liberated all remaining chloride. The results showed that the
addition of 3b initiated chloride efflux, and that ca. 80% of the
chloride was released within 5 minutes.w
to membrane-based applications, and we have shown that
cyclotrimer 3b can transport chloride ions across phospholipid
bilayers. There is potential for the recognition and transport of
other anionic species, and this will be the subject of future
research.
Further experiments with 3b revealed that the rate of trans-
port increased roughly linearly with concentration, and that the
use of less fluid phospholipid–cholesterol (7 : 3) vesicle mem-
branes lowered transport rates.w Both results tend to suggest
that transport is due to a carrier mechanism, as opposed to a
static, multicomponent channel. Addition of phosphate buffer
(pH ¼ 6.5–8) produced a further lowering of transport rates,
possibly due to competition for the binding site. Monomeric
control compounds 9 were tested to confirm the importance of
the toroidal architecture. Neither promoted chloride transport
to a measurable extent, suggesting that the macrocyclic structure
is necessary to shield the chloride from the membrane hydro-
carbon. 3b was also tested for bromide transport, by replacing
the KCl in the vesicles by KBr and employing a bromide-
selective electrode. Interestingly, rates were lower by a factor
of B2.4 at steady state,w perhaps due to slow release of the
lipophilic bromide anion. Finally, anion vs. cation selectivity was
tested by encapsulating KCl in the vesicles, suspending in
NaNO3, adding 3b, then following both Clꢁ and K1 efflux
using appropriate ion-selective electrodes. While Clꢁ emerged
from the vesicles as expected, the efflux of K1 was negligible
(Fig. 3). This experiment confirms the expected anion-selectivity,
and also shows that the macrocycle does not disrupt the vesicles.
Financial support from the BBSRC (BBS/B/11044), the
EPSRC (EP/C528859/1) and the University of Bristol is grate-
fully acknowledged. Dr Sean A. Davis and Jon A. Jones are
thanked for help with TEM imaging.
Notes and references
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Sudholter, Angew. Chem., Int. Ed., 2002, 41, 4275; (f) S. Walker,
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2000, 122, 3252; (h) Q. H. Zhang, X. Q. Ma, A. Ward, W. X. Hong,
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H. Gellman, J. Am. Chem. Soc., 1992, 114, 3943; (b) J. Elemans, R.
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Choi, B. Chen, R. J. Doerksen, D. J. Clements, J. D. Winkler, M.
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3 (a) S. Broderick, A. P. Davis and R. P. Williams, Tetrahedron
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4 We have used this term for bile acid cyclooligomers linked by
annular amides. See, for example, A. P. Davis and J. J. Walsh,
Chem. Commun., 1996, 449.
5 R. P. Bonar-Law and J. K. M. Sanders, Tetrahedron Lett., 1992,
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6 V. del Amo, L. Siracusa, T. Markidis, B. Baragana, K. M.
rez-Payan,
´ ´
In conclusion we have shown that cholic acid 1 can be used
to prepare a new class of amphiphilic molecules, by enhancing
facial amphiphilicity (converting –OH to –NH31) then cyclo-
oligomerising. The resulting systems 3 are toroidal facial
amphiphiles with hydrophobic outer surfaces and strongly
hydrophilic interiors. This combination of properties points
´
´
Bhattarai, M. Galobardes, G. Naredo, M. N. Perez-Payan and
´ ´
A. P. Davis, Org. Biomol. Chem., 2004, 2, 3320.
7 Some experiments also yielded a small amount (ca. 2%) of 8a,
identified by ESMS.
8 For a review of synthetic anion transporters, see: A. P. Davis, D.
N. Sheppard and B. D. Smith, Chem. Soc. Rev., 2007, 36, 348.
Recent examples: V. Gorteau, G. Bollot, J. Mareda, A. Perez-
Velasco and S. Matile, J. Am. Chem. Soc., 2006, 128, 14788; P. V.
Santacroce, J. T. Davis, M. E. Light, P. A. Gale, J. C. Iglesias-
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1886; X. Li, B. Shen, X. Q. Yao and D. Yang, J. Am. Chem. Soc.,
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9 A. V. Koulov, T. N. Lambert, R. Shukla, M. Jain, J. M. Boon, B.
D. Smith, H. Y. Li, D. N. Sheppard, J. B. Joos, J. P. Clare and A.
P. Davis, Angew. Chem., Int. Ed., 2003, 42, 4931. See also P. H.
Schlesinger, R. Ferdani, J. Liu, J. Pajewska, R. Pajewski, M. Saito,
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10 Chloride efflux was slower than in some other experiments, due to
the presence of buffer and the incorporation of cholesterol in the
membranes (see discussion in text, and Fig. S7 and S8 in the ESIw).
ꢁ
Fig. 3 Anion-selective transport by 3bꢀ(CF3CO2
)
6
through vesicle
3. Inside: KCl
membranes.w10 Vesicles: EYPC–cholesterol,
7
:
(500 mM)–phosphate buffer (pH ¼ 7, 10 mM). Outside: NaNO3 (500
mM)–phosphate buffer. Changes to Clꢁ and K1 external concentrations
were monitored simultaneously using ion-selective electrodes.
ꢂc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 3669–3671 | 3671