polar NO3
two Cl either side, near the cholates). The rationale for
−
−
placing more than one Cl simultaneously within the channel
1
was motivated by the literature reports, which demonstrate the
ion is easily transported into the vesicles by 1a with the
26
−
presence of multiple ions within natural channels when more
than one ion binding site is present. Moreover, it was done to
reduce the time of optimization. The all-atom model was also
optimized using the same method (see Figure 5, as well as
concomitant efflux of Cl , suggesting that the antiport
mechanism of ion transport is operative.
The effect of 1a on the lipid bilayer membrane was checked
by using vesicles with entrapped ANTS-DPX dye. The EYPC-
LUV⊃ANTS-DPX (λ = 520 nm with λex = 353 nm) were
em
prepared according to the known procedure (see the SI). No
significant leakage of the dye from vesicles confirmed that the
compound neither destroys the integrity of the lipid bilayer
membrane nor large transmembrane pores are formed by the
22
compound (see Figure S9B in the SI).
To understand whether the ion transport is facilitated by
either transmembrane channel or mobile carrier formed by 1a,
the ionic conductance across the planar lipid bilayer membrane
was measured. In this experiment, two compartments (cis and
trans chambers) containing KCl solution (1 M) were separated
by a planar lipid bilayer composed of diphytanoyl phospha-
Figure 5. Side view of computationally optimized full-channel
noncovalent interactions among fumaramides and anion−π with
3b,19b
tidylcholine (diPhyPC) lipid.
When compound 1a (20
μM) was added to the trans-chamber, distinct single channel
opening and closing events were observed at different holding
potentials, indicating the formation of ion channels in the lipid
bilayer membrane (see Figures 4A and 4B). The single-channel
conductance of this pore was determined to be 40.06 ± 0.9 pS
in 1 M KCl solution. The diameter of the channel was also
determined as 4.1 ± 0.12 Å, which is close to the diameter of
−
two Cl ions (green) placed near the end and one at center of the
channel. Cyan-colored dots represent the centroids of CC bonds.
Figure S12 in the SI). The resulting supramolecular structure
showed that many of the hydroxyl groups of the cholate
moieties are participating in the inter-stave hydrogen bonding
interactions, (O···H−O distance = 1.7−1.9 Å), thus, stabilizing
the channel structure. Some of the hydroxyl groups form
hydrogen bonds with the Cl ions (i.e., OH···Cl− bond
−
−
distances of 2.0−2.5 Å). The interactions of the Cl with
surrounding fumaramides were also evident.
In conclusion, we have designed a bis(cholate)-substituted
fumaramide for barrel-stave supramolecular anion channel
formation. The positioning of the steric and rigid cholate
moiety away from the fumaramide core favored their
hydrogen-bonded barrel-stave self-assembly. The hydroxyl
groups of cholate moieties and alkene π-electron cloud of
fumaramides provided the polar channel interior, which is
suitable for anion binding. Fluorescence-based ion transport
experiments indicated the formation of a supramolecular ion
channel by fumaramide molecules. Such channel allowed the
antiport of anions with the highest selectivity toward chloride.
Figure 4. Single-channel conductance of 1a (20 μM) recorded (A) at
+
30 mV and (B) at −100 mV under symmetrical KCl solutions. (C)
I−V plots of 1a under symmetrical and unsymmetrical concentrations
of KCl.
C
DOI: 10.1021/acs.orglett.8b02115
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Planar bilayer conductance measurements confirmed the
formation of ion channels 4.1 ± 0.12 Å in diameter and
provided an additional support to chloride selectivity.
Geometry optimized structure of the proposed channel with
internal chloride ions confirmed the formation of CO···H−
N hydrogen-bonded channel and anion recognition by anion-π
interactions from electron-deficient CC moieties and
hydrogen bonding from the hydroxyl groups.
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ASSOCIATED CONTENT
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(PDF)
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AUTHOR INFORMATION
Corresponding Author
E-mail: ptalukdar@iiserpune.ac.in.
Barboiu, M. J. Am. Chem. Soc. 2016, 138, 426−432. (c) Hu, X.-B.;
Chen, Z.; Tang, G.; Hou, J.-L.; Li, Z.-T. J. Am. Chem. Soc. 2012, 134,
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8
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ORCID
Hussain, S.; Cooper, J. A.; Jurcek, O.; Sparkes, H. A.; Sheppard, D. N.;
̌
Pinaki Talukdar: 0000-0003-3951-4335
Present Address
†Institute of Bioengineering and Nanotechnology, 31 Bioplis
Way, The Nanos, Singapore 138669.
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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Yamamura, M.; Satake, A.; Kobuke, Y. Org. Biomol. Chem. 2004, 2,
2619−2623.
We thank SERB, Govt. of India (Nos. EMR/2014/000873B
and EMR/2016/001897) for funding. A.R. thanks UGC, India
for research fellowship. The authors are thankful to Dr. Pankaj
Mandal and his student, Dr. Sohini Sarakar, for their help
during the photoisomerization experiment.
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DOI: 10.1021/acs.orglett.8b02115
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