Understanding the conformational analysis of gababutin based hybrid peptides

Article abstract of DOI:10.1039/c8ob00035b

Constrained γ-amino acid gababutin (Gbn) based peptides that form different conformations have been synthesized. Striving to rationalize the impact of side chain orientations framing tetrapeptide-based supramolecular organic frameworks and morphological entities, Gbn incorporated hybrid peptides Boc-Gbn-Aib-Aaa-Aib-OMe (where Aaa = Phe(F) for peptide 1, Leu(L) for peptide 2 and Tyr(Y) for peptide 3) were synthesized by changing the amino acid at the third position. The solution state dual folded conformation (C₁₂/C₁₀ H-bonded) is probed by 2D NMR spectroscopy in support of a DMSO-d₆ titration and VT NMR experiments. Peptides 1-3 adopt a C₁₂/C₁₀ type H-bonded dual folded conformation in the crystal state. In addition, distinct supramolecular frameworks result from the modification and orientation of the third residue side chain of peptides 1-3. A solvent induced morphological diversity of peptides 1-3 is attained by modifying the side chain backbone of the tetrapeptides, which are investigated by various microscopic (SEM and AFM) studies. Gbn-based peptides 1-3 show significant morphological and supramolecular packing properties, which are fairly different from those of their gabapentin (Gpn) based analogue peptides.

Full text of DOI:10.1039/c8ob00035b

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Page 1 of 21
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DOI: 10.1039/C8OB00035B
1 Understanding the Conformational Analysis of Gababutin
2 Based Hybrid Peptides†
3
4
Maruthi Konda,a Rohit G. Jadhav,a Sayan Maiti,a Shaikh M. Mobin,a Brice
Kauffmannb and Apurba K. Das*a
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a Department of Chemistry, Indian Institute of Technology Indore, Khandwa Road,
Indore 453552, India
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b Université de Bordeaux, CNRS, UMS 3033, INSERM US001 Institut Européen de
Chimie et de Biologie (IECB) 2 rue Escarpit, 33600 Pessac, France
10 E-mail: apurba.das@iiti.ac.in
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Abstract: A constrained γ-amino acid gababutin (Gbn) based peptides have been synthesized
that form different conformations. In a strive to rationalize the impact of side chain orientations
framing tetrapeptide-based supramolecular organic frameworks and morphological entities, Gbn
incorporated hybrid peptides Boc-Gbn-Aib-Aaa-Aib-OMe (where Aaa = Phe(F) for peptide 1,
Leu(L) for peptide 2 and Tyr(Y) for peptide 3) were synthesized by a change in amino acid at
third position. The solution state dual folded conformation (C12/C10 H-bonded) is probed by 2D
NMR studies in support of DMSO-d6 titration and VT NMR experiments. Peptides 1-3 adopt
C12/C10 type H-bonded dual folded conformation in crystal state. In addition, distinct
supramolecular frameworks are resulting from the modification and orientations of the third
residue side chain of peptides 1-3. A solvent induced morphological diversity of peptides 1-3 is
attained by modifying the side chain backbone of tetrapeptides, which are investigated by
various microscopic (SEM and AFM) studies. Gbn-based peptides 1-3 show significant
morphological and supramolecular packing properties which are fairly different from their
gabapentin (Gpn) based analogue peptides.
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37 Introduction
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Design and synthesis of synthetic building blocks to mimic naturally occurring biomolecules is
an emerging field of bio-organic and medicinal chemistry.1-2 Proteolytically stable β- and γ-
amino acids are considered as higher homologues to the natural counterparts which are utilized
to construct folded peptide structures (peptide foldamers) with the aim of numerous applications
in biomedical and material sciences.3-5 To study the influence on the secondary structures of
hybrid peptides, β- and γ-amino acids provide an opportunity to engineer the available backbone
through the incorporation of –(CH2)n− functionalization method.6-7 In fact, most of these amino
acids are designed to restrict the available conformational freedoms as well as to achieve stable
structural propensities both in solid and solution states.8 Another building block γ-aminobutyric
acid (GABA) is a neurotransmitter, which shows various conformational projections about C-C
bonds. Thus, structural modifications of GABA render various modified γ-residues and show
significant impact on folding and functional properties at atomic and supramolecular level.7a,g-i
Various constrained synthetic γ-amino acids via backbone cyclization at Cβ─Cα (θ2) were
reported to study the folding preferences of peptides (Fig. 1). The backbone of γ-amino acid is
restricted through gauche-gauche conformation in αγ-polypeptides to fold into
C═O(i)···H─N(i+3) and C═O(i)···H─N(i−1) H-bonded C12/C10 folded structure.9 A new rigid
aromatic thiazole-based γ-amino acid based oligomers were synthesized to construct highly
stable C9 folded structure both in organic and aqueous media.10 Extensive study has been done
on achiral β,β-disubstituted γ-amino acid gabapentin based peptides that showed a tendency to
form different C7 to C14 hydrogen-bonded folded structures.11 A chiral α,γ cyclized rigid γ-
building block has been utilized to construct several cyclic oligomers.12 Surprisingly, these cyclic
residues adopt anti-conformation and hierarchically form higher order self-assembled peptide
nanotubes (SPN) and peptide ion channels rather than forming intramolecular H-bonded turns.
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Fig. 1 Chemical structures of various backbone constrained γ-amino acids with backbone torsion angles
parameters.
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Molecular self-assembly plays a pivotal role to construct complex three-dimensional
structures from monomeric bio-molecules.13 In fact, functional properties of materials are
concomitant to their structural ingenuity of self-assembling entities. The nanostructured
assemblies have demonstrated a wide range of applications including gas storage, catalysis,
antimicrobial, drug delivery.14-16 Thus, there is an increasing demand for the development of
synthetic/ non-protein amino acids based functional peptide materials to execute unique features
and potential applications in various disciplines.17 Over the past few years, we have designed and
explored stimuli-responsive self-assembled peptide nanostructures for potential applications in
oil spill recovery, templates for the synthesis and catalysis of nanoparticles, development of
native chemical ligation strategies and dynamic combinatorial libraries, tissue engineering, and
nanoelectronics.18 Recently, we have reported structural and morphological investigation on
Gpn-based hybrid tetrapeptides (Boc-Gpn-Aib-Aaa-Aib-OMe; Gpn = gabapentin, Aaa =
Phe/Leu/Tyr), which adopted C12/C10 H-bonded dual folded structures and showed diverse
supramolecular propensities both in solid and solution states.18a To study the role of side chain of
γ-amino acid on structural and morphological propensities of hybrid tetrapeptides, one of our
major objective was to replace six-membered cyclic ring at β-position (Gpn) with five membered
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cyclic ring at β-position (Gbn). In this study, our objectives include (i) development of a
synthetic route to access a building block 1-(aminomethyl)cyclopentylacetic acid hydrochloride
(gababutin; abbreviated as Gbn), (ii) to synthesize a series of Gbn incorporated hybrid peptides
including Boc-Gbn-Aib-Aaa-Aib-OMe (where Aaa = Phe(F) for peptide 1, Leu(L) for peptide 2
and Tyr(Y) for peptide 3) by varying at side chain of third amino acid residue, (iii) to explore the
structural aspects of these hybrid peptides 1, 2 and 3 by means of switch over at the third amino
acid position both in crystal and solution states (Scheme 1) and (iv) to investigate nanostructural
morphological topographies of peptides in various solvents. In this work, we report the synthesis,
structural studies and diverse supramolecular propensities of gababutin based hybrid peptides. A
C12/C10 hydrogen-bonded double turn folded conformation, formation of self-assembled
supramolecular organic frameworks and self-assembled morphological diversity are also
reported.
92 Results and Discussion
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To investigate the role of five membered cyclic ring at β-position of γ-amino acid (Gbn) in
conformational and morphological propensities of hybrid tetrapeptides, a series of tetrapeptides
Boc-Gbn-Aib-Phe-Aib-OMe (1), Boc-Gbn-Aib-Leu-Aib-OMe (2), Boc-Gbn-Aib-Tyr-Aib-OMe
(3) were synthesized (Scheme 1). All the tetrapeptides were synthesized by employing fragment
condensation solution-phase strategy. A facile and efficient synthetic route was optimized to
prepare Gbn (Scheme 1) as a foldamer building block.19 α,β-Unsaturated ester 5 was easily
accomplished by employing a mild base (K2CO3) mediated Horner-Emmons modification from
cyclopentanone 4 with triethyl phosphonoacetate in THF solvent.20 Subsequently, compound 5
was subjected to Na2CO3 mediated Michael addition at 100-105 °C which yielded compound 6
with good yield in DMSO solvent.19,21 Hydrogenation of nitro functionality of compound 6 by
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activated Pd/C and hydrogen gas affords lactam 7, which is a cyclized form of Gbn.21 Eventually,
acid hydrolysis (6N HCl) of compound 7 gives the precursor amino acid 8 Gbn.HCl. The
precursor 8 was used as a synthetic foldameric unit to construct terminally protected peptide
scaffolds 1, 2 and 3 (Scheme S1†).
(i)
(ii)
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Scheme 1. (i) Synthetic outline of Gbn.HCl precursor. (ii) Chemical structures of peptide 1, peptide 2,
peptide 3 with backbone torsion angle parameters.
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Solution state conformations of peptides
NMR studies of peptides 1-3 were performed to elucidate the peptide conformation in CDCl3 at
298 K. The ROESY spectra (Fig. 2, S1 and S2) display a set of typical strong and medium intra
and inter residual NOE correlations which draw a doubly folded stable structure in solution.
Peptides 1, 2 and 3 show characteristic dNN[(i)↔(i+1)] NOEs (between the amide NHs of peptide
residues) and dαN[(i)↔(i+1)] NOEs (between Aaa(3) CαH ↔ Aib(4) NH) over the peptide backbone.
More essentially, long-range NOEs along Gbn(1) CγH ↔ Aaa(3) NH clearly explain the
observation of doubly folded conformation in solution (C12/C10 H-bonded fold). The inter-
proton dNN distances observed in the crystal state between dNN[(i)↔(i+1)] correlations and
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Gbn(1) CγH ↔ Aaa(3) NH (Aaa = Phe; peptide 1, Leu; peptide 2, Tyr; peptide 3) are in
the limit of NOE range, which supports the above conformation (Fig. S1-S8).7a,9 The
strength of H-bonding interactions and relative solvent-shielded/exposed nature of the
amide protons were investigated by DMSO-d6 titration and variable temperature
experiments in CDCl3 (Fig. 2, S9-S11). All the NHs except Gbn(1) NH display negligible
shift, signifying their engagement in intramolecular H-bonding (Table S1-S3)
interactions.7a,f The variable temperature NMR studies further support the involvement of
intramolecular H-bonding showing coefficient values Δδ/ΔT > -4 ppb/K for NH of Aib(2) and
Δδ/ΔT > -3 ppb/K for NH and CαH of Aaa(3). Thus, the observed NMR results suggest a
dual folded turn structure of peptides 1-3 in solution.
dNN[(i)↔(i+1)]
dαN[(i)↔(i+1)]
ii
other NOEs
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Aib (2) NH
Aib (4) NH
viii
Leu (3) NH
Gbn (1) NH
0
5
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40
Volume of DMSO-d6 added (µL)
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Fig. 2 1H-1H ROESY spectrum of peptide 1 (400 MHz, CDCl3 at 298 K, mixing time = 200 ms), showing
several representative NOEs over the peptide backbone, suggesting a double turn conformation. DMSO-
d6 solvent titrations plot for peptide 1 in CDCl3 supports the presence of hydrogen-bonded folded
structure.
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Crystal state structural analysis of peptide motifs
Local accessible conformations (Cγ─Cβ (θ1) and Cβ─Cα (θ2)) of Gbn residue are restricted due to
geminal substituents at central β-carbon atom. Thus, Gbn based hybrid peptides 1-3 are expected
to display gauche-gauche conformations of Cγ─Cβ and Cβ─Cα (θ1≈ θ2 ≈ ± 60°). Single crystal X-
ray diffraction studies (Table S4) reveal that all tetrapeptides 1, 2 and 3 adopt C12/C10 helical
double turn conformation with two 1←4 type successive intramolecular H-bonds (Fig. 3). The
inter-residual intramolecular hydrogen-bonding pattern for C12 and C10 are arranged as
C═O(i)···H─N(i+3).
(i)
(ii)
(iii)
C12
C10
C12
C12
C10
C10
water
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Fig. 3 Molecular conformations observed in crystal of (i) peptide 1, (ii) peptide 2 and (iii) peptide 3
displaying C12/C10 hydrogen-bonded double turn conformation and hydrogen atoms are removed for
clarity (except heteroatom and chiral centre attached). Hydrogen bonds are shown in dotted line.
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Despite the third amino acid residue varied in reporting tetrapeptide sequences, all three peptides
(1-3) fold into C12/C10 helical double turn conformation across γααα backbone in the crystal state
(Fig. S12-S14). A small switch of the side chain of gamma-amino acid residue from six member
ring (in gabapentin-based peptides) to five member ring in all reported gababutin-based
tetrapeptides (1-3), peptides 1-3 display a similar type of conformations (C12/C10 double turn)
and remarkably result in stable double turn signatures. The molecular conformations and the
hydrogen bonding patterns are moreover similar to our previously reported Gpn-tetrapeptides.18a
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An unusual 12-membered 1→4 type hydrogen-bonding interaction (Table S5) is formed between
C═O (Boc, i) and H-N (3, i+3) of Aaa (Aaa = Phe for peptide 1, Aaa = Leu for peptide 2 and
Aaa = Tyr for peptide 3). The relevant torsion angles about Cγ─Cβ (θ1) and Cβ─Cα (θ2) bonds
(Table S6) of Gbn residue in peptides 1-3 are found to be almost ±60° (gauche-gauche
conformations). These associated torsions of Gbn residues (in peptides 1-3) are comparatively
overlapped with reported Gpn-based peptides. Moreover, Gbn residues adopt more-rigid
conformations (Table S7). Thus, gem dialkyl substitution at Cβ position of Gbn confines the
allowed conformations about Cγ─Cβ (θ1) and Cβ─Cα (θ2) bonds to restrict into gauche-gauche
conformations which induce the formation of C12 hydrogen-bonded turn. Aib(2) [ϕ ≅ 48-60°, ψ ≅
27-39°] residues in peptides 1-3 adopt a helical propensity, however Aib(4) [ϕ ≅ 41-60°, ψ ≅
141-146°] residues adopt a semi extended conformation.11
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A C10 hydrogen-bonded β-turn is also observed next to the C12 hydrogen-bonded turn in peptides
1-3, which is originated due to Gbn(1)C═O···H─NAib(4) interaction across the ααα segment
(Table S5). A closer inspection of torsion angles of peptides 1-3 demonstrates that molecules A
and B of peptide 1 form a Type I β-turn conformation. In peptide 2, molecules A, C and B, D
form Type I β-turn and Type IIIʹ β-turn respectively. Moreover, molecules A and B of peptide 3
feature a Type III and Type IIIʹ β-turn conformation respectively.18a The cyclopentane ring of
peptides 1-3 adopts an envelope conformation and the amino methyl and carboxyl methyl
backbones found to be orientated with an angle of 110.02°. More importantly, the average
interior angle for the ring about ringC1─Cβ─C4ring is found to 102.247° which marginally deviated
from the average interior angle of Gpn residues (Fig. S15). Peptides 1-3 also exhibit well-defined
diverse supramolecular organic frameworks (Fig. 4-5 and Table 1).
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(i)
(ii)
c
a
b
a
c
b
Molecule A and B
Molecule A and B
Molecule C and D
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Fig. 4 The packing diagram and supramolecular helical view of peptides 1 and 2 in the crystal structure.
(i) Molecules A and B of peptide 1 are aligned and stacked with one on top of the other to form
supramolecular helix. (ii) Supramolecular helices resulted from self-association of molecules A (blue) and
B (red) and molecules C (purple) and D (yellow). Hydrogen atoms are removed for clarity (except
heteroatom and chiral centre attached). Hydrogen bonds are shown as dotted lines.
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Peptide 3 is crystallized with two individual molecules (A and B) along with two water
molecules in the ASU. Close investigation of supramolecular packing of peptide 3 in crystal state
discloses that the peptide subunits along with water molecules are properly aligned and
organized to form interesting higher-order supramolecular architectures using various non-
covalent interactions.
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i
ii
iii
Molecule A
Self-assembly
Water-mediated
higher order
self-assembly
Molecule B
b
a
c
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Fig. 5 A higher order-packing diagram of peptide 3 showing formation of supramolecular architectures
and the role of the water molecules (red ball-stick representation). (i) Individual linear-association of
molecules A (green) and B (blue) results to (ii) supramolecular helices. (iii) Supramolecular helix-helix
association into higher order supramolecular architectures with the help of water molecules. Hydrogen
atoms are removed for clarity (except heteroatom and chiral centre attached). Hydrogen bonds are shown
as dotted lines.
Table 1 List of various hybrid peptides and their supramolecular assemblies in crystal state
S.
No
.
Compound
Molecular
Formulae
Crystal
state
Conforma
-tion
Supramolecular Assembly
Axisa Ref
1
2
3
Boc-Gbn-Aib-Phe-Aib-OMe C31H48N4O7
1
Boc-Gbn-Aib-Leu-Aib-OMe C28H50N4O7
2
C12/C10
dual turn
C12/C10
dual turn
C12/C10
dual turn
supramolecular single helix
supramolecular double helix
a
c
Present
study
Boc-Gbn-Aib-Tyr-Aib-OMe
C31H48N4O8
solvent
mediated
3
supramolecular higher order
helices
b
4
5
6
Boc-Gpn-Aib-Phe-Aib-OMe C32H50N4O7
Boc-Gpn-Aib-Leu-Aib-OMe C29H52N4O7
C12/C10
dual turn
C12/C10
dual turn
C12/C10
dual turn
supramolecular helix- helix
higher order assembly
supramolecular single helix
b & a
b
Our
previou
s work
Boc-Gpn-Aib-Tyr-Aib-OMe
C32H50N4O8.
H2O
solvent
mediated
18a
supramolecular double helices
b
197
aaxis through which a supramolecular helix formed
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Fig. 5 clearly demonstrates the non-covalent participation of molecule A or B
individually via b-axis, of those further stack one on top of the other using intermolecular H-
bonds to form supramolecular helical arrays. Moreover, the individual supramolecular helical
arrays are connected to form highly packed higher-order supramolecular assembly by using
intervening bridged water molecules. Phenolic O─H group of Tyr(3) residue is hydrated with
bridged water molecule via (water) O⋯H─O Tyr(3) interaction. This side chain phenolic (O─H)
group plays a vital role in the formation of supramolecular arrangement among peptide subunits
and water molecules. These supramolecular helical arrangements by peptides 1, 2 and 3 are
formed along crystallographic a-, c- and b-axis respectively. Overall, these higher order diverse
supramolecular architectures are formed as a result of the side chain orientations and variable
third amino acid residue.18a,22
Morphological Features
Tuning the size and shape of the stimuli responsive self-assembled
nano/microarchitectures are vital which could be used for a specific application. To know
the morphological insights of peptides 1, 2 and 3 in different solvents, scanning electron
microscopy (SEM) and atomic force microscopy (AFM) were performed (Fig. 6-7 and
Table 2). Peptides 1-3 show solvent assisted diverse self-assembled morphological
structures.23-26 Evidently, we found that peptides 1-3 produced relatively different
morphological features in comparison to their Gpn-based tetrapeptides (Table S8).18a
SEM image (Fig. 6(i)) of peptide 1 in methanol : water (c = 3.0 mmol L-1) demonstrates
the formation of microrods. These microrods are grown from the origin point with width
ranging from 0.5 µm to 1 µm which are several micrometers in length. A highly dense
bristles type nanofibrous morphology are observed for peptide 2 in methanol : water
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solution (c = 3.0 mmol L-1) (Fig. 6(ii)). The average width of nanofiber structures is found
about 15 nm. Peptide 3 in methanol : water self-assembles to render a ribbon type
network.26a-b These ribbons are interwoven each other with an average width of 300 nm
and several micrometers long (Fig. 6(iii)). On the other hand, peptides 1, 2 and 3 in THF :
water (c = 3.0 mmol L-1) self-assemble into diverse micro/nano-architectures as compare
to methanol : water system.25e,26b As shown in SEM image (Fig. 6(iv)), aligned thick
fibrillar structures with diameter ranging from 200 to 1200 nm and length in several
micrometers are observed for self-assembled peptide 1 in THF : water solution.
Peptide 1
Peptide 2
Peptide 3
(i)
(ii)
(iii)
10 µm
20 µm
2 µm
(iv)
(v)
(vi)
2 µm
3 µm
10 µm
200 nm
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Fig. 6 FE-SEM images showing the evaporation induced microscopic features and solvent-assisted
morphological diversity of peptide 1, peptide 2 and peptide 3 in methanol : water (top row) and in THF :
water (bottom row) 1:1 v/v, c = 3.0 mmol L-1).
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Peptide 2 displays microtubular structures in THF: water. These microtubes exhibit
pentagonal cross-sectional shape with a hollow cavity (Fig. 6(v), S16-S17†). Precipitation
mass obtained from self-assembly of peptide 3 in THF : water displays dense entangled
nanotapes (Fig. 6(vi)) with an average width of 40 nm and several micrometers in length.
Atomic force microscopy measurements also reveal the formation of nanostructural features
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(THF : water) which are similar with SEM results (Fig. 7). AFM images of self-assembled
peptide 1 (Fig. 7(i)) display aligned flat fiber aggregates with an average height of 72 nm. Fig.
7(ii) shows crystalline type of networks which is formed by self-assembled peptide 2. These self-
assembled structural entities have an average width of 42 nm. AFM analysis of self-assembled
peptide 3 exhibits bunch of thin nanotapes. AFM images clearly show nanotape morphology
which ensues from the hierarchical assembly of thin fibrils (Fig. 7(iii)). The microscopic analysis
demonstrates that the hydrophobicity of the amino acids in peptides as well as solvent polarity
play a vital role in supramolecular morphological diversity.26a-b
Peptide 1
Peptide 2
Peptide 3
(ii)
(iii)
(i)
thin nanofibrils
nanotape aggregate
500 nm
1.0 µm
2 µm
400 nm
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249
250
251
252
253
254
Fig. 7 AFM images depicting the microscopic features of peptides 1, 2 and 3 in THF : water (1:1 v/v, c =
3.0 mmol L-1). Insets indicating the 3D image of the organization of fiber textures and aggregated
nanostructures.
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256
Table 2 Self-assembled morphological diversity of peptides 1-3 in various solvent mixturesa
Self-assembled morphology
Solvent system
Peptide 1
Methanol : water
Microrods
THF : water
Aligned thick fibrillar structures
Rectangular cross-sectioned microtubes
Peptide 2
Dense bristles type nanofibrous
Peptide 3
Interwoven ribbons
Entangled nanotapes
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a concentration of peptide solution c = 3.0 mmol L-1
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259 Conclusion
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We have described synthetic route, structural aspects of gababutin precursor and gababutin
incorporated hybrid tetrapeptides. The extensive 2D NMR studies revealed the existence of
C12/C10 dual folded conformation in CDCl3. In crystal state, peptides 1, 2 and 3 adopted double
turn conformations through C12 and C10 intramolecular hydrogen-bonds, regardless of their third
residue. Gbn residue in all the peptides accommodates nicely ±gauche conformations about
Cγ─Cβ (θ1) and Cβ─Cα (θ2) bonds with backbone parameters of ±60° which are closely
overlapped with existing backbone parameters of Gpn residues. Gbn residues formed a more-
rigid conformation than Gpn analogue residues due to rigid interior angle. The interior angle of
Gbn ring 102.247° fairly deviated from interior angle of Gpn ring. On consideration of these
data, we have observed that peptides 1-3 (Gbn-based) showed structural similarity in folding
patterns with Gpn based peptides. Remarkably, gababutin-based peptides (1-3) display relatively
different supramolecular packing patterns and morphologies in comparison to the results
obtained for gabapentin-based peptides. Several morphological investigations demonstrated
solvent dependent evaporation induced morphological diversity of peptides 1-3 at ambient
conditions. Overall, our study demonstrates the impact of flexible side chain orientations at the
third position and the rigidity of Gbn residue in folded structures of reported peptide sequences
which could greatly affect their discreet supramolecular structural and functional attributes. It is
expected that these interesting gababutin-based peptide scaffolds and corresponding
nano/microstructures may find desirable applications in biomedical and material sciences.
279 Acknowledgements
280
281
AKD sincerely acknowledges Department of Science & Technology (Project No. SR/NM/NS-
1458/2014), New Delhi, India for financial support. MK is thankful to the IIT Indore for his
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postdoctoral fellowship and RGJ is thankful to UGC, New Delhi for his doctoral fellowship. The
sophisticated instrumentation centre (SIC), IIT Indore is acknowledged for providing access to
the instrumentation. This work has benefited from the facilities and expertises of the Biophysical
and Structural Chemistry Plateform (BPCS) at IECB, CNRS UMS3033, Inserm US001,
Bordeaux University.
287
288
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†Electronic supplementary information (ESI) available: ESI Figures, Tables, Crystal and
diffraction parameters, microscopic and optical images, NMR, and HRMS mass spectra of all
new compounds. X-ray data for peptides 1-3 have been deposited with the Cambridge
Crystallographic Data Centre. CCDC 1542080 (peptide 1), 1542088 (peptide 2), 1542089 and
(peptide 3). For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/x0xx00000x
294 Notes and References
295
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