Rigid oligonaphthalenediimide rods as transmembrane anion-π slides

Article abstract of DOI:10.1021/ja0665747

We report the design, synthesis, and evaluation of rigid oligonaphthalenediimide (O-NDI) rods that are expected to act as transmembrane anion-π slides. Studies in fluorogenic large unilamellar egg yolk phosphatidylcholine vesicles reveal that rigid O-NDI

Full text of DOI:10.1021/ja0665747

Published on Web 10/27/2006
Rigid Oligonaphthalenediimide Rods as Transmembrane Anion-π Slides
Virginie Gorteau, Guillaume Bollot, Jiri Mareda, Alejandro Perez-Velasco, and Stefan Matile*
Department of Organic Chemistry, UniVersity of GeneVa, GeneVa, Switzerland
Received September 12, 2006; E-mail: stefan.matile@chiorg.unige.ch
We report the design, synthesis, and evaluation of π-acidic,
shape-persistent
(O-NDI) rods 1-3 that can transport anions across lipid bilayer
membranes with a rare halide VI selectivity (Cl- > F- > Br-
oligo-(p-phenylene)-N,N-naphthalenediimide
>
I-)1 and a substantial anomalous mole fraction effect (AMFE, Figure
1 and Scheme 1).2 Dynamic cation-π interactions have been
confirmed theoretically3 and experimentally4 to provide access to
ion channels/transporters with the biologically relevant Eisenman
IV cation selectivity topology.5 This experimental support for
π-basic rigid p-oligophenyl rods as functional scaffolds4 suggested
that electron-deficient rigid O-NDI rods6 could give the comple-
mentary anion-π slides (Figure 1). The development of strategies
to design synthetic anion channels/transporters7,8 beyond ion pairing
and hydrogen bonding is of quite general interest considering the
importance of anion channels in diseases such as cystic fibrosis.1,2,8
Anion-π interactions are appealing for this purpose because they
are theoretically attractive,9 poorly explored in solution,10 absent
in ion channel proteins,1,2,8 and unexplored in the context of
synthetic ion channels and pores.7,8
Figure 1. The concept of anion-π slide in lipid bilayers (A) with DFT-
computed electrostatic potential maps (mesh surface) for rigid O-NDI rod
1 (B) and solid surfaces for the model NDI 4 (C) compared to the comple-
mentary model pyrene 5 (D); red: electron-rich, blue: electron-poor.
Scheme 1 a
NDI, a compact, organizable, colorizable, and functionalizable
organic n-semiconductor6,11 was considered as an ideal module for
the creation of transmembrane anion-π slides (Figure 1). Our high-
level DFT calculations12 for model NDI 4 revealed a global
quadrupole moment Qzz ) +19.4 B (Buckinghams) that promised
anion-π interactions beyond hexafluorobenzene (Qzz ) +9.6 B)13
and cation-π interactions with the complementary model pyrene
5 (Qzz ) -13.8 B). Comparison with rigid p-oligophenyl rods14
suggested that the alignment of three NDI acceptors separated by
phenyl spacers would afford rods with appropriate length (l ) 32.6
Å, Figure 1B) for hydrophobic matching with common lipid bilayer
membranes.
Rigid O-NDI rods 1-3 were readily accessible from the
commercially available dianhydride 6 (Scheme 1). Reaction with
excess diamine 7 gave the central NDI module 8. Unlikely to affect
the fixed phenyl-NDI torsion angle of ω ≈ 90°, reduction of the
number of methyls in diamine 8 was nevertheless found to be
undesirable because of increasingly poor solubility of higher rods
(not shown). The terminal module 9 was prepared by reaction of
monoamine 10 with excess dianhydride 6 under controlled pH.
Coupling of the central diamine 8 with two terminal diacids 9
yielded the desired rigid O-NDI scaffold 11. Z-Removal and
elongation of diamine 12 with Boc-Gly-OH gave target rod 1. Mild
Boc-deprotection produced the asymmetric ammonium salt 2 in
up to 64% conversion yield, together with 30% of the fully
deprotected, symmetric diammonium salt 3.
Egg yolk phosphatidylcholine large unilamellar vesicles (EYPC
LUVs) loaded with the pH-sensitive fluorescent probe 8-hydroxy-
1,3,6-pyrenetrisulfonate (HPTS) and exposed to a pH gradient were
used to evaluate the activity of rigid O-NDI rods 1-3. In this
assay, transport activity is reported as velocity of pH gradient
collapse and can imply facilitated cation (H+/Mn+) or anion
exchange (OH-/An-).4,15 Consistent with transmembrane rod ori-
a Conditions: (a) N,N-Dimethylacetamide, 135 °C, 12 h, 90%; (b) (1)
H2O, pH 6.4, reflux; (2) AcOH; 88%; (c) N,N-dimethylacetamide, 135 °C,
12 h, 57%; (d) TFA, 50 °C, 2 h, 61%; (e) Boc-Gly-OH, HBTU, TEA,
DMF/DMSO 1:1, rt, 2 h, 54%; (f) 2% TFA, CH2Cl2, rt, 50 min, 64% 2,
30% 3 (conversion yield).
entation, the overall quite poor activities of rigid O-NDI rods in
the HPTS assay were best with one charged and one uncharged
terminus and worst with two charged termini (2 > 1 > 3).
Replacement of the extravesicular NaCl with isoosmolar KCl, RbCl,
and CsCl did not much change the apparent activity of rigid O-NDI
rod 1 (Figure 2A). The changes provoked by external anion
exchange were clearly stronger (Figure 2B). Sensitivity to external
anion and insensitivity to external cation exchange indicated that
rigid O-NDI rod 1 operates by OH-/An- rather than H+/Mn+
exchange, that is, anion selectivity. Recent direct comparison
suggested that relative activities obtained by external ion exchange
in HPTS-loaded vesicles may relate directly to permeability ratios
from Goldman-Hodgkin-Katz analysis of planar bilayer conduc-
tance experiments.15
9
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J. AM. CHEM. SOC. 2006, 128, 14788-14789
10.1021/ja0665747 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
answer to the dilemma of how to be fast and selective,2,16 AMFE
thus supported multi-Cl- hopping along the π-acidic NDI modules
of rigid rod 1 and disfavored the Gly-Boc termini as origin of
activity and selectivity.
The rare halide VI sequence of neutral O-NDI rods, together
with reduced selectivity and halide sequence but increased activ-
ity with one cationic rod terminus, were all in agreement with
operational dynamic anion-π interactions; the AMFE confirmed
the existence of multiple anion-π sites for transmembrane anion
hopping, that is, anion-π slide 1 (Figure 1). However, these
surprisingly consistent results should not distract from the fact that
further studies are necessary to gain corroborative insights on the
here introduced novel and complex system.
Acknowledgment. We thank M. Julliard for contributions to
synthesis, D. Jeannerat, A. Pinto, and S. Grass for NMR measure-
ments, P. Perrottet and the group of F. Gu¨lac¸ar for MS measure-
ments, and the Swiss NSF for financial support.
Figure 2. Anion/cation selectivity (A, B), anion selectivity topology (C),
and mole fraction behavior (D) of rigid O-NDI rods 1 (A-D, b9) and 2
(C, O), with rods being added either after (A-D, bO) or before the base
Supporting Information Available: Experimental details and
complete ref 12a. This material is available free of charge via the
Internet at http://pubs.acs.org.
pulse (C, 9). (A, B) Fractional HPTS emission Y (λex ) 450 nm, λem
)
510 nm) as a function of time during addition of base (∆pH 0.9) followed
by 1 (1.5 µM) and excess gramicidin A (gA, for calibration only) to EYPC-
LUVs⊃HPTS (10 mM HEPES, pH 7.0, 100 mM MX, A: X ) Cl, M as
indicated; B: M ) Na, X as indicated. The baseline (same without 1) was
subtracted after calibration). (C, D) Fractional HPTS emission Y 200 s after
beginning of an experiment as a function of the reciprocal anion radius (C)
or the mole fraction x (D, expected: dashed line, found: solid line).
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