β-Strand Mimicry: Exploring Oligothienylpyridine Foldamers

Article abstract of DOI:10.1002/ejoc.201600882

Protein–protein interactions (PPIs) are involved in many cellular processes; consequently, the discovery of small molecules as modulators of PPIs has become an important challenge in medicinal chemistry. Structural mimetics of α-helices, β-turns or β-strands could maintain or restore biological functions and should possess biological activity. At this time, the most challenging classes of PPIs are those mediated by β-sheet interactions, which are implicated in a number of diseases. Only a few β-strand mimics have been published to date. This study presents an evaluation of oligothienylpyridyl scaffolds in view of their ability for β-strand mimicry. In this study, theoretical ring twist angle predictions for these scaffolds have been validated by X-ray diffraction and molecular dynamics simulations with NMR constraints. Careful choice of substituent and heavy-atom positions in the foldamer units opens the way to produce reasonably coplanar compounds mimicking β-strand side-chain distribution.

Full text of DOI:10.1002/ejoc.201600882

A Journal of
Accepted Article
Title: Beta strand mimicry: Exploring oligothienylpyridines foldamers
´
´
Authors: Marie Jouanne; Anne Sophie Voisin-Chiret; Remi Legay; Sebastien Couf-
ourier; Sylvain Rault; Jana Sopkova-De Oliveira Santos
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600882
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European Journal of Organic Chemistry
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Beta strand mimicry: Exploring oligothienylpyridines foldamers
Marie Jouanne, Anne Sophie Voisin-Chiret,* Rémi Legay, Sébastien Coufourier, Sylvain Rault and
Jana Sopkova-de Oliveira Santos*[a,b]
Abstract: Protein-protein interactions (PPIs) are involved in many
cellular processes; consequently, the discovery of small molecules
as modulators of PPIs has become an important challenge in
medicinal chemistry. Structural mimetics of α-helices, β-turns or β-
strands could maintain or restore biological functions and should
possess biological activity. At this time, the most challenging classes
of PPIs are those mediated by β-sheet interactions, which are
implicated in a number of diseases. Only few β-strand mimes were
published to date. This study presents the evaluation of
oligothienylpyridyl scaffolds in view of their ability for β-strand
mimicry. In this study, theoretical ring twist angle predictions for
these scaffolds have been validated by X-ray diffraction and
molecular dynamics simulations with NMR constraints. Careful
choice of substituent and heavy atom positions in the foldamer units
opens the way to produce reasonably coplanar compounds
mimicking β-strand side chain distribution.
mediates an interaction between proteins[5], but β-strand mimicry
remains little studied.[6] A β-sheet consists of several β-strands,
kept together by a network of hydrogen bonds between the
backbone N-H and C=O groups (see Figure 1). In the fully
extended β-strand, successive side chains are coplanar and
point straight up, then straight down, then straight up, etc.
Distances between Cα(i) and Cα(i+2nd) and between Cα(i) and
Cα(i+4th) are approximately 6.8 Å and 13.6 Å respectively. To
target the interaction of a -strand in the middle of a β-sheet
there is a need for nonpeptide mimetics capable to reproduce
the characteristics of a β-strand.
Figure 1. Illustration of the hydrogen bonding patterns, represented by dotted
lines, in a parallel (A) and an antiparallel (B) beta sheet.
i
i
~ 13.6 Å
Introduction
~ 6.8 Å
i+2nd
Protein-protein interactions (PPIs) play an essential role in most
biological events within a cell. The interacting macromolecules
carry out cellular processes such as DNA synthesis, gene
expression, signal transduction and immune responses.[1] At the
same time, aberrant PPIs are at the heart of pathological
processes, such as for example cancer and neurodegenerative
diseases. Atomic level structural knowledge of protein-protein
complexes has shown that PPIs contain hot-spot regions on
secondary structural elements, whose contribution dominates
binding enthalpy.[2] To target these interactions there is a need
for nonpeptide mimics able to reproduce key distances and
angular characteristics of the protein surface.[3] Ideally, the non
peptide scaffold mimic should be easily synthesized, stable
under physiological conditions and allowing easy variation of the
groups attached to them.
i+4th
To date, few β-strand mimetics have been described even
though higher-level association of β-sheet has been implicated
in the formation of protein aggregates and fibrils observed in
many human diseases. Therefore, there is a considerable
interest in developing small-molecule β-strand mimetics that can
disrupt such interactions. Pioneer work of Hirschman and Smith
used successfully pyrrolinone-based to design non peptide
mimics of β -pleated strands and sheets.[7] Since several years,
Hamilton’s group has focused on mimetics of one recognition
surface of the strand (the i, i+2nd, and i+4th side chain residues),
The most common type of secondary structure in proteins is the
α-helix and a large body of work has already been carried out to
design and synthesize α-helix mimetics.[4] The β-sheet is the
second form of regular secondary structure and it also often
using different scaffolds, such as 2,2-disubstituted-indolin-3
derived [8], aryl-linked hydantoins
and, in a very recent work,
[6b]
this group was interested in aryl- and pyridyl-linked imidazolidin-
2-ones[6d], in which dipolar repulsion is a central determinant of
conformation.
Our laboratory has described a methodology to design potential
protein secondary structure mimes, using as structural chemical
units, pyridyl, thienyl and phenyl rings: the garlanding concept. [9]
Previously, we have demonstrated the α-mimetic ability of
oligopyridyl and oligophenylpyridyl scaffolds.[10] [11] Today, in this
article, we are interested in the capacity of oligothienylpyridyl
scaffold to mimic β-strands. In this study we have evaluated if
these scaffolds are able to produce coplanar entities and if they
will be able to mimic the side chain distribution of a β-strand.
Studies were conducted in three steps: first, theoretical
simulations were carried out in order to evaluate preferential
[a]
[b]
Dr M. Jouanne, Prof. A. S. Voisin-Chiret, Dr. R. Legay, S.
Coufourier, Prof. S. Rault and Prof. J. Sopkova-de Oliveira Santos
Université Caen Normandie, France
Dr M. Jouanne, Prof. A. S. Voisin-Chiret, Dr. R. Legay, S.
Coufourier, Prof. S. Rault and Prof. J. Sopkova-de Oliveira Santos
UNICAEN, CERMN - EA 4258, FR CNRS 3038 INC3M, SF 4206
ICORE
bd Becquerel, F-14032 Caen, France
E-mail : jana.sopkova@unicaen.fr
Homepage : http://cermn.unicaen.fr/
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
10.1002/ejoc.201600882
FULL PAPER
torsion angles between rings in thienylpyridyl systems; second,
the theoretical predictions were validated by experimental data
from structural studies in solution (NMR study associated with
dynamic simulations) as well as in the solid state (X-ray
diffraction). Finally, we assessed the ability of oligothienylpyridyl
substituents to mimic β-strand side chain distribution.
Results and Discussion
Ab initio simulation
First of all, theoretical simulations have been carried out on
systems constituted of one pyridyl and one thienyl ring
unsubstituted or monosubstituted with one methyl group. In the
monosubstituted system, the methyl substituent was placed
either on the pyridyl or the thienyl ring in different positions. The
nitrogen position in the pyridyl ring and the sulfur position in the
thienyl ring also varied. In total, 4 unsubstituted and 28
monosubstituted models were built, of which 16 were substituted
on the pyridyl ring and 12 on the thienyl ring. Among the models,
only the pyridyl ring with a nitrogen atom in the ortho and in
meta positions (relative to the ring junction) are described in this
paper. We do not present results concerning diaryls with
nitrogen atom in the para position, because they are
substantially similar to the meta position results.
For each model the internal potential energy barrier was
calculated by ab initio simulation at (B3LYP/6-31+G(d,p)) level
as a function of torsion angle between the two rings. The results
for monosubstituted and unsubstituted thienylpyridine are
summarized in Table 1 and Figure 2.
Interestingly, our computational analysis showed that when the
N and S atoms are both located in the vicinity of the junction
(Table 1 and Figure 2), the rings are systematically in the
coplanar arrangement (group A1 and A2) and this even in the
presence of a methyl substituent in the ortho position relative to
the ring junction (group A2). The introduction of a methyl
substituent in the proximity of the junction decreased the energy
barrier height by about 2 kcal/mol, but did not destabilize the co-
planar arrangement. These results are in agreement with
previously published theoretical calculations in which an electron
deficient divalent S atom has two areas of positive electrostatic
potential, a consequence of the low-lying σ* orbitals of the C-S
bond, that are available for interaction with an electron donor
such as nitrogen.[12] Consequently, the intermolecular N...S
interaction was pointed out as a conformational stabilizing
element introducing “N,S-cis locked” coplanar arrangement in
biaryl systems in the analogous manner as non-covalent S…O
interaction has used as conformational control element in α-
helical mimetic benzothiazol-thiophene scaffold synthesized by
Hamilton’s group.[13] Moreover, we observed also that the
coplanar arrangement in biaryl can be achieved when N atom
lies in the direct neighborhood of the junction and the other three
atoms are Har (group A3). The nitrogen lone pair introduces a
negative partial charge in the ring and thus a weak electrostatic
interaction between N and Har occurs and plays also a role of a
stabilizing element.
A
detailed analysis of the results showed that the 28
monosubstituted and 4 unsubstituted models can be divided into
3 groups depending on the preferential twist angle between
adjacent thienyl/pyridyl moieties and the energy barrier height
associated with this twist.
Figure 2. Evolution of potential energy as a function of torsion angle between
the rings in unsubstituted thienyl/pyridyl systems or monosubstituted by methyl
ones.
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European Journal of Organic Chemistry
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Finally the adjacent thienyl/pyridyl rings are balanced by four
competing factors; (i) the interaction between the electron-
donating N atom and the acceptor S atom,[12] (ii) electrostatic
interaction due to the presence of nitrogen, (iii) a symmetric
interaction between π orbitals of the aromatic rings, (iv) a steric
repulsion between overlapping ortho hydrogen atoms and
substituents.[14] Our simulation results suggested that we can
Table 1. Structural parameters of minimum energy conformers of methyl
substituted thienylpyridine obtained from PES at B3LYP/6-31+G(d,p) level.
Preferential
angle
Potential
energy
barrier
Group
Compound
between the
ring planesa
[kcal/mol]
introduce
a coplanar or near coplanar arrangement in
Co-planar
1
5.5-6
(0° - 20°)
oligothienylpyridines in several ways contrary to the biphenyl for
which the co-planar arrangement has never been achieved.
Despite that the fact that the introduction of substituent in ortho
in oligothienylpyridines deviates the adjacent rings from coplanar
arrangement, the energy barriers related to the twist angles
Prefered conformation N,S-cis-locked
Prefered conformation N,S-cis-locked
Co-planar
(0° - 30°)
A
2
3
3.5
4.5
remain small (<
4
kcal/mol) allowing flexibility in the
Co-planar
(0° - 25°)
thienylpyridyl scaffolds. Contrariwise the ortho substituents in
biphenyl have increased significantly the energy barrier (from 4
kcal/mol to 12 kcal/mol.[9e, 15] So, the thienylpyridyl scaffolds will
more easily reach coplanar arrangements with smaller energies
penalties in comparison with oligophenyl scaffolds and is
therefore more suitable for beta strand mimicry.
30°
(0° - 50°)
1
2-3
Prefered conformation N,S-trans-
locked
B
30°
(0° - 50°)
2-2.5
2
3
Compound Synthesis
2
30°
In order to validate our theoretical predictions, calculated for
simple two-unit systems, various thienylpyridines with three or
five diversely substituted units were synthesized (Table 2). Our
laboratory is specialized in the preparation and use of boronic
species[16] and in the study of their ability to be good cross-
coupling partners.[9f, 17]. With this expertise, oligothienylpyridines
using Suzuki-Miyaura cross-coupling reaction were synthesized.
Three unit compounds 2a-c (scheme 1A) and 4a-b (scheme 1B)
were prepared from a Suzuki-Miyaura cross-coupling reaction
between a 2,5-dibromothiophene and two equivalents of a
pyridylboronic acid. Under to the same conditions, starting from
dibromothienylpyridines 4a-b, five unit compounds 5a-d
(scheme 1B) have been obtained. This last synthesis procedure
allows the preparation of symmetrical molecules only. To
evaluate more finely the impact of sulfur/nitrogen interactions on
the overall molecule conformation, dissymmetrical three unit
compounds (8a-b) were also synthesized using a sequence
Suzuki-Miyaura reaction - bromination - Suzuki-Miyaura reaction
(scheme 2).
(15° - 50°)
45
(30° - 70°)
1
2
2-2.5
3-4
C
50°
(30° - 75°)
[a] values in brackets correspond to a 0.5 kcal/mol limit.
Nevertheless, in the latter case, the methyl substituent in the
vicinity of the junction disrupts the coplanar arrangement and the
ring preferential twist angle becomes about 30° with a small
energy barrier (∆E ~ 2-3 kcal/mol) (group B1). In this case, the
steric repulsion between the ortho substituents dominates
somewhat over the weak N…Har electrostatic interaction. A
similar preferential twist angle ~30° occurred also when the four
atoms in the junction vicinity were Har or when S atom and three
Har were present (group B2 and B3, respectively).
Scheme 1A. A mixture of pyridylboronic acid 1a or 1b (2.5 equiv), 2,5-
Interestingly, in biaryls of group B2 with an S atom in the
junction vicinity, the introduction of a methyl group in the ortho
position to the junction (group C1) changes the preferential twist
angle from 30° to 45° but does not change the energy barrier
which remains about ∆E ~ 2-2.5 kcal/mol. A similar phenomenon
can be achieved also in a system with only Har in the junction
vicinity (group B3); the introduction of a methyl substituent
increased the preferential ring twist angle to 50° (group C2). In
these systems, the bulky methyl group in the ortho position to
the junction introduces a more important steric repulsion and so
the potential energy barrier increases from 2 to 4 kcal/mol.
dibromothiophene
or
2,5-dibromo-3-methylthiophene
(1.0
equiv),
tetrakis(triphenylphosphine) palladium (10 mol %), and aqueous Na2CO3 (5
equiv) in 1,4-dioxane was heated to reflux for 20h until the complete
consumption of dibromothiophene (TLC). Crude products were purified by
silica gel column chromatography to give 3-[5-(3-pyridyl)-2-thienyl]pyridine 2a,
4-methyl-3-[5-(4-methyl-3-pyridyl)-2-thienyl]pyridine 2b and 3-[3-methyl-5-(3-
pyridyl)-2-thienyl]pyridine 2c with 77%, 30% and 48% yield, respectively.
1,4-dioxane
A
Pd(PPh3)4, Na2CO3
(2,5 eq.)
2a 77 % (R1=H; R2=H)
2b 30 % (R1=H; R2=CH3)
2c 48 % (R1=CH3; R2=H)
R1=H,CH3
1a (R2=H)
1b (R2=CH3)
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European Journal of Organic Chemistry
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FULL PAPER
Scheme 1B. A mixture of bromopyridylboronic acid 3a or pinacol ester 3b (2.5
equiv), 2,5-dibromothiophene (1.0 equiv), tetrakis(triphenylphosphine)
palladium (10 mol %), and aqueous Na2CO3 (5 equiv) in 1,4-dioxane was
heated to reflux for 20h until the complete consumption of dibromothiophene
(TLC). Crude products were purified by silica gel column chromatography to
give 3-bromo-5-[5-(5-bromo-3-pyridyl)-2-thienyl]pyridine 4a and 3-bromo-5-[5-
(5-bromo-4-methyl-3-pyridyl)-2-thienyl]-4-methyl-pyridine 4b with 51% and
68% yield, respectively. Then 4a or 4b (1.0 equiv) was dissolved in 1,4-
dioxane and 3-pyridylboronic acid or 4-methyl-3-pyridylboronic acid (2.5 equiv),
tetrakis(triphenylphosphine) palladium (10 mol %), and aqueous K3PO4 (5
equiv) were added. The reaction mixture was heated to reflux for 20h until the
complete consumption of dibromopyridylthienylpyridine (TLC). Crude products
were purified by silica gel column chromatography to give 3-(3-pyridyl)-5-[5-[5-
Table 2. Synthetized thienylpyridines for this study.
Name
Molecular diagram
2a
2b
(3-pyridyl)-3-pyridyl]-2-thienyl]pyridine
5a,
4-methyl-3-[5-[4-methyl-5-(3-
2c
pyridyl)-3-pyridyl]-2-thienyl]-5-(3-pyridyl)pyridine 5b, 3-(4-methyl-3-pyridyl)-5-
[5-[5-(4-methyl-3-pyridyl)-3-pyridyl]-2-thienyl]pyridine 5c and 4-methyl-3-[5-[4-
methyl-5-(4-methyl-3-pyridyl)-3-pyridyl]-2-thienyl]-5-(4-methyl-3-
pyridyl)pyridine 5d with 70%, 30%, 64% and 37% yield, respectively.
8b
8a
5a
1,4-dioxane
B
Pd(PPh3)4, Na2CO3
(2,5 eq.)
4a 51 % (X=Br; R1=H; R2=H)
4b 68 % (X=Br; R1=H; R2=CH3)
3a (R2=H, R=H)
3b (R2=CH3, R=pinacol)
1,4-dioxane
Pd(PPh3)4, K3PO4
5b
(2,5 eq.)
R3=H,CH3
5c
5d
5a 70 % (R2=H; R3=H)
5b 30 % (R2=CH3; R3=H)
5c 64 % (R2=H; R3=CH3)
5d 37 % (R2=CH3; R3=CH3)
Scheme 2. 2-thienylboronic acid (1.0 equiv), 2-bromopyridine or 2-bromo-3-
methylpyridine (1.0 equiv), tetrakis(triphenylphosphine) palladium (5 mol %),
and aqueous Na2CO3 (2.5 equiv) were added in 1,4-dioxane and the mixture
reaction was heated to reflux for 12h until the complete consumption of
bromopyridine (TLC) to obtain 2-(2-thienyl)pyridine 6a (67%) and 3-methyl-2-
(2-thienyl)pyridine 6b (78%) after purification by silica gel column
chromatography. Then, to a stirred solution of 6a or 6b in a 50/50 (v/v) mixture
of dichloromethane and glacial acetic acid was added N-bromosuccinimide
(NBS) (1.1 equiv). The resulting solution was stirred at 40°C for 3-12h and the
crude product was subjected to column chromatography to give desired
bromothienylpyridine 7a (50%) and 7b (91%). Finally, 7a (1.0 equiv) was
dissolved in 1,4-dioxane and 3-pyridylboronic acid (1.2 equiv),
tetrakis(triphenylphosphine) palladium (5 mol %), and aqueous K3PO4 (2.5
equiv) were added. The reaction mixture was heated to reflux for 20h until the
complete consumption of 7a (TLC). Crude product was purified by silica gel
column chromatography to give 2-[5-(3-pyridyl)-2-thienyl]pyridine 8a with 60%
yield. The same procedure was conducted with 7b and 4-methyl-3-
NMR
First, an NMR structural study was carried out with the aim of
analyzing 3D structures of synthesized compounds in solution.
In the first step of this study, a complete assignment of all
protons and carbons was realized using conventional 1D and 2D
experiments: DEPT135, COSY (1H−1H), HSQC (1H−13C), and
HMBC (1H−13C). The proton and carbon chemical shift values
and 1H−1H coupling constants of 5b are reported in Table 3
(NMR data for all studied compounds are available in the
Supporting Information Table S1). In a second step, the NOESY
(1H−1H) experiment was used to access compound
conformations in solution.[18] Indeed a correlation peak between
two protons observed in the 2D spectrum indicates that these
two nuclei are close through space (strong NOE intensities:
distance between protons ≤ 2.5 Å; medium NOE intensities:
distance between protons ≤ 3.7 Å; weak NOE intensities:
distance between protons ≤ 5.0 Å). For example in the NOESY
spectrum of 5b, Figure 3A depicts a spatial proximity between
methyl groups and some protons of adjacent rings and Figure
3B gives measured intracycle NOE correlations between
neighboring protons in the aromatics region.
pyridylboronic
acid
to
obtain
3-methyl-2-[5-(4-methyl-3-pyridyl)-2-
thienyl]pyridine 8b with 50% yield.
R1
N
R1
R1
1,4-dioxane
Br
CH2Cl2/AcOH
NBS
S
S
+
Br
Pd(PPh3) , Na2CO3
4
(HO)2
B
N
S
N
6a 67
6b 78
%
%
(R1=H)
7a 50
7b 91
%
%
(R1=H)
(R1=CH3
R1=H,CH3
(R1=CH3
)
)
R2
B(O H)2
1,4-dioxane
Pd(PPh3 K3PO4
)
,
4
N
R1
R2
S
N
N
(R1=R2=H)
(R1=R2=CH3
8a 60
8b 50
%
%
)
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European Journal of Organic Chemistry
10.1002/ejoc.201600882
FULL PAPER
Figure 3. NOESY spectrum of thienylpyridine 5b: (A) correlations with methyl
groups; a spatial proximity between methyl group protons of neighboring
pyridine rings A/E (H2, H4) and protons of the central thiophene ring C (H3,
H4). (B) measured intracycle NOE correlations between neighboring protons
in the aromatics area: first, correlations between neighboring hydrogens of the
same ring (H4, H5 and H6 in A/E rings) and second, intercycle spatial
proximity correlations between protons located on each side of the ring
junctions (H6 of B/D rings with H2 and H4 of rings A/E, H2 of B/D rings with
H3 or H4 of C ring).
introduction of supplementary dihedral force field parameters
based on our quantum mechanics simulations. For each
derivative the 10 lowest energy conformers (as shown in Table
S2 of SI) were retained for subsequent analysis from 50 ns
simulations.
Table 3. 1H/13C NMR data for thienylpyridine 5b and estimated distances from
NMR spectra and the X-ray structure.
1H13
C
13C
δ (ppm)
J (Hz)
δ (ppm)
150.0
N
N
6
6
2
2
E
A
CH3
H3C
3
4
5
H2
H3
8.67
-
d (1.5)
C2
C3
5
4
3
3
5
5
3
C
3
4
4
5
2
S
B
D
-
133.7
6
6
2
2
N
N
dt (7.8,
Rings
A / E
H4
H5
7.73
7.45
C4
C5
136.8
123.4
CH3B/2A
CH3H/2E
1.7)
CH3B/4A
CH3D/4E
CH3B/3C
CH3D/4C
dd (7.8,
4.9)
H6
H2
8.70-8.69
m
m
-
C6
C2
149.2
150.1
130.7
143.2
134.8
149.5
18.3
8.70-8.69
H3
-
C3
H4
-
-
C4
Rings
B / D
H5
-
-
C5
N
N
4A/5A
4E/5E
6
6
H6
8.44
2.40
-
s
s
-
C6
2
2
E
A
CH3
H3C
3
4
5
5
4
3
3
5
5
3
C
CH3
H2 / H5
H3 / H4
CH3
C2 / C5
C3 / C4
3
2
4
4
5
2
S
B
D
6
6
2
139.9
128.4
N
N
Ring
C
7.20
s
6B/4A
6D/4E
2A/6B
2E/6D
6A/5A
6E/5E
2B/3C
2D/4C
X-ray distance
(Å)
Estimated NOE
distance (Å)
NOE
CH3B/2A ; CH3D/2E
CH3B/4A ; CH3D/4E
CH3B/3C ; CH3D/4C
3C/2B ; 4C/2D
2.901
4.850
2.880
4.430
2.280
2.359
2.422
4.187
3.3±0.3
3.2±0.3
3.2±0.3
3.0±0.3
2.5±0.2
2.2±0.2
3.2±0.3
3.2±0.3
Furthermore, NOESY experiments allow
a
quantitative
estimation of internuclear distances in small to intermediate size
molecules.[19] NOE correlation intensities (I) depend on
distances between two protons as follows: I = k/r6. The constant
k is estimated from the integration of a NOE correlation spot
between two intracycle protons separated by a distance r,
known or determined by X-ray crystallography and a priori
independent of molecule conformation. We performed
calculations using several different references whenever it was
possible. Integrating the correlation spot volumes and using the
relation (I = k/r6), an estimate of the corresponding distances
with an error margin of 20 to 25% was obtained (due to spin
diffusion, other relaxation mechanisms, complicated modes of
motion, affecting NOEs intensities). The estimated distances
from NMR spectra for 5b are given in Table 3 and those for all
studied compounds are available in the Supporting Information
(Table S1).
Then molecular dynamic simulations at 300 K were carried out
with the application of 1H−1H distance constraints determined
from the NMR study (NMR constraints). Starting from initial
coordinates built using the Discovery Studio software [20], these
simulations led to NMR thienylpyridyl 3D structures. In
simulations we used only the force field derived by the Discovery
Studio and experimental NMR constraints without the
*5A/6A ; 5E/6E
*5A/4A ; 5E/4E
4A/6B ; 4E/6D
6B/2A ; 6D/2E
* notes the distance used as reference for NOE estimation
The ten most stable NMR conformers of 2a, 2b, 2c, 8a and 8b
generated, which are three unit scaffolds, were close each other
in terms of absolute values of ring torsions. The observed
differences among NMR conformers in one compound were
related to a rotation of the same angle but in the opposite sense
to one or two scaffold outside rings. This observation is in
agreement with the theoretical simulations that have predicted
that all thienylpyridines can rotate left and right with equal
probability. For 2b, 2c, 8a and 8b, the ten conformers could be
divided into two groups which differ from each other only by the
torsion of one outside ring (Figure 3). In 2a both outside rings, A
and C, turned, but nonetheless its ten NMR conformers cluster
also in 2 groups, because the A and C rings turned on the
opposite sense at the same time.
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European Journal of Organic Chemistry
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The NMR structures of three-unit scaffolds generated were
compared to the theoretical predictions (Figure 4). For each
compound, the twist angle values of NMR data presented in
Figure 4 correspond to the average calculated from absolute
twist angle values of the ten conformers (see Table S2 in
Supporting Information). An overview of these results indicated
that three-unit 3D NMR structures fall fully into predicted twist
angles interval from the theoretical study. Nevertheless, the
predicted N,S-cis locked conformation from the simulation of
nitrogen and sulfur situated in the junction proximity was not fully
confirmed by NMR structures. The N,S-cis conformation was
observed in 8a but it was not observed in 8b.
 Ring A-Ring B
 Ring B–Ring C
2b
Prediction
30° - 70°
(E2-2.5 kcal/mol)
30° - 70°
(E2-2.5 kcal/mol)
5.1 Å
NMR data
66.50.1
66.60.3
6.9 Å
A
C
X-ray data
Conf. 1
B
-29.28
+29.28
+33.01
-33.01
7.272 Å
Conf. 2
In the three-unit compounds with two substituents, 2b and 8b,
methyl groups were situated in one cluster of conformers on the
same side of the molecule, while in the other cluster they were
positioned on the opposite side. The distance between methyl
 Ring A-Ring B
 Ring B – Ring C
2c
Prediction
0° - 50°
(E2-2.5 kcal/mol)
30° - 70°
(E2-2.5 kcal/mol)
groups in conformers with substituents on the same side was
A
about 5.1 Å in 2b and 6 Å in 8b, somewhat closer to the target
NMR data
32.80.9
612
one between i, i+2nd side chains of a β-strand (6.8 Å).
For all five-unit scaffolds studied, the ten NMR conformers
generated were very close to each other and the rings have
remained in the same direction. The observed twist angles in the
NMR structures coincide with the predicted twist angle intervals
with the exception of the B ring–C ring and C ring-D ring twist
angles in 5b and in 5d (Figure 4). These four torsion angles
match with the same motif, 4-methyl-3-(2-thienyl)pyridine, which
in both compounds lie inside the five unit scaffold. In 5b, the B
ring–C ring and C ring-D ring twist angles were slightly out of the
predicted value interval and deviations were small, about 4°.
Moreover, these deviations introduce only small energy
penalties (ΔEpenalty ~ 0.5 kcal/mol, Figure 2). In 5d, the deviation
is more significant (close to 20°), but it does not introduce any
greater energy penalty (ΔEpenalty ~ 0.6 kcal/mol, Figure 2). The
affected twist angle in these two compounds is one with a very
small energy barrier that does not exceed overall 2.5 kcal/mol,
consequently a wide deviation from optimal twist angle value
introduces only a small energy penalty.
A
C
B
X-ray data
Conf. 1
+7.38
-7.39
+44.71
+44.71
Conf. 2
 Ring A-Ring B
 Ring B – Ring C
8a
Prediction
0° - 50°
(E2-2.5 kcal/mol)
0° - 20°
(E5.5-6 kcal/mol)
NMR data
31.850.03
0.50.2
X-ray data
Conf. 1
A
C
B
-10.10
+10.11
+2.73
-2.73
Conf. 2
Figure 4. Stick presentations of NMR structures and ORTEP views of the
crystal structures with twist angle values of 2a-c, 5a-d and 8a-b. In ORTEP
diagrams, the displacement ellipsoids are drawn at the 50% probability level
and H atoms are shown as small spheres of arbitrary radii.
 Ring A-Ring B
 Ring B – Ring C
8b
Prediction
0° - 30°
(E3.5 kcal/mol)
30° - 70°
(E2-2.5 kcal/mol)
 Ring A-Ring B
 Ring B–Ring C
2a
Prediction
7.3 Å
B
0° - 50°
(E2-2.5 kcal/mol)
0° - 50°
(E2-2.5 kcal/mol)
A
NMR data
22.90.5
591
C
6 Å
NMR data
28.10.1
28.10.1
X-ray data
Conf. 1
A
C
B
6.92
-4.62
Conf. 2
-6.92
+4.62
 Ring A-
Ring B
 Ring B
– Ring C
 Ring C-
Ring D
 Ring D
– Ring E
5a
Prediction
35° - 70°
(E3
kcal/mol)
0° - 50°
(E2-2.5
kcal/mol)
0° - 50°
(E2-2.5
kcal/mol)
35° - 70°
(E3
kcal/mol)
B
D
C
NMR data
69.270.02
24.90.4
24.90.5
69.30.02
A
E
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European Journal of Organic Chemistry
10.1002/ejoc.201600882
FULL PAPER
structures have been solved (Figure 4). Crystal observation
under microscope showed for each derivative only one kind of
crystals (needles) and there is probably no polymorphism.
Therefore, the X-ray structures can be considered as
representative. For each crystallized compound, the crystal
space group contains a symmetric center and consequently two
axial atropoisomers are present each time in the crystal with the
opposite side ring rotation.
 Ring A-
Ring B
 Ring B
– Ring C
 Ring C-
Ring D
 Ring D
– Ring E
5b
Prediction
55° - 90°
(E9.5
kcal/mol)
30° - 70°
(E2-2.5
kcal/mol)
30° - 70°
(E2-2.5
kcal/mol)
55° - 90°
(E9.5
kcal/mol)
NMR data
88.770.02
73.980.01
73.960.02
88.780.02
5.1 Å
B
D
C
X-ray data
Conf. 1
A
E
7.018 Å
+46.70
+46.70
-36.60
+36.60
+36.60
-36.60
-46.76
+46.76
Globally, deviations between rings observed in the X-ray
structures were systematically of lesser magnitude compared to
those observed in the NMR analysis. Consequently, crystal
structures of 2a and 8a, were planar and those of 2b, 2c, 5b and
5c were quite coplanar. The predicted values from the ab initio
simulations on thienylpyridine systems were in good agreement
with the observed twist angles in the X-ray structures, even for
5b for which we observed a small deviation from the predicted
value during NMR analysis. The B ring-C ring and C ring-D ring
crystal twist angles were of about 37° instead of 74° observed in
NMR structures. Therefore the global X-ray structure of 5b is
more planar than the NMR one. Unfortunately, we have not
obtained suitable crystals for X-ray diffraction for 5d, but we can
assume that the 5d twist angle values will be smaller as was
observed for all studied compounds.
Furthermore, the simulations have suggested that for the
compounds with a sulfur and nitrogen atom in the proximity of
the junction, intermolecular N...S interactions should lead to a
“N,S-cis locked” coplanar arrangement. Indeed in the crystal
structure of 8a, as well as for 5-[5-(2-pyridyl)-2-thienyl]pyrimidine
(unpublished data) with sulfur and nitrogen atoms in the junction
vicinity, N,S-cis lock was observed and rings were coplanar.
Unfortunately, we did not obtain crystals of 8b for which the
NMR structure analysis proposed a N,S-trans arrangement
contrary to our prediction.
Conf. 2
 Ring A-
Ring B
 Ring B
– Ring C
 Ring C-
Ring D
 Ring D
– Ring E
5c
Prediction
55° - 90°
(E9.5
kcal/mol)
0° - 50°
(E2-2.5
kcal/mol)
0° - 50°
(E2-2.5
kcal/mol)
55° - 90°
(E9.5
kcal/mol)
14.2 Å
NMR data
77.960.02
26.00.4
25.50.4
65.280.02
B
D
C
A
X-ray data
Conf. 1
E
+54.22
-54.22
-13.00
+13.00
-13.00
+13.00
+54.22
-54.22
14.747 Å
Conf. 2
 Ring A-
Ring B
 Ring B
– Ring C
 Ring C-
Ring D
 Ring D
– Ring E
5d
Prediction
60° - 90°
(E25
kcal/mol)
30° - 70°
(E2-2.5
kcal/mol)
30° - 70°
(E2-2.5
kcal/mol)
60° - 90°
(E25
kcal/mol)
A
7.3 Å
D
C
NMR data
84.40.1
883
835
84.20.1
B
E
10.6 Å
For the five-unit compounds, we observed that in compounds
with two substituents, 5b and 5c, methyl groups were situated
on the same side of the compounds. While in the compound with
four substituents (5d), methyl groups on the inside rings pointed
to the opposite side of compound but methyl groups on the
outside rings were located once more on the same side. The
distance between the methyl substituents on outside rings in 5c
and in 5d was about 14.2 Å and 10.5 Å, respectively, and the
methyl distance on inside rings in 5b was about 5.1 Å. The
observed methyl interdistances in the NMR structures are
somewhat further from the target for β-strand mimes, 6.8 and
13.6 Å. However, the selected NMR structures reflect only one
part of the conformational space, for example for compound 5b
ten structures in energy range of 61.2975 to 61.2976 kcal/mol
(Table S2 in Supporting Information) were selected from 10000
in energy range of 61.2975 to 67.8870 kcal/mol generated in
molecular dynamic simulation. For more information on the
ability of thienylpyridyl scaffold to mimic a β-strand, an X-ray
diffraction analysis in solid state was carried out.
In all X-ray structures of compounds with two methyl
substituents (2b, 5b, 5c), methyl groups were positioned on the
same side and their interdistances were longer to those
observed in NMR structures related to greater planarity of
compounds in crystal. Consequently, the observed methyl
interdistances in crystal structures were much closer to those
desired for β-strand mimes (see Figure 1 and Figure 4). In the
three-unit scaffold 2b, methyl groups were at a distance of 7.272
Å and in the five-unit scaffold 5b at a distance of 7.018 Å. Even
if, in the structure of 5c, methylpyridines located at both
extremities deviate somewhat from coplanar arrangement (the
ring twist angle related with the end pyridine was about 54°), the
whole compound remained relatively coplanar and the distance
between methyl groups was about 14.747 Å. In view of these
results, we can expected that compounds 2b and 5b could be
potential mimes for the i, i+2nd side chains of a β-strand and 5c
could mime the i, i+4th β -strand side chains. Alignments of X-ray
structures of these three compounds with the ideal polyalanine
β-strand have demonstrated that methyl substituents are
projected close to the desired positions, even for the less planar
compound 5c (Figure 5).
X-ray structures
Suitable crystals for X-ray diffraction study were obtained for 6
derivatives from the 9 studied by NMR analysis and their 3D
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European Journal of Organic Chemistry
10.1002/ejoc.201600882
FULL PAPER
Figure 5. Superposition of a polyalanyl β-strand (in green) and X-ray structure
(in purple) of thienylpyridines with two or four substituents.
Conclusions
We have demonstrated that we can obtain
a coplanar
arrangement in thienylpyridyl systems in several different ways.
The presence of a nitrogen and sulfur atom in the junction
vicinity introduces a coplanar arrangement (regardless of the
substituent position) as well as the presence on nitrogen in the
non-ortho substituted systems. The introduction of an ortho
substituent in a system with nitrogen in the junction vicinity
deviates somewhat the two rings (±30°), but the system can
achieve the same close coplanar arrangement since the energy
barrier corresponding to the 0° twist angle is very low in these
systems, about of 0.5 kcal/mol. The same behavior was
observed in a non-ortho substituted biaryl with only a sulfur in
the junction vicinity. The X-ray structures showed that the
compounds have a tendency to generally adopt a nearly
coplanar conformation so that the positions of methyl
substituents coincide well with those of i, i+2nd or i, i+4th β-strand
side chains. Interestingly, the crystal structure analysis showed
that 5b is itself able to form a sheet-like structure. Therefore, the
thienylpyridine scaffold opens the way to produce coplanar
compounds mimicking β-strand side chain distributions.
i
i+2
i
i+2
i
i+4
Furthermore, in the crystal packing of 5b and 5c, weak
electrostatic interactions occurred between the pyridine N atoms
and aromatic Har of a neighboring molecule. These interactions
lead to the formation of a complex arrangement in the crystal. In
the 5c crystal, the N atom of an outside pyridine interacted with
Har of the neighboring molecule inside pyridine, the nitrogen
atoms of each outside pyridine lying in a different neighboring
molecule. Consequently, the 5c forms a “zigzag” chain across
the entire crystal (Figure 6). In 5b the nitrogen of both inside
pyridines established weak electrostatic interactions with an
outside pyridine Har and with the methyl group of a neighboring
compound. Moreover, in 5b packing, the two inside N atoms
related to the same neighboring molecule. Therefore, the 5b
compound established a sheet-like arrangement in the crystals
(Figure 6). The Har committed in these weak electrostatic
interactions within crystals were systematically those situated at
ortho of the N atom.
Experimental Section
Conformational Analysis.
3D models for thienylpyridines as a function of the pyridyl nitrogen,
thienyl sulfur and methyl position were built using the Discovery Studio
software.[20] This corresponds to 28 thienylpyridyl models substituted with
one methyl group and
4 unsubstituted models. The Cartesian
coordinates of each model were used as input for the ab initio simulation.
All ab initio calculations reported in the present study were carried out
using the Gaussian 03 software.[21] Potential energy scan (PES) studies
Figure 6. A general view of the crystal packing of 5c (A) and 5b (B).
A
of all thienylpyridines consisted of
a (−180°, +180°) geometry
optimization with the specified coordinate freezing and a 5° increment in
order to obtain the internal energy barrier to rotation at the B3LYP/6-
31+G(d,p) level.
Compounds synthesis
General Procedure for Suzuki-Miyaura Cross-Coupling used for
compound synthesis is presented in Schemes 1 and 2. Commercial
reagents were used without further purification. Chromatography was
carried out on a column using flash silica gel 60 Merck (0.063-0.200 mm)
as the stationary phase. Flash chromatographies were performed with a
Biotage Isolera One flash chromatography. The eluting solvent, indicated
for each purification, was determined by thin layer chromatography (TLC)
performed on 0.2 mm precoated plates of silica gel 60F-264 (Merck) and
spots were visualized using an ultraviolet-light lamp. Melting points (Mp)
were determined using a Köfler heating bench. Infrared (IR) spectra were
B
recorded on
a Perkin Elmer FT-IR spectrophotometer. The band
positions are given in reciprocal centimeters (cm-1). Mass data were
recorded on a liquid chromatography-mass spectrometer Waters SQD in
ESI+ or ESI- mode. High resolution mass spectra were performed at 70
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European Journal of Organic Chemistry
10.1002/ejoc.201600882
FULL PAPER
eV by electronic impact (HRMS/EI) or by positive or negative
electrospray (HRMS/ESI).
by heating (during 3 ps) and equilibration (25 ps) steps. During the
production phase (50 ns), conformations were saved every 5 ps and
energy minimized to a root-mean-square gradient of less than 0.001
kcal/(mol·Å2). The 10 lowest-energy conformations obtained for each
thienylpyridyl compound were used in the subsequent analysis. The
selected structures were analyzed and displayed using Mercury
NMR Measurements
software.[24]
.
All NMR experiments were carried out using a Bruker AVANCE III 500
spectrometer equipped with a 5 mm BBFO {1H, X} including shielded z-
gradients. Solutions in concentration range of 20-30 mg·ml-1 in CDCl3
were used. Experiments were carried out at 500 MHz for 1H and 125
MHz for 13C. 1H and 13C chemical shifts are expressed in parts per million
(ppm) and referenced according to the CDCl3 solvent signal used as a
secondary internal reference (1H, δ=7.26 ppm; 13C, δ=77 ppm, with
respect to TMS, 0 ppm). The 1D and 2D NMR spectra were measured at
295 K. Complete assignment of all protons and carbons was carried out
using conventional 2D experiments: COSY (1H−1H), HSQC (1H−13C), and
HMBC (1H−13C). For all 2D spectra, a total of 4096 points in F2 and 512
experiments in F1 were recorded. For the HMBC experiment, an
evolution delay of 65 ms was chosen in such a way that correlations
involving long-range J coupling around 10 Hz could be observed. To
observe through space correlations, NOESY (1H−1H) experiments were
performed using mixing times of 1.5 s. Processing and analysis of the
NMR spectra was performed with the Topspin 3.2 software from Bruker.
Acknowledgements
The authors gratefully acknowledge the CRIHAN (Centre de
Ressources Informatiques de Haute Normandie), as well as the
European Community (FEDER) for the molecular modelling
software.
Keywords: -strand mimetic • foldamers • oligothienylpyridines •
NMR and X-ray studies • molecular modelling
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field parameters based on our mechanic quantum simulations. During all
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structure, a dynamic simulation of 50 ns was carried out for each
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European Journal of Organic Chemistry
10.1002/ejoc.201600882
FULL PAPER
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European Journal of Organic Chemistry
10.1002/ejoc.201600882
FULL PAPER
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FULL PAPER
Protein-protein interactions (PPIs) are
involved in many cellular processes
and the design of small molecules as
modulators of PPIs is an important
challenge. Actually, the most
Marie Jouanne, Anne Sophie Voisin-
Chiret,* Rémi Legay, Sébastien
Coufourier, Sylvain Rault and Jana
Sopkova-de Oliveira Santos*
Page No. – Page No.
challenging PPIs classes are those
mediated by β-sheet interactions. This
study reports the use of S…N
interactions as a conformational
control in oligothienylpyridyl scaffolds
in view of their ability for β-strand
mimicry
Beta strand mimicry: Exploring
oligothienylpyridines foldamers
Key Topic: Foldamer; β-strand
This article is protected by copyright. All rights reserved