Conformationally Programmable Chiral Foldamers with Compact and Extended Domains Controlled by Monomer Structure

Article abstract of DOI:10.1002/anie.201802822

Foldamers are an important class of abiotic macromolecules, with potential therapeutic applications in the disruption of protein–protein interactions. The majority adopt a single conformational motif such as a helix. A class of foldamer is now introduced where the choice of heterocycle within each monomer, coupled with a strong conformation-determining dipole repulsion effect, allows both helical and extended conformations to be selected. Combining these monomers into hetero-oligomers enables highly controlled exploration of conformational space and projection of side-chains along multiple vectors. The foldamers were rapidly constructed via an iterative deprotection-cross-coupling sequence, and their solid- and solution-phase conformations were analysed by X-ray crystallography and NMR and CD spectroscopy. These molecules may find applications in protein surface recognition where the interface does not involve canonical peptide secondary structures.

Full text of DOI:10.1002/anie.201802822

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Accepted Article
Title: Conformationally Programmable Chiral Foldamers with Compact
and Extended Domains Controlled by Monomer Structure
Authors: Peter Clarke Knipe and Zachariah Lockhart
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802822
Angew. Chem. 10.1002/ange.201802822
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Conformationally Programmable Chiral Foldamers with Compact
and Extended Domains Controlled by Monomer Structure
Zachariah Lockhart and Peter C. Knipe*
Abstract: Foldamers are an important class of abiotic
macromolecules, with potential therapeutic applications in the
disruption of protein-protein interactions. The majority adopt a single
conformational motif such as a helix. Here we introduce a new class
of foldamer where the choice of heterocycle within each monomer –
coupled with a strong conformation-determining dipole repulsion
effect – allows both helical and extended conformations to be selected.
Combining these monomers into hetero-oligomers enables highly
controlled exploration of conformational space and projection of side-
chains along multiple vectors. The foldamers were rapidly constructed
via an iterative deprotection-cross-coupling sequence, and their solid-
and solution-phase conformations were analysed by X-ray
crystallography and NMR and CD spectroscopy. These molecules
may find applications in protein surface recognition where the
interface does not involve canonical peptide secondary structures.
synthesize foldamers to reliably adopt conformations analogous
to protein secondary structures.[15]
Efforts have been made to go beyond forming simple
secondary structural motifs. Super-secondary helical foldamer
bundles and beta helices have been reported,[16] and recently
Horne has used β-, N-methyl- and other modified amino acids to
stabilize a natural zinc finger domain.[17] Similarly, Kirshenbaum
has used the presence of peptoids, in combination with cation-π
interactions, to form stable β-loop-PPII helix tertiary
peptidomimetics.[18] The task of combining entirely unnatural
secondary domains in a single foldamer capable of mimicking
tertiary structure (called ‘tyligomers’ by Moore[3c]) remains a
central challenge, although Huc recently disclosed a remarkable
helix-sheet-helix tertiary foldamer.[19]
Nature’s oligomers carry out many of the biological functions
necessary to sustain life and carry genetic information. The
majority of proteins adopt a structure determined entirely by the
primary sequence of amino acids,[1] containing α-helical, β-
strand/sheet and loop domains combined in a tertiary fold. A key
determinant of protein conformation is the secondary structural
propensity (SSP) of the constituent amino acids, i.e. the structure
of each creates a thermodynamic driving force for it to occupy a
particular secondary structural environment (Figure 1A).[2]
For decades chemists have sought to mimic the structural and
functional diversity of biopolymers using synthetic oligomers, a
field now known as foldamer chemistry.[3] As well as catalytic[4]
and signalling applications,[5] foldamers have enjoyed success
when applied to problems in chemical biology[3b] such as
modulating protein-protein interactions (PPIs).[6] One approach to
controlling global conformation is to exploit non-covalent
interactions between adjacent monomers. Gong[7] and Huc[8] have
used hydrogen bonding to control curvature in aryl amide
foldamers, while Aggarwal[9] employed the syn-pentane
interaction as
a controlling force in simple hydrocarbon
foldamers.[10] Lehn pioneered the use of dipolar repulsion as a
controlling element in foldamer design, and exploited aromatic
heterocycles as ‘shape codons’[11] for helix formation due to their
well-defined bond angles and strong dipoles.[12] Dipole repulsion
between carbonyl groups has also been explored;[13] Clayden
used this effect as a stereochemical relay to achieve remote
(1,23)-asymmetric induction in an oligoxanthene foldamer.[14] As
a result of these and other approaches, chemists are now able to
Figure 1. A) Nature’s control of tertiary structure with amino acid secondary
structural propensities (SSPs) as a determinant. Shown is a truncate of ephrin
A2 receptor protein kinase (PDB: 5NKB). Side-chains A664 and V681 are
highlighted. B) Left: aryl-imidazolidin-2-one monomers preferring an extended
(linear) conformation due to dipolar repulsion. Selected dipoles are indicated.
Right: pyrimidine-imidazolidin-2-one monomers preferring
a
helical
conformation. Centre: representation of multi-domain foldamer structures.
Inspired by Thompson and Hamilton’s use of dipole repulsion
to stabilize extended foldamer β-strand mimetics,[15d,e] here we
report the rational design of a range of monomers with different
innate folding preferences, analogous to amino acid SSPs.[20]
These allow the selective formation of helical or extended
domains within a single foldamer, formed by an iterative cross-
coupling strategy. We theorized that use of three isomeric
aromatic linkers – pyrazine, pyridazine, and pyrimidine – would
lead to different conformational preferences in aryl-linked
imidazolidine-2-one oligomers, as determined by dipolar
repulsion between the urea carbonyl groups and adjacent arene
[*]
Z. Lockhart, Dr. P. C. Knipe
School of Chemistry and Chemical Engineering, Queen’s University
Belfast, David Keir Building, Belfast, BT9 5AG (UK)
E-mail: p.knipe@qub.ac.uk
Homepage: www.knipechem.co.uk
Supporting information for this article is given via a link at the end of
the document.
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nitrogen lone pairs (Figure 1B). The effect would be that the
pyrazine and pyridazine linkers would stabilize extended
conformations, while the pyrimidine linker would form curved or
helical structures.[11,12]
thiophenol and K2CO3 liberated ureas 7 and 9, and cross-coupling
of the former with 3, and the latter with 4 and 5, afforded dimeric
compounds 10, 11 and 12 in 72%, 99% and 91% yields
respectively. The conformations of all dimers[23] were examined
by single crystal X-ray diffraction (Figure 2).[22] In all cases the
urea C=O bonds are oriented anti to the ortho-nitrogen lone pair
of the adjacent heteroaromatic ring. For pyrimidine 10 this has the
effect that the molecule is highly curved; the monomer induces an
86° turn in the backbone, such that a helix composed of this motif
would contain ~4 residues per turn. For 11 and 12, the presence
of para-substituted pyridazine and pyrazine linkers led to greater
linearity, with monomer-induced curvatures of 154° and 139°
respectively. It is likely that longer pyrazine-containing foldamers
would form overall linear conformers due to the alternating
disposition of the ureas (Figure 2, cartoon). The control exacted
by dipole repulsion also leads to predictable positioning of the
side-chains (Figure 2, right). While the distances between the Cα-
positions are largely unchanged across the three homo-dimers
(8.1-8.7 Å), the facial projection of substituents from the plane of
the foldamer is dependent on the heterocyclic linker. Thus, for the
pyrimidine and pyridazine foldamers, side-chains are projected
from the same face of the molecule, while the pyrazine linker
leads to adjacent side-chains occupying opposite faces.
Scheme 1. Synthesis of monomers 3-5 via Buchwald-Hartwig cross-coupling.
Single crystal X-ray structures show all compounds adopting the conformation
in which dipoles are opposed. Coupling conditions: aryl dihalide (5 eq.), Pd2dba3
(5 mol%), Xantphos (15 mol%), Cs2CO3, PhMe, reflux, 30 min – 4 h. Bn = benzyl,
dba = dibenzylideneacetone, Ns = 2-nitrobenzenesulfonyl, Xantphos = 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene.
Our iterative approach to the foldamers required the synthesis
of pyrimidine (3), pyridazine (4) and pyrazine (5) monomers,
which was achieved from common intermediates 1 and 2
(Scheme 1).[21] Buchwald-Hartwig coupling of 2 with 4,6-
dichloropyrimidine, and of 1 with 3,6-dibromopyridazine and 2,5-
dibromopyrazine, afforded monomers 3, 4 and 5 in 73%, 63% and
53% yields respectively. The conformations of monomers 3-5
were examined by single crystal X-ray diffraction.[22] In all cases
the urea carbonyl is oriented anti to the ortho-nitrogen atom on
the adjacent heterocycle, in line with the dipole repulsion
hypothesis.
Figure 2. X-ray crystal structures of dimeric foldamers 10 (top), 11 (middle) and
12 (bottom). Left: the top elevation gives the deviation (in degrees) each
monomer induces in the foldamer, where an angle of 180° would represent
perfect linearity. Side-chains are highlighted in green and red. Cartoon
representations of the extrapolated conformation of larger homo-oligomers are
given below each structure. Right: the edge elevation shows the disposition of
side-chain residues relative to the plane of the foldamer, and the distances
between the Cα positions (in Å).
Scheme 2. Synthesis of dimers 10 (top), 11 (middle), and 12 (bottom) from
terminal monomers 7 and 9. Imidazolidin-2-one side-chains are highlighted in
circles. *After 22 h an additional charge of Pd2dba3 (5 mol%) and Xantphos
(15 mol%) was added. The reaction proceeded to completion after a further 3 h.
The solution-phase conformational behaviour of the dimers was
examined through nuclear Overhauser effect (nOe) correlations.
For pyrimidine 10 these indicate a strong preference towards the
dipole-opposed, curved conformation (Figure 3).
The conformational preferences of the corresponding oligomers
were then investigated. Ureas 6 and 8 were formed according to
literature methods,[21] and used as the starting point for the
iterative synthesis of oligomers (Scheme 2), with the N-Ph acting
as a terminal inert capping group and internal standard for
subsequent nOe analyses (vide infra). Deprotection with
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Figure 3. nOe correlations from the ROESY spectrum of 10 (CDCl3, 600 MHz,
tmix 200 ms). Solid black arrows = strong cross-peaks; dashed red arrows =
weak cross-peaks. Selected atomic numbering given in blue. Numbers (in
boxes) given to 1 d.p. indicate measured inter-proton distances from the X-ray
crystal structure (in Å). *H15 and H15’ are isochronous in the 1H spectrum so
distances for both diastereotopic hydrogens are given.
The rotating frame nuclear Overhauser effect (ROESY) cross-
peaks of both H7 and H15 with both H11 and H12 were of similar
intensity, in agreement with the distances observed in the crystal
structure. Similarly, the observed H8↔H11 nOe indicates that the
solid- and solution-phase conformations are in agreement, since
these hydrogens would be too distant for an observable nOe in
the alternative, dipoles-syn conformation. In line with previous
analyses,[15e,21] the N-Ph group was used as an internal standard
to assess conformation – it is assumed that a freely rotating N-C13
bond would lead to an observed nOe intensity ratio between
H12↔H15 and H3↔H6 of 1:2. The observed ratio was 1:25 in
CDCl3,[24] indicating a strong biasing effect in solution. In 100%
d6-DMSO at 298 K the H12↔H15:H3↔H6 nOe ratio was 1:41, and
an additional H3↔H12 signal was observed, suggesting the
molecule retains its strong preference for the dipole-opposed
conformation in highly polar solvents. When warmed to 355 K the
H12↔H15:H3↔H6 nOe ratio in d6-DMSO fell to 1:11, suggesting a
reduction in (but not loss of) conformational rigidity at elevated
temperature. Analogous results (excluding d6-DMSO and VT
experiments) were obtained for pyridazine and pyrazine dimers
11 and 12 (see supporting information).
Figure 4. Top: library of homo-oligomers 13-16 synthesized through iterative
cross-coupling. Bottom: arrows indicate observed long-range nOes of
pyrimidine tetramer 16 (left) and its unconstrained lowest energy conformation
(middle).[25] Atom numbers are indicated in blue. The distances given (right) are
from the energy-minimized structure. Where distances are measured to H9’, the
values given are an average across the three hydrogen atom positions.
Tetramer 16 gave several long-range nOe correlations (Figure 4),
indicating that its ends sit in close proximity, as expected on the
basis of the 86° turn per monomer outlined in Figure 2. When
compared with the computed low-energy structure,[25] these nOes
correspond to close contacts in the global minimum, suggesting
the (P)-helical conformation is significantly populated in solution.
The circular dichroism spectrum of 16 displayed positive and
negative Cotton effects at 300 nm and 285 nm respectively that
were absent from the spectra of homologous pyrimidine dimer 10
and trimer 13, and may be diagnostic of (P)-helix formation.[26]
Lastly we examined whether the conformational preferences
established above were borne out in hetero-oligomers. These are
expected to form structures containing distinct conformational
domains, as determined by the constituent monomers. Trimers 21
and 22 were synthesized by the iterative route detailed in Scheme
2, while pentamer 20 was formed in 50% yield via a convergent
strand-coupling approach from trimeric fragment 17 and dimeric
19 (Figure 5; for complete synthetic details refer to the supporting
information). The solution-phase conformations of these
foldamers were probed by examining their ROESY spectra.
Homo-trimers 13, 14, and 15, and tetramer 16 (Figure 4) were
formed by the same iterative deprotection-coupling protocol
outlined in Scheme 2. Their ROESY spectra were consistent with
these foldamers adopting the conformations predicted by the
dipole repulsion hypothesis, with indicative couplings analogous
to those in Figure 3 (see supporting information).
Figure 5. Left: fragment coupling approach to pyrimidine-pyridazine pentamer 20. For coupling conditions, see Scheme 2. Middle and right: hetero-trimers 21 and
22 formed via iterative deprotection-cross-coupling. Structures are drawn in the dipole-opposed conformations. Right: structure and truncated ROESY spectrum of
22 (CDCl3, 600 MHz, tmix 200 ms). Solid arrows indicate selected, conformationally relevant nOe correlations. Dashed arrows indicate nOe signals which were
absent from the spectrum. Regions of the 2D spectrum are highlighted in white to show the relative intensity of peaks.
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1177; d) J. W. Checco, S. H. Gellman, Curr. Opin. Struct. Biol. 2016, 39,
96–105.
On the basis of the results obtained for the homo-oligomers,
hetero-trimer 22 (Figure 5, right) was expected to favour a
conformation curved at the pyrimidine and linear at the pyridazine
linkers along its backbone. This was found to be the case, with
the observation of several key nOe correlations – namely H3↔H11,
H7↔H13, H8↔H13 and H13↔H15 – indicating a strong preference
for the predicted conformations about both N-Cpyrimidine bonds (as
shown). Similarly, the absence of H16↔H20 and H21↔H24
correlations is consistent with the illustrated conformation around
both N-Cpyridazine bonds. Foldamers 20 and 21 displayed
analogous spectral features, indicating that they adopt the
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In conclusion, we have developed a chiral amino alcohol-derived
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repulsion argument, even in highly polar solvents. As well as
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projection of side-chains from multiple faces of the foldamer by
choice of linker, enabling rapid and programmable exploration of
macromolecular conformational space.
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Acknowledgements
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We acknowledge financial support from the Royal Society
(RG160614, PCK), the EPSRC (EP/R021481/1, PCK) and
Queen’s University Belfast (start-up grant, PCK), and thank
Professor Eric V. Anslyn for helpful discussions in the preparation
of this manuscript.
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Keywords: foldamers • oligomerization • conformational
analysis • protein-protein interactions
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[23] We use the terms monomer, dimer, trimer etc. to indicate the number of
imidazolidin-2-one rings present within a given molecule.
[24] The sum of H3↔H6 and H3↔H6’, relative to the sum of H12↔H15 and
H12↔H15’ cross-peak integrals.
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[26] CD spectra of all foldamers in this study are supplied and discussed in
the supporting information.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Know when to fold 'em: the use of
isomeric heterocyclic linkers afforded
a foldamer where the choice of
Zachariah Lockhart and Peter C. Knipe*
Page No. – Page No.
monomer predictably controls the
conformation of the macromolecule,
analogous to a model car racing set
constructed from individual pieces
(see graphic). The conformation is
enforced by a strong dipole repulsion
effect, and was demonstrated using
X-ray and 2D NMR techniques.
Conformationally Programmable
Chiral Foldamers with Compact and
Extended Domains Controlled by
Monomer Structure
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