A DNA-inspired synthetic ion channel based on G-C base pairing

Article abstract of DOI:10.1021/ja510470b

A dinucleoside containing guanosine and cytidine at the end groups has been prepared using a modular one-pot azide-alkyne cycloaddition. Single channel analysis showed that this dinucleoside predominantly forms large channels with 2.9 nS conductance for the transport of potassium ions across a phospholipid bilayer. Transmission electron microscopy, atomic force microscopy, and circular dichroism spectroscopy studies reveal that this dinucleoside can spontaneously associate through Watson-Crick canonical H-bonding and π-π stacking to form stable supramolecular nanostructures. Most importantly, the ion channel activity of this G-C dinucleoside can be inhibited using the nucleobase cytosine.

Full text of DOI:10.1021/ja510470b

Subscriber access provided by CORNELL UNIVERSITY
Communication
A DNA-Inspired Synthetic Ion Channel Based on G-C Base Pairing
Rabindra Nath Das, Y. Pavan Kumar, Ole Mathis Schütte, Claudia Steinem, and Jyotirmayee Dash
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja510470b • Publication Date (Web): 16 Dec 2014
Downloaded from http://pubs.acs.org on December 18, 2014
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
A DNA-Inspired Synthetic Ion Channel Based on G-C Base
Pairing
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Rabindra Nath Das,†‡ Y. Pavan Kumar,‡ Ole Mathis Schütte,§ Claudia Steinem*§ and
Jyotirmayee Dash*†,‡
†Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkataꢀ700032,
India, ‡Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata Mohanpur,
§
West Bengal 741252, India, Institute of Organic and Biomolecular Chemistry, Georg August University Göttinꢀ
gen, Tammannstr. 2, 37077 Göttingen, Germany
Supporting Information Placeholder
tate the transport of ions. Guanosine has ionophoric properꢀ
ties and in the presence of potassium ions guanosine can
assemble to form Gꢀquadruplexes,10ꢀ12 while guanosine and
cytidine can be stabilized by WatsonꢀCrick hydrogen
bonds.13 Synthetic analogues of the natural GꢀC hydrogen
bonding motifs have been used to assemble supramolecular
structures.13 Additionally, cytidine diphosphate diacylglycꢀ
erol is the most common natural nucleolipid, which plays an
important role in the biosynthesis of membrane phosphoꢀ
lipids.14
ABSTRACT: A dinucleoside containing guanosine and
cytidine at the end groups has been prepared using a moduꢀ
lar oneꢀpot azideꢀalkyne cycloaddition. Single channel analꢀ
ysis showed that this dinucleoside predominantly forms
large channels with 2.9 nS conductance for the transport of
potassium ions across a phospholipid bilayer. Transmission
electron microscopy (TEM), atomic force microscopy (AFM)
and circular dichroism (CD) spectroscopy studies reveal
that this dinucleoside can spontaneously associate through
WatsonꢀCrick canonical Hꢀbonding and πꢀπ stacking to
form stable supramolecular nanostructures. Most imꢀ
portantly, the ion channel activity of this GꢀC dinucleoside
can be inhibited using the nucleobase cytosine.
In an attempt to prove the principle, herein we delineate a
modular access to the synthesis of a GꢀC dinucleoside via a
triazole linkage that can spontaneously assemble into stable
supramolecular nanostructures with the potential to form
ion channels in the membrane and whose conductance can
be selectively inhibited. For the synthesis, we incorporated
an acetylene unit in guanosine and an azide unit in cytidine
(Scheme 1, Supporting Information, S.I., Scheme S1). The
guanosine alkyne 1 underwent smooth Cu(I)ꢀcatalyzed azꢀ
ideꢀalkyne 1,3ꢀdipolar cycloaddition15 with the azido cytiꢀ
Natural ion channels are essential for life processes.1 They
are highꢀmolecular weight pore forming proteins that proꢀ
mote transport of ions across biological membranes. Inꢀ
spired by nature, there is an increased interest in developing
artificial ion channels which can mimic the fundamental
functions of natural ion channels.2ꢀ5 The creation of artificial
ion channels may improve our understanding of natural ion
channels and open up possible applications in materials and
biological sciences. Therefore it is important to devise easily
synthesizable, costꢀeffective and bioꢀcompatible transmemꢀ
brane channels with tailored physiological properties.
dine
2 using Naꢀascorbate and CuSO4•5H2O in tꢀ
BuOH/H2O (1:1) as solvent to give the triazole linked guaꢀ
nosineꢀcytidine dinucleoside 3 (GꢀC) in 55% yield.
O
NH2
N3
N
NH
N
O
O
N
N
NH2
O
N
O
O
HO
O
O
While peptide based synthetic ion channels have been
widely studied,2,3,5 only a few examples of synthetic ion
channels based on nucleobases have been reported.6ꢀ8 Mostꢀ
ly guanine derivatives have been demonstrated to form synꢀ
thetic ion channels in the membrane.7,8 In these examples,
guanine can selfꢀassemble in the presence of cations to form
macrocyclic Gꢀquartets which further stack to form Gꢀ
quadruplexes.7,8 Recently, Langecker et al reported that
selfꢀassembled DNA nanostructures can form ion channels
in the lipid bilayer.9
HO
OH
2
1
CuSO4
sodium ascorbate
tBuOH: H2O (1:1)
rt, 55%
O
N
N
HN
H2N
N
N
O
NH2
N
O
N
N
O
O
O
3 (G-C)
O
N
O
HO
HO
OH
We intended to utilize selfꢀcomplementary guanosine (G)
and cytidine (C) nucleobases to program biomimetic suꢀ
pramolecular structures in the membrane, which can faciliꢀ
Scheme 1. Modular synthesis of a G-C dinucleo-
side.
To test its ability to transport the physiologically imꢀ
portant cation K+ across membranes, voltageꢀclamp experꢀ
iments were employed on planar solventꢀfree bilayers in 1 M
KCl, phosphate (2 mM) buffer at pH 7.4. Planar solventꢀfree
bilayers were produced by spreading giant unilamellar vesiꢀ
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
cles (GUVs) consisting of 1,2ꢀdiphytanoylꢀsnꢀglyceroꢀ3ꢀ
Next, we investigated if GꢀC dinucleoside can induce reꢀ
lease of carboxyfluorescein (CF) from vesicles.19 GꢀC dinuꢀ
cleoside (4 X 25 ꢁM in DMSO) was added to the CF encapꢀ
sulating vesicles and the fluorescence intensity was moniꢀ
tored over time at 520 nm (excitation at 492 nm). A release
of the dye from the vesicles would increase its fluorescence
intensity and indicate pore formation. Figure 2 shows the
fluorescence time course of CFꢀcontaining LUVs over a time
period of 130 min. No release of CF was observed in the
absence of GꢀC dinucleoside or using DMSO as a control. In
the presence of GꢀC dinucleoside, a slow increase in fluoresꢀ
cence intensity was observed indicating the formation of
pores. The value after disruption of the vesicles using Triꢀ
tonꢀX corresponds to 100% release of CF. GꢀC dinucleoside
induced CF release was concentration dependent and apꢀ
proximately 23% of the entrapped carboxyfluorescein was
released at 100 ꢁM concentration of GꢀC after 2 h.
1
2
3
4
5
6
7
8
phosphocholine (DPhPC) and cholesterol (9:1) on a small
aperture in glass.16 Current traces were recorded after inserꢀ
tion of GꢀC into the membrane. Similar to the natural ion
channels, synthetic ion channels formed by the GꢀC diꢀ
nucleoside exhibit conductance values that appeared and
disappeared for several minutes (Figure 1, Figure S1ꢀa). The
histogram of conductance values showed existence of two
distinct conductance levels, one around 0.64 nS and one
around 2.9 nS. It is noteworthy that largeꢀconductance
channels were present in a majority of experiments (80%)
with conductance values of 1ꢀ8 nS with a mean value of 2.9
nS. GꢀC also formed channels (~20%) with conductance
values of 0.1ꢀ1 nS with a mean value of 0.64 nS. The presꢀ
ence of distinct channel types indicates the formation of
two different species in the membrane. The lifetime of GꢀC
channels spans a wide range from <10 ms to 5 s (Figure S1ꢀ
b). Control experiments showed no measurable conductꢀ
ance in the absence of the GꢀC dinucleoside. No current
changes in the presence of GꢀC were observed using BaCl2,
which suggests an influence of the electrophoretic mobility
of the cation or the inability of the GꢀC channels to adapt
the cation.17
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Transmission electron microscopy (TEM) and atomic
force microscopy (AFM) images were taken to investigate
possible structure formation due to the selfꢀassembly of GC
dinucleoside. TEM imaging revealed coiled helical filamenꢀ
tous nanostructures in addition to linear nanoꢀfibers of
width 4.8 nm and ranging up to a few micrometers (Figure
S3). The primary nanofibrils were even interconnected to
form thick bundles up to 14.9 nm in width. The formation of
the higher order structures is a result of the Hꢀbonded headꢀ
toꢀtail polymeric ability of the dinucleoside as it contains
guanosine and cytosine at its two ends (Figure 5). The forꢀ
mation of helical nanoꢀfilaments and subsequent bundle
formation in TEM may be explained based on iterative inꢀ
termolecular Hꢀbonding between complementary nucleoꢀ
bases in combinations with πꢀπ stacking and hydrophobic
interactions (Figure 5), where the triazole ring may contribꢀ
ute to enhanced πꢀπ interactions between two adjacent
stacks. Further AFM analysis supported formation of a netꢀ
work of crossꢀlinked fibrils of the GꢀC with an average
height of 5.5 nm (Figure 3 and Figure S4). PXRD patterns
for GꢀC exhibited a broad peak at 2θ = 28.9 (d = 0.33 nm),
which could be related to guanosineꢀcytidine stacking beꢀ
tween two adjacent vertical GꢀC stacks (Figure S5). Dynamic
light scattering (DLS) also confirmed the aggregation beꢀ
havior of the dinucleoside in solution with an average diamꢀ
eter of ~28 nm (Figure S6).
Figure 1. (a) Traces of singleꢀchannel recordings obꢀ
tained by the insertion of GꢀC dinucleoside (20 ꢁM) to the
cis side of the chamber after the planar bilayer was formed.
Distribution of the two distinct conductance states (1557
events) of GꢀC dinucleoside: (b) 0.1ꢀ1 nS (mean conductance
0.64 ± 0.05 nS) for the conductance trace shown in the top
panel (a); (c) 1ꢀ8 nS (mean conductance 2.9 ± 0.4 nS) for
the conductance trace shown in the bottom panel of (a).
Figure 3. (a) TEM image; scale bar: 50 nm and (b) AFM
image; scale bar: 200 nm.
Spectroscopic studies were performed in order to get inꢀ
sights into the supramolecular assemblies of GꢀC in the abꢀ
sence or presence of LUV suspensions (Figure 4). The UVꢀ
Vis spectrum of GꢀC dinucleoside showed peaks at 247 nm,
278 nm corresponding to the πꢀπ stacking of the nucleobasꢀ
es. Observation of a shoulder at 306 nm was attributed to
the πꢀπ stacking of the triazole ring. The addition of LUV
suspensions to a solution of GꢀC dinucleoside resulted in a
marginal hypochromicity of the absorption peak at 247 nm
Figure 2. Plot of percentage of CF release from lipoꢀ
somes (DPhPC /cholesterol = 9:1) induced by the GꢀC dinuꢀ
cleoside (4 X 25 ꢁM) as a function of time. The black arrows
indicate the addition of GꢀC. Complete release of CF was
determined after destroying the liposomes with Triton Xꢀ
100 (red arrow).
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
along with a blue shift of ca. 5 nm, suggesting its interaction
assembly of the GꢀC monomer may just form cyclic dimers
1
2
3
4
5
6
7
8
with the membrane. Circular dichroism (CD) spectroscopy
revealed a negative peak at 235 nm, a positive peak at 250
nm and a broad positive peak at 288 nm in accordance with
the absorption peaks in the corresponding UV spectra, sugꢀ
gesting presence of supramolecularly oriented chirality of
the GꢀC irrespective of the LUVs (Figure 4b). Moreover, the
UV and CD prediction spectra are quite comparable with the
experimental UV and CD spectra (Figure S10).
(Figure 5dꢀC). The cyclic dimers can further selfꢀassemble
sideꢀbyꢀside to form aggregated pores (Figure 5dꢀF, Figure
S9).
As the guanosine (G) and cytidine (C) motifs are involved
in Hꢀbonding, the triazole ring and the ester carbonyl may
weakly coordinate to the potassium ion and contribute to
the K+ transport. The slow release of CF can be rationalized
as follows: i) the size of CF (~1 nm) is close to that of these
channels and ii) the negative charge of CF may lead to reꢀ
pulsion due to the presence of the partially negative charged
carboxyl group in the GꢀC dinucleoside. The opening and
closing of the channels at an applied potential may be due to
the dynamic conformational change in the selfꢀassembly of
GꢀC in the membrane. The observed smaller conductance
values (0.1ꢀ0.5 nS) may be explained based on the forꢀ
mation of a ‘barrelꢀrosette’ model using Gꢀquartets as the
basic building blocks (Figure 5c).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Molecular disassembly was investigated primarily by two
approaches; (i) competition with guanosine and (ii) inhibiꢀ
tion with cytosine. Ion channel blockers/inhibitors are
compounds which bind to the pores or break the selfꢀ
assembly and inhibit the activity of a channel in the memꢀ
brane. When a solution of guanosine (5 mM) was added to
the GꢀC ion channels in the lipid bilayer, the GꢀC ion chanꢀ
nels conductance of 2.9 nS disappeared and much smaller
conductance values were monitored with a mean conductꢀ
ance value of 0.24 nS and a mean open life time of 0.71 s
(Figure S2). This smaller conductance can be attributed to
the formation of competitive Gꢀquadruplex type ion chanꢀ
nels by guanosine.7,8 However, a complete disappearance of
the GꢀC ion channel conductance was observed when excess
cytosine (5 mM) was added to the lipid bilayers (Figure 6b).
CD spectroscopy was used to investigate the structural
changes of the GꢀC channels upon addition of guanosine
and cytosine (Figure S7). As the concentration of guanosine
was increased, a reduction in the molar ellipticity of all the
peaks was observed in a dose dependent manner till the
pores are populated with Gꢀquadruplex scaffold in the presꢀ
ence of K+.8,11 Upon titration with cytosine, several peaks
were observed with the disappearance of the negative peak
at 235 nm and a positive peak at 250 nm. This suggests that
cytosine can induce disassembly of the supramolecular orꢀ
ganization of GꢀC in the membrane.
Figure 4. (a) UV and (b) CD spectra of GꢀC dinucleoside
(20 ꢁM) in the absence and in the presence of vesicles in
PBS (2.7 mM KCl, 136.9 mM NaCl, 1.5 mM KH2PO4 and 8.1
mM Na2HPO4, pH 7.4).
Figure 5. (a) Energy minimized structure of GꢀC monꢀ
omer obtained using B3LYP/6ꢀ31G level (Gaussian03); proꢀ
posed model the GꢀC ion channels: (b) oligomer based on Gꢀ
C base pairing and (c) Gꢀquartet; (d) schematic representaꢀ
tion of ion channel formation.
Density functional theory (DFT) structural analysis of the
GꢀC dinucleoside reveals that the triazole containing linker
between the two end nucleosides is flexible to make a peꢀ
ripheral pore of 0.79 nm diameter (Figure 5a, dꢀA, S8). The
endꢀtoꢀend distance of the lowest energy conformer of the
GꢀC dinucleoside is determined to be 1ꢀ1.5 nm (Figure S8).
The larger TEM diameter compared to the molecular length
of GꢀC indicates lateral association of the vertically stacked
GꢀC on top of each other. We propose the presence of a flexꢀ
ible linker between G and C end groups may facilitate ‘barꢀ
relꢀstave’ type structures with nanoꢀpore channels of ~0.79ꢀ
1.6 nm (Figure 5dꢀE), where the triazole rings and the nuꢀ
cleobases facilitate selfꢀassembly of linear chains to fibrous
structures by πꢀπ stacking. However, we certainly cannot
rule out the possibilities, where a linear chain of GꢀC dinuꢀ
cleoside can form helical pores (Figure 5dꢀD, Figure S9,
S.I.). Despite the flexibility of the small linker, the selfꢀ
Figure 6. Inhibition of ion channel formed from GꢀC diꢀ
nucleoside using (a) guanosine and (b) cytosine.
In summary, we created the first biomimetic artificial
transmembrane ion channel construct using
a self-
complementary G-C dinucleoside. The biomimetic ion
channel shows a halfꢀlife in the range of seconds and exhibꢀ
its two distinct conductance levels for potassium ions. A
competitive assay with guanosine and channel inhibition
with cytosine confirms the role of a GC hydrogen bonded
framework for channel formation. In contrary to the natural
ion channel systems, this synthetic ion channel possesses
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
(7) (a) Ma, L.; Harrell, Jr. W. A.; Davis, J. T. Org. Lett. 2009, 11,
1599ꢀ1602. (b) Ma, L.; Melegari, M.; Colombini, M.; Davis, J. T. J.
Am. Chem. Soc. 2008, 130, 2938ꢀ2939.
tunability with flexibilities in choosing functionality and
length of the linker.
1
2
3
4
5
6
7
8
9
(8) Kumar, Y. P.; Das, R. N.; Kumar, S.; Schütte, O. M.; Steinem,
C.; Dash, J. Chem. Eur. J. 2014, 20, 3023ꢀ3028.
ASSOCIATED CONTENT
Supporting Information
Experimental details, synthetic procedures, 1H NMR and 13
NMR spectra, voltageꢀclamp experiment traces, AFM, TEM
analysis and CD spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(9) Langecker, M.; Arnaut, V.; Martin, T. G.; List, J.; Renner, S.;
Mayer, M.; Dietz H.; Simmel, F. C. Science, 2012, 338, 932ꢀ936.
(10) (a) Balasubramanian, S.; Hurley, L. H.; Neidle, S. Nat. Rev.
Drug Discov. 2011, 10, 261ꢀ275. (b) Collie, G. W.; Parkinson, G. N.
Chem. Soc. Rev. 2011, 40, 5867ꢀ5892. (c) Riou, J. F.; Guittat, L.;
Mailliet, P.; Laoui, A.; Renou, E.; Petitgenet, O.; MegninꢀChanet, F.;
Helene; Mergny, J. L. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 263ꢀ
267.
(11) Davis, J. T. Angew. Chem. Int. Ed. 2004, 43, 668ꢀ698.
(12) (a) Lena, S.; Cremonini, M. A.; Federiꢀconi, F.; Gottarelli,
G.; Graziano, C.; Laghi, L.; Mariani, P.; Masiero, S.; Pieraccini, S.;
Spada, G. P. Chem. Eur. J. 2007, 13, 3441ꢀ3449. (b) Araki, K.; Yoꢀ
shikawa, I. Top. Curr. Chem. 2005, 256, 133ꢀ165.
(13) (a) Mascal, M.; Farmer, S. C.; ArnallꢀCulliford, J. R. J. Org.
Chem. 2006, 71, 8146ꢀ8150. (b) Sessler, J. L.; Jayawickramarajah,
J.; Sathiosatham, M. Org. Lett. 2003, 5, 2627ꢀ2630. (c) Marsh, A.;
Silvestri, M.; Lehn, J. M. Chem. Comm. 1996, 1527ꢀ1528.
(14) Allain, V.; Bourgaux, C.; Couvreur, P. Nucleic Acids Re-
search, 2012, 40, 1891ꢀ1903
C
AUTHOR INFORMATION
Corresponding Author
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ocjd@iacs.res.in
csteine@gwdg.de
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This paper is dedicated to Professor HansꢀUlrich Reiβig
on the occasion of his 65th birthday. This work was supꢀ
ported by the (BNRS), Department of Atomic Energy (DAE)
and Department of Biotechnology (DBT) India. RND and
YPK thank CSIR India for research fellowships. We thank
Bibudha Parasar and Dr. G. Dan Pantoș for useful discusꢀ
sions.
(15) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2002, 41, 2596ꢀ2599.
(16) (a) Kurz, A.; Bunge, A.; Windeck, A. K.; Rost, M.; Flasche,
W.; Arbuzova, A.; Strohbach, D.; Müller, S.; Liebscher, J.; Huster,
D.; Herrmann, A. Angew. Chem. Int. Ed. 2006, 45, 4440ꢀ4444. (b)
Mathivet, L.; Cribier, S.; Devaux, P. F. Biophys. J. 1996, 70, 1112ꢀ
1121.
(17) Johnson, R. P.; Fleming, A. M.; Burrows, C. J.; White, H. S.
J. Phys. Chem. Lett. 2014, 5, 3781ꢀ3786.
REFERENCES
(18) Ferdani, R.; Li, R.; Pajewski, R.; Pajewska, J.; Winter, R. K.;
Gokel, G. W. Org. Biomol. Chem. 2007, 5, 2423ꢀ2432.
(19) (a) Dolder, M.; Zeth, K.; Tittmann, P.; Gross, H.; Welte, W.;
Wallimann, T. J. Struct. Biol. 1999, 127, 64ꢀ71. (b) Derrington, I.
M.; Butler, T. Z.; Collins, M. D.; Manrao, E.; Pavlenok, M.; Niederꢀ
weis M.; Gundlach, J. H. Proc. Natl. Acad. Sci. U.S.A. 2010, 107,
16060ꢀ16065. (c) Venkatesan B. M.; Bashir, R. Nature Nanotech-
nology, 2011, 6, 615ꢀ624.
((2) (a) Szymański, W.; Beierle, J. M.; Kistemaker, H. A. V.; Veꢀ
lema, W. A.; Feringa, B. L. Chem. Rev. 2013, 113, 6114ꢀ6178. (b)
Chui, J. K. W.; Fyles, T. M. Chem. Soc. Rev. 2012, 41, 148ꢀ175. (c)
Gokel, G. W.; Carasel, I. A. Chem. Soc. Rev. 2007, 36, 378ꢀ389.(d)
Sisson, A. L.; Shah, M. R.; Bhosale, S.; Matile, S. Chem. Soc. Rev.
2006, 35, 1269ꢀ1286.
(3) (a) Montenegro, J.; Ghadiri, M. R.; Granja, J. R. Acc. Chem.
Res. 2013, 46, 2955ꢀ2965. (b) Reiß, H.; Koer, U. Acc. Chem. Res.
2013, 46, 2773ꢀ2780. (c) Itoh, H.; Inoue M. Acc. Chem. Res. 2013,
46, 1567ꢀ1578. (d) Otis, F.; Auger, M.; Voyer, N. Acc. Chem. Res.
2013, 46, 2934ꢀ2943. (e) Fyles, T. M. Acc. Chem. Res. 2013, 46,
2847ꢀ2855. (f) Gokel, G. W.; Negin, S. Acc. Chem. Res. 2013, 46,
2824ꢀ2833. (g) Gong, B.; Shao, Z. Acc. Chem. Res. 2013, 46, 2856ꢀ
2866.
(4) (a) Otis, F.; RacineꢀBerthiaume, C.; Voyer, N. J. Am. Chem.
Soc. 2011, 133, 6481ꢀ6483. (b) Cazacu, A.; Tong, C.; Van Der Lee,
A.; Fyles, T. M.; Barboiu, M. J. Am. Chem. Soc. 2006, 128, 9541ꢀ
9548.
(5) For selected examples of peptide based ionophores: (a) Itoh,
H.; Matsuoka, S.; Kreir, M.; Inoue, M. J. Am. Chem. Soc. 2012, 134,
14011ꢀ14018. (b) SánchezꢀQuesada, J.; Isler, M. P.; Ghadiri, M. R. J.
Am. Chem. Soc. 2002, 124, 10004ꢀ10005. (c) Schlesinger, P. H.;
Ferdani, R.; Liu, J.; Pajewska, J.; Pajewski, R.; Saito, M.; Shabany,
H.; Gokel G. W. J. Am. Chem. Soc. 2002, 124, 1848ꢀ1849.
(6) Sakai, N.; Kamikawa, Y.; Nishii, M.; Matsuoka, T.; Kato, T.;
Matile, S. J. Am. Chem. Soc. 2006, 128, 2218ꢀ2219.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
Insert Table of Contents artwork here
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
ACS Paragon Plus Environment