Stabilisation of peptide foldamers in an aqueous medium by incorporation of azapeptide building blocks

Article abstract of DOI:10.1002/chem.200900724

Stable foldamers in water: Helical peptidic foldamers including H12 and H10/12 helices were constructed and stabilised in water. The foldamers' extra rigidity stems from the strong hydrogen bonding network of the azapeptide groups (see graphic).

Full text of DOI:10.1002/chem.200900724

DOI: 10.1002/chem.200900724
Stabilisation of Peptide Foldamers in an Aqueous Medium by Incorporation
of Azapeptide Building Blocks
Anasztꢀzia Hetꢁnyi,[a, b] Gꢀbor K. Tꢂth,[b] Csaba Somlai,[b] Elemꢁr Vass,[c]
Tamꢀs A. Martinek,*[a] and Ferenc Fꢃlçp*[a]
Foldamers stabilised by long-range H-bonding interac-
tions constitute a thoroughly studied class of protein-mim-
icking materials and are currently attracting considerable in-
terest.[1] There are two major approaches to the modification
of natural a-amino acid building blocks: 1) homologation of
the amino acid residues (this results in aliphatic b- and g-
peptides[2] and aromatic oligoamide foldamers)[3] and 2) re-
placement of the amide moiety with functional groups capa-
ble of forming a strong H-bonding network (this leads to in-
triguing foldameric oligoureas[4] and azapeptides).[5] The sec-
ondary structure models of both helical oligoureas[4b,6] and
strand-like homooligo-azapeptides[5d,7] display bifurcated H-
bonds in the backbone; this arrangement is theoretically
predicted for azapeptides.[8] Although our preliminary DFT
calculations indicate that the stabilisation energy calculated
for azapeptide H-bonds is at least 10% higher, even in a
non-bifurcated arrangement, than that of the parent pep-
tide–peptide H-bond, helical geometry for azapeptides has
not been found experimentally thus far. This is possibly due
to the preferred short-range bifurcations that stabilise the
strand-like geometries.
lise either sidechains or chain termination to attain an ener-
getically favourable construction; this increases their stabili-
ty in H-bond-destroying water. Although polar solvents can
successfully compete for the H-bond pillars, ureas and aza-
peptides potentially offer stronger H-bonds in the backbone,
and thus are reasonable candidates as foldamer-stabilising
building blocks.
In this work, a novel backbone stabilisation approach is
proposed as a means of increasing the stability of the folda-
meric structures in an aqueous medium. We demonstrate
that incorporation of 1-aminoproline aza-ACPC (ACPC=2-
aminocyclopentanecarboxylic acid) building blocks into b-
peptide chains leads to well-defined secondary structures
that are unusually stable in water.
Oligomers of the ACPC diastereomers can form four
major types of secondary structures:[13,14] a homochiral H12
helix, an alternating heterochiral H10/12 helix, a homochiral
non-polar strand and an alternating heterochiral polar
strand. While the H10/12 helix constructed from ACPC resi-
dues partially retains its structure in an aqueous medium,
the H12 helix does not fold in water. In an aqueous medium
the folding of the H12 helix can be facilitated by substituting
nitrogen in the sidechain moiety of the five-membered
ring.[15] The non-polar and polar strands of ACPC oligomers
exhibit fibrillar aggregates in a polar solvent, due to infinite
sheet formation. Because of their versatility, the ACPC olig-
omers provide an ideal starting model through which to
study the effects of azapeptide incorporation on secondary
structure preference and stability. In this work, the following
sequences were studied (Scheme 1): Ac-[(1S,2R)-ACPC-2S-
aza-ACPC]3-NH2 (1), Ac-[(1R,2S)-ACPC-2S-aza-ACPC]3-
NH2 (2), Ac-[(1S,2S)-ACPC-2S-aza-ACPC]3-NH2 (3) and
Ac-[(1R,2R)-ACPC-2S-aza-ACPC]3-NH2 (4).
Because of their promising biomedical applications,[9] the
stabilisation of foldamers in an aqueous medium is a great
current challenge, and various methods have been proposed
to stabilise them: macrodipole stabilisation,[10] sidechain ion
pairs[11] and disulfide bridges.[12] All of these approaches uti-
[a] Dr. A. Hetꢀnyi, Dr. T. A. Martinek, Prof. Dr. F. Fꢁlçp
Institute of Pharmaceutical Chemistry, University of Szeged, 6720
Szeged, Eçtvçs u. 6 (Hungary)
Fax : (+36)62-545705
E-mail: fulop@pharm.u-szeged.hu
[b] Dr. A. Hetꢀnyi, Prof. Dr. G. K. Tꢂth, Dr. C. Somlai
Department of Medical Chemistry, University of Szeged, 6720
Szeged, Dꢂm tꢀr 8 (Hungary)
The four Boc-ACPC diaACTHNUTRGNEsNUG tereomers and Boc-2S-aza-
ACPC were prepared by using literature methods.[16] Chain
assembly was carried out on a solid support, with Boc
chemistry and DCC/HOBt coupling, by following standard
methodology. The products were isolated by RP-HPLC
(RP=reverse phase) and characterised by means of ESI-
[c] Dr. E. Vass
Institute of Chemistry, Eçtvçs Lorꢃnd University, Pꢃzmꢃny P. s. 1 A,
1117 Budapest (Hungary)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900724.
10736
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 10736 – 10741

COMMUNICATION
coupling constants were also
extracted (see Supporting Infor-
mation). These values were not
sensitive to temperature varia-
tions; this reinforced the view
that the relatively quick proton
exchange for the azapeptide
NH is not a consequence of
conformational inhomogeneity.
To determine the high-resolu-
tion structures, ROESY experi-
ments were run in CD3OH or
[D6]DMSO at 298 K and in
aqueous buffer at both 298 K
Scheme 1. Structures of the Ac-[cis- and trans-ACPC-2S-aza-ACPC]3-NH2 oligomers.
MS.
A
complete 1H NMR
signal assignment was achieved
for 1–4 through the combined
use of COSY, TOCSY and
ROESY. The concentrations
were 4 mm, and various solvents
were utilised, including aqueous
buffer (pH 7.4) at both 277 K
and 298 K, and CD3OH and
[D6]DMSO at 298 K. The solu-
bilities of 1–4 were excellent
under the studied conditions. In
an aqueous medium, line
broadening was observed for
the azapeptide-NH signals at
298 K (Figure S1); this could be
eliminated at the lower temper-
Figure 1. Temperature gradients of the chemical shifts for the protons of the b-peptide (black) and azapeptide
(grey) moieties measured in [D6]DMSO. Panel A) 1, B) 2, C) 3 and D) 4.
ature. Self association was tested in aqueous solution by
means of DOSY and TEM measurements, but aggregation
phenomena were not detected (Figure S2-S3). The line
broadening is attributed to the inherently higher rate of aza-
NH–solvent exchange, which is due to the considerably
higher H-bond acidity of the azapeptide-NH moiety.[17] This
is supported by the relatively intense azapeptide NH–solute
chemical exchange ROESY crosspeaks in water. It is impor-
and 277 K. In all the solvents applied, signal-rich ROESY
spectra were obtained, and a number of long-range (i–i+2)
NOE interactions could readily be observed for 1 and 4
(Figure 2); this offered useful input for the further structure
refinement. Importantly, long-range NOEs were also detect-
ed in the aqueous medium at 298 K for the slowly-exchang-
ing amide nuclei and for all nuclei at 277 K; this is excep-
tional for such short oligomers. For 2, a single i–i+4 NOE
was found, in good accord with a shielded NH3. No long-
range interaction was detected for 3.
Since the backbone contains basic nitrogen atoms, the pH
can affect the folding process and consequently the NMR
features. The NMR experiments were repeated in water buf-
fered to pH 2.0 for 1 and 4 in which the long-range NOEs
at neutral pH indicated helical folding. The acidic medium
resulted in three new signals in the 1H NMR spectra that
could be assigned to the protonated aza nitrogen atoms. In-
terestingly, neither chemical shift changes nor broadening
were observed for the peptide NH signals upon decrease of
the pH. Moreover, the long-range NOE signals remained
intact. These findings strongly suggest that protonation
takes place on the aza-ACPC residues in water at sufficient-
ly acidic pH, but backbone protonation cannot induce un-
folding of the helical structures (see ECD results).
1
tant that H resonances of quaternary nitrogen origin (pro-
tonated aza nitrogen) were not detected in the NMR spectra
recorded in the organic solvents or in aqueous buffer at
pH 7.4.
For assessment of the conformational stabilities of the
peptides, the NH chemical shift temperature gradients (Dd/
DT)[18] were measured in [D6]DMSO in the range 298–318 K
(Figure 1). Unfortunately, Dd/DT reference data for the aza-
peptide moiety could not be found in the literature. In our
models, the Dd/DT values were systematically lower than
those for the amide hydrogens, but this can be explained by
the increased H-bond acidity. The values obtained for the
non-terminal amides (Dd/DT <3 ppb/K) in 1, 3 and 4 clearly
indicate strong H-bonding interactions attributable to the
well-defined secondary structure. For 2, only NH3 displayed
3
strong shielding; this suggests a partial aperiodic fold. JNHCH
Chem. Eur. J. 2009, 15, 10736 – 10741
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10737

F. Fꢁlçp, T. A. Martinek et al.
Figure 2. Characteristic long-range NOE interactions observed. A) 1,
B) 2 and C) 4.
For the 3D structural refinement, an NMR restrained
hybrid Monte Carlo molecular dynamics (MCMD) confor-
mational search was carried out by using the MMFF94x
force field, and cluster analyses were performed for the re-
sulting conformational ensembles. Since the NMR results
pointed to unprotonated backbones in organic solvents and
in water at pH 7.4, the initial structures were constructed
without protonation. For 1, the long-range restraints defined
a single cluster corresponding to the alternating H10/12
helix (RMSV=0.007 ꢅ). For 4, the structure refinement re-
sulted in a single cluster corresponding to the H12 helix
(RMSV=0.003 ꢅ). No consistent violations of distance re-
straints were observed, and the NOEs predicted by the ten
lowest-energy conformations were detected in the spectra
(Figure 3). Inspection of the refined helical structures re-
vealed that the lone pairs of the aza nitrogen atoms are not
involved directly in the backbone H-bonds and are accessi-
ble from the solvent. The molecular mechanics calculations
carried out with the implicit solvation model (water)
showed that both helices remain stable even with a fully
protonated backbone, and this is in accord with NMR find-
ings (Figure S4).
For 2, the calculations resulted in a single cluster, which is
a meandering structure in which NH3 is involved in a bifur-
cated H-bond. On the other hand, the NOE interactions
predicted in the C-terminal part of the sequence by the low-
energy structures could not be identified in the ROESY
spectrum; this suggests that 2 exhibits a fairly stable turn-
like motif in the N terminal, together with a flexible C ter-
minal. Two clusters with similar energies were found for 3,
both of which exhibit 8-membered H-bonded pseudo-rings:
1) a bent 8-strand cluster and 2) a circular fold cluster. Since
strong shielding was indicated by the temperature gradient
data, it can be concluded that the stable 8-membered rings
are constant features of the structure, but the overall shape
of the molecule undergoes fluctuation.
Figure 3. The ten lowest-energy structures obtained from the NMR struc-
ture refinement for A) 1, B) 2, C) 3 (cluster 1), D) 3 (cluster 2) and E) 4.
cal geometry optimisations,[19] the HF/3-21G level of theory
in a vacuum was utilised first, as this has been reported to
provide a good approximation to the geometry of the b-pep-
tides.[20] The structures converged to the corresponding local
minimum of the potential energy surface. To take into ac-
count the effects of more diffuse basis sets and the electron
correlation, the optimisations were performed at the
B3LYP/6-311G** level and the vibration circular dichroism
(VCD) curves were simulated at this level of theory. The
VCD spectra recorded for 1 and 4 in [D6]DMSO exhibit a
well-defined negative couplet between 1650 and 1700 cmꢀ1,
which can be assigned to the coupled amide-I vibrational
modes with higher contributions from the middle and N-ter-
minal amino acid residues. They show fairly good agreement
with the ab initio calculated theoretical VCD curves, espe-
cially in reproducing the negative couplet-like feature in the
amide-I region; this strongly suggests that the left-handed
helical folds have been captured correctly with NMR struc-
ture refinements and ab initio modelling. Moreover, the cor-
respondence between the curves is indicative of the confor-
mational stability of the secondary structures (Figure 4). The
higher intensity of the amide-I VCD couplet seen in the
case of 4 is compatible with a more regular structure of the
H12 helix as compared to the H10/12 helix proposed for 1.
There are, however, some discrepancies between the calcu-
The lowest-energy conformations for 1 and 4 were select-
ed and further optimised. For the ab initio quantum chemi-
10738
www.chemeurj.org
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 10736 – 10741

Stable Peptide Foldamers in Water
COMMUNICATION
Figure 4. VCD curves for A) 1 and B) 4, measured in [D6]DMSO (thick
black, continuous line), and the calculated results (dashed grey line,
given in scaled VCD units).
Figure 5. ECD curves measured in aqueous buffer with pH 7.4 (thick
curves) and in MeOH (thin curves). A) 1 (grey) and 4 (black); B) 2
(black) and 3 (grey).
lated and experimental VCD curves, such as some addition-
al high- or low-wavenumber amide-I features in the calculat-
ed spectra and differences in the less characteristic and
rather weak amide-II region between 1500 and 1570 cmꢀ1.
(This is mostly due to the coupled in-plane bending vibra-
tions of the amide NH bonds). These differences may result
from small deviations from the calculated geometries, espe-
cially at the more flexible C-terminal part of the helices
(note that VCD is very sensitive to small deviations in the
dihedral angles), as well as from specific interactions with
the solvent molecules, as recently shown in the case of Ac-
Ala-NHMe by comparative VCD studies in organic solvents
and solid noble gas matrices.[21]
Electronic circular dichroism (ECD) measurements were
carried out to gain supporting evidence for the presence of
the structures in aqueous buffers and MeOH solutions
(Figure 5). Symmetric positive Cotton effects were found for
both 1 and 4. The positive bands at around 210 nm and the
negative bands at around 195 nm indicate their helix geome-
try. For both 2 and 3, the largely asymmetric features with
the negative bands at around 190 nm indicate the presence
of elongated strand-like structures.[14] In line with the NMR
findings, the ECD curves in an aqueous medium are similar
to those in MeOH; this suggests the presence of highly
stable secondary structures that can withstand the destruc-
turing effect of the water. Moreover, the ECD curves of the
helical foldamers (1 and 4) recorded at physiological and
acidic pH were virtually identical (Figure 6). This is in
agreement with NMR findings and indicates that the studied
Figure 6. ECD curves of 1 (grey) and 4 (black) measured in buffers with
pH 7.4 (thick curves) or pH 3 (thin curves).
helices do not undergo protonation-induced unfolding even
at pH 2.0.
The effects of the incorporation of aza-ACPC building
blocks into the b-peptide chain were tested. The NMR
structural refinements based on the ROESY data revealed
that the secondary structure type enforced by the stereo-
chemical pattern along the backbone is well accommodated
by the azapeptide moieties. The alternating stereochemical
pattern with cis-ACPC residues in the sequence induced the
H10/12 helix (1), while the homochiral sequence with trans-
ACPC monomers gave rise to the H12 helix (4). The exis-
tence of the helical folds is strongly supported by the ECD
Chem. Eur. J. 2009, 15, 10736 – 10741
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10739

F. Fꢁlçp, T. A. Martinek et al.
NMR experiments: NMR measurements were performed on Bruker
AV600 spectrometers with a multinuclear probe with a z-gradient coil in
4 mm CD3OD or [D6]DMSO at 298 K, and in aqueous phosphate buffer
solutions at 277 K and 298 K. The ROESY measurements were carried
out with a WATERGATE solvent suppression scheme. For the ROESY
spinlock, mixing times of 225 and 400 ms were used; the number of scans
was 64. The TOCSY measurements were made with homonuclear Hart-
man–Hahn transfer with the MLEV17 sequence, with a mixing time of
80 ms; the number of scans was 32. For all the 2D spectra, 2024 time
domain points and 512 increments were applied. The processing was car-
ried out by using a cosine-bell window function, with single zero filling
and automatic baseline correction. The PFGSE NMR measurements
were performed by using the stimulated echo and longitudinal eddy cur-
rent delay (LED) sequence with water suppression. A time of 2 ms was
used for the dephasing/refocusing gradient pulse length (d), and 250 ms
for the diffusion delay (D). The gradient strength was changed quadrati-
cally (from 5% to 95% of the maximum value B-AFPA 10 A gradient
amplifier), and the number of steps was 32. Each measurement was run
with 256 scans and 2 K time domain points. For the processing, an expo-
nential window function and single zero filling were applied. During the
diffusion measurements, the fluctuation of the temperature was less than
0.1 K. Prior to the NMR scans, all the samples were equilibrated for
30 min. The aggregation numbers were calculated from the Stokes-Ein-
stein equation and lactose was utilised as an external volume standard.
VCD experiments: VCD spectra at a resolution of 4 cmꢀ1 were recorded
in DCM and [D6]DMSO solutions with a Bruker PMA 37 VCD/PM-
IRRAS module connected to an Equinox 55 FTIR spectrometer. The
ZnSe photoelastic modulator of the instrument was set to 1600 cmꢀ1, and
an optical filter with the transmission range 1960–1250 cmꢀ1 was used in
order to increase the sensitivity in the carbonyl region. The instrument
was calibrated for VCD intensity with a CdS multiplewave plate. A CaF2
cell with a path length of 0.207 mm and a sample concentration of
10 mgmLꢀ1 were used. VCD spectra were obtained as averages of 25000
scans, corresponding to a measurement time of 7 h. Baseline correction
was achieved by subtracting the spectrum of the solvent obtained under
the same conditions.
and the VCD findings. Interestingly, the incorporation of
the aza-ACPC building blocks in an alternating manner pre-
vented the i–i+1 sequential H-bonding interactions ob-
served in the X-ray structures of the homo-oligo-azapep-
ACHTUNGTRENNUNG
tides,[7] and thereby facilitated formation of the helix for 1
and 4. The long-range NOE interactions for these geome-
tries were also found in water, and the ECD intensities were
not decreased in an aqueous medium; this indicates that
they are highly stable, even in a destructuring solvent. Al-
though elevated proton concentration resulted in protonated
backbones for both 1 and 4, no signs of unfolding were ob-
served. It is likely that the free nitrogen lone pairs are acces-
sible, and the positive charges are shielded by the solvent
and the counter ions. While the homochiral cis-ACPC and
the heterochiral alternating trans-ACPC oligomers exhibited
fibril-forming strands,[22] 2 and 3 displayed a propensity for
the formation of intramolecular H-bonds. The NMR behav-
iour of the azapeptide-NH resonances strongly suggested
that their H-bond acidity is higher than that of the amide
protons. This thereby explains the stronger H-bonds, and in
turn the secondary structure-stabilising effect of the azapep-
tide moiety.
Besides their stabilisation effect, the aza-ACPC residues
increased the water solubilities of the foldameric structures
over a wide pH range; this underlines the future applicabili-
ty of these building blocks in foldamer design, especially in
the field of bioactive foldamers.
CD measurements: CD spectra were measured on a Jasco J810 instru-
ment at 258C in a 0.02 cm cell. Eight spectra were accumulated for each
sample. The baseline spectrum recorded with the solvent only was sub-
tracted from the raw data. The concentration of the sample solutions was
4 mm in CD3OH and 1 mm in the aqueous buffers.
Experimental Section
Peptide synthesis: The synthesised hybrid oligomers were numbered as
follows: H-[(1S,2R)-ACPC-2S-aza-ACPC]3-NH2 (1), H-[(1R,2S)-ACPC-
2S-aza-ACPC]3-NH2 (2) H-[(1S,2S)-ACPC-2S-aza-ACPC]3-NH2 (3) and
H-[(1R,2R)-ACPC-2S-aza-ACPC]3-NH2 (4). The sequences were synthe-
Molecular mechanics calculations: Molecular mechanical simulations
were carried out in the Molecular Operating Environment (MOE) of the
Chemical Computing Group. For the energy calculations, the MMFF94x
force field was used, without a cut-off for van der Waals and Coulomb in-
teractions, and the distance-dependent dielectric constant (er) was set to
e=1.8 (corresponding to CH3OH). For the protonated backbones, the
implicit water model of GB/VI (Generalized Born) was applied. The con-
formational sampling was carried out by using the hybrid MCMD simula-
tion (as implemented in MOE) at 300 K with a random MC sampling
step after every ten MD steps. The MC-MD was run with a step size of
2 fs for 20 ns, and the conformations were saved after every 1000 MD
steps, and this resulted in 104 structures. For the NMR-restrained simula-
tion, the upper distance limits were calculated by using the isolated spin
pair approximation and classified by following the standard method
(strong: 2.5 ꢅ, medium: 3.5 ꢅ, and weak: 5.0 ꢅ). The lower limit was set
to 1.8 ꢅ. Restraints were applied as a flat-bottomed quadratic penalty
term with a force constant of 5 kcalꢅꢀ2. The final conformations were
minimised to a gradient of 0.05 kcalmolꢀ1 and the minimisation was ap-
plied in a cascade manner, using the steepest-descent, conjugate gradient
and truncated Newton algorithm.
ACHTUNGTRENNUNG
sised by using a solid-phase technique that utilised tBoc chemistry.[23] The
2S-aza-ACPC (l-N-aminoproline) was synthesised in the following
manner: 1-nitrosoproline was prepared from l-proline by using a stan-
dard literature procedure (3m sulfuric acid and sodium nitrite).[16d] The
resulting 1-nitrosoproline was dissolved in acetic acid (50 v/v%) and was
reduced with zinc dust. The resulting compound was Boc protected in
sodium hydrocarbonate solution by reaction with di-tert-butyl dicarbon-
ate. The peptide chains were elongated on an MBHA resin
(1.03 mmolgꢀ1) and the syntheses were carried out manually. Couplings
of the ACPC and aza-ACPC isomers were performed with DCC/HOBt,
without difficulties. The incorporation of hydrazino building blocks with
an unprotected alpha nitrogen usually leads to numerous side reac-
tions,[24] but in our case the imino nitrogen avoided these side reactions.
The N-terminal acetylation was achieved with Ac2O (20% in DCM). The
completed peptide resins were treated with liquid HF/dimethyl sulfide/p-
cresol/p-thiocresol (86:6:4:2, v/v) at 08C for 1 h. The HF was then re-
moved and the resulting free peptides were solubilised in aqueous acetic
acid (10%), filtered and lyophilised. The crude peptides were investigat-
ed by RP-HPLC on a Phenomenex Jupiter C18 column (4.6ꢆ250 mm).
The solvent system used was as follows: TFA (0.1%) in water, acetoni-
trile (80%) in water, gradient: 25%!45% in 15 min, flow rate
1.2 mLminꢀ1, detection at 220 nm. The model peptides were character-
ised by mass spectrometry with a Finnigan TSQ 7000 tandem quadrupole
mass spectrometer equipped with an electrospray ion source. The above
peptides were purified on an HPLC system on a 21.2 mm semiprepara-
tive column.
Ab initio calculations: The optimisations were carried out in two steps
with the Gaussian 03 program: first by using the HF/3–21G basis set, and
then by using density-functional theory at the B3LYP/6–311G** level
with a default setup. For the protonated models, the level of B3LYP/6–
31G* with PCM water model was utilised. The theoretical VCD spectra
of 1 and 4 were calculated with the Gaussian 03 program at the B3LYP/
6–31G* level of theory, for geometry optimised in vacuum at the same
10740
www.chemeurj.org
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 10736 – 10741

Stable Peptide Foldamers in Water
COMMUNICATION
level. The calculated vibrational frequencies were scaled by a factor of
0.963. VCD curves were simulated from the calculated wavenumber and
rotatory strength data by using Lorentzian band shape and a half-width
[11] a) P. I. Arvidsson, M. Rueping, D. Seebach, Chem. Commun. 2001,
649–650; b) R. P. Cheng, W. F. DeGrado, J. Am. Chem. Soc. 2001,
123, 5162–5163; c) M. Rueping, Y. R. Mahajan, B. Jaun, D. Seebach,
Chem. Eur. J. 2004, 10, 1607–1615.
at a half-height value of 6 cmꢀ1
.
[12] a) M. Rueping, B. Jaun, D. Seebach, Chem. Commun. 2000, 2267–
2268; b) R. P. Cheng, W. F. DeGrado, J. Am. Chem. Soc. 2002, 124,
11564–11565.
[13] D. H. Appella, L. A. Christianson, D. A. Klein, D. R. Powell, X.
Huang, J. J. Barchi, S. H. Gellman, Nature 1997, 387, 381.
[14] a) T. A. Martinek, G. K. Tꢂth, E. Vass, M. Hollꢂsi, F. Fꢁlçp, Angew.
Chem. 2002, 114, 1794–1797; Angew. Chem. Int. Ed. 2002, 41, 1718–
1721; b) T. A. Martinek, I. M. Mꢃndity, L. Fꢁlçp, K. G. Tꢂth, E.
Vass, M. Hollꢂsi, E. Forrꢂ, F. Fꢁlçp, J. Am. Chem. Soc. 2006, 128,
13539–13544.
[15] a) X. Wang, J. F. Espinosa, S. H. Gellman, J. Am. Chem. Soc. 2000,
122, 4821–4822; b) H.-S. Lee, F. A. Syud, X. Wang, S. H. Gellman,
J. Am. Chem. Soc. 2000, 122, 7721–7722.
Acknowledgements
A.H. thanks the Magyary Zoltꢃn Foundation, E.V. the Economic Com-
petitiveness Operational Program GVOP-KMA (GVOP-3.2.1–2004–04–
0345/3.0) and T.M. the Hungarian Research Foundation (NF69316) and
the HAS for a Jꢃnos Bolyai Research Fellowship. The computational re-
sources of HPC U-Szeged (ALAP4–00092/2005) are acknowledged.
[16] a) P. R. LePlae, N. Umezawa, H. S. Lee, S. H. Gellman, J. Org.
Chem. 2001, 66, 5629–5632; b) E. Forrꢂ, F. Fꢁlçp, Org. Lett. 2003, 5,
1209–1212; c) E. Forrꢂ, F. Fꢁlçp, Mini-Rev. Org. Chem. 2004, 1, 93–
102; d) H. J. Klosterman, G. L. Lamorueux, J. L. Parsons, Biochem-
istry 1967, 6, 170–177.
Keywords: amino acids · chirality · foldamers · peptides ·
peptidomimetics
[1] a) D. H. Appella, L. A. Christianson, D. A. Klein, D. R. Powell, X.
Huang, J. J. Barchi, S. H. Gellman, Nature 1997, 387, 381; b) P. Le
Grel, G. Guichard in Foldamers: Structure, Properties and Applica-
tions: Foldamers Based on Remote Intrastrand Interactions (Eds.: S.
Hecht, I. Huc), Wiley-VCH, Weimheim, 2007, pp. 35–74; c) C. M.
Goodman, S. Choi, S. Shandler, W. F. DeGrado, Nat. Chem. Biol.
2007, 3, 252–262; d) D. Seebach, A. K. Beck, D. J. Bierbaum, Chem.
Biodiversity 2004, 1, 1111–1239.
[2] D. Seebach, D. F. Hook, A. Glattli, Biopolymers 2006, 84, 23–37.
[3] a) I. Huc, Eur. J. Org. Chem. 2004, 17–29; b) C. Li, G. T. Wang,
H. P. Yi, X. K. Jiang, Z. T. Li, R. X. Wang, Org. Lett. 2007, 9, 1797–
1800.
[4] a) V. Semetey, C. Hemmerlin, C. Didierjean, A. P. Schaffner, A. G.
Giner, A. Aubry, J. P. Briand, M. Marraud, G. Guichard, Org. Lett.
2001, 3, 3843–3846; b) A. Violette, M. C. Averlant-Petit, V. Seme-
tey, C. Hemmerlin, R. Casimir, R. Graff, M. Marraud, J. P. Briand,
D. Rognan, G. Guichard, J. Am. Chem. Soc. 2005, 127, 2156–2164.
[5] a) M. Thormann, H. J. Hofmann, J. Mol. Struct. 1999, 469, 63–76;
b) R. Gꢁnther, H. J. Hofmann, J. Am. Chem. Soc. 2001, 123, 247–
255; c) A. Cheguillaume, A. Salaun, S. Sinbandhit, M. Potel, P. Gall,
M. Baudy-Floc’h, P. Le Grel, J. Org. Chem. 2001, 66, 4923–4929;
d) P. Le Grel, A. Salaun, M. Potel, B. Le Grel, F. Lassagne, J. Org.
Chem. 2006, 71, 5638–5645.
[17] M. H. Abraham, R. J. Abraham, J. Byrne, L. Griffiths, J. Org. Chem.
2006, 71, 3389–3394.
[18] a) H. N. Andersen, W. J. Neidigh, M. S. Harris, M. G. Lee, Z. Liu, H.
Tong, J. Am. Chem. Soc. 1997, 119, 8547–8561; b) D. Ranganathan,
V. Haridas, S. Kurur, R. Nagaraj, E. Bikshapathy, A. C. Kunwar,
A. V. S. Sarma, M. Vairamani, J. Org. Chem. 2000, 65, 365–374;
c) R. Threlfall, A. Davies, N. M. Howarth, J. Fisher, R. Cosstick,
Chem. Commun. 2008, 5, 585–587; d) I. M. Mꢃndity, E. Weber,
T. A. Martinek, G. Olajos, G. K. Toth, E. Vass E, F. Fꢁlop, Angew.
Chem. 2009, 121, 2205–2209; Angew. Chem. Int. Ed. 2009, 48, 2171–
2175.
[19] Gaussian 03, Revision C.02, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomer-
y, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyen-
gar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N.
Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J.
Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C.
Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cio-
slowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaro-
mi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng,
A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc.: Pitts-
burgh PA, 2003.
[6] C. Hemmerlin, M. Marraud, D. Rognan, R. Graff, V. Semetey, J. P.
Briand, G. Guichard, Helv. Chim. Acta 2002, 85, 3692–3711.
[7] A. Salaꢁn, M. Potel, T. Roisnel, P. Gall, P. Le Grel, J. Org. Chem.
2005, 70, 6499–6502.
[8] A. Salaꢁn, A. Favre, B. Le Grel, M. Potel, P. Le Grel, J. Org. Chem.
2006, 71, 150–158.
[9] a) P. I. Arvidsson, N. S. Ryder, H. M. Weiss, G. Gross, O. Kretz, R.
Woessner, D. Seebach, ChemBioChem 2003, 4, 1345–1347; b) E. P.
English, R. S. Chumanov, S. H. Gellman, T. J. Compton, J. Biol.
Chem. 2005, 281, 2661–2667; c) E. A. Porter, X. Wang, H.-S. Lee, B.
Weisblum, S. H. Gellman, Nature 2000, 404, 565–565; d) J. A. Krit-
zer, N. W. Luedtke, E. A. Harker, A. Schepartz, J. Am. Chem. Soc.
2005, 127, 14584–14585; e) J. A. Kritzer, J. D. Lear, M. E. Hodsdon,
A. Schepartz, J. Am. Chem. Soc. 2004, 126, 9468–9469; f) D. Liu, W.
DeGrado, J. Am. Chem. Soc. 2001, 123, 7553–7559.
[10] a) S. A. Hart, A. B. F. Bahadoor, E. E. Matthews, X. Y. J. Qiu, A.
Schepartz, J. Am. Chem. Soc. 2003, 125, 4022–4023; b) J. A. Kritzer,
J. Tirado-Rives, S. A. Hart, J. D. Lear, W. L. Jorgensen, A. Sche-
partz, J. Am. Chem. Soc. 2005, 127, 167–178.
[20] a) T. Beke, I. G. Csizmadia, A. Perczel, J. Comput. Chem. 2004, 25,
285–307; b) K. Mçhle, R. Gunther, M. Thormann, N. Sewald, H.
Hofmann, J. Biopolym. 1999, 50, 167–184.
[21] G. Pohl, A. Perczel, E. Vass, G. Magyarfalvi, G. Tarczay, Phys.
Chem. Chem. Phys. 2007, 9, 4698–4708.
[22] T. A. Martinek, A. Hetꢀnyi, L. Fꢁlçp, I. M. Mꢃndity, G. K. Tꢂth, I.
Dꢀkꢃny, F. Fꢁlçp, Angew. Chem. 2006, 118, 2456–2460; Angew.
Chem. Int. Ed. 2006, 45, 2396–2400.
[23] R. B. Merrifield, J. Am. Chem. Soc. 1963, 85, 2149–2154.
[24] L. Guy, J. Vidal, A. Collet, A. Amour, M. Rebound-Ravaux, J. Med.
Chem. 1998, 41, 4833–4843.
Received: March 20, 2009
Published online: September 11, 2009
Chem. Eur. J. 2009, 15, 10736 – 10741
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10741