An expeditious synthetic route to proteomimetic foldamers

Article abstract of DOI:10.1039/c8nj04758h

α-Helix proteomimetics such as oligobenzamides have been shown to successfully inhibit a broad array of protein-protein interactions (PPIs) mediated by α-helices. Here we report the synthesis of a protected oligobenzamide intermediate, which can be selectively deprotected and alkylated with desired side chains to rapidly afford a library of α-helix proteomimetics.

Full text of DOI:10.1039/c8nj04758h

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An expeditious synthetic route to proteomimetic
foldamers†
Vaibhav V. Karekar, ‡a Bapurao A. Bhoge‡a and Ishu Saraogi
Cite this: New J. Chem., 2019,
43, 556
ab
*
Received 18th September 2018,
Accepted 29th November 2018
DOI: 10.1039/c8nj04758h
rsc.li/njc
a-Helix proteomimetics such as oligobenzamides have been shown
to successfully inhibit a broad array of protein–protein interactions
(PPIs) mediated by a-helices. Here we report the synthesis of a
protected oligobenzamide intermediate, which can be selectively
deprotected and alkylated with desired side chains to rapidly afford
a library of a-helix proteomimetics.
Interactions between proteins play a vital role in a large number
of cellular processes.1 a-Helices, which are one of the most
common secondary structures in proteins, have been shown to
mediate a large number of protein–protein interactions (PPIs)
in cells. Hence, any misregulation at the a-helix mediated
protein–protein interface might lead to a pathological condition.
For example, aberrant a-helix mediated PPIs have been shown to
be involved in diseases such as amyloid aggregation,2 cancer3 etc.
Therefore, the modulation of PPIs using small molecules is
vital for therapeutic intervention.4–7 However, identification of
a specific small molecule that regulates a protein–protein
interface is a difficult task7,8 due to the lack of well-defined
small molecule binding sites on the protein surface. Despite
the challenges, several reports have documented the modula-
tion of PPIs using foldamers, which are structural and func-
tional mimics of protein secondary structures.8–18 A particularly
successful approach to targeting helix-mediated PPIs has been
to mimic key side chain residues i, i + 4 and i + 7 on one face of
the a-helix using proteomimetic foldamers (Fig. 1A).8,19–23
Several families of a-helix based proteomimetics have been
described by Hamilton and others with potential activity in vitro
and in vivo.7,13,16,19,24–28 Within this class of modulators, the
oligobenzamide scaffold has been used to successfully inhibit
an array of a-helix mediated PPIs.7,13,24,25 A practical limitation
of several of these proteomimetics is that each molecule has to
Fig. 1 A strategy for disruption of a-helix mediated PPIs using a-helix
proteomimetics. (A) A scheme depicting competitive inhibition of a-helix
mediated PPIs by a proteomimetic foldamer (orange) at the interface of
two proteins. (B) Facile library generation by subjecting the o-protected
oligobenzamide intermediate to selective deprotection followed by incor-
poration of the desired side chains.
be synthesized individually through a series of steps. For the
oligobenzamide scaffold, two methods have been largely
reported. The first one involves iterative amide coupling on
the N-terminal side of the p-amino benzoic acid building block,
containing the helix mimetic side chain ortho to the amino
group.24,29 The second method follows chain elongation on the
carboxyl terminal side of the molecule, either by coupling in
solution30 or on a solid phase.31,32 This process is repeated to
synthesize each oligobenzamide molecule. As testing for bio-
logical activity against the desired PPI usually requires several
such molecules, a library of oligobenzamides needs to be
generated which is synthetically demanding.
a Department of Chemistry, Indian Institute of Science Education and Research
Bhopal, MP, India. E-mail: ishu@iiserb.ac.in
b Department of Biological Sciences, Indian Institute of Science Education and
Research Bhopal, MP, India
Herein, we report a new approach for synthesizing an
oligobenzamide library. Our method proceeds through a key
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8nj04758h
‡ These authors contributed equally to this paper.
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intermediate, which is amenable to late stage modification to and sodium toluene sulfinate,30,33 while the prenyl ether can be
generate a library of a-helix mimetics in a facile manner cleaved selectively with CeCl3Á7H2O and NaI.33,34
(Fig. 1B). We use selective deprotection of phenolic hydroxy
To generate the library of a-helix mimetic oligobenzamides,
groups followed by alkylation to introduce desired side chains, we directly subjected molecule 8 to alkylation. In the given
rapidly generating a oligobenzamide library containing a example, we have used benzyl or isopropyl groups as represen-
diverse combination of amino acid mimicking side chains.
tative side chains yielding compounds 9a and 10a. Subsequent
We first synthesized a key molecule 8 containing one free deprotection of the prenyl group by treating with CeCl3Á7H2O
hydroxyl group, and two hydroxyl groups protected as ethers. and NaI yielded 9b and 10b. Under the reaction conditions, the
The phenolic ethers, which are inert under our amide coupling cleavage was selective for the prenyl ether, leaving the allyl ether
conditions, can be selectively cleaved to incorporate the desired intact. The alkylation and arylation of 9b and 10b yielded mole-
side chains as required, yielding final molecules containing cules 9c and 10c respectively, each containing two a-helix mimetic
helix mimetic side chains at the three phenolic oxygen atoms. side chains. The deallylated compounds 9d and 10d obtained
This strategy allowed us to generate a library with varied side from 9c and 10c were subjected to the third O-alkylation by
chain combinations, and indeed made the route expeditious.
reacting with the desired bromo derivative to yield the final
The synthesis (Scheme 1) began with monomer 4 as the compounds 9e, 9f, and 10e (Scheme 2). This sequential deprotec-
building block, synthesized using the reported procedures30 tion and alkylation scheme allowed us to generate helix mimetics
from 1 via intermediates 2–3 (Scheme S1, ESI†). The allyl ether with three different side chains i.e. R1 a R2 a R3. Each of the
was chosen as the first protecting group for phenol. The allyloxy above steps proceeded in good to excellent yields giving 24–47%
aniline 4 was coupled to 3-hydroxy-4-nitrobenzoic acid 1 using overall yield over five steps for the final molecules containing
PPh3Cl2 to yield the bisbenzamide 5 with one free hydroxyl non-identical side chains starting from 8 (Table 1).
group. This reaction is chemoselective and affords 86% con-
In cases where the same side chain is desired at more than
version to the desired amide. Next, we alkylated the bisbenza- one of the three positions, the above procedure can be further
mide 5 with prenyl bromide to yield molecule 6. The prenyl
ether serves as the second phenol-protecting group. Reduction
of the nitro bisbenzamide 6 by treating with Fe and aq. NH4Cl
yielded the corresponding amino compound 7, which was
coupled with 1 to yield the key oligobenzamide trimer 8. The
molecule 8 was subsequently used as a starting material to
generate a library of proteomimetic foldamers by selective
deprotection and alkylation of phenolic ethers to afford all
possible combinations of side chains. The allyl ether in mole-
cule 8 can be cleaved selectively by treating it with Pd(PPh3)4
Scheme 2 Generation of proteomimetics with three non-identical side
Scheme 1 Synthesis of the key protected oligobenzamide intermediate.
chains (R1 a R2 a R3).
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Table 1 Library of molecules synthesized using the selective deprotection
and alkylation route
Overall yield
starting
from 8 (%)
Molecule R1 R2
R3
9e
9f
Bn 2-Methylnaphthalene iPr
Bn 2-Methylnaphthalene iBu
24
33
47
22
32
36
33
10e
11c
12c
12d
13b
13c
14b
14c
15a
15b
16a
16b
16c
iPr 3-Pentyl
Bn Bn
Bn
3-Pentyl
iPr 3-Pentyl
iPr Bn
iPr
iPr
Bn iPr
iPr
Bn 2-Methylnaphthalene 2-Methylnaphthalene 15
iPr 3-Pentyl
iPr Et
3-Pentyl
Et
18
19
33
34
57
47
45
iPr iPr
iPr
Bn Bn
Bn
Pr
iPr iPentyl
iPr 3-Pentyl
iPr iPentyl
Pr
iPr
Scheme 4 Generation of proteomimetics with two identical side chains
(R1 a R2 = R3).
stream-lined making it more efficient. As an example, we
deprotected the prenyl group in 8 to afford molecule 11
(Scheme 3, right). Alkylation of molecule 11 yielded molecules and iodoethane yielded the corresponding molecules 13b, 13c,
with two identical side chains at the top. This has been 14b and 14c (Scheme 4).
demonstrated with benzylation (11a). The deallylation of 11a
In cases where the same side chain was required in all
followed by alkylation using 3-bromopentane afforded molecule positions, the prenyl ether from compound 12 was removed
11c (Scheme 3, right). This strategy can be used for generating a to yield the fully deprotected oligobenzamide 15. Alkylation of
second combination i.e. R1 = R2 a R3, where two identical –R 15 with the desired bromide substrate readily resulted in
groups can be incorporated simultaneously. The third combi- molecules where all three side chains were identical i.e. R1 =
nation R1 = R3 a R2 was synthesized similarly by deprotecting the R2 = R3 (Scheme 5A). To generate additional diversity, we
allyl ether30 in intermediate 8 to afford compound 12 leaving the subjected the intermediate molecule bearing the prenyl and allyl
prenyl ether intact. The alkylation of the two phenolic hydroxy groups 10a, 10c and 12a to hydrogenation to yield molecules 16a,
groups with desired alkyl halides such as 2-bromopropane 16b and 16c (Scheme 5B and Table 1). Using the deprotection and
resulted in compound 12a. Subsequent removal of the prenyl alkylation strategy described above, we synthesized a representa-
group and further alkylation with 3-bromopentane or benzyl tive library of molecules listed in Table 1, which will be used to
bromide resulted in the final molecules 12c and 12d screen against a-helix mediated PPIs.
(Scheme 3, left).
In summary, we have developed a new synthetic approach to
To yield the fourth combination R1 a R2 = R3, we directly synthesize a library of o-alkoxy oligobenzamides, which act as
deallylated the intermediates 9b and 10b to yield molecules 13a a-helix mimetics. Our approach involves the selective deprotec-
and 14a. Further, dialkylation with desired alkyl halides such as tion and alkylation of a key intermediate to readily generate all
2-bromo propane, 2-bromo(methyl)naphthalene, 3-bromopentane possible combinations of side chains, thus making the route
Scheme 3 Generation of proteomimetics with two identical side chains. The right route affords combination R1 = R2 a R3 whereas the left route affords
combination R1 = R3 a R2 (* yields are over two steps).
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There are no conflicts to declare.
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