Control of duplex formation and columnar self-assembly with heterogeneous amide/urea macrocycles

Article abstract of DOI:10.1002/anie.200804019

(Chemical Equation Presented) The perfect blend : A new class of self-assembling cyclooligomers with mixed urea/amide backbone is described (see figure). A high level of hierarchical and directional control is achieved: depending on the level of backbone

Full text of DOI:10.1002/anie.200804019

Angewandte
Chemie
DOI: 10.1002/anie.200804019
Self-Assembling Macrocycles
Control of Duplex Formation and Columnar Self-Assembly with
Heterogeneous Amide/Urea Macrocycles**
Lucile Fischer, Marion Decossas, Jean-Paul Briand, Claude Didierjean, and Gilles Guichard*
Owing to their diversity in size and shape, easy access, and
biocompatibility, peptides are versatile units for the con-
struction of H-bonded tubular assemblies and other biomim-
etic materials with potentially useful applications.[1] Peptide
nanotubes (PNTs) have been obtained through multiple and
complementary approaches,[1,2] including the formation of
hollow b helices,[3] barrel–hoop motifs from stacked macro-
cyclic peptides,[4] barrel–stave motifs from rigid-rod peptide
conjugates,[5] helical pores from cationic, zwitterionic,[6] and
dendritic dipeptides,[7] and large tubes from linear and cyclic
amphiphilic peptides.[8]
Originally designed from a-peptides made of d- and l-
amino acids,[4,9] the range of flat macrocyclic systems forming
cylindrical b-sheet-like assemblies has been expanded to
include oligoamides formed of higher amino acid homologues
(e.g. b- and d-peptides)[10] and peptide hybrids (e.g. a,b-,[11a]
a,g-,[11b–f] and a,e-peptides[11g]). Tubular sheet-like assemblies
are however not restricted to oligoamides. The urea group for
example, which shares a number of features with the amide
linkage, namely rigidity, planarity, polarity, and hydrogen
bonding capacity, is an interesting surrogate. Macrocyclic
biotic and abiotic N,N’-linked oligoureas have a unique
propensity to self-organize into polar H-bonded nano-
tubes.[12–14]
Partial peptide backbone N-methylation has been intro-
columnar and tubular self-assembly, 2) parallel versus anti-
parallel stacking can be controlled by the degree of backbone
rigidification, and 3) structural water molecules may function
as bridging units to direct tubular and columnar growth.
Our approach to Cn (n = 1 to 5) hybrid amide/urea
macrocycles of type A is based on cyclooligomerization of
the dipeptide-derived precursor, +H-Xaa-gXbb-COOSu
(B).[15] Small-ring formation leading to the 1,3,5-triazepan-
2,6-dione dipeptidomimetic skeleton C[15a–c] readily occurs
when the cis-conformation around the amide bond in B is
populated (R3 ¼ H). To promote cyclooligomerization, we
thus focused on starting dipeptide sequences featuring a
secondary amide bond, and N-alkylated on Xaa (R3 = H, R1 ¼
H).[16] A series of four enantiopure 14-membered C2 sym-
metric macrocycles (1–4) have been prepared starting from
homochiral NMeVal-Val, NMeLeu-Leu, Pro-Val, and Pro-
Phe dipeptide sequences, respectively.
duced as a general strategy to generate truncated stacks (i.e.,
H-bonded dimers), which are useful in gaining access to the
thermodynamics of nanotube formation.[9c,d,11b–e] Herein, we
describe biotic macrocyclic amide/urea hybrids with partially
N-alkylated backbones A as new candidates for the formation
of H-bonded dimers. In these systems, we show that 1) back-
bone N-alkylation does not necessarily compromise extended
[*] L. Fischer, Dr. M. Decossas, Dr. J.-P. Briand, Dr. G. Guichard
CNRS, Institut de Biologie Molꢀculaire et Cellulaire
Laboratoire d’Immunologie et Chimie Thꢀrapeutiques
15 rue Renꢀ Descartes, 67000 Strasbourg (France)
Fax: (+33)3-8861-0680
E-mail: g.guichard@ibmc.u-strasbg.fr
Dr. C. Didierjean
LCM3B, UMR-CNRS 7036, Groupe Biocristallographie
Universitꢀ Henri Poincarꢀ
BP 239, 54506 Vandœuvre (France)
Single crystals of 1 and 2 suitable for X-ray crystallo-
graphic analysis were grown by slow evaporation of a solution
of acetonitrile and methanol. The crystal structures were
solved in the P1 and I41 space groups,[16] respectively. In both
structures (Figure 1a,b), the main chain adopts a rectangular
shape with sides of length 3.8 ꢀ ꢁ 4.8 ꢀ.
The amide and urea groups are perpendicular to the mean
plane of the ring, and their carbonyl groups point in opposite
directions. Whereas f angles of l-amino acid residues in 1 and
2 adopt standard negative values (ca. ꢀ978), gem-diamino
[**] This research was supported in part by Centre National de la
recherche Scientifique (CNRS), and Agence Nationale pour la
Recherche (grant number NT05_4_42848). The authors thank
Lionel Allouche and Roland Graff for their assistance with NMR 1H-
and DOSY experiments and the “plateforme RIO d’imagerie
cellulaire Strasbourg Esplanade” for the use of the TEM.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804019.
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Figure 2. Formation of columnar stacks by axial packing of H-bonded
dimers in 1 (a) and 2 (b); individual molecules are shown in gray and
green. c),d) Close-ups of the interfaces between duplex in 1 (c) and
2 (d) illustrating the different modes of column stabilization. C gray,
N blue, O red, H white, H-bonds yellow. H atoms of side chains are
omitted for clarity.
Figure 1. Representations of cylindrical H-bonded dimers of 1 (a) and
2 (b). Left: individual molecules shown in gray and green. Right:
C gray, N blue, O red, H white, H-bonds yellow. Hydrogen atoms of
side chains are omitted for clarity.
=
H···O C bonds (C···O 3.11 ꢀ, H···O 2.61 ꢀ, C-H-O 111.38)
between methyl groups and amide carbonyl of two H-bonded
dimers and by van der Waals interactions between interdigi-
tated isobutyl side chains of adjacent columns (Figure 2b,d).
A totally different mode of column stabilization is observed in
the structure of 1, in which two H-bonded dimers are
interconnected by two bridging water molecules (W1 and
W2) that are an integral part of the tube architecture
(Figure 2a,c). Indeed, W1 and W2 lie on the edge of the
tube approximately in the alignment of the gVal aC atoms and
equidistant from two dimers. However, the two molecules
differ in their bridging mode. W1 acts as a donor and bridges
two amide carbonyl groups, whereas W2 acts as both an
acceptor and a donor to bridge urea NH and amide carbonyl
groups.
Substituting proline for the N-methyl amino acids in urea/
amide cyclodimers has dramatic consequences on both ring
geometry and self-assembly properties of resulting cyclo-
dimers. Compound 3 crystallized from CHCl3 in the P21212
space group. Crystals of 4, obtained by slow evaporation of a
mixture of acetonitrile and water, formed in the space group
I41.[16] Both 3 and 4 have a very similar rectangular shape with
sides of length 3.8 ꢀ ꢁ 4.8 ꢀ (Figure 3). In contrast to 1 and 2,
gem-diaminoalkyl residues in 3 and 4 feature negative pseudo
f angle values, and as a result, amide and urea NH groups are
now pointing on one side of the ring, the carbonyl groups
being sequestered on the other side (Figure 3a). This novel
ring geometry in 3 and 4 leads to the formation of a novel type
of columnar arrangement in the crystal. Although backbone–
backbone H-bonding is not observed, rings are linked in a
parallel orientation by bridging water molecules (Figure 3b–
d). Each water molecule is tightly sandwiched between two
neighboring rings with the following H-bonding regime: The
water oxygen atom is doubly hydrogen-bonded to the amide
protons on one ring (N···Ow distance: 2.99 in 4 and 3.08 ꢀ in 3)
and to urea carbonyls of a second unit (O···Ow distance: 2.68
in 4 and 2.73 ꢀ in 3). In this regime, the urea carbonyl groups
and amide protons point more toward the water oxygen than
along the column axis. The columns of cyclo(Pro-gPhe-CO)2
alkyl residues are characterized by positive pseudo f angle
values (ca. + 608), which are generally accessible to the d-
amino acid residues. As a result, the two NH groups of gem-
diamino alkyl residues point in opposite directions. By
analogy to partially N-methylated d,l-a-peptides and a,g-
peptides,[9c,d,11b–e] the cyclic urea/amide oligomers 1 and 2 self-
assemble in an antiparallel manner to form H-bonded dimers
maintained by a set of four strong H-bonds between urea
carbonyl groups and amide NH groups. N···O distances range
from 2.79–2.94 ꢀ for 1 and 2.88–2.90 ꢀ for 2. 1H NMR studies
of 1 and 2 suggest that the geometry of the ring observed in
the solid state is essentially retained in solution.[16] The
formation of a sheet-like arrangement in solution was
inferred from FTIR spectrum of 2 recorded in CHCl3
(20 mm) which shows amide A, I, and II bands at 3356,
1642, and 1521 cmꢀ1 similar to previously reported peptide
and oligourea nanotubes.[16,17] Concentration-dependent
NMR experiments provided further evidence for the forma-
tion of H-bonded dimers in solution (in CDCl3 or CD2Cl2
stored over 4 ꢀ molecular sieves). In agreement with the
proposed antiparallel dimerization, proton resonances of
amide NH but not urea NH groups experienced a significant
downfield shift (d = 7.43 to 8.03 ppm at 223 K for 2) as the
concentration increased from 0.1 mm to 109 mm. The pres-
ence of a unique set of signals suggested fast equilibrium
between monomer and dimer on the NMR timescale.[16]
Fitting urea NH chemical shifts by a dimerization isotherm
gave Kdim (CD2Cl2) of 41mꢀ1 at 223 K.[18] Vanꢂt Hoff plot
analysis over the range 213–253 K afforded values of
ꢀ34.8 kJmolꢀ1 and ꢀ136.3 JKꢀ1 molꢀ1 for the enthalpy and
entropy of dimerization of 2 in CD2Cl2, respectively.
Interestingly, both dimers of 1 and 2 form columnar stacks
parallel to the b axis and c axis, respectively, with a mean
distance between H-bonded dimers of ca 4.5 ꢀ (Figure 2).
ꢀ
Column stabilization in 2 is essentially driven by weak C
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hybrids 1–4 and of larger ring systems will be part of future
development of this work.
Received: August 14, 2008
Revised: November 22, 2008
Published online: January 23, 2009
Keywords: macrocycles · nanotubes · peptidomimetics ·
.
self-assembly · solid-state structures
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