Fluorinated Aromatic Monomers as Building Blocks to Control α-Peptoid Conformation and Structure

Article abstract of DOI:10.1021/jacs.8b13498

Peptoids are peptidomimetics of interest in the fields of drug development and biomaterials. However, obtaining stable secondary structures is challenging, and designing these requires effective control of the peptoid tertiary amide cis/trans equilibrium.

Full text of DOI:10.1021/jacs.8b13498

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Communication
Fluorinated Aromatic Monomers as Building Blocks
to Control #-Peptoid Conformation and Structure
Diana Gimenez, Guangfeng Zhou, Matthew F.D Hurley, Juan A Aguilar, Vincent A. Voelz, and Steven L. Cobb
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b13498 • Publication Date (Web): 09 Feb 2019
Downloaded from http://pubs.acs.org on February 10, 2019
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Fluorinated Aromatic Monomers as Building Blocks to Control α-
Peptoid Conformation and Structure
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Diana Gimenez,† Guangfeng Zhou,‡ Matthew F. D. Hurley,‡ Juan A. Aguilar,† Vincent A. Voelz*,‡
and Steven L. Cobb*,†
†
Durham University, Department of Chemistry, South Road, Durham, DH1 3LE, U.K.
‡
Temple University, Department of Chemistry, Philadelphia, Pennsylvania 19122, U.S.
Supporting Information Placeholder
values reported, the use of charged monomers puts
restrictions on designed
ABSTRACT: Peptoids are peptidomimetics of interest in the
fields of drug development and biomaterials. However,
obtaining stable secondary structures is challenging and
designing these requires effective control of the peptoid
tertiary amide cis/trans equilibrium. Herein, we report new
fluorine containing aromatic monomers that can control
peptoid conformation. Specifically, we demonstrate that a
fluoro-pyridine group can be used to circumvent the need for
monomer chirality to control the cis/trans equilibrium. We
also show that incorporation of a trifluoro-methyl group
(NCF3Rpe) rather than a methyl group (NRpe) at the α-carbon
of a monomer gives rise to a 5-fold increase in cis-isomer
preference.
α-Peptoids (Figure 1a) are resistant to protease
degradation1 and are thermally stable.2 They are of interest as
therapeutics1,3–8 and as biomaterials.9 However, because a
peptoid is composed of N-alkyl amide bonds, there is no
capacity to use hydrogen bonding to stabilize folded
structures. Accessing and designing stable structures, such as
helices,10–13 ribbons,14 loops15 or sheets16,17 relies on utilizing a
limited number of peptoid monomers that can predictably
restrict the amide bond isomerism. An early advance was
reported by Zuckermann and Barron, who showed that
monomers with N-α-chiral aromatic side-chains, such as
NSpe (2)(Figure 1b), can stabilise all cis-amide polyproline I
helices (PPI).10,18 Gorske and Blackwell explored non-covalent
interactions (NCI) including sterics, hydrogen bonding and
electronic n→π* effects to control the cis/trans equilibrium
in model peptoid systems, through which they identified new
chiral peptoid monomers such as NS1npe (3) and NSfe (4)
(Figure 1b), able to impose larger Kcis/trans values than NSpe
(2).19–21 Monomers such as 3 and 4 exert their effects through
Figure 1. a) α-peptides and α-peptoids; b) cis-amide
preference due to steric and n→ π* electronic effects (2-4);
c) cis-amide preference due to inductive effects (5-8); d)
Kcis/trans (CD3OD) for monomers 1-8; e) Application of
fluorine to enhance cis-isomer preference.
peptoid sequences.
While some work has been carried out to exploit fluorine
in the design of new peptoid monomers (e.g. NSfe, 4), we
sought to investigate the application of perfluoro-
heteroaromatics,
such
as
tetrafluoropyridine.
We
a
synergystic combination of steric factors (e.g. α-
hypothesized that such highly electron-deficient systems
would favor even stronger n→π*Ar interactions, overcoming
the need for monomer chirality. To investigate this
hypothesis, three model di-peptoids based on the non-chiral
benzylamine (Npm, 1), pyrinidylmethanamine (Npym, 9),
and (tetrafluoropyrinidyl)methanamine (N4fpym, 10) were
prepared for conformational analysis (Figure 2b).
methylation) and electronic n→π*Ar interactions. While all of
the aforementioned monomers are neutral, pioneering work
by Taillefumier and Faure demonstrated that positively
charged triazolium-type monomers impart an impressive
level of conformational control into a peptoid backbone.22
Yet, while this approach gives some of the largest Kcis/trans
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We recently reported that fluorine atom(s) β to the amide
preference exhibited by 12, computational studies were
performed using both ab initio QM and replica exchange
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bond nitrogen promote enhanced cis-amide preference in
non-chiral alkyl type monomers (Figure 1c).23 This cis-amide
preference was found to rely on fluorine induced dipolar
interactions. Following this we envisaged that incorporation
of a trifluoromethyl (CF3) group into an aromatic monomer
might allow both electronic (dipolar interactions) and steric
effects to be utilized in tandem to access systems in which
the cis/trans equilibrium completely favors one isomer. To
explore this, we prepared the α-trifluoromethyl (NCF3Rpe)
model peptoid 12 (Figure 2c). For comparison, the non-
fluorinated reference 11 was also prepared. The synthetic
route employed to model peptoids (1, 9-12) is shown in
Figure 2a.20,21
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1
1
We employed H-NMR and H-1H-NOESY to evaluate the
cis/trans ratios present within the model systems (see SI for
further details).24,20,21 Analysis of 1 showed that, as reported,
the benzyl side-chain induces
a
solvent dependent
conformational preference (Figure 2d).21 In CDCl3, a trans-
amide geometry is favored by 0.79 kcal mol-1, while in more
polar solvents no conformation preference was found (e.g.
ΔG~0 in both CD3CN and CD3OD, Figure 2d). Replacement
of the aromatic ring with a hetero-aromatic group caused a
significant increase in the cis-isomer preference seen across
all of the solvents tested (1 versus 9 in Figure 2d). When the
electron-withdrawing character of the aromatic ring was
Figure 2. a) Synthesis of model peptoids; b) Non-chiral di-
peptoids 1, 9-10; c) Chiral di-peptoids 11, 12. d) Average
Kcis/trans values for 1, 9-12. From each replica, ΔG= –
RTLn(Kcis/trans) at 25 ºC. Averages and SD values given for
n=6; [a]n=5 and [b]n=3. [c]Major isomer assigned as cis, in
agreement with MD data.
further increased, through the incorporation of
a
tetrafluoropyridine group (N4fpym), an impressive increase
in the Kcis/trans values was seen (10 in Figure 2d and Figure
3). Indeed, 10 showed a 3-fold higher Kcis/trans value in CDCl3
than its non-fluorinated analogue 9 (Kcis/trans= 1.41 vs. 0.47,
Figure 3). The conformational preference of 10 was
enhanced in polar solvents where highly biased cis-
populations were seen (Kcis/trans(CD3CN)= 3.22, 76% cis-
isomer; Kcis/trans(CD3OD)= 2.22, 69% cis-isomer content;
Figure 2d). Interestingly, analysis of the NOE correlations
within 10 implied that the fluoro-pyridine ring sits facing the
N-terminal carbonyl group in the cis-isomer (Figure 3). This
result supports a mechanism in which the cis conformation
is stabilized by means of fluorine enhanced n→π*Ar
interactions. The Kcis/trans values recorded for 10 are among
the highest ever reported for a neutral non-chiral monomer
in this type of peptoid model system. What is more
remarkable is that despite being a non-chiral monomer, the
cis-isomer preferences induced by N4fpym are comparable or
even greater than those produced by the widely utilized α-
chiral monomers such as 2 and 4 (Figure 2b and Figure 2d).
Figure 3. a) Amide bond geometry in systems 1, 9 and 10. b)
Experimental 1H-1H NOESY correlations within cis/trans
conformers of 10. All Kcis/trans values as determined in CDCl3.
molecular dynamics (REMD).
Scans of side-chain and backbone dihedral angles were
performed using DFT at the B3LYP/6-311G+(2d,p)//HF/6-
31G(p) level of theory (Figure 4). To identify side-chain
conformational minima, χ1 and χ2 angles were first scanned
from 0˚ to 360˚ in 30˚ intervals starting from typical
backbone conformations of peptoids: cis-amide αD (φ,ψ = -
90˚, 180˚), trans-amide αD (φ,ψ = -90˚, 180˚), and trans-
amide C7β (φ,ψ = -130˚, 80˚), with all remaining dihedral
angles unrestrained during geometry optimization (Figure
4b, Fig. S115). The results showed a preference for χ1, χ2 near
(-90˚, +15˚) in cis-amide structures, and a mixture of (-90˚,
+15˚) and (+90˚, +15˚) preferences in trans-amide structures,
consistent with similar work for related molecules.25 Next,
full backbone dihedral scans of φ and ψ angles (15˚ intervals)
were performed starting from cis-amide and trans-amide
isomers with -90˚ and +90˚ χ1 angles, with all dihedral angles
We then turned our attention to the effects imparted by
fluorine at the α-methyl position. The results obtained for
the reference (11) agreed fully with those previously reported
for the (S)-enantiomer (NSpe, 2) (Figure 2d).21 11 exhibited
almost no conformational preference in CDCl3 (Kcis/trans ~ 1.0).
Again, in line with the literature, in polar solvents its
cis/trans equilibrium shifted in favour of the cis-isomer,
particularly in CD3CN (Kcis/trans= 2.07).21 In stark contrast,
however, the NCF3Rpe containing di-peptoid 12 displayed a
1
high degree of conformational preference. Both the H and
the 19F NMR data of 12 revealed the presence of one isomer in
solution with a predominance of ≥84% (Figure 2d). It was
1
not possible to use H-1H NOESY correlations within 12 to
assign the configuration of the major isomer present (e.g see
Fig. S95). Therefore, to better understand the conformational
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except φ and ψ unrestrained during optimization (Fig. S116).
oxygen to the nearest fluorine in the electronegative CF3
group for the cis-amide negative φ-angle conformation (5.2 Å
for the positive φ-angle conformation).
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3
4
From these studies, the cis-amide energy minimum was
found to be 1.26 kcal mol-1 lower than the trans-amide, in
excellent
Comparative analysis of model systems 1, 9, 10, 11 and 12
using natural bond orbital (NBO) analysis (see SI for details)
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Figure 4. a) The lowest-energy conformation of 12,
annotated with dihedral angle definitions (see SI for details).
b) Lowest-energy minima found in φ, ψ backbone dihedral
scans started from cis- and trans-amide conformations with
side-chain orientations χ1 = -90º and +90º. c) REMD
simulations of oligomeric analogues of 12, Ac-[NCF3Rpe]n-Pip
(n=1,2,3,4,5) showing an increasing preference to form right-
handed cis-amide helices. d) Space-filling model of the
predicted pentamer structure (n=5). e-f) Longitudinal views
of a representative frame of the oligomer from the lowest
temperature replica (300 K).
Figure 5. a) Structure of peptoid oligomers 13-15. b) Main 1H-
NMR parameters of NSpe and NCF3Rpe residues as analyzed
in 15. c) Structure and average CD spectra (n=3) of peptoid
hetero-oligomers 13 (shown in red) and 14 (shown in blue).
All measurements in CH3CN.
suggests the presence of n→π*effects, as seen by a decrease
in the natural charge of the carbonyl oxygen atom and
increase in the total π* occupancy of the aromatic system.
The extent of these effects is strongly correlated with the
experimental Kcis/trans ratios, and are most significant for
system 10. These effects are less significant for system 12,
supporting a mechanism of cis-isomer stabilization in 12 in
which a combination of inductive and steric factors, rather
agreement with the experimental Kcis/trans values measured
(Figure 2d). In comparison, similar calculations for NSpe
show a cis/trans energy minima gap of only 0.2 kcal mol-1.26
These results, in combination with the experiments above,
strongly indicated that the single isomer seen experimentally
corresponded to the cis-amide conformation.
than n→π* interactions per se, act to achieve such a large
Kcis/trans ratio. This result also agrees with the orientation of
the carbonyl and aromatic groups in the minimum energy
structure of 12.
To predict the conformational preferences of NCF3Rpe
oligomers, we performed replica exchange molecular
dynamics (REMD) simulations26,27 of 12 as well as the related
The computed backbone dihedral (φ,ψ) landscape of 12
resembles that of the NSpe monomer,25,26 but unlike NSpe,
which favors a negative backbone φ-angle (near -90˚) by ~1
kcal mol-1 over the positive angle (near +90˚), 12 favors the
positive angle by ~0.8 kcal mol-1 (Fig. S116). This may partly
be due to unfavorable proximity (3.1 Å) of the carbonyl
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oligomeric species Ac-[NCF3Rpe]n-Pip, for n = 1,2,3,4,5.
ASSOCIATED CONTENT
Supporting Information
1
2
3
4
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7
8
(Figure 4c). The simulations agreed with QM studies (Table
S6), with cis-amide populations above 95% for all residues
(Fig. S117). Strikingly, simulations also predicted that larger
oligomers are increasingly prone to form stable right-handed
helices (e.g. negative φ-angle), with NCF3Rpe pentamers
displaying cis-amide helix populations of nearly 100%
(Figure 4c-f). These results likely stem from the large
Kcis/trans value for 12, which is additionally rewarded by the
excellent side-chain packing achieved in the helical
conformation. The difference between the φ-angles seen in
the model (12) and the NCF3Rpe oligomers we believe arises
due to 12 being unconstrained by the side chain packing that
is present within the oligomers.12,14
The Supporting Information is available free of charge on the
ACS Publications website. This material includes:
Experimental procedures and characterization data for
peptoid monomers 1, 9-12 and oligomers 13-17 (PDF). X-ray
crystallographic data for by-product from 12 (CIF).
AUTHOR INFORMATION
9
Corresponding Authors
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* s.l.cobb@durham.ac.uk; voelz@temple.edu
Author Contributions
The REMD simulations were experimentally validated by
19F-NMR (Fig. S126) and circular dichroism (CD) (Fig. S140)
analysis of oligomers 13-15 (Figure 5). By comparison of 13
and 14 it can be seen that increasing the number of
sequential NCF3Rpe residues leads to an increase in the
conformational homogeneity. Similarly, removal of NCF3Rpe
residues from the sequence (e.g. 14 versus 15) leads to a
decrease in conformational homogeneity. In addition,
HSQC-TOCSY and NOESY analysis of peptoid 14
demonstrated the enhanced cis-amide preference of the
NCF3Rpe residues (Kcis/trans= 2.3) compared to the NSpe
(Kcis/trans= 0.7) (Figure 5b; Figs. S127 and S130). To further
explore the application of NCF3Rpe as a tool to stabilize the
helical conformation of longer peptoids two model hetero-
oligomers were prepared (16 and 17, Figure 5c). When the
secondary structures of 16 and 17 were analyzed by CD clear
differences beyond the opposing helical chirality enforced by
both monomers (e.g. left-hand helix for NRpe and a right-
handed helix for NCF3Rpe) were seen. Specifically, 17 showed
a dramatic 42% increase in the Mθ,218 compared to 16. This
result provides clear evidence that the substitution of non-
fluorinated NRpe residues by their α-trifluoromethyl
analogues (NCF3Rpe) offers a route to enhance the peptoid
secondary helical structure.
The manuscript was written with contributions from all
authors who have given their approval to the final submitted
version.
ACKNOWLEDGMENTS
We thank Graham E. Dobereiner for expertise with Natural
Bond Orbital calculations. This work was financially
supported by the Initial Training Network, FLUOR21, funded
by the FP7 Marie Curie Actions of the European Commission
(FP7-PEOPLE-2013-ITN-607787). In addition, V.A.V., G.Z.
and M.H. were supported by National Institutes of Health
(NIH) grant 1R01GM123296. This research includes
calculations performed on Temple University's HPC
resources partially supported by the National Science
Foundation through MRI grant 1625061 and by the US Army
Research Laboratory under contract number W911NF-16-2-
0189.
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In summary, we report the application of fluorine as a tool
to design monomers which enhance the conformational
stability of α-peptoids. The Kcis/trans values recorded for the
N4fpym containing di-peptoid 10 are among the largest ever
reported for a non-chiral monomer. N4fpym also represents
the first example of a non-chiral, non-charged aromatic
monomer that can induce a strong cis-amide preference. The
N4fpym residue achieves its high Kcis/trans values by pushing
the electronic n→π* effects to the limit of what is possible in
a neutral system. We recently reported the application of
fluorine inductive/ di-polar effects as a new tool to modulate
Kcis/trans ratios23 but the NCF3Rpe monomer demonstrates the
benefits of combining fluorine induced steric and fluorine
induced inductive electronic effects. Indeed, as evidenced by
NMR analysis, ab initio and molecular dynamics calculations,
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equilibrium to essentially favor one single isomer. REMD
simulations of NCF3Rpe oligomers predicted the formation of
highly stable right-handed helices and this was
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Dumonteil, G.; Faure, S.; Jouffret, L., Kriznik, A.; Taillefumier, C.
Highly homogeneous and robust PolyProline type I helices from
peptoids with non-aromatic α-chiral side chains. J. Am. Chem. Soc.
2017, 139 (38), 13533–13540.
(14) Crapster, J. A.; Guzei, I. A.; Blackwell, H. E. A Peptoid Ribbon
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Figure 1. a) α-peptides and α-peptoids; b) cis-amide prefer-ence due to steric and n→ π* electronic effects
(2-4); c) cis-amide preference due to inductive effects (5-8); d) Kcis/trans (CD3OD) for monomers 1-8; e)
Application of fluorine to enhance cis-isomer preference.
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Figure 2. a) Synthesis of model peptoids; b) Non-chiral di-peptoids 1, 9-10; c) Chiral di-peptoids 11, 12. d)
Average Kcis/trans values for 1, 9-12. From each replica, ΔG= –RTLn(Kcis/trans) at 25 ºC. Averages and SD
values given for n=6; [a]n=5 and [b]n=3. [c]Major isomer assigned as cis, in agreement with MD data.
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Figure 3. a) Amide bond geometry in systems 1, 9 and 10. b) Experimental 1H-1H NOESY correlations within
cis/trans conformers of 10. All Kcis/trans values as determined in CDCl3.
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Figure 4. a) The lowest-energy conformation of 12, annotat-ed with dihedral angle definitions (see SI for
details). b) Lowest-energy minima found in φ, ψ backbone dihedral scans started from cis- and trans-amide
conformations with side-chain orientations χ1 = -90º and +90º. c) REMD simula-tions of oligomeric
analogues of 12, Ac-[NCF3Rpe]n-Pip (n=1,2,3,4,5) showing an increasing preference to form right-handed
cis-amide helices. d) Space-filling model of the pre-dicted pentamer structure (n=5). e-f) Longitudinal views
of a representative frame of the oligomer from the lowest tem-perature replica (300 K).
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Figure 5. a) Structure of peptoid oligomers 13-15. b) Main 1H-NMR parameters of NSpe and NCF3Rpe
residues as analyzed in 15. c) Structure and average CD spectra (n=3) of peptoid hetero-oligomers 13
(shown in red) and 14 (shown in blue). All measurements in CH3CN.
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