Synthesis of Diverse N-Substituted Muramyl Dipeptide Derivatives and Their Use in a Study of Human NOD2 Stimulation Activity

Article abstract of DOI:10.1002/chem.201501557

A flexible synthetic strategy toward the preparation of diverse N-substituted muramyl dipeptides (N-substituted MDPs) from different protected monosaccharides is described. The synthetic MDPs include N-acetyl MDP and N-glycolyl MDP, known NOD2 ligands, and this methodology allows for structural variation at six positions, including the muramic acid, peptide, and N-substituted moieties. The capacity of these molecules to activate human NOD2 in the innate immune response was also investigated. It was found that addition of the methyl group at the C1 position of N-glycolyl MDP significantly enhanced the NOD2 stimulating activity.

Full text of DOI:10.1002/chem.201501557

DOI: 10.1002/chem.201501557
Communication
&
Bioorganic Chemistry
Synthesis of Diverse N-Substituted Muramyl Dipeptide Derivatives
and Their Use in a Study of Human NOD2 Stimulation Activity
Kuo-Ting Chen,[a, b] Duen-Yi Huang,[c] Cheng-Hsin Chiu,[a] Wan-Wan Lin,*[c] Pi-Hui Liang,*[b]
and Wei-Chieh Cheng*[a]
nition is iE-DAP (Figure 1).[7–10] N-Acetyl muramyl dipeptide (N-
Abstract: A flexible synthetic strategy toward the prepara-
tion of diverse N-substituted muramyl dipeptides (N-sub-
acetyl MurNAc-l-Ala-d-iso-Gln) is the minimum structure for
the NOD2 activation and recently it has been demonstrated to
directly bind to NOD2, stimulating NF-kB production.[11–14]
stituted MDPs) from different protected monosaccharides
is described. The synthetic MDPs include N-acetyl MDP
The presence of N-glycolyl PGNs in bacteria has several in-
and N-glycolyl MDP, known NOD2 ligands, and this meth-
teresting biological effects.[15] For example, N-glycolyl PGNs
odology allows for structural variation at six positions, in-
were observed to resist lysozyme degradation. In contrast, N-
acetyl PGNs were sensitive to lysozyme.[3] As for the innate
cluding the muramic acid, peptide, and N-substituted moi-
eties. The capacity of these molecules to activate human
immune response of these compounds, N-glycolyl MDP (2),
NOD2 in the innate immune response was also investigat-
a more potent NOD2 ligand structurally inspired by mycobac-
ed. It was found that addition of the methyl group at the
terial PGN, was recently reported.[16] Although many efforts
C1 position of N-glycolyl MDP significantly enhanced the
have been made to investigate the effects on the peptide
NOD2 stimulating activity.
moiety of MDP, little is known about the role of sugar moiety
of MDP (especially at the C2 position of MDP), perhaps due to
the lack of a flexible synthesis.[17,18]
Peptidoglycans (PGNs) are the major component of bacterial
cell walls. They comprise of a repeating disaccharide unit com-
monly known as N-acetyl glucosamine-N-acetyl-muramic acid,
which is cross-linked by short peptide chains. In most myco-
bacterial PGNs, the occurrence of N-glycolyl is more prevalent
than N-acetyl muramic acid.[1–3] Several unique biomolecules
such as Park’s nucleotide, Lipid I, and Lipid II are involved in
the late stage of biosynthesis of PGNs (Figure 1). During the
course of bacterial infection,[4] PGNs and their fragments are
recognized by the host pattern recognition receptors (PRRs) to
stimulate the innate immune responses.[5,6] Two host cytosolic
PRRs, nucleotide-binding oligomerization domain-like recep-
tors 1 and 2 (NOD1 and NOD2) have been identified as trigger-
ing innate immune responses through the NF-kB pathway,
through sensing those PGN fragments. Among various frag-
ments from PGNs, the minimal structure for host NOD1 recog-
Over the last few years, we have developed new chemical
approaches by using the orthogonally protected building
blocks 3–5 to prepare peptidoglycan components and bio-pre-
cursors such as Lipid II, N-glycolyl Lipid II, and Lipid IV
(Figure 2).[19–22] In addition, preparation of chiral iE-DAP and its
analogues for the study of NOD1 activation has also been re-
ported recently.[23] In contrast, our literature survey of the
NOD2 ligands showed that the present reported studies
mainly focus on the peptide modification of N-acetyl MDP.[24–27]
However, to the best of our knowledge, no extensive structural
modification and activity study of MDPs at different positions,
such as the C2 amino group or C1 position, has been reported.
Herein, we described a flexible synthetic strategy using accessi-
ble building blocks 3–5 or others to prepare diverse MDP ana-
logues with six modified positions (Figure 3), and a study of
their NOD2-mediated NF-kB stimulating activities.
Building block 5 was selected for initial studies, because
1) its preparation is practical; 2) it has greater potential for
structural diversity, including N-substituent diversity and C1-
and C3-diversity; and 3) its stereoisomer 6 with a glucosamine
type scaffold can be used directly to increase the core diversity
(Figure 4). Initially, preparation of N-glycolyl MDP (2) and its de-
rivatives from 5 was identified as the priority. Due to the supe-
rior NOD2 activity of 2, we stayed with the N-glycolyl moiety
on the skeleton during the exploration of other modified posi-
tions.
[a] K.-T. Chen, C.-H. Chiu, Dr. W.-C. Cheng
Genomics Research Center
Academia Sinica No. 128
Academia Road Sec. 2, Nankang District, Taipei, 115 (Taiwan)
E-mail: wcheng@gate.sinica.edu.tw
[b] K.-T. Chen, Dr. P.-H. Liang
School of Pharmacy
National Taiwan University
No. 17, Xuzhou Road, Taipei 100 (Taiwan)
E-mail: phliang@ntu.edu.tw
[c] Dr. D.-Y. Huang, Dr. W.-W. Lin
Department of Pharmacology
Our synthesis of N-glycolyl MDP (2) from 5 is depicted in
Scheme 1. N-Phthalimide deprotection of 5, followed by N-gly-
colylation, gave N-glycolyl 7 in 82% yield, but O-alkylation of 7
at the C3-postion proved problematic (Table 1). Use of 2-(S)-
chloro-propionic acid at RT did not work (Table 1, entry 1), and
National Taiwan University
No. 1, Jen-Ai Road, Sec. 1, Taipei 100 (Taiwan)
E-mail: wwllaura1119@ntu.edu.tw
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501557.
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Figure 1. Biosynthesis of bacterial peptidoglycan and the minimal fragments required for NODs recognition.
Figure 4. Our original design for structural diversities from protected mono-
saccharides 5 and 6.
Figure 2. Building blocks 3–5 applied for the synthesis of PGN precursors in
our previous works.
Scheme 1. Synthesis of N-glycolyl MDP (2) from 5. Reagents and conditions:
a) i. ethylenediamine, EtOH, reflux, 18 h; ii. N-succinimidyl-2-benzyloxylace-
tate, dioxane/H2O, NaHCO3, RT, 4 h, 82% over two steps. b) i. methyl (S)-lac-
tate triflate, NaH, 4 Š molecular sieve, THF, 08C to RT, 87%; c) KOH, MeOH,
RT, 4 h, 62%; d) i. l-alanine-g-benzyl ester d-isoglutamine, EDCI, Et3N, DMF,
RT, 16 h; ii. TFA/CH2Cl2, 08C, 0.5 h; iii. NBS, acetone/H2O, RT, 1 h; iv. Pd(OH)2/
H2 (80 psi), MeOH, RT, 18 h, 77% over four steps.
Figure 3. General structures of diverse N-substituted MDP analogues with
proposed modified positions.
methyl (S)-lactate triflate was more fruitful, and a yield of 87%
was obtained after 2 h in the presence of 4 Š molecular sieves
(Table 1, entry 6). Basic hydrolysis of 8 yielded muramic acid 9
(62%), which was coupled with l-alanine-g-benzyl ester d-iso-
a higher temperature (608C) resulted in an intractable mixture
of products (Table 1, entry 2). Through our efforts to investi-
gate various conditions, use of the more reactive electrophile
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Table 1. O-Alkylation of intermediate 7.
Entry Conditions
Product Isolated
yield
[%]
[a]
1
2
3
4
5
6
NaH (2 equiv), 2-(S)-chloro-propionic acid
(1.5 equiv), 1,4-dioxane, RT, 2 h
NaH (4 equiv), 2-(S)-chloro-propionic acid
(1.5 equiv), 1,4-dioxane, 608C, 24 h
NaH (2 equiv), methyl (S)-lactate mesylate
(2 equiv), THF, 0 to 408C, 2 h
NaH (2 equiv), methyl (S)-lactate mesylate
(2 equiv), THF, 0 to 408C, 24 h
NaH (2 equiv), methyl (S)-lactate triflate
(2 equiv), THF, 0 to 408C, 2 h
9
9
8
8
8
8
–
N.D.[b]
18
31
71
NaH (2 equiv), methyl (S)-lactate triflate
(2 equiv), THF, 0 to 408C, 2 h, 4 Š molecular
sieve
87
[a] No desired product was observed, and 7 was almost recovered.
[b] N.D.=not determined.
Scheme 2. Preparation of C-1 modified N-glycolyl MDPs 16–18 from 5. Re-
agents and conditions: a) 2-allylethanol, TMSOTf, NIS, CH2Cl2, 4 Š molecular
sieve, 08C to RT, 4 h, 68%; b) i. ethylenediamine, EtOH, reflux, 18 h; ii. N-suc-
cinimidyl- 2-benzyloxylacetate, dioxane/H2O, NaHCO3, RT, 4 h, 69% over two
steps; c) i. (S)-ethyl lactate triflate, NaH, 4 Š molecular sieve, THF, 08C to RT;
ii. KOH, MeOH, RT, 4 h; iii. l-alanine-g-benzyl ester-d-isoglutamine, EDCI, Et3N,
DMF, RT, 16 h, 70% over three steps; d) i. TFA/CH2Cl2, 08C, 0.5 h; ii. Pd(OH)2,
H2, THF, 24 h, 84%; e) i. 1-octene, Grubb’s 1 st, CH2Cl2, reflux, 18 h; ii. TFA/
CH2Cl2, 08C, 0.5 h; iii. Pd(OH)2, H2, THF, 24 h, 65% over three steps; f) i. O3,
MeOH, À788C, 5 min, then Et3N; ii. NH4OAc, NaBH3CN, EtOH, AcOH, RT, 24 h;
iii. TFA/CH2Cl2, 08C, 0.5 h; iv. Pd(OH)2, H2,THF, 24 h, 34% over four steps.
glutamine. A series of typical deprotection steps resulted in
our first target molecule, N-glycolyl MDP (2), in 77% yield over
four steps.
Having proved the feasibility of this approach, it was extend-
ed to prepare N-glycolyl MDPs 10, 11, and 12 (Figure 5). By
conjugating the proper peptide moieties, N-glycolyl MDPs 10
and 11 were prepared in yields of 72 and 78%, respectively.
through N-phthalimide deprotection and N-glycolylation in
69% yield over two steps. O-Alkylation of 14 with methyl-(S)-
lactate triflate, followed by hydrolysis, and conjugation with l-
alanine-g-benzyl ester d-isoglutamine, gave the alkene 15 in
a good yield (70% over three steps). Alkene 15 was used as
a common intermediate for the preparation of the three C1-al-
kyloxyl MDPs 16–18: hydrogenation under acidic conditions
gave 16 in a yield of 84%; conjugation with 1-octene in the
presence of Grubb’s catalyst, followed by hydrogenation, gave
17 in 65% yield, and ozonolysis and subsequent reductive ami-
nation and hydrogenation gave 18 in 34% yield over three
steps.
Considering a more practical procedure for the N-substitu-
ent diversity at the C2 position, we designed the scaffold 22
and scheduled the elaboration of the N-substitution at the last
stage. Initial attempts to perform the N-phthalimide deprotec-
tion of 19 were not successful and the side product 21 was de-
tected instead of the desired 20 (Scheme 3). After re-evaluation
of the synthetic routes and building blocks, we started again
from the N-Boc 4 and reached desired core 22 through O-alky-
lation, conjugation with the dipeptide, and acidic hydrogenoly-
sis in 60% yield over three steps. Next, 22 was submitted for
N-substitution by amide formation with six carboxylic acids
containing a range of hydrophilic and hydrophobic functional
groups to obtain 27–32. Similarly, 33–38 were generated from
scaffold 26. As shown in Table 2, thirteen N-substituted MDPs
27–38, including N-glycolyl MDP (2), were prepared to exem-
plify the feasibility of this synthetic protocol.
Figure 5. Preparation of N-glycolyl MDPs 10–12 and N-acetyl MDP (1) from
different building blocks.
Likewise, the orthogonally protected 6 was conveniently ap-
plied to generate 12, the C4-epimer of 2, in a yield of 61%
over three steps. Moreover, N-acetyl MDP (1) could be pre-
pared from 3 or 5 (see the Supporting Information).
Next, our attention turned to the preparation of N-glycolyl
MDP analogues bearing a variety of alkyl chains at the C1-posi-
tion, because the hydrophobic character of substituents at this
position was postulated to affect the innate immunity re-
sponse.[28] As shown in Scheme 2, Fischer glycosylation of thio-
glycoside 5 with 2-allylethanol afforded the adduct 13 bearing
a terminal olefin in 68% yield. Following a similar procedure to
that depicted in Scheme 1, N-glycolyl 14 was obtained from 13
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Figure 6. Stimulation of NOD2 by synthetic MDPs (1 mm). Control means no
compound was added.
HEK293T cell lines.[23,29] As shown in Figure 6, all analogues
except 30 were found to be more potent stimulators than N-
acetyl MDP (1). Interestingly, 26, bearing the equatorial C1 me-
thoxyl group (b-form), and with no substituent attached to the
C2 amine group, was found to be the most potent NOD2 stim-
ulator. N-Decanoyl MDP 30 bearing a longer alkyl chain was
almost inactive, presumably due to steric hindrance or molecu-
lar aggregation.
Scheme 3. Preparation of C-2 modified MDPs 27–38. Reagents and condi-
tions: a) i. NaH, 2-(S)-chloro-propionic acid, 1,4-dioxane, 608C, 24 h; ii. l-ala-
nine-g-benzyl ester d-isoglutamine, EDCI, Et3N, DMF, RT, 16 h; b) ethylenedia-
mine, EtOH, reflux, 18 h; c) i. methyl (S)-lactate triflate, NaH, THF, 08C to RT;
ii. KOH, MeOH, RT, 4 h, 72% (for 24) or 69% (for 25) over two steps; d) i. l-
alanine-g-benzyl ester d-isoglutamine, EDCI, Et3N, DMF, RT, 16 h; ii. Pd(OH)2,
H2, THF/TFA, RT, 24 h, 84% (for 22) or 81% (for 26) over two steps. e) R-
COOH, HBTU, HOBT, DIEA, DMF, RT, 2 h, 27–76%. HBTU = 2-(1H-benzotria-
zole-1-yl)-1,1,3,3-tetramethyluronium, HOBT = 1-hydroxybenzotriazole, DIEA
= N,N-diisopropylethylamine.
In addition, several interesting observations were found.
Compound 22 (no N-glycolyl moiety) was found to have simi-
lar potency to N-glycolyl MDP (2), but it was still more effective
than N-acetyl MDP (1). A similar trend was observed between
33 and 2. In addition, comparing 2 with other compounds,
MDP 12, the C4-epimer of 2, showed slightly higher activity;
compound 11, lacking the methyl group of the corresponding
lactate of 2, was a more potent activator. In contrast, the po-
tency of 10 (lacking the methyl group of the l-alanine unit of
2) was a weaker activator. The activities of 16–18, bearing suc-
cessively longer alkyl chains (C5–C11) at the equatorial (b) C1
position, showed similar potency to 2, but were less active
than 33 (bearing the only methoxyl group at this position).
This finding strongly indicates that a hydrophobic moiety of
the proper size at the C1 position serves to greatly increase
NOD2 stimulation activity.
Table 2. Structures of N-substituted MDP analogues.
Compound
R1 =OH
Yield
[%][a]
Compound
R1 =b-OMe
Yield
[%][b]
R2
2
68
53
64
35
33
–
64
–
27
28
29
34
35
57
51
Likewise, compounds 26 and 33–38, all bearing equatorial
C1-methoxyl groups, showed a higher potency than their cor-
responding molecules 2, 22, and 28–32, bearing anomeric hy-
droxyl groups instead. The activity of 36 compared to 30
could be interesting because of the additional methyl group at
the C1 position.
30
31
29
76
36
37
27
70
In addition, the C-1 modified MDPs 17, 26, and 33, as well
as reference 1 and 2, were selected to evaluate their activity at
different dosages. As shown in Figure 7, reference 1 and 2
were able to active NOD2 in a dose-dependent manner,[17] and
a clear trend showed that 2 was more potent than 1, even at
a low concentration (0.1 mm). The activity trend of 17 was simi-
lar to 2, indicating that the increased C1-lipophilicity has less
effect on NOD2 activation. C1-Methylated 33 and 26 were
found to be more potent than others. Interestingly, a high con-
centration (100 mm) of C1-methylated 33 led to significantly
higher NOD2 activity (1.7-fold compared with 2).
32
52
38
58
[a] Isolated yield from 22. [b] Isolated yield from 26.
In this work, a total of 22 N-substituted MDPs were synthe-
sized, all of which were novel except reference compounds
1 and 2.
Biological evaluation took place at a 1 mm concentration in
the NOD2-dependent NF-kB activation assay system, in human
In conclusion, a flexible synthesis of N-substituted muramyl
dipeptide analogues from a variety of interchangeable, pro-
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Acknowledgements
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Keywords: peptides
·
bioorganic chemistry
·
synthetic
methods · NOD2 · N-substituted muramyl dipeptide
Received: April 22, 2015
Published online on July 16, 2015
Chem. Eur. J. 2015, 21, 11984 – 11988
www.chemeurj.org
11988
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim