Submonomer synthesis of a hybrid peptoid-azapeptoid library

Article abstract of DOI:10.1021/co3000852

We recently reported efficient conditions for the synthesis of N-azapeptoid libraries via the typical submonomer strategy of peptoid synthesis but that substitutes N-acyl hydrazides for primary amines as submonomers. Unfortunately, this approach is not applicable to the synthesis of mixed azapeptoid-peptoid libraries. When an oligomer containing an N-terminal side chain derived from an acyl hydrazide is bromoacetylated and treated with a primary amine, a chain-terminating intramolecular ring-closure to form an oxadiazinone competes with the desired displacement of the bromide by the amine. Here we overcome this limitation and demonstrate that a hybrid peptoid-azapeptoid library derived from primary amines, acyl hydrazides, carbazates, and semicarbazides can be made efficiently using standard peptoid submonomer chemistry. We find that the unwanted, chain-terminating cyclization reaction is competitive with chain extension only when aryl acyl hydrazides are present. Alkyl or heteroaromatic acyl hydrazides do not cyclize under the conditions used for peptoid-azapeptoid synthesis. We also find that carbazates and semicarbazides work well for chain extension. Using primary amines, acyl hydrazides, carbazates, and semicarbazides as submonomers, a high-quality one bead one compound library of tetramers suitable for screening against protein targets was made by split and pool synthesis.

Full text of DOI:10.1021/co3000852

Research Article
pubs.acs.org/acscombsci
Submonomer Synthesis of A Hybrid Peptoid−Azapeptoid Library
Bani Kanta Sarma and Thomas Kodadek*
Departments of Chemistry and Cancer Biology, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #3A2, Jupiter,
Florida 33458, United States
S
* Supporting Information
ABSTRACT: We recently reported efficient conditions for
the synthesis of N-azapeptoid libraries via the typical
submonomer strategy of peptoid synthesis but that substitutes
N-acyl hydrazides for primary amines as submonomers.
Unfortunately, this approach is not applicable to the synthesis
of mixed azapeptoid−peptoid libraries. When an oligomer
containing an N-terminal side chain derived from an acyl
hydrazide is bromoacetylated and treated with a primary
amine, a chain-terminating intramolecular ring-closure to form
an oxadiazinone competes with the desired displacement of
the bromide by the amine. Here we overcome this limitation
and demonstrate that a hybrid peptoid−azapeptoid library
derived from primary amines, acyl hydrazides, carbazates, and
semicarbazides can be made efficiently using standard peptoid submonomer chemistry. We find that the unwanted, chain-
terminating cyclization reaction is competitive with chain extension only when aryl acyl hydrazides are present. Alkyl or
heteroaromatic acyl hydrazides do not cyclize under the conditions used for peptoid−azapeptoid synthesis. We also find that
carbazates and semicarbazides work well for chain extension. Using primary amines, acyl hydrazides, carbazates, and
semicarbazides as submonomers, a high-quality one bead one compound library of tetramers suitable for screening against
protein targets was made by split and pool synthesis.
KEYWORDS: submonomer, hybrid petoid−azapetoid library, one bead one compound, split and pool synthesis
Cα or the Cα-N bonds in the backbone. Hence, strategies to
introduce structural constraints into peptoid-like oligomers,
without sacrificing the many advantages of submonomer
synthesis, have attracted significant interest.8−11 Our group has
also turned its attention to this issue, with a companion goal of
introducing greater chemodiversity into the molecules. Recently,
we reported that aryl-substituted acyl hydrazides can be used
efficiently as submonomers to generate N-azapeptoid
oligomers.12 These compounds (Figure 1) are structurally
distinct from azapeptoids,13 hydrazino azapeptoids,14 and
retrohydrazino azapeptoids15 reported previously. The presence
of hydrogen bond donor and acceptor units in the side chain of
acyl hydrazides may prove useful in engaging protein targets.
Moreover, unlike peptoids, the 1H NMR spectra of these
compounds are dominated by one isomer (>90%) and, based on
the X-ray crystal structure of one such compound, we suggested
that the amide bonds of these azapeptoids exist almost
exclusively in the trans conformation.12
INTRODUCTION
■
There is great interest in the development of peptidomimetic
compounds as ligands for proteins and RNAs. Of the many
classes of peptide-like compounds, peptoids1 (oligo-N-alkyl-
glycines) are exceptional with respect to their ease of
construction. The submonomer solid-phase synthesis of
peptoids involves two steps.2 A resin-bound amine is first
acylated with an activated form of 2-bromoacetic acid, followed
by displacement of bromide by a primary amine. Because of the
ready availability of thousands of different primary amines, huge,
diverse combinatorial libraries can be created by split and pool
synthesis.3 When library synthesis is carried out on hydrophilic
TentaGel beads, the library can be screened directly against
protein targets of interest and the identity of “hits” can be easily
deduced by mass spectrometry following cleavage of the
compound from the bead.4 An additional advantage of peptoids
is that they are serum stable5 and generally cell permeable.6 Thus,
peptoid libraries are a powerful tool for the discovery of useful
tool compounds or drug leads.
Ideally, we would like to employ acyl hydrazides along with
more traditional amine submonomers in the synthesis of mixed
peptoid−azapeptoid libraries. However, our attempts to imbed
N-azaacyl units into a chain of standard peptoids were
Unfortunately, the utility of peptoids is limited by their lack of
conformational constraints, or “floppiness”, which is thought to
limit their affinity for macromolecular targets. Very few peptoids
with a nanomolar affinity for their protein target have been
reported.7 Unlike peptides, the tertiary amide bond in peptoids
does not exhibit a strong preference for the trans geometry, nor
are there significant constraints to rotation about the carbonyl-
Received: August 8, 2012
Revised: September 6, 2012
Published: September 7, 2012
© 2012 American Chemical Society
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semicarbazides, which also contain similar hydrogen donor−
acceptor moieties in their side chains, can be used as
submonomers along with amines. Given that many amines,
carbazates, semicarbazides and acyl hydrazides are commercially
available and hundreds more can be made easily, this chemistry
allows access to new types of large combinatorial libraries of
diverse peptoid oligomers.
RESULTS AND DISCUSSION
■
New Hydrazide Submonomers. We first decided to
explore if carbazates (Figure 2A), which differ from acyl
hydrazides by the presence of an oxygen atom attached to the
acyl group rather than a phenyl ring, might avoid the undesired
cyclization reaction. We used methyl and ethyl carbazates to
synthesize peptoid-azapeptoid hybrid 7. For that purpose we
synthesized compound 1 by using standard microwave assisted
synthesis conditions (see Supporting Information) and sub-
sequently incorporated methyl and ethyl carbazates to synthesize
compound 7. Gratifyingly, when methyl and ethyl carbazates
were inserted between benzyl amines to synthesize a peptoid-
azapeptoid hybrid (7) (see Figure 2A), the desired peptoid−
azapeptoid product was obtained in high purity, with no
observable ring closure product, as determined by HPLC (see
Figure 2B) and MALDI-TOF mass spectrometry (see Figure
2C).
This favorable result led us to explore more fully how the
nature of the unit attached to the carbonyl group in the side chain
influences the ratio of desired chain extension and undesired ring
closure. Therefore, compounds 8−11 (Figure 3) were
synthesized and subjected to chain extension using isopropyl-
amine as the submonomer. As anticipated from our previous
work,12 when R = Ph the ring closure reaction was relatively
efficient and a mixture of ring-closed and chain-extended
Figure 1. In addition to the desired chain extension (top reaction), a
chain-terminating ring closure reaction occurs when N-bromoacylated
azapeptoids are treated with primary amines.
unsuccessful due to a competing side reaction involving ring
closure to form 2-aryl-4H-1,3,4-oxadiazin-5(6H)-ones (Figure
1).12 The identities of the side products were confirmed by NMR
and mass spectrometric studies.12 In this reaction, the amine acts
as a base to deprotonate the side chain N−H, aiding in the
cyclization of the carbonyl oxygen onto the methylene group of
the 2-bromoacetyl unit. The cyclization reaction does not occur
when an acylhydrazide is employed as the submonomer,
presumably because of its reduced basicity relative to a primary
amine. Thus, while the synthesis of libraries using solely N-
acylhydrazides as submonomers works well, this cyclization
frustrates attempts to make mixed high quality libraries of mixed
azapeptoid−peptoid chains.
Herein, we report a solution to this problem that allows N-
azapeptoid units to be imbedded into a standard peptoid chain.
We further show that related molecules such as carbazates and
Figure 2. (A) Synthesis of peptoid-azapeptoid hybrid 7: (a) 37 °C, 1 h; (b) BrCH2COOH (2 M in DMF), DIC (2 M in DMF), 37 °C, 10 min; (c) benzyl
amine (2 M in DMF), 37 °C, 1 h; (d) 37 °C,1 h ; (e) TFA cocktail, 1 h, rt. (B) HPLC spectrum of crude reaction mixture obtained after TFA cleavage of
6. (C) MALDI TOF MS spectra of HPLC purified 7.
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Figure 3. (a) Reaction of 8−11 with isopropyl amine. (b) HPLC chromatogram of crude reaction mixtures obtained from reaction of 8−11 with
isopropyl amine.
Table 1. Cyclic Six-Membered Ring Formation (%) with
Respect to the Expected Chain Elongation Product
a
R
amine
cyclic product (%)
Ph
isopropyl amine
63
ND
ND
ND
4
CH2Ph
isopropyl amine
OCH2Ph
NHPh
isopropyl amine
isopropyl amine
4-OMe-Ph
4-Br-Ph
2-methoxyethyl amine
2-methoxyethyl amine
2-methoxyethyl amine
2-methoxyethyl amine
2-methoxyethyl amine
2-methoxyethyl amine
2-methoxyethyl amine
2-methoxyethyl amine
2-methoxyethyl amine
15
4-Cl-Ph
16
4-NO2−Ph
3-F-Ph
45
15
thiophene
furan
10
6
CH2CH2CH2CH3
CH3
ND
ND
a
ND = Not detected based on MALDI MS and HPLC of crude
reaction mixture.
center adjacent to nitrogen and thus should be a better
nucleophile, to synthesize compounds 20−28 (Figure 4).16 We
observed that the amount of ring-closed side product increases
with an increase in the electron-withdrawing ability of the
substituent in the phenyl ring. The electron-withdrawing group
increases the acidity of the NH hydrogen of the side chain due to
which the incoming amine base can easily abstract the NH
hydrogen and assist the carbonyl oxygen to undergo intra-
molecular cyclization. We also explored the use of aliphatic and
heterocyclic-substituted acyl hydrazides in the synthesis of mixed
oligomers (Figure 4). For compounds 27 and 28, where R =
furan and thiophene, respectively, only small amounts of ring
closure products (∼10% for 2-thiophene hydrazide and ∼5% for
2-furoic hydrazide) were detected by HPLC and MALDI-TOF
MS (see Supporting Information). When R = an alkyl group, only
chain elongation products 34 and 35 were observed and the
corresponding ring closure products (43 and 44) were not
Figure 4. Reaction of 20−28 with 2-methoxyethylamine.
products was observed (Figure 3). However, when R = CH2Ph
the ring closure product 17 was not observed and the desired
chain-extended species 13 was produced in high purity. Similarly,
when benzyl carbazate and 4-phenyl semicarbazide were used,
followed by isopropyl amine, the ring-closed species 18 and 19
were not observed by MALDI TOF MS and HPLC analysis of
the crude reaction mixtures. Only the chain-extended products
14 (R = OCH2Ph) and 15 (R = NHPh) were produced.
Aryl Acyl Hydrazides Cannot Be Chain Extended
Cleanly. These results suggest that the ring closure reaction
competes with the desired SN2 bromide displacement by amine
only when R is a phenyl ring directly attached to the acyl group.
To probe this further, we used several substitued phenyl
hydrazides and 2-methoxyethylamine, which lacks a branched
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Figure 5. Primary amine, acyl hydrazide, carbazate, and semicarbazide submonomers used in the tetramer hybrid peptoid−azapeptoid library.
Figure 6. Representative MALDI TOF MS and MSMS spectra of two compounds of the tetramer peptoid−azapeptoid hybrid library obtained after
single bead cleavage by using CNBr.
observed by MALDI-TOF MS and HPLC. These findings are
summarized in Table 1. We conclude that acyl hydrazides,
carbazates and semicarbazides can be employed as submonomers
for the synthesis of mixed azapeptoid−peptoid oligomers so long
as R is not a phenyl ring.
Library Synthesis. As it is not realistic to synthesize
individual compounds to test the compatibility of different R
groups in acyl hydrazides with every other primary amine, we
decided to construct an OBOC library to screen the R groups
that provide the expected chain elongation products without
undergoing the undesired ring termination reaction. This is
determined by looking at the MALDI MS spectra of the
individual peptoid-azapeptoid obtained after CNBr treatment.
For that purpose, we used solid-phase split and pool synthesis to
create an OBOC hybrid peptoid-azapeptoid library of tetramers
on 160 μm TentaGel Macrobeads NH2 resin using amines, acyl
hydrazides (R ≠ aryl), carbazates, and semicarbazides (see Figure
5) with a theoretical diversity of 28 561 compounds. Several
individual beads were picked at random, separated into the wells
of a microtiter plate, and the compounds were released into
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Figure 7. Peptoid−azapeptoid library synthesized by using primary amines and aryl acyl hydrazides at positions 1 and 3. Alkyl or benzyl acyl hydrazides,
carbazates and semicarbazides are used at positions 2 and 4 as spacers between aryl acyl hydrazides and amines.
Figure 8. Representative MALDI TOF MS and MSMS spectra of two compounds obtained after single bead cleavage by using CNBr from the tetramer
peptoid−azapeptoid hybrid library described in Figure 7.
solution by reacting individual beads with a 0.3 M CNBr solution,
which results in cleavage of a methionine present in the invariant
linker. MALDI TOF/TOF MS analysis showed strong molecular
ions, which indicates the high quality of the library. The MALDI
TOF MS and MSMS of two single beads are shown in the Figure
6 and remaining MALDI TOF MS and MSMS spectra are shown
in the Supporting Information. Only in cases when primary
amines were used after 2-thiophene carboxylic acid hydrazide
and 2-furoic acid hydrazide, we observed minor peaks
corresponding to the ring closed products, which is consistent
with our earlier observation (Figure 4, compound 27 and 28 and
Table 1). Therefore, we eliminated 2-thiophene carboxylic acid
hydrazide and 2-furoic acid hydrazide from our subsequent
studies. Importantly, like peptoids, the molecular ions when
fragmented, provided unequivocal sequence data (see Support-
ing Information).4 We conclude that this is a high quality library
suitable for screening against various macromolecular targets.17
Mixing Amine and Aryl Acyl Hydrazides at the Same
Position in the Library. To achieve maximum diversity in a
library synthesis, it would be desirable to employ both standard
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K.; Spellmeyer, D. C.; Tan, R.; Frankel, A. D.; Santi, D. V.; Cohen, F. E.;
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amine and acyl hydrazide submonomers of all types at any
position in the oligomer. However, this will cause problems in
the addition of the next unit of the oligomer when the preceding
residue has an aryl acyl hydrazide side chain (Figure 1).
Presumably, one way to abrogate this problem is to employ at the
position following an aryl acyl hydrazide only submonomers that
cannot trigger the chain-terminating cyclization reaction and, in
addition, are tolerant of the use in any submonomer at the next
residue.
To demonstrate this point, we used solid-phase split and pool
synthesis to create an OBOC hybrid peptoid-azapeptoid library
of tetramers on 75 μm TentaGel resin by using primary amines
and aryl acyl hydrazides in positions 1 and 3 (position 1 is the
most C-terminal variable residue), but restricted the submo-
nomers used at positions 2 and 4 to alkyl or benzyl acyl
hydrazides, carbazates and semicarbazides (see Figure 7). Finally,
we incorporated methylamine at the N-terminus.18 The
theoretical diversity of the library was 14 641 compounds.
Several individual beads were picked at random, separated into
the wells of a microtiter plate, and the compounds were released
into solution by reacting individual beads with a 0.3 M CNBr
solution, which results in cleavage of a methionine present in the
invariant linker. MALDI TOF/TOF MS analysis showed strong
molecular ions, which indicates the high quality of the library.
The MALDI TOF MS and MSMS spectra of two such single
beads are shown in Figure 8.
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SUMMARY
■
We have shown that peptoid-azapeptoid hybrid libraries derived
from amines, acyl hydrazides, carbazates and semicarbazides can
be made conveniently and efficiently using standard peptoid
submonomer chemistry and that the structure of a compound
displayed on a single bead can be determined by tandem mass
spectrometry. Further, we show that acyl hydrazides, carbazates
and semicarbazides monomers can be used as spacers between
aryl acyl hydrazides and amines to synthesize peptoid-azapeptoid
hybrid library without losing any diversity. Given that many
carbazates, semicarbazides and hydrazides are commercially
available and hundreds more can be made easily, these building
blocks, together with amines, represent a rich source of
submonomers for the synthesis of interesting oligomeric
libraries.
(7) Zuckermann, R. N.; Martin, E. J.; Spellmeyer, D. C.; Stauber, G. B.;
Shoemaker, K. R.; Ken, J. M.; Figliozzi, G. M.; Goff, D. A.; Siani, M. A.;
Simon, R. J.; Banville, S. C.; Brown, E. G.; Wang, L.; Richter, L. S.;
Moos., W. H. Discovery of nanomolar ligands for 7-transmembrane G-
protein-coupled receptors from a diverse N-(substituted)glycine
peptoid library. J. Med. Chem. 1994, 37 (17), 2678−2685.
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Bradley, E. K.; Truong, K. T. V.; Dill, K. A.; Cohen, F. E.; Zuckermann,
R. N. Sequence-specific polypeptoids: A diverse family of hetero-
polymers with stable secondary structure. Proc. Natl. Acad. Sci. U. S. A.
1998, 95 (8), 4303−4308. (b) Armand, P.; Kirshenbaum, K.;
Goldsmith, R. A.; Farr-Jones, S.; Barron, A. E.; Truong, K. T. V.; Dill,
K. A.; Mierke, D. F.; Cohen, F. E.; Zuckermann, R. N.; Bradley, E. K.
NMR determination of the major solution conformation of a peptoid
pentamer with chiral side chains. Proc. Natl. Acad. Sci. U. S. A. 1998, 95
(8), 4309−4314. (c) Wu, C. W.; Kirshenbaum, K.; Sanborn, T. J.; Patch,
J. A.; Huang, K.; Dill, K. A.; Zuckermann, R. N.; Barron, A. E. Structural
and spectroscopic studies of peptoid oligomers with α-chiral aliphatic
side chains. J. Am. Chem. Soc. 2003, 125 (44), 13525−13530. (d) Shah,
N. H.; Butterfoss, G. L.; Nguyen, K.; Yoo, B.; Bonneau, R.; Rabenstein,
D. L.; Kirshenbaum, K. Oligo(N-aryl glycines): A new twist on
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(e) Lee, J. H.; Zhang, Q.; Jo, S.; Chai, S. C.; Oh, M.; Im, W.; Lu, H.; Lim,
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, HPLC traces, MALDI TOF MS and
MSMS spectra of different compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kodadek@scripps.edu.
■
Funding
This work was supported by a contract from the National Heart
Lung and Blood Institute (NHLBI Proteomics Center, NO1-
HV-00242).
Notes
The authors declare no competing financial interest.
(9) Huang, K.; Wu, C. W.; Sanborn, T. J.; Patch, J. A.; Kirshenbaum, K.;
Zuckermann, R. N.; Barron, A. E.; Radhakrishnan, I. A threaded loop
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(18) When the library was constructed without the methylamine at the
N-terminus [M + H + 43] ion peak dominated the mass spectra with
very low intensity signal coming from [M + H]. And in some cases [M +
H] signal was not at all observed. However, when we incorporated
methylamine at the N-terminus in the same library, we mostly observed
[M + H] peak with very low peaks from [M + H + 43]. This is observed
when CNBr cleavage was carried out in 0.1 N HCl or a cocktail of 5:4:1
CH3CN/acetic acid/H2O.
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