Transmembrane halogen-bonding cascades

Article abstract of DOI:10.1021/ja4013276

Halogen bonds have recently been introduced as ideal to transport anions across lipid bilayer membranes. However, activities obtained with small transporters were not impressive, and cyclic arrays of strong halogen-bond donors above a calix[4]arene scaffold gave even weaker activities. Here, we report that their linear alignment for anion hopping along transmembrane rigid-rod scaffolds gives excellent activities with an unprecedented cooperativity coefficient m = 3.37.

Full text of DOI:10.1021/ja4013276

Communication
pubs.acs.org/JACS
Transmembrane Halogen-Bonding Cascades
Andreas Vargas Jentzsch and Stefan Matile*
Department of Organic Chemistry, University of Geneva, Geneva, Switzerland
S
* Supporting Information
ABSTRACT: Halogen bonds have recently been intro-
duced as ideal to transport anions across lipid bilayer
membranes. However, activities obtained with small
transporters were not impressive, and cyclic arrays of
strong halogen-bond donors above a calix[4]arene scaffold
gave even weaker activities. Here, we report that their
linear alignment for anion hopping along transmembrane
rigid-rod scaffolds gives excellent activities with an
unprecedented cooperativity coefficient m = 3.37.
alogen bonds originate mainly from the localized positive
Hcharge density, the so-called σ-hole, that appears best on
highly electron-deficient halogen atoms, particularly iodines.1
However, other contributions to halogen bonds should also not
be underestimated (polarization, charge transfer, etc).1
Halogen-bond donors can interact with electron-rich sites,
such as lone pairs on oxygens or nitrogens, or with anions. Like
hydrogen bonds, halogen bonds are strong, particularly in
nonpolar environments, and excel with unique directionality.
Halogen bonds have attracted much interest in theory and are
quite routinely used in crystal engineering.1 More recently,
several examples for anion binding2 and catalysis3 with halogen
bonds have appeared, and applications in chemical biology
become more frequent.4
Anion transport5 with halogen bonds has been reported last
year to be particularly attractive because, unlike hydrogen-bond
donors, halogen-bond donors are intrinsically hydrophobic.6
For this reason, anion transport is already possible with very
small molecules, such as pentafluoroiodobenzene 1 or even
trifluoroiodomethane, a gas with a boiling point of −22 °C
(Figure 1, Table 1). For comparison, anion−π interactions with
hexafluorobenzene 2 were insufficient for anion transport in
Figure 1. (A) Schematic representation of anion hopping along
transmembrane halogen-bonding cascades. (B) Halogen-bond donors
as monomers (1),6 in cyclic arrays (3),7 and in linear arrays (5−8),
together with the controls for anion−π interactions (2, 4, 9−12).
this minimalist format. However, the positioning of four
tetrafluoroiodobenzyls in a cyclic array above the calix[4]arene
scaffold in 3 gave much weaker activities.7 This suggested that,
contrary to the weaker anion−π interactions in 4, anion binding
by halogen bonds in 3 is thermodynamically as well as
kinetically too strong for transport.7 To promote anion
transport rather than binding, we concluded that cyclic arrays
of halogen-bond donors would have to be unrolled into linear
arrays for transmembrane anion hopping and decided to
synthesize and evaluate the series 5−12.
or iodide.11 The control series 9−12 to compare for anion−π
interactions was obtained analogously.
Ion transport activity was determined with the HPTS assay
under routine conditions.6,7,11 In this assay, large unilamellar
vesicles (LUVs) composed of egg yolk phosphatidylcholine
(EYPC) are loaded with 8-hydroxy-1,3,6-pyrenetrisulfonate
(HPTS). Then a pH gradient is applied with a base pulse, the
Early work on the complementary hydrogen-bonded chains8
has identified p-oligophenyls as privileged scaffolds.9,10 The
halogen-bonding cascades in homologues 5−8 were obtained
by coupling of the original p-oligophenyls with carboxylic acids
along the scaffold with tetrafluoroiodobenzyl chloride, bromide,
Received: February 5, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4013276 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
In summary, this study on halogen-bonding cascades merges
current topics with a comprehensive research program that has
been launched in 1997.8 The results fully confirm the power of
transmembrane rigid-rod scaffolds on the one hand and
halogen bonds in the other hand to achieve efficient anion
hopping across lipid bilayer membranes.
Table 1. Ion Transport Activity of 1−12
b
c
d
e
N
cpd
EC50 (μM)
EC50 (μM)
n
f
1
260
>2000
∼1000
25
260
−
4000
3.6
f
2
−
0.7
g
3
g
4
−
1.1
5
6
7
8
9
9.2 0.8
18.4
2.9
1.0 0.2
1.0 0.1
1.3 0.1
0.8 0.1
1.1 0.1
0.8 0.1
0.5 0.1
0.6 0.1
ASSOCIATED CONTENT
* Supporting Information
Details on experimental procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
0.72 0.04
0.13 0.01
0.11 0.02
32.5 3.4
12.6 3.0
1.3 0.5
S
0.78
0.88
65.0
50.4
7.8
10
11
12
AUTHOR INFORMATION
Corresponding Author
Stefan.Matile@unige.ch
Notes
■
2.9 0.4
23.2
a
Determined from HPTS assay in EYPC-LUVs⊃HPTS (100 mM
NaCl, 10 mM HEPES, pH 7, external NaOH pulse).11 Compounds,
b
c
The authors declare no competing financial interest.
see Figure 1. Effective concentration needed to see 50% activity.
Effective concentration per monomer unit in an oligomer. Hill
coefficient. From ref 6. From ref 7.
d
e
f
g
ACKNOWLEDGMENTS
■
We thank the NMR and the mass spectrometry (SMS)
platforms for services and the University of Geneva, the
European Research Council (ERC Advanced Investigator), the
National Centre of Competence in Research (NCCR) in
Chemical Biology, and the Swiss NSF for financial support.
transporter is added, and the ability of the transporter to
accelerate the dissipation of the pH gradient is measured with
the intravesicular, ratiometric pH probe. The conditions were
selected to report, presumably, on Cl−/OH− antiport.
The new linear arrays 5−12 were analyzed under conditions
identical to the ones used for monomers and cyclic arrays 1−
4.6,7 For all compounds, dose response curves were recorded.
Their Hill analysis gave the effective concentrations EC50, i.e.,
the monomer concentration needed to reach 50% of the
activity at saturation. Routine control experiments confirmed
the absence of nonspecific dye leakage during anion transport
and afforded a length-independent, moderate selectivity for
nitrate and chloride on a very weak anti-Hofmeister anion
selectivity background.11
Transporters 5−8 with linear halogen-bonding arrays were
3.5−26 times more active than their homologous controls 9−
12 for anion−π interactions (Table 1). Gratifyingly, the
transport activities increased with increasing length of the
rigid-rod scaffold. The EC50N, that is the EC50 per monomer N,
decreased for both “halogen-bond” transporters 5−8 and
“anion−π” transporters 9−12. Saturation was reached around
scaffolds long enough to enable transmembrane10 linear arrays
(Table 1).12 According to eq 1:13
REFERENCES
■
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EC50 ∝ N−m
(1)
the dependence of the EC50 on the number N of monomers per
oligomer gave a cooperativity coefficient m = 2.13 for anion−π
transporters 9−12. This value is already slightly above the usual
range for intrinsic multivalency contributions with oligomers
and polymers (1 < m < 2).13 With linear arrays of halogen-bond
donors in 5−8, m = 3.37 was found. This exceptionally high
value provided quantitative evidence for the existence of
transmembrane halogen-bonding cascades for cooperative
anion transport as outlined in Figure 1A. In the best
transporter, i.e., octamer 8, halogen-bonding cascades gave
2360 times higher activity compared to monomer 1.
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transmembrane rigid-rod scaffolds, either intra- or intermolec-
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assumption (Table 1). They only demonstrate that these
bundles are thermodynamically stable.15
(11) See SI.
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increased the EC50 (e.g., 1.25 mM EYPC: 7, 700 nM; 8, 1.75 μM).11
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Soc. 2008, 130, 10338−10344.
(14) Direct evidence from functional studies supports that, not
surprisingly, perfluoroiodoarenes self-assemble in lipid bilayers.6
(15) Bhosale, S.; Matile, S. Chirality 2006, 18, 849−856.
B
dx.doi.org/10.1021/ja4013276 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX