A cyclic hexapeptide comprising alternating α-aminoxy and α-amino acids is a selective chloride ion receptor

Article abstract of DOI:10.1002/chem.200500098

In nonpolar solvents, the cyclic hexapeptide 2, which comprises alternating D-α-amino and D-α-aminoxy acids, adopts a C₃-symmetric conformation with alternating eight (N-O turns)- and seven (γ turns)-membered-ring hydrogen bonds. A series of anion-binding studies has suggested that 2 can function as an effective anion receptor that not only displays a high selectivity for chloride ions, but also the capability to extract chloride ions from aqueous solutions into organic phases.

Full text of DOI:10.1002/chem.200500098

FULL PAPER
A Cyclic Hexapeptide Comprising Alternating a-Aminoxy and a-Amino
Acids is a Selective Chloride Ion Receptor
Dan Yang,*[a] Xiang Li,[a] Yao Sha,[b] and Yun-Dong Wu*[b, c]
Abstract: In nonpolar solvents, the cyclic hexapeptide 2, which comprises alternat-
ing d-a-amino and d-a-aminoxy acids, adopts a C3-symmetric conformation with
Keywords: amino acids
receptors · chloride ions · hydrogen
bonds · peptides
·
anion
À
alternating eight (N O turns)- and seven (g turns)-membered-ring hydrogen
bonds. A series of anion-binding studies has suggested that 2 can function as an ef-
fective anion receptor that not only displays a high selectivity for chloride ions,
but also the capability to extract chloride ions from aqueous solutions into organic
phases.
Introduction
high selectivity through hydrogen bonds alone.[4] Receptors
with a high net positive charge,[5] and those containing
Lewis acid moieties,[6] can bind chloride ions selectively;
however, because of their insolubility in nonpolar solvents
and potential heavy metal toxicity, respectively, they are
considered to be unsuitable for application in biological
membrane systems.[7] In response to this problem, we have
developed a new class of anion receptors that have a special
preference for chloride ions.
Simulation of the recognition, binding, and transport proc-
esses of physiologically important anions is the driving force
behind the development of artificial anion receptors.[1] Chlo-
ride ions are ubiquitous in the biosphere and are critical for
a large number of biological processes.[2] In nature, the
transport of chloride ions across cell membranes is regulated
by neutral anion binding proteins (chloride channels). The
dysfunction of chloride channels has been implicated in sev-
eral human diseases, including cystic fibrosis, Bartterꢀs syn-
drome, and Dentꢀs disease,[2b] and, consequently, chloride
channels have become significant targets for drug develop-
ment. The high specificity of chloride channels toward chlo-
ride ions is due to a recognition site in which the anion is
completely desolvated and bound exclusively through hy-
drogen bonds.[3] Unfortunately, there are few electroneutral
artificial anion receptors that can bind to chloride ions with
Previously, we demonstrated that a-aminoxy acids have a
strong tendency to induce an eight-membered-ring intramo-
À
lecular hydrogen bond (the N O turn) when incorporated
into peptides.[8] Aminoxy amide NH units have high acidities
relative to regular amide NH groups, and are, therefore, the
better hydrogen-bond donors when binding anions. Our
group has developed a cyclic hexapeptide 1, comprising d,l-
a-aminoxy acids, that binds selectively to chloride ions (as-
sociation constant Ka =11880mÀ1).[9] Herein, we report that
cyclic hexapeptide 2, comprising alternating d-a-amino and
d-a-aminoxy acids, functions as a more effective anion re-
ceptor, displaying a high selectivity for chloride ions and a
good ability to extract chloride ions from aqueous solutions
into organic phases.
[a] Prof. Dr. D. Yang, X. Li
Department of Chemistry, The University of Hong Kong
Pokfulam Road, Hong Kong (China)
Fax : (+852)285-92-159
E-mail: yangdan@hku.hk
[b] Y. Sha, Prof. Dr. Y.-D. Wu
State Key Laboratory of Molecular Dynamics and Stable Structures
College of Chemistry, Peking University, Beijing (China)
E-mail: chydwu@chem.pku.edu.cn
Results and Discussion
[c] Prof. Dr. Y.-D. Wu
Synthesis and characterization of linear hexapeptide 3 and
cyclic hexapeptide 2: Linear hexapeptide 3, of alternating d-
a-amino and d-a-aminoxy acids, was prepared according to
our previously developed, convergent synthetic scheme.[10]
The H NMR spectroscopy study in CDCl3 showed that the
chemical shifts of all regular amide NH groups of 3 were
Department of Chemistry
Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, Hong Kong (China)
E-mail: chydyu@ust.hk
1
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2005, 11, 3005 – 3009
DOI: 10.1002/chem.200500098
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3005

À
similar to that observed between the O NHi+1 and CaHi
protons. This agrees with our previously reported inverse g
turn conformation,[11] in which the a proton resides in an
axial position. Therefore, we believe that all of the subunits
À
of 2 adopt cyclic conformations possessing alternating N O
and g turns. This supposition is supported by the results of a
conformational search[13] that suggested 2a as the global
minimum (Figure 3). In this structure, the backbone of 2
À
folds into alternating N O and g turns, and adopts a C3-
symmetric conformation.
Anion binding studies: We examined the anion binding abil-
ity of cyclic hexapeptide 2. Initially we screened the follow-
ing anions in a chloroform solution of 2 by using the electro-
spray ionization mass spectrometry (ESI-MS) technique
(negative-ion mode): FÀ, ClÀ, BrÀ, IÀ, NO3À, NO2À, N3
,
.
À
3À
HCO3À, CO32À, HSO4À, SO42À, H2PO4À, HPO42À, and PO4
We observed peaks in the spectra corresponding only to free
[2ÀH]+ (m/z 701.3) and the complexes [2+Cl]À (m/z 737.1),
[2+Br]À (m/z 783.1), and [2+NO3]À (m/z 764.1).[10]
rather downfield (7.3–7.9 ppm) and independent of concen-
tration.[10] This indicates that they form strong, intramolecu-
We studied the anion binding properties of 2 in a solution
of CD2Cl2 by using the 1H NMR spectroscopic titration tech-
1
lar hydrogen bonds, most likely the N O turns. The un-
nique.[14] The H NMR spectra of 2 display dramatic changes
À
changed downfield chemical shifts of aminoxy amide pro-
tons (9.6–10.0 ppm) during 1H NMR dilution tests implied
the formation of seven-membered-ring intramolecular hy-
in the values of chemical shifts of both the aminoxy and reg-
ular amide protons upon addition of the anions (Figure 2);
the signals of the aminoxy amide protons moved downfield,
À
drogen bonds (g turns) between aminoxy amide O NHi and
À
C OiÀ2, as we had previously reported.[11]
Hexapeptide 3 was then deprotected at both ends and
treated with diphenylphosphoryl azide (DPPA) to give
cyclic hexapeptide 2 in 30% overall yield for three steps. In
the H NMR spectrum of 2 recorded in CD2Cl2,[8c,10] we ob-
1
served only two sets of sharp peaks that originate from the
a-amino and a-aminoxy acid residues, respectively. The sig-
nals of both the regular (8.3 ppm) and aminoxy (9.6 ppm)
amide NH units of 2 appear quite downfield at very low
concentration (4 mm); their appearance is independent of
concentration,[10] indicating that they form intramolecular
hydrogen bonds. Furthermore, we found that in nonpolar
solvents, the NOE pattern[10] of the aminoxy acid residues of
À
2 was in accordance with the second-lowest-energy N O
turn conformation that we determined previously by theo-
retical calculations.[12] As Figure 1a indicates, the NOE ob-
À
À
served between the O NHi and O CaHi protons was of a
À
similar intensity to that observed between the NHi+1 and O
Figure 2. The amide NH region of overlaid 1H NMR spectra of free 2
and 1:1 mixtures of 2 with Ph4PCl, Ph4PBr, or Bu4NNO3 (4 mm in CD2Cl2
at 298 K).
CaHi protons. For each a-d-alanine residue of 2, the NOE
intensity observed between the NHi and CaHi protons is
whereas those of the regular amide protons shifted upfield.
Quantitative assessments of the anion binding affinities of 2
in CD2Cl2 (a nonpolar solvent) reveal that 2 is not only ef-
fective in forming a 1:1 complex with anions, but is also se-
lective for chloride ions (Table 1). Comparison with our pre-
viously reported cyclic hexapeptide 1, comprising d,l-a-ami-
noxy acids, reveals that the cyclic hexapeptide 2, which has
fewer aminoxy amide NH units, displays enhanced binding
Figure 1. Summary of the NOEs observed for (a) free 2 and (b) a 1:2.5
mixture of 2 and Ph4PCl (4 mm in CD2Cl2 at 298 K; s, strong NOE; m,
medium NOE; w, weak NOE).
3006
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Chloride Ion Receptors
FULL PAPER
NOESY spectrum of 2 complexed with a chloride ion;[10]
this spectrum exhibits a different NOE pattern for the a-d-
alanine residues (medium-intensity NOEs between the NHi
À
and CaHi protons, and weak NOEs between the O NHi+1
and CaHi protons) to that of free 2 under the same condi-
tions (Figure 1). Such a conformational change in the a-d-
À
alanine residues would also disturb the original N O turns
to such an extent that the signals of the regular amide pro-
tons become shifted upfield.
Extraction studies: As a preliminary step toward ion trans-
port, we also studied the extraction capabilities of cyclic
hexapeptide 2 toward chloride and nitrate ions by using the
single extraction method.[15] As expected, 2 proved capable
of extracting anions from aqueous solution into chloroform.
1H NMR spectroscopic analysis of the extracts revealed that
the extraction efficiency[16] of chloride ions (77%) was clear-
ly higher than that of nitrate ions (35%). This is in agree-
ment with the relative association constants of 2 toward
these anions, even though nitrate ions are more lipophilic
than chloride ions. Control experiments established that no
significant extraction of anions took place in the absence of
receptor 2.
Figure 3. Calculated structures of conformations 2a and 2b of cyclic hex-
apeptide 2.
Theoretical calculations: The conformational search of 2
was first performed by using the MACROMODEL pro-
gram[17] and AMBER94 force field.[18] A total of four struc-
tures with a pseudo C3-symmetry were found. These struc-
tures and anion-bound structures were subjected to full geo-
metrical optimization by the B3LYP method[19] using a
hybrid basis set: C, H, N: 6–31G*; O, Cl, Br: 6–31+G*; the
six amide hydrogens: 6–311++G**. Each structure was
confirmed to be minimum by harmonic vibration frequency
calculation, from which the thermal property of the struc-
ture was evaluated. Solvent effect was also estimated by
using the IEFPCM solvent model with UAKS radii.[20] The
free energy of each structure in solution was derived from
the calculated free energy in the gas phase corrected by the
solvent effect on the electronic energy. All quantum me-
chanics calculations were performed by using the Gaussi-
an 03 program.[21]
Table 1. Association constants for the binding of 2 with anions[a] in
CD2Cl2 at 298 K.
[b]
[c]
À
Anion
Ka [mÀ1
]
Ddmax(O NH)
Ddmax(NH)[c]
ClÀ
BrÀ
IÀ
15000Æ1500
910Æ43
51Æ3
2.39
1.70
À1.39
À1.07
[d]
[d]
–
–
À
NO3
440Æ42
1.43
À0.55
[a] Anions were added as concentrated CD2Cl2 solutions of Ph4PCl,
Ph4PBr, Bu4NI, or Bu4NNO3. To account for dilution effects, these anion
solutions also contained receptor 2 at its initial concentration (2–4 mm).
[b] Determined by following the changes that occurred to the resonances
of the aminoxy amide NH protons. [c] Estimated maximum change in
chemical shift (ppm). [d] Cannot be estimated from the titration curve.
toward anions, whilst maintaining good selectivity toward
the chloride ion. To account for the stronger anion binding
À
that 2 displays relative to 1, we note that the N O turn is
In the case of anion-free cyclic peptide 2, we found two
significant conformations, 2a and 2b (Figure 3). Structure
2a is the global minimum. It is in a fully hydrogen-bonded
geometry with alternating seven- and eight-membered-ring
hydrogen bonds. In structure 2b, all six hydrogen bonds are
more stable than the g turn.[12] The backbone of 2, compris-
À
ing alternating N O and g turns, should be more flexible
than that of cyclic hexapeptide 1, whose d,l-a-aminoxy acid
residues adopt consecutive N O turns. Consequently, it is
easier for 2 to adjust its conformation upon binding to an
anion than it is for 1.
Notably, the aminoxy amide NH group is not only a
better hydrogen-bond donor than the regular amide NH
unit, it is also involved in a relatively weak intramolecular
hydrogen bond (the g turn). Upon binding to the chloride
ion, the three acidic aminoxy amide NH units may form hy-
drogen bonds with the anion by breaking the original g
turns adopted by the a-d-alanine residues of 2, resulting in
the downfield shift of the signal of the aminoxy amide pro-
tons. This hypothesis is supported by the two-dimensional
À
À
broken and all six N H bonds point inward; therefore, it
can be regarded as the conformation for anion binding.
Structure 2b was found to be less stable than 2a by around
10.0 kcalmolÀ1.
Structure 2b was used to bind ClÀ or BrÀ ions. The opti-
mized structures of the 2-ClÀ and 2-BrÀ complexes are rep-
resented in Figure 4. Upon binding with the ClÀ ion, all six
of the hydrogen bonds initially present in 2 become disrupt-
ed. The backbone of 2 rearranges into a rather flat confor-
mation with all of the amide NH hydrogen atoms pointing
inward. The ClÀ ion sits above the plane of the peptide
Chem. Eur. J. 2005, 11, 3005 – 3009
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D. Yang, Y.-D. Wu et al.
Experimental Section
General methods: All reagents and solvents were of analytical grade and
were dried and distilled as necessary. 1H and 13C NMR spectra were re-
corded at 600 MHz for protons and at 75.5 or 100.0 MHz for carbons by
using Bruker Avance DPX 300, 400, or 600 Fourier Transform Spectrom-
eters. Infrared spectra were obtained by using a Bio-Rad FTS 165 FTIR
spectrometer. Melting points were determined by using an Axiolab
ZEISS microscope and were uncorrected. Optical rotations were mea-
sured by using a Perkin–Elmer 343 polarmeter. Both low and high resolu-
tion mass spectra were recorded by using a Finnigan MAT 95 mass spec-
trometer.
Characterization data for compound 1: Colorless oil; [a]2D0 =+114.08 (c=
1.00, CHCl3); 1H NMR (600 MHz, CDCl3): d=9.98 (s, 1H), 9.59 (s, 1H),
7.91 (d, J=6.7 Hz, 1H), 7.79–7.76 (m, 5H), 7.35–7.02 (m, 16H), 4.68 (t,
J=5.1 Hz, 1H), 4.54 (dd, J=8.3, 3.0 Hz, 1H), 4.50–4.42 (m, 1H), 4.31–
4.26 (m, 2H), 4.17–4.16 (br, 1H), 3.48 (dd, J=14.4, 4.9 Hz, 1H), 3.27 (dd,
J=14.4, 5.5 Hz, 1H), 3.18–3.12 (m, 2H), 3.01–2.97 (m, 1H), 2.93–2.87 (m,
1H), 1.42 (s, 9H), 1.29–1.23 (m, 6H), 1.05 ppm (d, J=7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=171.46, 170.53, 170.27, 170.13, 169.97,
169.27, 163.66, 136.54, 136.12, 135.12, 134.52, 129.85, 129.46, 129.38,
128.35, 128.30, 128.05, 127.24, 126.83, 126.50, 124.08, 88.48, 87.92, 86.26,
81.36, 48.58, 47.65, 46.47, 37.90, 37.82, 27.90, 17.14, 16.42 ppm; IR
(CH2Cl2): n˜ =3311 (br), 1735, 1677 cmÀ1; LRMS (fast atom bombard-
ment, FAB): m/z: 907 [M+1]+; HRMS (FAB): m/z calcd for C48H55N6O12
[M+1]+: 907.3800; found: 907.3896.
Figure 4. Calculated structures of complexes 2-ClÀ and 2-BrÀ.
backbone and forms strong hydrogen bonds with the three
Characterization data for compound 2: Colorless oil; [a]2D0 =+99.58 (c=
1.00, CHCl3); 1H NMR (600 MHz, CD2Cl3): d=9.61 (s, 1H), 8.30 (d, J=
5.9 Hz, 1H), 7.32–7.23 (m, 5H), 4.32 (dd, J=5.1, 3.6 Hz, 1H), 4.12–4.09
(m, 1H), 3.25 (dd, J=14.5, 3.7 Hz, 1H), 2.92 (dd, J=14.4, 2.6 Hz, 1H),
1.24 ppm (d, J=7.0 Hz, 3H); 13C NMR (75 MHz, CD2Cl2): d=170.87,
170.32, 136.35, 129.46, 129.28, 128.34, 126.83, 87.93, 46.58, 37.83,
15.84 ppm; IR (CH2Cl2): n˜ =3280 (br), 1673 cmÀ1; LRMS (FAB): m/z:
703 [M+1]+; HRMS (FAB): m/z calcd for C36H43N6O9 [M+1]+: 703.3013;
found: 703.3101.
À
O NH hydrogen atoms, as indicated by Cl···H distances of
2.21 ꢂ. The three regular amide NH groups do not undergo
strong binding with the ClÀ ion (Cl···H distance is 3.00 ꢂ),
but these hydrogen atoms are positioned close to the back-
bone oxygen atom (O···H distance is 2.13 ꢂ). This structure
is consistent with the experimental observation that the
1
signal of the aminoxy amide protons in the H NMR spec-
trum shifts significantly downfield upon binding of the chlo-
ride ion, whereas that of the regular amide protons shifts
upfield (Table 1). The calculated interatomic H···H distances
between the a protons and their adjacent amide protons
1H NMR titration: The CD2Cl2 solution of 2 (2–4 mm) was titrated by ad-
dition of the concentrated CD2Cl2 solution of the anions (in the form of
their tetrabutylammonium salts for nitrate and iodide, and their tetraphe-
nylphosphonium salts for chloride and bromide). To account for dilution
effects, these anion solutions also contained receptor 2 at its initial con-
centration. The data were fitted to a 1:1 binding profile, according to the
method of Wilcox,[22] by using changes in both the aminoxy and regular
À
À
À
À
(O CaH/O NH, 2.88 ꢂ; O CaH/NH, 3.19 ꢂ; CaH/O NH,
3.55 ꢂ; CaH/NH, 2.96 ꢂ) in both the aminoxy and amino
acid residues correspond well with the NOE patterns ob-
served for the 2-ClÀ complex (Figure 1b).
1
amide NH resonances in their respective H NMR spectra.
Extraction experiment: An aqueous solution of Ph4PCl (or Ph4PNO3)
(1 mL, 5 mm) was added to a solution of 2 in CHCl3 (0.6 mL, 5 mm). The
resulting biphasic solution was shaken vigorously in a closed glass tube
for 2 h and then left to settle for 10 min. The organic layer was dried
over anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure at temperatures<358C. The residue was dissolved in CDCl3
Conclusion
1
Cyclic hexapeptide 2, which consists of alternating d-a-
amino and d-a-aminoxy acids, adopts a highly C3-symmetri-
(0.6 mL) and the H NMR spectrum was recorded.
À
cal conformation featuring alternating N O and g turns. Its
anion binding properties demonstrates that, as a electroneu-
tral receptor, it has great potential to be an effective anion
receptor. In particular, it not only has a high selectivity for
chloride ions, but it can also extract chloride ions from
aqueous solutions into organic phases. This discovery may
afford new opportunities for studies of chloride ion trans-
port. In view of aminoxy amide protons being excellent hy-
drogen-bond donors, we believe that aminoxy acids will be
useful building blocks for various anion receptors with prac-
tical applications.
Acknowledgements
This work was supported by the University of Hong Kong, the Hong
Kong University of Science and Technology, and the Hong Kong Re-
search Grants Council (HKU 7367/03M). The Croucher Foundation is ac-
knowledged for providing Senior Research Fellowships (to D.Y. and Y.-
D.W.). D.Y. thanks Bristol–Myers–Squibb for providing Unrestricted
Grants in Synthetic Organic Chemistry.
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Chloride Ion Receptors
FULL PAPER
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Received: January 27, 2005
Published online: March 10, 2005
Chem. Eur. J. 2005, 11, 3005 – 3009
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3009