Controlling helix formation in the γ-peptide superfamily: Heterogeneous foldamers with urea/amide and urea/carbamate backbones

Article abstract of DOI:10.1002/anie.201209838

One fold to rule them all: New heterogeneous aliphatic backbone foldamers belonging to the γ-peptide superfamily and containing various combinations of urea/amide (U/A) and urea/carbamate (U/C) units are reported. Structural studies at atomic resolution reveal hydrogen-bonded helical structures akin to that formed by cognate U_n homooligomers. Copyright

Full text of DOI:10.1002/anie.201209838

Angewandte
Chemie
DOI: 10.1002/anie.201209838
Peptidomimetics
Controlling Helix Formation in the g-Peptide Superfamily:
Heterogeneous Foldamers with Urea/Amide and Urea/Carbamate
Backbones**
Nagendar Pendem, Yella Reddy Nelli, Cꢀline Douat, Lucile Fischer, Michel Laguerre,
Eric Ennifar, Brice Kauffmann, and Gilles Guichard*
Structures and functions of biopolymers have inspired the
design, synthesis, and characterization of a multitude of
synthetic oligomeric backbones with well-defined and pre-
dictable folding patterns, termed foldamers.[1,2] The diversity
of foldamer structures originates from the chemical diversity
of constituent units which have been developed to impose
conformational restriction and promote folding. Like nucleic
acids and proteins, many foldamer backbones are built from
one type of subunit, and diversity is generally created through
side chains (e.g. aliphatic b and g peptides,[3] aromatic
d peptides,[4] hydrazinopeptides,[5] aminoxy peptides,[6] ali-
phatic oligoureas[7]). Foldamer synthesis is, however, not
limited to homogenous backbones. Approaches based on
sequences combining two or more types of monomers, that is,
heterogeneous foldamers, have recently been the subject of
much interest as they considerably expand the diversity of
foldamer backbones accessible from a limited set of building
blocks.[8–10] For example, peptide helices with different surface
topologies and functions have been created by combining
aliphatic a-, b-, and g-amino acid residues at different
periodicities.[8,11] Alternatively, various combinations of iso-
steric building units may be used to create isomorphic
foldamer backbones which subtly differ from their homoge-
neous counterparts in terms of physicochemical properties
(e.g. water solubility, backbone polarity, conformational
stability, side-chain projection) and ultimately biological
activities.[12,13] We have previously demonstrated that hetero-
geneous backbone sequences consisting of isosteric amide
(A) and urea (U) units with proteinogenic side chains
(Figure 1a) can be used to tune and optimize biological
[*] Dr. N. Pendem, Dr. Y. R. Nelli, Dr. C. Douat, Dr. L. Fischer,
Dr. M. Laguerre, Dr. G. Guichard
Figure 1. a) Formulae of the isosteric units U, A, and C with associated
nomenclature of main chain atoms. b) Sequences of heterogeneous
oligomers 1–5 combining various ratios of U/A and U/C units and
sequence of cognate hexaurea uU5. The lower case u and a stand for
terminal urea and amide linkages.
Universitꢀ de Bordeaux-CNRS UMR5248
Institut Europꢀen de Chimie et Biologie
2 rue Robert Escarpit, 33607 Pessac (France)
E-mail: g.guichard@iecb.u-bordeaux.fr
Dr. E. Ennifar
Universitꢀ de Strasbourg-CNRS UPR9002, Architecture et Rꢀactivitꢀ
de l’ARN, IBMC, CNRS, Strasbourg (France)
activities of corresponding homooligomers (i.e., helical g4-
peptides An and N,N’-linked oligoureas Un). Whereas amphi-
philic helical g4-peptides An, designed to mimic host defense
peptides, failed to display any significant antimicrobial
activity, the insertion of discrete A units in Un sequences led
to active sequences with increased selectivity for bacterial
membranes compared to the cognate Un homooligomer.[13]
To our knowledge, high-resolution structures of hetero-
geneous backbones in this family of foldamers are not
available to date. Such insight would provide useful guidelines
for future designs of bioactive mixed foldamers, thus facili-
tating structure–activity relationship studies. Herein, we
report the detailed structural characterization of heteroge-
neous aliphatic oligomers belonging to the g-peptide line-
age[1b] and consisting of various combinations of acyclic U and
Dr. B. Kauffmann
Universitꢀ de Bordeaux-CNRS UMS3033
Institut Europꢀen de Chimie et Biologie, Pessac (France)
[**] This work was supported by the CNRS, the University of Bordeaux
(UB), the Conseil Rꢀgional d’Aquitaine, and ANR (Grant ANR-10-
RPDOC-016). A fellowship from the University of Strasbourg (N.P.)
is gratefully acknowledged. The crystallographic data have been
collected at the IECB X-ray facility (UMS3033 CNRS and UB, US001
INSERM), at ESRF in Grenoble (France) and at the Swiss Light
Source (SLS) in Villigen (Switzerland). Beamline scientists from
ESRF ID29 and FIP BM30A are warmly acknowledged for beamtime
and help during data collection. We thank Vincent Olieric for his
support at the SLS synchrotron and Axelle Grꢀlard for her assistance
with NMR measurements.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209838.
Angew. Chem. Int. Ed. 2013, 52, 4147 –4151
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4147

.
Angewandte
Communications
A units, and for the first time isosteric C (carbamate[14]
)
The substitution of a CH2 for N’H at position P3 in 1a is
very conservative with little effect on the local geometry
(Figure 1). In addition, one aCH proton of the A unit behaves
as a hydrogen-bond donor and together with the amide NH
proton is in close contact with the carbonyl oxygen atom at
P5. This three-centered hydrogen bond is reminiscent of the
canonical hydrogen-bonding pattern of oligoureas.[19] Similar
bifurcated hydrogen bonds involving intermolecular CH···O
contacts have been observed previously in parallel sheet
structure arrangements formed by cyclopropane g-amino acid
derivatives.[20] The introduction of a carbamate unit into 2
replacements (1–5, Figure 1b). Although they share an
isosteric relationship, U, A, and C units are endowed with
different folding propensities. In solution and in the crystal,
aliphatic urea oligomers Un adopt well-defined right-handed
helical conformations stabilized by remote three-centered
hydrogen bonds.[7,15] The g4-peptide backbone An also shows
propensity to form helices, albeit of lower stability compared
to g2,4 and g2,3,4-substituted peptides.[3b,c,16,17] In contrast, there
is no evidence that the oligocarbamates Cn adopt a well-
defined fold.[18]
=
To assess the extent to which the canonical helical
structure of oligoureas can propagate across A and C units,
we first prepared analogues of uU5 containing one central
amide (1) or carbamate (2) linkage (P3 position). Crystals of
uU5, 1a, and 2b suitable for X-ray diffraction analysis were
obtained and structures were solved in the P212121 (uU5 and
1a) and P43212 (2b) space groups, respectively.[19] The crystal
structure of 2b contains two independent molecules (I) and
(II) in the asymmetric unit (ASU). All three oligomers are
fully helical in the solid state (Figure 2). A and C units
causes C O(5) to shift away from the main chain carbamate
oxygen atom [the distance between the two oxygen atoms is
3.7 ꢀ and 3.3 ꢀ in molecules (I) and (II), respectively] to
reduce the electronic repulsion between the carbamate and
carbonyl oxygen atoms. The carbamate NH at P3 nevertheless
=
remains within a hydrogen-bonded distance to C O(5) [D
(N···O) = 2.7 ꢀ (I and II), (N-H-O) = 155.28 (I) and 127.08
(II)]. Superimposition of the two independent molecules I
and II in the crystal structure of 2b is shown in Figure 2d. The
overall conformation of 2b(I) and 2b(II) is similar, but the
hydrogen-bonding scheme differs perceptibly between the
two independent molecules, thus reflecting backbone dynam-
ics. Complementary hydrogen-bonding sites are fully satisfied
in 2b(I) with NH and N’H of U units at positions P1, P2, and
P4 engaged in three-centered hydrogen bonds as in uU5. In
contrast, the carbonyl groups are slightly shifted in 2b(II) and
remaining hydrogen bonded to only one NH [i.e., N’H(U1),
N’H(U2), N’H(U4)].
The helical character of 1 and 2 was further investigated
by 1H NMR spectroscopy in CD3OH. As an indicator of
folding propensity, the diastereotopicity values of main chain
methylene protons (Dd) were measured and compared for all
three oligomers.[19,21]
The Dd values measured for backbone U methylene
protons in 1a (0.73 < Dd < 1.07 ppm) and 2a (0.60 < Dd <
0.97 ppm) compared to those of uU5 (0.81 < Dd < 1.31 ppm)
suggest folding, but also possible distortion from the original
helix geometry. This destabilization is likely to arise from the
loss of one hydrogen bond, an increased flexibility and/or
from local backbone rearrangement (e.g. as a result of
electronic repulsion in 2). The significant diastereotopicity
observed for methylene protons in the A and C units at P3
Figure 2. Structures of uU5, 1a, and 2b in the crystalline state. a) X-ray
crystal structure of uU5. b) X-ray crystal structure of 1a. c) Comparison
of helical conformations formed by the two independent molecules
2b(I) and 2b(II) in ASU. d) Overlay of 2b(I) and 2b(II) (side chains
are omitted). Carbon atoms in A and C units are depicted in orange
and green, respectively.
b
a
(Dd = 0.77 ppm and 1.09 ppm for CH2 in A unit and CH2
protons in C unit, respectively) is also indicative of a folded
b
accommodate the helix geometry with torsion angles f, q1,
and q2 (A unit in 1: À110.78, 55.08, 65.68; C unit in 2b:
À121.88, 54.38, 79.68), in the range of values measured for the
corresponding U unit in uU5 (À101.48, 54.48, 77.68). The mean
torsion angles f, q1, and q2 in U units do not vary significantly
between uU5, 1a (À108.88, 54.88, 77.18), and 2b [À111.58,
60.68, 78.98(I)) and (À107.68, 54.38, 87.08(II)]. An overlay of
the structures of 1a and 2b with that of uU5, by fitting the five
pairs of b-carbon atoms (U and C units) or g-carbon atoms
(A unit), indicated a close match between uU5 and 1a (root-
mean square deviation values (RMSD) of 0.150 ꢀ) and
pointed to larger differences between the backbone confor-
mations of uU5 and 2b [RMSD of 0.535 ꢀ (I) and 0.760 ꢀ
(II)].
conformation in 1a and 2a. The Dd value observed for CH2
in the Aunit of 1a compares favorably with that measured for
central residues in a helically folded g4 hexapeptide (ca. 0.43–
0.47 ppm in CD3OH).[16] Evidence that 1 adopts a helical
conformation akin to that of uU5 in solution came from the
observation of characteristic medium to strong i/(i+1) and
i/(i+2) nuclear Overhauser enhancements (nOes).[19]
Although a detailed NMR investigation of 2a was hampered
by resonance overlaps in the NH/CH fingerprint region,
several medium to weak inter-residue nOes consistent with
helical folding were unambiguously assigned in the ROESY
spectrum of 2a.[19] These results confirm that the 2.5-helix
geometry can accommodate discrete replacement of U units
by A and C units. Additional insight into the relative stability
4148
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 4147 –4151

Angewandte
Chemie
of short helices uU5 and 1 was gained by determining urea H–
D exchange rate constants (in CD3OD at 158C). The finding
that H–D exchange rates of NH at P4 are similar in magnitude
in uU5 and 1 but that NHs at P2 exchange significantly faster
in 1 (e.g. 69 and 113 ꢁ 10À3 minÀ1 versus 12 and 16 ꢁ 10À3 minÀ1
in uU5) provides further evidence that A locally destabilizes
the helix, and is in line with diastereotopicity measure-
ments.[19]
Figure 3. Hybrid oligomers with aliphatic side chains, analogous to 4
and 5 which gave crystals suitable for X-ray diffraction studies.
We next investigated the synthesis[19] and conformational
preferences of heterogeneous oligomers containing an
increasing number of A and C monomeric units. Hexamers
3 and 4 are made of alternating U/A and U/C units (1:1
pattern), respectively, whereas the hexamer 5 consists of U
and A units arranged in a 2:2 pattern. Again, the extent of
diastereotopicity of methylene protons in U, A, and C units
provided a first hint about the propensity of the different
oligomers to fold. It is worth noting that despite overall
similarity, the three oligomers display very distinct solubility
Circular dichroism (CD) was also used to gain insight into the
folding behavior of 6 and 7. The CD spectra in TFE (0.2 mm,
258C) reveal a signature with a maximum of positive molar
ellipticity at about 195 and 201 nm for 6 and 7, respectively,
thus supporting folded conformations. It is noteworthy that
the CD signature of 7 in TFE, which also includes zero-
crossing at about 194 nm and a weaker minimum at 188 nm, is
similar to that of cognate 2.5-helical urea oligomers.[19,23]
Crystal structures of the short oligomers 3 (P212121), 6
(P21), and 7 (P212121) reveal the formation of helices akin to
that of urea homooligomers (Figure 4).[19] In 1:1 hetero-
behavior, thus precluding
a head-to-head comparison.
Whereas the U/A hexamer 3 was found to be fully soluble
at millimolar concentrations in MeOH, both the U/A
hexamer 5 and U/C hexamer 4 were only soluble in nonprotic
solvents (e.g. MeCN, CHCl3). DQF-COSY and TOCSY
experiments were used to assign proton resonances of all
residues. Unequivocal sequence-specific assignment for the
U/A oligomers 3 and 5 was accomplished by analyzing short-
range N’H(i)/NH(i) (U units) and aCH(i)/NH(i) nOes
(A units) in the ROESY experiment. Qualitative inspection
of nOes (tm = 300 ms) in the spectra of 3 and 5 revealed the
presence of a number of inter-residue nOe connectivities
along the sequence consistent with helical folding [e.g.,
NH(A4)/gCH(A6) and NH(A2)/bCH(U3) in 3, NH(A3)/
gCH(A4) and NH(U5)/bCH(U6) in 5].[19] The absence of
short-range NOEs across the carbamate linkage in the U/C
hexamer 4, together with redundancy of side chains (i.e.,
benzyl groups) precluded full sequence assignment. Never-
theless, chemical-shift differences between methylene diaste-
reotopic protons within U, A, and C units are large (ꢀ 0.8 ppm
for nonterminal U units, ꢀ 0.7 ppm for A and C units) in all
three oligomers,[19] and compare well with that of homooli-
goureas and singly substituted 1 and 2. The extent of
diastereotopicity of backbone methylene protons in all
three oligomers 3–5 thus suggests that the ratio of U units
can be reduced to 50% in favor of A or C units without
causing major rearrangement of the helix conformation. A
similar templating effect, whereby global folding behavior is
dictated by a small number of residues of one class has been
observed previously among hybrid aromatic oligoamides
containing two types of d-amino acid residues with different
folding propensities.[22]
Figure 4. Comparison of structures of heterogeneous oligomers 3, 6,
and 7 in the crystalline state. Carbon atoms of A and C units are
depicted in orange and green, respectively.
oligomers 3 and 6, ureas are hydrogen bonded to ureas,
amides to amides, and carbamates to carbamates. In contrast,
each amide unit is hydrogen bonded with two urea units in 7.
Urea NHs are generally involved in three-centered hydrogen
bonds except in 3 at P3 where only one of the two NHs is
within a hydrogen-bonding distance of the carbonyl oxygen
atom at P5. As shown in Table 1, the mean backbone torsion
angles of U units are globally conserved over all three
structures. The comparison of dihedral angles in U and C
units also confirms that the carbamate insertion is conserva-
tive and does not lead to major structural rearrangements.
Overlay of the three structures of 6 with that of uU5 by fitting
the five pairs of bC gives RMSDs in the range 0.311–
0.693 ꢀ.[19]
Crystallinity was not improved by changing the nature of
the terminal u group in 4 and 5 (4-CF3C6H4, 4-BrC6H4, Bn, iPr,
data not shown). However, single crystals were obtained from
analogues, namely the pentamer 6 and hexamer 7, bearing
aliphatic side chains (Figure 3). The NMR spectra of 6 in
CDCl3 and in CDCl3/[D6]DMSO (7:3), and 7 in CD3OH
display the hallmarks of helically folded conformations: large
diastereotopicity values as in the cognate 4 and 5 and
representative of medium-range i/(i+1) and i/(i+2) nOes.[19]
Although geometrically close, the helices of the 2:2 U/A
hybrid and the cognate urea oligomer show some differences
in the projection of their side chains. For example, the
distances between side chains at P1, P3, and P6 positions in 7
Angew. Chem. Int. Ed. 2013, 52, 4147 –4151
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4149

.
Angewandte
Communications
Alezra, Amino Acids 2011, 41, 687 – 707; c) T. A. Martinek, F.
Fulop, Chem. Soc. Rev. 2012, 41, 687 – 702.
Table 1: Mean backbone torsion angles [8] for A, C, and U units in the
crystal structures of 3, 6, and 7.
[4] E. R. Gillies, F. Deiss, C. Staedel, J.-M. Schmitter, I. Huc, Angew.
Chem. 2007, 119, 4159 – 4162; Angew. Chem. Int. Ed. 2007, 46,
4081 – 4084.
Compd
Unit
f
q1
q2
Y
3
U[a]
A[a,b]
U[a]
C[a]
U[c]
A
À116.8
À126.2
À116.5
À106.3
À107.0
À130.9
56.2
56.0
54.8
56.6
54.0
51.2
87.3
66.6
77.4
85.0
83.4
65.2
À172.8
À139.2
À173.1
À171.4
À177.1
À143.6
[5] a) A. Salaꢄn, M. Potel, T. Roisnel, P. Gall, P. Le Grel, J. Org.
Chem. 2005, 70, 6499 – 6502; b) C. Mocquet, A. Salaꢄn, P.
Claudon, B. L. Grel, M. Potel, G. Guichard, B. Jamart-Grꢃgoire,
P. Le Grel, J. Am. Chem. Soc. 2009, 131, 14521 – 14525.
[6] X. Li, D. Yang, Chem. Commun. 2006, 3367 – 3379.
[7] For reviews, see: L. Fischer, G. Guichard, Org. Biomol. Chem.
2010, 8, 3101 – 3117; N. Volz, J. Clayden, Angew. Chem. 2011,
123, 12354 – 12361; Angew. Chem. Int. Ed. 2011, 50, 12148 –
12155.
[8] For reviews, see : a) W. S. Horne, S. H. Gellman, Acc. Chem. Res.
2008, 41, 1399 – 1408; b) P. G. Vasudev, S. Chatterjee, N. Sha-
mala, P. Balaram, Chem. Rev. 2011, 111, 657 – 687; c) L. Pilsl, O.
Reiser, Amino Acids 2011, 41, 709 – 718; d) A. Roy, P. Prabha-
karan, P. K. Baruah, G. J. Sanjayan, Chem. Commun. 2011, 47,
11593 – 11611.
[9] Y. Ferrand, A. M. Kendhale, B. Kauffmann, A. Grelard, C.
Marie, V. Blot, M. Pipelier, D. Dubreuil, I. Huc, J. Am. Chem.
Soc. 2010, 132, 7858 – 7859.
[10] P. Prabhakaran, S. S. Kale, V. G. Puranik, P. R. Rajamohanan, O.
Chetina, J. A. Howard, H. J. Hofmann, G. J. Sanjayan, J. Am.
Chem. Soc. 2008, 130, 17743 – 17754.
[11] a) Ł. Berlicki, L. Pilsl, E. Wꢃber, I. M. Mꢅndity, C. Cabrele, T. A.
Martinek, F. Fꢄlçp, O. Reiser, Angew. Chem. 2012, 124, 2251 –
2255; Angew. Chem. Int. Ed. 2012, 51, 2208 – 2212; b) K.
Basuroy, B. Dinesh, N. Shamala, P. Balaram, Angew. Chem.
2012, 124, 8866 – 8869; Angew. Chem. Int. Ed. 2012, 51, 8736 –
8739; c) T. Sawada, S. H. Gellman, J. Am. Chem. Soc. 2011, 133,
7336 – 7339; d) R. Rezaei Araghi, C. Baldauf, U. Gerling, C.
Cadicamo, B. Koksch, Amino Acids 2011, 41, 733 – 742; e) L.
Guo, A. M. Almeida, W. Zhang, A. G. Reidenbach, S. H. Choi,
I. A. Guzei, S. H. Gellman, J. Am. Chem. Soc. 2010, 132, 7868 –
7869; f) G. V. Sharma, V. B. Jadhav, K. V. Ramakrishna, P.
Jayaprakash, K. Narsimulu, V. Subash, A. C. Kunwar, J. Am.
Chem. Soc. 2006, 128, 14657 – 14668.
6
7
[a] Mean angles from the three independent molecules I–III in the ASU.
[b] Excluding A6(II) for which f, q1, q2, and Y values are À94.18, 170.08,
À59.88, and À69.28, respectively. [c] Excluding U1 for which f, q1, q2, and
Y values are À110.08, 558, À144.78, and 167.18.
(5.6, 6.1, 9.9 ꢀ) differ from that measured in the structure of
the corresponding homooligourea (6.1, 8.1, 9.9 ꢀ)[15] and
could match more closely the spatial arrangement of side
chains at i + 7, i + 4, and i positions in an a helix. It is
noteworthy that the different helices also differ in their
resulting macrodipoles. In particular, the 1:1 urea/carbamate
helical backbone exhibits a reduced average dipole per
residue (D/n ꢁ 2.0 Debye; calculated from the crystal struc-
ture of 6) compared to that of corresponding helical
homooligourea (D/n ꢁ 2.5 Debye calculated from the crystal
structure of uU5).[19]
We have demonstrated that singly substituted, acyclic
units forming urea (U), amide (A), or carbamate (C) linkages
can be combined in multiple ways (e.g., 1:1 and 2:2 patterns)
to generate heterogeneous backbone oligomers with well-
defined helical secondary structures. This design allows
conformational control over a range of building blocks with
different folding propensities. Folding is believed to be largely
governed by U units whose prominent helical-folding char-
acter counterbalance the somewhat lower or limited helix
forming ability of A and C units, respectively. Structures at
atomic resolution reported here provide guidelines for the
design and development of a large ensemble of structurally
related, but chemically distinct helical backbones. We look
forward to exploring this area of chemical space that has
opened up to modulate biological functions of foldamers.
[12] A. Hetꢃnyi, G. K. Tꢆth, C. Somlai, E. Vass, T. A. Martinek, F.
Fꢄlçp, Chem. Eur. J. 2009, 15, 10736 – 10741.
[13] P. Claudon, A. Violette, K. Lamour, M. Decossas, S. Fournel, B.
Heurtault, J. Godet, Y. Mꢃly, B. Jamart-Grꢃgoire, M.-C.
Averlant-Petit, J.-P. Briand, G. Duportail, H. Monteil, G.
Guichard, Angew. Chem. 2010, 122, 343 – 346; Angew. Chem.
Int. Ed. 2010, 49, 333 – 336.
[14] C. Y. Cho, E. J. Moran, S. R. Cherry, J. C. Stephans, S. P. A.
Fodor, C. L. Adams, A. Sundaram, J. W. Jacobs, P. G. Schultz,
Science 1993, 261, 1303 – 1305.
Received: December 9, 2012
Published online: March 4, 2013
[15] a) G. Guichard, A. Violette, G. Chassaing, E. Miclet, Magn.
Reson. Chem. 2008, 46, 918 – 924; b) L. Fischer, P. Claudon, N.
Pendem, E. Miclet, C. Didierjean, E. Ennifar, G. Guichard,
Angew. Chem. 2010, 122, 1085 – 1088; Angew. Chem. Int. Ed.
2010, 49, 1067 – 1070; c) J. Fremaux, L. Fischer, T. Arbogast, B.
Kauffmann, G. Guichard, Angew. Chem. 2011, 123, 11584 –
11587; Angew. Chem. Int. Ed. 2011, 50, 11382 – 11385.
[16] T. Hintermann, K. Gademann, B. Jaun, D. Seebach, Helv. Chim.
Acta 1998, 81, 983 – 1002.
[17] 14-Helical structures reported for g peptides consisting of
conformationally constrained g-amino acids are significantly
more stable: a) S. Hanessian, X. Luo, R. Schaum, S. Michnick, J.
Am. Chem. Soc. 1998, 120, 8569 – 8570; b) D. Seebach, M.
Brenner, M. Rueping, B. Jaun, Chem. Eur. J. 2002, 8, 573 – 584;
c) L. Guo, W. Zhang, A. G. Reidenbach, M. W. Giuliano, I. A.
Guzei, L. C. Spencer, S. H. Gellman, Angew. Chem. 2011, 123,
5965 – 5968; Angew. Chem. Int. Ed. 2011, 50, 5843 – 5846.
Keywords: foldamers · helical structures · peptidomimetics ·
protein folding · X-ray diffraction
.
[1] For reviews on foldamers, see: a) S. H. Gellman, Acc. Chem. Res.
1998, 31, 173 – 180; b) D. J. Hill, M. J. Mio, R. B. Prince, T. S.
Hughes, J. S. Moore, Chem. Rev. 2001, 101, 3893 – 4012; c) C. M.
Goodman, S. Choi, S. Shandler, W. F. DeGrado, Nat. Chem. Biol.
2007, 3, 252 – 262; d) G. Guichard, I. Huc, Chem. Commun. 2011,
47, 5933 – 5941.
[2] Foldamers: Structure, Properties, and Applications (Eds.: S.
Hecht, I. Huc), Wiley-VCH, Weinheim, 2007.
[3] For selected reviews on b and g peptides, see: a) D. Seebach,
A. K. Beck, D. J. Bierbaum, Chem. Biodiversity 2004, 1, 1111 –
1239; b) F. Bouillꢂre, S. Thꢃtiot-Laurent, C. Kouklovsky, V.
4150
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 4147 –4151

Angewandte
Chemie
[18] Data collected from 1H NMR spectra of a 7 mer oligocarbamate
(C7) in [D5]pyridine show no evidence supporting the formation
of a well-defined secondary structure (data not shown).
[19] See the Supporting Information.
[20] M. K. N. Qureshi, M. D. Smith, Chem. Commun. 2006, 5006 –
5008.
[22] D. Sꢅnchez-Garcꢇa, B. Kauffmann, T. Kawanami, H. Ihara, M.
Takafuji, M. H. Delville, I. Huc, J. Am. Chem. Soc. 2009, 131,
8642 – 8648.
[23] Because U/C and U/A backbones contain two types of
chromophores, their CD spectra and that of corresponding
homooligomers must be compared with some caution.
[21] C. Hemmerlin, M. Marraud, D. Rognan, R. Graff, V. Semetey,
J.-P. Briand, G. Guichard, Helv. Chim. Acta 2002, 85, 3692 – 3711.
Angew. Chem. Int. Ed. 2013, 52, 4147 –4151
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4151