Design, Synthesis, and Conformational Analysis of Oligobenzanilides as Multifacial α-Helix Mimetics

Article abstract of DOI:10.1021/acs.orglett.9b01115

The design, synthesis, and conformational analysis of an oligobenzanilide helix mimetic scaffold capable of simultaneous mimicry of two faces of an α-helix is reported. The synthetic methodology provides access to diverse monomer building blocks amenable to solid-phase assembly in just four synthetic steps. The conformational flexibility of model dimers was investigated using a combination of solid and solution state methodologies supplemented with DFT calculations. The lack of noncovalent constraints allows for significant conformational plasticity in the scaffold, thus permitting it to successfully mimic residues i, i+2, i+4, i+6, i+7, and i+9 of a canonical α-helix.

Full text of DOI:10.1021/acs.orglett.9b01115

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Design, Synthesis, and Conformational Analysis of
Oligobenzanilides as Multifacial α‑Helix Mimetics
Theo Flack, Charles Romain, Andrew J. P. White, Peter R. Haycock, and Anna Barnard*
Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, U.K.
S
* Supporting Information
ABSTRACT: The design, synthesis, and conformational
analysis of an oligobenzanilide helix mimetic scaffold capable
of simultaneous mimicry of two faces of an α-helix is reported.
The synthetic methodology provides access to diverse
monomer building blocks amenable to solid-phase assembly
in just four synthetic steps. The conformational flexibility of
model dimers was investigated using a combination of solid
and solution state methodologies supplemented with DFT
calculations. The lack of noncovalent constraints allows for
significant conformational plasticity in the scaffold, thus
permitting it to successfully mimic residues i, i+2, i+4, i+6, i
+7, and i+9 of a canonical α-helix.
rotein−protein interactions (PPIs) are central to all
P
biological processes and offer a vast array of potential
therapeutic targets.1−3 However, selective targeting of
protein−protein interfaces remains an enormous challenge.
In comparison to the small, well-defined pocket of an enzyme−
substrate interaction (300−500 Å2), the interface of a typical
PPI is large (1000−2000 Å2) and topographically featureless.4,5
The most common molecular recognition scaffold in multi-
protein complexes is the α-helix, and as such, numerous
strategies to target this class of PPI using rationally designed
molecules have been reported, including both peptidic and
nonpeptidic approaches, a concept known as peptidomimet-
ics.6,7
Typically, helix mimetics possess two common features: a
rigid scaffold to mimic the rod-like morphology of the helical
backbone and side chains to recapitulate the spatial orientation
of hotspot residues on the native helix.8 The majority of
scaffolds reported have focused on mimicry of key recognition
residues located on a single face of an α-helix (i, i+3/4, and i
+7).
Figure 1. Previously published multifacial α-helix mimetics: bis-
benzamides, benzoylureas, diphenylacetylenes, azaoctanes, and our
novel oligobenzanilide.
However, given that roughly one-third of PPIs interact
through more than one helical face, there is an obvious
requirement for helix mimetics that simultaneously mimic
more than one helical face.9 Embellishment of previously
reported scaffolds has resulted in multifacial helix mimetics
such as bis- and tris-benzamides, and benzoylureas and novel
scaffolds such as diphenylacetylenes and azaoctanes have also
been developed (Figure 1).10−15
Common to all two-faced helix mimetics published are
lengthy, complex syntheses that limit their potential as generic
tools for PPI inhibition. As part of our interest in developing
methods to inhibit complex protein−protein interactions, we
sought to design a novel synthetically accessible two-faced α-
helix mimetic scaffold. Given the prevalence of oligobenzamide
scaffolds, we chose to develop a two-faced scaffold based upon
this linkage. Herein, we describe the design, synthesis, and
conformational analysis of a novel 3-O-alkyated, 4-N-
dialkylated helix mimetic that is capable of simultaneously
mimicking residues i, i+2, i+4, i+6, i+7, and i+9 of a canonical
α-helix.
Our novel scaffold was designed by combining two
previously published scaffolds onto a single helix mimetic:
Wilson’s N-alkylated triaryl amide and Boger’s 3-O-alkylated
Received: March 29, 2019
© XXXX American Chemical Society
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triaryl amide were combined to give a 3-O-,4-N-dialkylated
scaffold capable of simultaneous mimicry of two helical faces
(Figure 1).16,17 The synthetic route to the individual
monomers is shown in Scheme 1. Notable features of the
Table 1. 3-O, 4-N-Dialkylated Monomers Synthesized
Scheme 1. Synthesis of Fmoc-Protected Monomers
synthetic route are (i) a common starting material to access
most monomers, (ii) compatibility with the Fmoc/tBu
protocol for solid-phase synthesis (SPS), and (iii) the wide
variety of functionality, both natural and unnatural, that may
be incorporated at both positions on the individual monomers.
3-Fluoro-4-nitrobenzoic acid was used as the starting
material for monomer synthesis. The nitro group simulta-
neously activates the 3′-position for nucleophilic aromatic
substitution and “protects” the aniline required for installation
of the second side chain and subsequent coupling reactions.
Using this SNAr approach, it is possible to incorporate
functionality found across the majority of proteinogenic
amino acids as well as the enormous chemical space that has
not been sampled by nature. For most monomers, catalytic
hydrogenation afforded the primary aniline in near quantitative
yields. For monomers with functionality susceptible to
hydrogenation, a tin(II) chloride-based reduction was used.
The second side chain was introduced onto the primary aniline
through a one-pot reductive amination using a picoline−
borane complex (pic-BH3) as the stoichiometric reductant. All
aldehydes corresponding to hydrophobic amino acids side
chains are commercially available. Unoptimized yields for these
hydrophobic aldehydes were typically >80%. Aldehydes for
installation of polar side chains were typically obtained by
oxidation of the hydroxycarbamate to the aldehyde with Dess−
Martin periodinane.
Scheme 2. Monomer Resin Loading
purifications. To exemplify the methodology, three dimers and
two trimers were successfully produced bearing a range of
hydrophobic and polar side chains (Figures 2 and S2 and
Table 2).
It is well established that N-alkylated benzanilides
preferentially adopt a “folded” conformation about the amide
bond in which the aryl rings are cis (formally E/s-trans).19−21
Clearly, a permanent cis relationship about the amide bond
is not representative of the elongated structure of the α-helix
and as such is unlikely to lead to effective perturbation of α-
helix-mediated PPIs. However, the N-alkylated benzanilide
scaffolds have been shown to be as potent as both (i) the
native peptide and (ii) benzamide scaffolds with preorganiza-
tion endowed through intramolecular hydrogen bonding
networks.16
To study the conformational space of our scaffold, we
selected a triage of ab initio, solution-, and solid-state
techniques. For ease of analysis, representative dimers 14−16
were chosen as model compounds for experimental studies.
These dimers (Figure 2) contain all the features common to
more extended oligomers: (i) a central amide linkage and thus
the potential for cis−trans isomers, (ii) the potential for syn/
anti conformers with regards to the O-alkoxy substituent, and
To render the monomers compatible with Fmoc/tBu SPS,
the secondary anilines were Fmoc protected to afford the
tertiary amide in reasonable yields (40−70%). Using this four-
step protocol, we generated a library of 13 diverse monomers
containing charged, polar, and hydrophobic functionality in
both positions (Table 1 and Figure S1).
In comparison to previously published helix mimetics,
oligomers were assembled by loading the monomers directly
onto a solid support (Scheme 2). HATU mediated coupling
under microwave heating allowed the Fmoc-protected
monomers to be loaded onto a rink amide resin, whereas
monomers could be loaded on a 2-chlorotrityl resin at room
temperature by stirring with DIPEA. To effect amide bond
formation, the benzoic acid was activated in situ to the acyl
chloride using Ghosez’s reagent in anhydrous N-methyl-2-
pyrollidone (NMP) according to previously published method-
ology (Scheme 3).18 Products were isolated by mass-directed
B
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(iii) the potential for restricted rotation about the aryl-nitrogen
(Ar−N) bond.
Scheme 3. Solid Phase Oligomer Synthesis
Single crystals suitable for X-ray diffraction of compound 16
were generated by slow evaporation of a solution of
hexane:ethyl acetate (1:1). The unit cell contained two
chemically identical but crystallographically independent
structures (Figure 3). As expected, both structures clearly
demonstrate the cis-isomer about the amide bond with the two
3-O-substituents on opposing faces, presumably minimizing
unfavorable steric clashes. A1,3 strain between phenyl rings
results in the aromatic rings lying roughly perpendicular to the
plane of the amide bond with the aromatic rings partially facing
each other. This perpendicular cis-anti conformer is consistent
with previous solid-state structures of tertiary benzanilides.22
Interestingly, the amide bond displays a significant distortion
from planarity (12.1° for 16-A, 16.3° for 16-B, Table S1)
placing the latter within the top 5% of the acyclic amides in
which the amide bond is not constrained with a ring
(nonlactam).
An important feature highlighted by the solid-state structure
is the presence of axial chirality. Restricted rotation about the
Ar−N axis of benzanilides is long known, and many ortho-
substituted anilides displaying axial chirality have been
documented.22−25 This bond rotation in helix mimetics is
significant in allowing scope for side chains to recapitulate
native interactions through an induced-fit binding mechanism.
In multifacial helix mimetics, rotation about the Ar−N bond
corresponds to interconversion between helical faces (Figure
2).
To calculate the barrier to rotation about the Ar−N bond,
variable temperature (VT) NMR spectroscopy was used.
Given rotation about the Ar−N bond of unsymmetrically
substituted anilides interconverts not only enantiomeric
conformers but diastereotopic protons, it is possible to
measure the rate of, and therefore barrier to, rotation. The
1H NMR spectra of 14−16 at 298 K in DMSO-d6 all displayed
a single set of broadened resonances indicative of an exchange
process but with no distinction between the putative
diastereotopic protons (Figure S3). This is indicative of
“fast” exchange in solution at room temperature.
To investigate the nature of the exchange, low temperature
NMR spectra were taken at the slow-exchange limit. As
expected, equal intensity signal doubling due to restricted
rotation about the Ar−N axis was observed. For dimers 14, 15,
and 16, anisochronicity was observed for all methylene protons
on the 3-O-alkoxy and amide substituents (spin-systems: 14 =
AB; 15 = ABX3; 16 = varies). In addition, dimer 3
demonstrated diastereotopic methyl doublets (spin-system =
AX3X3′). For all dimers studied, no magnetic inequivalence
was observed for protons on the secondary aniline substituent
due to the increased distance from the chiral Ar−N axis.
Modeling the coalescence of the methylene protons in dimer
14 gave a barrier to rotation of 14.9 kcal mol−1 0.59. For
dimer 16, modeling the coalescence of the methyl doublets
gave a barrier to rotation of 13.9 kcal mol−1 0.41 (Figures 4,
S4, and S5). Both values correspond to an estimated
millisecond half-life for racemization. Thus, although inter-
conversion between enantiomers is slow on the NMR time
scale, the helix mimetic scaffold is not atropisomeric at room
temperature (Oki’s definition >1000 s at 25 °C26), and as such,
the “helical” faces mimicked by the scaffold are interconverting
rapidly at 298 K and thus sample a vast array of conformational
space. Unfortunately, spectral crowding prevented us from
Figure 2. 3-O, 4-N-Dialkylated benzanilide dimers synthesized and
the conformational and stereochemical isomerization available to the
helix mimetic scaffold.
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Table 2. 3-O, 4-N-Dialkylated Benzanilide Dimers and Trimers Synthesized
formations. However, no characteristic correlation showing
existence of a trans conformation was observed by 2D NMR
spectroscopy, presumably due to the large distance (>5 Å)
between the two aromatic moieties of interest in the trans
conformation.
To further explore the barriers to rotation about the Ar−N
and amide bonds, DFT calculations were carried out, and
energy barriers of the rotations about the amide, Ar−C(O)
and Ar−N bonds were calculated based on methods previously
used by Miller27 (details in Supporting Information). A
simplified model dimer was used in which all alkyl groups
were replaced by methyl groups (I, Figure 2). Rotations solely
about the amide bond were found to have energy barriers as
low as ΔG298 = 14.1 kcal/mol (I-TS2, Figures 5, S12, and S15)
Figure 3. X-ray structures of 16 (16-Sa and 16-Ra).
Figure 5. Examples of energy barriers ΔG298 for selected bond
rotations (see details in the Supporting Information)
and only led to cis/trans conformational exchanges (i.e., no
anti/syn conformational exchange, Figures S12 and S15).
Interestingly, as previously reported by others,27−29 concerted
amide and Ar−N bond rotations occurred with slightly lower
energy barriers of ΔG298 = 12.1 kcal/mol (I-TS1, Figures 5,
S10, and S19) and led to concerted cis/anti and syn/trans
conformational exchanges (i.e. anti/cis ↔ syn/trans or syn/cis
↔ anti/trans, Figures S10 and S19). These concerted rotations
are a consequence of the amide carbonyl oxygen and the ortho-
O-alkoxy group of the benzamide “pushing” each other during
the rotations (Figure 5). Rotations about the Ar−C(O) bond
were found to occur with low energy barriers ΔG298 < 10 kcal/
mol for both trans and cis conformations about the amide bond
(Figures S21 and S22). Finally, rotations about the Ar−N
bond in a cis conformation were found to have the highest
energy barrier ΔG298 = 16.7 kcal/mol due to a steric clash
between the ortho-O-alkoxy group of the benzamide and the N-
Me group of the amide moiety (III-TS5, Figure 5).
Figure 4. Experimental and simulated NMR spectrum of 16 at the
slow-exchange limit.
obtaining accurate energies for Ar−N bond rotation for
compound 15.
2D NOESY and selNOE experiments at 298 K revealed
through-space correlations characteristic of a cis conformation
about the central amide bond (Figure S6), in line with a fast
exchange at room temperature and existence of cis con-
Numerous pathways are possible for the exchange between
the two crystallographically observed enantiomers. However,
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Accession Codes
exchange between the two enantiomers via constant cis
conformations is likely to be the least favorable pathway due
to the high energy barrier of the Ar−N bond rotation (Figure
5). Alternatively, pathways via extended conformations are
more favorable, involving bond rotations with lower energy
barriers with a maximum of 14.1 kcal/mol (Figure S30), in
good agreement with the experimental values of 14.9 and 13.9
kcal/mol.
The Boltzmann population of both conformers was
calculated based on the energy required for rotation about
the amide bond or Ar−N bond or a concerted rotation (Table
S15). Given the energy difference between the cis and trans
conformations, it is not surprising to find that at equilibrium,
>99% of the scaffold exists in the folded conformation at 298
K. However, this does not preclude the molecule from
adopting a trans conformation. The low energy barriers
associated with these bond rotations strongly suggests that
our scaffold can sample an extended “helix mimetic”
conformation at room temperature.
CCDC 1902316 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033. Complementary FAIR
data36 are available from the Imperial College Data Repository
at DOI: 10.14469/hpc/5108.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: a.barnard@imperial.ac.uk.
ORCID
Charles Romain: 0000-0002-1851-8612
Anna Barnard: 0000-0002-1327-3417
Notes
We described the design, synthesis, and conformational
analysis of a novel oligo 3-O, 4-N-dialkylated benzanilide helix
mimetic scaffold capable of simultaneous mimicry of side
chains i, i+2, i+4, i+6, i+7, and i+9 of a canonical α-helix. The
synthetic route is the shortest and most straightforward
described to date for multifacial helix mimetics. A combination
of solid-state, solution-phase, and in silico analyses show that
the helix mimetic scaffold rapidly samples a wide variety of
conformations in solution and can successfully mimic the
relevant helical pharmacophore. The increased conformational
plasticity in comparison with previous helix mimetic design is a
shift for the proteomimetic field. To this date, the analysis of
helix mimetics has focused on reporting RMSD values
obtained from energy-minimized or solid-state structures. As
noted by Burgess, it is evident that this is not representative of
the equilibrating conformations present in solution.30−32 This
work goes part way to demonstrating that a more sophisticated
approach to characterization of helix mimetics is required if the
values are to be considered a determinant in the quality of a
scaffold. Furthermore, a degree of conformational plasticity has
been noted to be advantageous for protein−surface recognition
through an induced-fit-type mechanism. This is even more
pertinent given that most secondary structure elements at
protein interfaces are perturbed from geometric ideality.
Future work on this scaffold will focus initially on inhibition
of complex helix−protein interactions that are mediated by the
binding of more than one helical face. For example, malaria
parasite invasion of host red blood cells is critically dependent
on the fully buried interaction which exists between myosin tail
interacting protein (MTIP) and myosin A (MyoA),33 and in
oncology, the Wnt signaling pathway is centered around β-
catenin, which forms multifacial PPIs with T-cell factor 4 (Tcf-
4)34 and B cell lymphoma 9 (BCL9).35
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Dr. Lisa Haigh, Imperial College London
for mass spectrometry and Prof. Ed Tate, Imperial College
London for support and advice. A.B. and C.R. thank Imperial
College London for their Junior Research Fellowships. A.B.
would like to thank the Wellcome Trust for funding for her
JRF (Grant 105603/Z/14/Z).
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DOI: 10.1021/acs.orglett.9b01115
Org. Lett. XXXX, XXX, XXX−XXX