Aspartic Acid Side-Chain Benzyl Ester as a Multifunctionalization Precursor for Synthesis of Branched and Cyclic Arginylglycylaspartic Acid Peptides

Article abstract of DOI:10.1055/s-0036-1588870

Here, we report a peptide aspartic acid side-chain benzyl ester as a useful precursor that can be efficiently converted into various functional groups, including acid, amide, carbonyl hydrazide, carbonyl azide, or thio ester groups, without other protection for the peptide. With this strategy, we synthesized a series of novel branched and cyclic arginylglycylaspartic acid peptides through successive peptide C-terminal ligation and side-chain ligation based on a side-chain carbonyl azide or thio ester.

Full text of DOI:10.1055/s-0036-1588870

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Aspartic Acid Side-Chain Benzyl Ester as a Multifunctionalization
Precursor for Synthesis of Branched and Cyclic Arginylglycylaspar-
tic Acid Peptides
Xiaobo Tiana,b◊
Pengqiu Yua,b◊
Yubo Tanga
9 examples
yield >90%
S
S
COOBn
CONHNH2
HN CRGDRGDC
Zhiping Le*b
Wei Huang*a,c
O
unprotected
peptide
f
H
D
RGDRGD
N
K
side-chain
ligation
4
G
R
a CAS Key Laboratory of Receptor Research, CAS Center for Excellence in
Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai
201203, P. R. of China
b Department of Chemistry, Nanchang University, 999 Xuefu Avenue,
Nanchang 330031, P. R. of China
c University of Chinese Academy of Sciences, No.19A Yuquan Road,
Beijing 100049, P. R. of China
branched cyclic RGD peptide
huangwei@simm.ac.cn
zple@ncu.edu.cn
◊ These authors contributed equally to this work.
Published as part of the Cluster Recent Advances in Protein and Peptide Synthesis
Received: 16.04.2017
Accepted after revision: 16.05.2017
Published online: 29.06.2017
zide functional group on the asparagine (Asn) side chain,
and successive azidation with NaNO2, thio ester formation
with (4-sulfanylphenyl)acetic acid (MPAA), and peptide
side-chain ligation with an N-terminal cysteine (Cys) pep-
tide then gave the target branched peptides, following Liu
and co-workers’ approach of linear peptide hydrazide liga-
tion.16,17 Compared with other methods for branched-pep-
tide synthesis, such as selective deprotection of side-chain
carboxylic acid or amine groups18,19 or incorporation of
nonnatural amino acids for side-chain conjugation,20,21 this
method permits efficient ligation of unprotected peptides
with a common amide linkage.
In our previous work, we used an Asn building block
with a benzyloxycarbamate (Cbz)-protected side-chain hy-
drazine moiety [Fmoc-Asn(NHNHCbz)-OH] to introduce
the hydrazide onto a peptide side chain. However, the use of
the strong acid trifluoromethanesulfonic acid in the depro-
tection of the Cbz moiety led to a moderate yield and, con-
sequently, this protecting strategy is not suitable for sub-
strates with an acid-labile structure, such as the glycosidic
bond in glycopeptides. Here, we present a better protection
strategy that uses an Asp side-chain benzyl ester, which can
be efficiently converted into various functional groups, in-
cluding acid, amide, hydrazide, carbonyl azide, or thio ester
groups, under mild conditions. With this strategy, we pre-
pared a series of novel RGD branched and cyclic peptides
through side-chain ligation using a carbonyl azide or thio
ester. A dual-ligation approach involving successive C-ter-
minal and side-chain ligations was employed to synthesize
complicated RGD branched peptides.
DOI: 10.1055/s-0036-1588870; Art ID: st-2017-w0265-c
Abstract Here, we report a peptide aspartic acid side-chain benzyl es-
ter as a useful precursor that can be efficiently converted into various
functional groups, including acid, amide, carbonyl hydrazide, carbonyl
azide, or thio ester groups, without other protection for the peptide.
With this strategy, we synthesized a series of novel branched and cyclic
arginylglycylaspartic acid peptides through successive peptide C-termi-
nal ligation and side-chain ligation based on a side-chain carbonyl azide
or thio ester.
Key words peptide side-chain ligation, side-chain benzyl ester, pep-
tide hydrazide, arginylglycylaspartic acid peptides, branched cyclic pep-
tides
Branched and cyclic peptides have recently attracted in-
creased research interest because of their biological func-
tions in protein domain simulation,1–4 vaccine design,1,5,6
receptor-binding investigations,7 and enhanced stability
and optimized half-lives for therapeutic peptide drugs8,9
.
The arginylglycylaspartic acid (RGD) tripeptide unit is a
common motif that is involved in interaction with integ-
rins,10 and previous research has shown that a series of cy-
clic RGD peptides11 are selective inhibitors of particular in-
tegrins such as αVβ3, which is overexpressed in many can-
cers and mediates tumor metastasis.12 The development of
novel RGD peptides as tumor-targeting reagents or antican-
cer therapeutics has potential applications in cancer treat-
ment.13,14
In our previous work,15 we employed peptide side-chain
hydrazide ligation for the synthesis of branched and cyclic
peptides. This strategy permitted the assembly of a hydra-
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CONH2
COOH
H2N RGDRGDRGD OH
H2N RGDRGDRGD OH
3
2
COOBn
H2N RGDRGDRGD OH
1
2 steps
e
d
CONHNH2
CON3
COSAr
H2N RGDRGDRGD OH
H2N RGDRGDRGD OH
H2N RGDRGDRGD OH
4
5
6
Scheme 1 Peptide side-chain functional-group conversions from a benzyl ester. Reaction conditions: (a) 10 mM aq K2CO3, r.t., 20 min, 90%; (b) 1% NH3
in DMF, r.t., 30 min, 85%; (c) 5% N2H4 in DMF, r.t., 15 min, 95%; (d) NaNO2, pH 2, –10 °C, 15 min, 90%; (e) MPAA, pH 5.5, –10 °C, 15 min, 95%.
We chose Fmoc-Asp(OBn)-OH as a building block for
peptide synthesis. The benzyl ester exhibited good stability
in Fmoc-based solid-phase peptide synthesis (SPPS) and
later-stage ligation reactions. The RGD peptide 1 carrying a
side-chain benzyl ester was prepared for side-chain func-
tional-group conversion. As shown in Scheme 1 and Figure
1, the benzyl ester, as a useful precursor, could be efficiently
converted into various functional groups. On hydrolysis
with potassium carbonate or aminolysis with ammonia, the
native Asp or Asn peptides 2 and 3, respectively, were ob-
tained in 85–90% yields within 20–30 min (Figures 1b and
1c). When treated with 5% NH2NH2 in DMF at r.t. for 15 min,
benzyl ester 1 underwent complete hydrazinolysis to give
the side-chain hydrazide peptide 4 in an excellent yield
(Figure 1d). More examples of side-chain conversions of
benzyl ester groups into hydrazide groups are available in
the Supplementary Information. By following the approach
of Liu and co-workers16 and our previous method,15 the
side-chain hydrazide group was converted into the carbonyl
azide 5 (Figure 1e) by treatment with NaNO2 in acidic solu-
tion. Azide 5 was subsequently converted into the thio ester
6 (Figure 1f) by treatment with MPAA. These results
demonstrated that a side-chain benzyl ester, acting as a
multifunctionalization precursor, can be applied in tempo-
rary protection of Asp and Asn moieties or in introducing
side-chain ligation handles such as hydrazide (one-step
conversion), azide (two-step conversion), or thio ester
(three-step conversion) in high yields under mild and expe-
ditious conditions. The RGD peptides with a side-chain car-
bonyl azide group 5 or thio ester group 6 were able to per-
form ligations through direct amidation (using peptide 5)
with a peptide N-terminal amine or side-chain native
chemical ligation (NCL) with an N-terminal Cys-peptide to
give the corresponding branched RGD peptides.
our previous work,15 a byproduct from the intramolecular
cyclization of the side-chain thio ester with the neighboring
amide nitrogen was observed. Here, we optimized the liga-
tion condition in a pH 6.0 solution at a lower temperature
of 4 °C to minimize the competitive intramolecular cycliza-
tion. Figure 2b shows the ligation of 6 and the Cys-peptide
under these optimal conditions. Ligation product 7a was
Figure 1 HPLC profiles of RGD peptide side-chain functional-group
conversion of benzyl ester 1 into acid 2, amide 3, hydrazide 4, azide 5,
and thio ester 6. (a) HPLC profile of 1; (b) 1 was treated with 10 mM
K2CO3 at r.t. for 20 min; (c) 1 was treated with 1% ammonia in DMF at
r.t. for 30 min; (d) 1 was treated with 5% N2H4·H2O in DMF at r.t. for 15
min; (e) 4 was treated with NaNO2 at –10 °C for 15 min; (f) 5 was treat-
ed with MPAA at –10 °C for 15 min.
The efficient conversion of the side-chain benzyl ester
into a thio ester suggested that this might be a useful strate-
gy for synthesizing branched peptides. Therefore, we em-
ployed the thio ester 6 to perform side-chain NCL with the
N-terminal Cys-peptide CRGDRGDC, which contains two
RGD units and a potential disulfide motif for cyclization. In
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obtained in an improved yield (70%), with much less cy-
clization byproduct compared with the previous reported
results.15 With the purified branched peptide 7a in hand,
we conducted the disulfide-bond-formation reaction at a
concentration of 0.25 mM in a sodium phosphate buffer
(pH 7.5, 0.2 M) containing 20% DMSO and bubbled with air.
After four hours, the branched cyclic peptide 7 was ob-
tained in 95% yield. A general procedure for side-chain hy-
drazide conversion and successive ligation is described in
the Notes and References section.22
tides by a two-step ligation approach involving successive
C-terminal and side-chain ligations. As shown in Scheme 2,
an RGD hexapeptide 8 containing a C-terminal carbonyl hy-
drazide and an Asp side-chain benzyl ester was prepared as
the starting material. It is noteworthy that in a previous
study,16 the peptide C-terminal Asp-hydrazide could not be
obtained without side-chain protection because of cycliza-
tion during the peptide cleavage from the resin. However,
with two-step cleavage or side-chain protection, this cy-
clization was blocked and C-terminal Asp-hydrazide liga-
tion was possible.23 The side-chain protection also blocked
thio ester exchange between the side-chain thio ester and
the C-terminal thio ester, consequently avoiding the forma-
tion of the corresponding byproduct by side-chain liga-
tion.23
First, we performed a C-terminal ligation with 8. The
hydrazide was converted into the carbonyl azide 9, which
underwent direct amidation with the lysine side-chain
amino group of the cyclic RGD peptide cyclo(KRGDf) (f = D-
Phe)11 in a pH 8.5 solution. The reaction was complete
within 30 minutes, and gave the cyclic RGD peptide 10 in
excellent yield (Figure 3b). We then attempted to perform a
second ligation on the side chain of 10. The side-chain ben-
zyl ester of 10 was converted into the corresponding car-
bonyl hydrazide 11 by treatment with 5% hydrazine mono-
hydrate in DMF (Figure 3c). Successive treatment with Na-
NO2 and MPAA then gave the side-chain thio ester 13. Side-
chain ligation of 13 with the Cys-peptide CRGDRGDC pro-
vided the branched peptide 14a in 60% yield (Figures 3d
and 3e). The side-reaction between the side-chain thio es-
ter and the nitrogen of the neighboring amino acid15 gave a
cyclic byproduct with a more significant rate of formation
than that of thio ester 6. This result is probably due to the
lower steric hindrance of the amide in peptide 13 Asp-
(side-chain)Lys compared with that of the amide of the
Asp-Arg moiety in 6, when these amide nitrogen atoms
were involved in the cyclization side-reaction. Finally, di-
sulfide-bond formation under oxidative conditions gave the
dual-ring branched cyclic RGD peptide 14 in high yield (Fig-
ure 3f).
Figure 2 Synthesis of branched cyclic RGD peptide 7. Reaction condi-
tions: (a) Cys-peptide CRGDRGDC, pH 6.0, 4 °C, 8 h, 70%; (b) 20%
DMSO, air, 4 h, 95%. HPLC profiles of the reactions: (a) ligation of thio
ester 6 and peptide CRGDRGDC at 0 min; (b) ligation of thio ester 6 and
peptide CRGDRGDC at 8 h; (c) purified branched peptide 7a; (d)
branched cyclic peptide 7.
The successful synthesis of branched cyclic RGD peptide
7 from the side-chain benzyl ester 1 encouraged us to pre-
pare more complicated dual-ring branched cyclic RGD pep-
S
S
HN CRGDRGDC OH
R1
H2N RGDRGD R2
R1
b
f
H
N
O
f,g
D
H2N RGDRGD
K
f
H
G
D
4
R
H2N RGDRGD
N
K
10 R1 = COOBn
G
4
R1 = COOBn, R2 = CONHNH2
R1 = COOBn, R2 = CON3
R
8
14
c
a
11 R1 = CONHNH2
9
d
e
12 R1 = CON3
13 R1 = COSAr
Scheme 2 Synthesis of dual-ring branched RGD peptide 14 by successive C-terminal and side-chain ligations. Reaction conditions: (a) NaNO2, pH 2, –10 °C,
15 min, 95%; (b) cyclo(KRGDf) (5 equiv), pH 8.5, –10 °C, 30 min, 95%; (c) 5% NH2NH2 in DMF, r.t., 30 min, 95%; (d) NaNO2, pH 2, –10 °C, 15 min, 95%; (e)
MPAA, pH 5.5, –10 °C, 15 min, 95%; (f) CRGDRGDC (5 equiv), pH 6.0, 4 °C, 12 h, 60%; (g) 20% DMSO, air, r.t., 4 h, 95%.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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Figure 3 HPLC profiles of the procedures for the synthesis of the dual-ring branched cyclic RGD peptide 14 by successive C-terminal and side-chain
ligations. (a) In situ hexapeptide carbonyl azide 9; (b) C-terminal ligation of 9 and cyclo(KRGDf) for 30 min; (c) in situ carbonyl hydrazide peptide 11; (d)
side-chain ligation of thio ester 13 and CRGDRGDC for 0 min; (e) side-chain ligation of thio ester 13 and CRGDRGDC for 12 h; (f) in situ dual-ring
branched cyclic RGD peptide 14 after disulfide-bond formation.
Next, we preformed successive side-chain and C-termi-
nal ligations in the reverse order to prepare the homo-dual-
ring branched cyclic RGD peptide 20. As shown in Scheme
3, hexapeptide 15 containing a C-terminal benzyl ester and
an Asp side-chain carbonyl hydrazide was employed as the
starting material. Another building block, Fmoc-Asn(OH)-
OBn, was used in SPPS for the synthesis of 15, and the side-
chain acid of the first amino acid Asp was coupled to the
NH2NH-CTC resin. To avoid the intramolecular cyclization
side-reaction, we conducted ligation on the side chain prior
to C-terminal ligation. All the processes are shown in Figure
4. The first step was to convert the side-chain hydrazide
hexapeptide 15 into the carbonyl azide 16 (Figure 4a); this
was followed by direct amidation with cyclo(KRGDf) to give
the cyclic RGD peptide 17 (Figure 4b). Then, hydrazinolysis
of the C-terminal benzyl ester on 17 was performed to give
O
f
H
O
H
D
N
K
f
H
N
G
R2
4
R
D
N
K
RGDRGD
20
e,f
b
f
4
H
N
G
N3
H2N RGDRGD R1
H2N RGDRGD R1
R
3
D
K
O
G
R
4
17 R1 = COOBn
15 R1 = COOBn, R2 = CONHNH2
16 R1 = COOBn, R2 = CON3
c
d
a
18 R1 = CONHNH2
19 R1 = CON3
Scheme 3 Synthesis of dual-ring branched RGD peptide 20 by successive side-chain and C-terminal ligations. Reaction conditions: (a) NaNO2, pH 2, –10 °C,
15 min, 95%; (b) cyclo(KRGDf) (5 equiv), pH 8.5, –10 °C, 30 min, 85%; (c) 5% NH2NH2 in DMF, r.t., 30 min, 95%; (d) NaNO2, pH 2, –10 °C, 15 min, 95%;
(e) cyclo(KRGDf) (5 equiv), pH 8.5, –10 °C, 30 min, 80%; (f) N3(CH2)3COOSu (5 equiv), pH 7.5, r.t., 15 min, 95%.
Figure 4 HPLC profiles of procedures in the synthesis of the dual-ring branched cyclic peptide 20. (a) In situ RGD peptide 16 with a side-chain carbonyl
azide; (b) side-chain ligation of 16 and cyclo(KRGDf); (c) in situ RGD peptide 18 bearing a C-terminal hydrazide synthesized by hydrazinolysis of 17; (d) in
situ RGD peptide 19 bearing a C-terminal carbonyl azide; (e) C-terminal ligation of 19 and cyclo(KRGDf); (f) azide labeling of dual-ring branched peptide
20 with N3(CH2)3COOSu.
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the corresponding carbonyl hydrazide 18 in excellent yield
(Figure 4c). After treatment with NaNO2, the C-terminal
carbonyl azide 19 was obtained (Figure 4d), which was
treated with cyclo(KRGDf) for a second round of ligation
(Figure 4e), affording the homo-dual-ring branched cyclic
RGD peptide 20a. Finally, to facilitate future bioactivity
testing, an azide tag was added to the N-terminal amino
group of 20a by using N3(CH2)3CO2Su (Su = succinimidyl), to
give the azido-labeled branched cyclic RGD peptide 20.
In conclusion, we present here a peptide side-chain
benzyl ester that acts as a multifunctionalization precursor
that can be efficiently converted into side-chain acid, am-
ide, hydrazide, carbonyl azide, or thio ester groups in excel-
lent yields under mild conditions. The resulting side-chain
carbonyl azide and thio ester permit side-chain peptide li-
gation for branched peptide synthesis. With this strategy
and successive C-terminal and side-chain ligations, a series
of novel branched cyclic RGD peptides were prepared. Our
method provides a simplified approach for the synthesis of
branched cyclic peptides, with the advantage of selective
activation of side-chain acids without other protection on
the peptide chain. Furthermore, the convenient functional-
group conversion on side-chain Asp in excellent yields and
mild conditions makes this approach very robust in appli-
cation. This method will facilitate the development of
branched cyclic RGD peptides for therapeutic purposes.
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(22) Side-Chain Peptide Hydrazide Synthesis and Successive Side-
Chain Ligation; General Procedure
Funding Information
This work was supported by the National Natural Science Foundation
of China (NNSFC, No. 21372238 and 21572244) and the Personalized
Medicines: Molecular Signature-Based Drug Discovery and Develop-
ment Strategic Priority Research Program of the Chinese Academy of
Sciences, Grant No. XDA12020311.
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The side-chain benzyl ester peptide (2 mM) was treated with 5%
N2H4 in DMF at r.t. for 15–30 mins until conversion was com-
plete (HPLC). The product was purified by preparative HPLC,
and the resulting side-chain peptide hydrazide was then treated
with NaNO2 (10 equiv) in a pH 2 buffer of 6.0 M guanidine
hydrochloride and 0.2 M aq NaH2PO4 at –10 °C for 15 min to
give the corresponding carbonyl azide. MPAA (50 equiv) was
then added, the pH of the residue was adjusted to pH 5.5 with
1.0 M aq NaOH, and the mixture was kept at –10 °C for 15 min
to give the side-chain thio ester. A Cys-peptide (2 equiv) or an
amino-RGD peptide (5 equiv) was added then for side-chain
ligation at r.t. for 4–8 h. The ligation product of the branched
peptide was purified by preparative HPLC. For details and HPLC
and MS data, see the Supplementary Information.
Acknowledgements
We thank the mass spectrometry facility of the iHuman Institute for
providing us with the LC–MS and peptide-synthesizer instruments.
We thank Dr. Fei Zhao, Dr. Houchao Tao, Dr. Jingjing Shi, Dr Wei Yi,
and Dr. Eric H. Xu for their kind help in LC-MS detection.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588870.
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Notes and References
(23) Tian, X.; Li, J.; Huang, W. Tetrahedron Lett. 2016, 57, 4264.
(1) Robinson, J. A. J. Pept. Sci. 2013, 19, 127.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E