Identification of synthetic compounds active against VRE: The role of the lipidated aminoglucose and the structure of glycopeptide binding pocket

Article abstract of DOI:10.1016/j.bmcl.2005.06.098

A modified vancomycin binding pocket (D-O-E ring) incorporating an α-hydroxy-β-amino acid at the AA4 position is designed and synthesized. Some of these compounds display potent bioactivities against both sensitive- and resistant-strains (8 μg/ml against

Full text of DOI:10.1016/j.bmcl.2005.06.098

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4594–4599
Identification of synthetic compounds active against VRE: the
role of the lipidated aminoglucose and the structure of
glycopeptide binding pocket
a
Yanxing Jia, Eduardo Gonzalez-Zamora, Nianchun Ma, Zuosheng Liu,
b
a
a
a
c
c
Mich e` le Bois-Choussy, Adriano Malabarba, Cristina Brunati and Jieping Zhu
a,
*
a
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Universidad Aut o´ noma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Col. Vicentina Iztapalapa, 09340 M e´ xico, D. F, Mexique
b
c
Vicuron Pharmaceuticals, Italy Research Center, via R. Lepetit, 34, I-21040 Gerenzano, VA, Italy
Received 27 April 2005; revised 25 June 2005; accepted 27 June 2005
Available online 15 August 2005
Abstract—A modified vancomycin binding pocket (D–O–E ring) incorporating an a-hydroxy-b-amino acid at the AA4 position is
designed and synthesized. Some of these compounds display potent bioactivities against both sensitive- and resistant-strains (8 lg/ml
against VREF). Both the lipidated aminoglucose and the structure of the 16-membered macrocycle are found to be important for
the anti-VRE activities. The polyamine appendage at the C-terminal, on the other hand, improved the activity against vancomycin-
sensitive strains.
Ó 2005 Elsevier Ltd. All rights reserved.
Vancomycin (1) and teicoplanin are two drugs used
worldwide for the treatment of infections due to
methicillin-resistant Staphylococcus aureus and other
Gram-positive organisms in patients allergic to b-lactam
N-Ac-D-Ala-D-Ala, due to one missing hydrogen bond
and the ground state repulsion between the two oxygen
lone-pairs in the former complex. The reduced binding
affinity translated into the 1000-fold reduced sensitivity
of vancomycin-resistant bacteria to drug (Fig. 1).
4
,5
1
antibiotics. They act by binding to the D-Ala-D-Ala
dipeptide of peptidoglycan precursors, preventing matu-
2
ration of the bacterial cell-wall. After more than 30
OH
NH
2
years of clinical use, resistance to drugs of the vancomy-
cin family has been recognized in the late 1980s and the
frequency of resistance has increased significantly over
the past decade, reaching 30% among hospitalized
patients in 2000 in the USA. Since vancomycin-resistant
enterococci (VRE) also carry resistance to virtually all
other known antibiotics, it represents thus a serious
threat to public health. Reprogramming of the peptido-
glycan termini from D-Ala-D-Ala dipeptide to D-Ala-D-
Lac depsipeptide has been proposed as the principal
OH OH
O
OH
O
O
O
O
Cl
O
O
C
D
E
Cl
HO
O
OH
O
H
N
O
O
H
H
N
N
2 3
NH CH
N
N
H
H
3
O
H
mechanism of resistance. In fact, in vitro binding studies
have shown that the affinity of vancomycin for N-Ac-D-
Ala-D-Lac is about 1000 times lesser than its affinity for
NH
A
O
OOC
NH2
1
OH
OH
O
O
HO
H
N
-
N
O
Keywords: Antibiotic; Biaryl ether; Intramolecular nucleophilic
H
O
N
aromatic substitution (S Ar) reaction; Macrocycle; Vancomycin type
glycopeptide; Vancomycin-resistant enterococci (VRE).
*
Vancomycin (1) and D-Ala-D-Ala complex
Figure 1. Structure of vancomycin and its N-Ac-D-Ala-D-Ala complex.
Corresponding author. Tel.: +33 1 69823131; fax: +33 169077247;
e-mail: zhu@icsn.cnrs-gif.fr
0
960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.06.098

Y. Jia et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4594–4599
4595
ularly challenging and to date most of the chemical
transformations have been localized on the peripheral
of the macrocycles relying mainly on the simple chemi-
cal reactions. Indeed, it would be extremely difficult, if
it is not impossible, to reengineer the carboxylate-bind-
ing pocket (D–O–E ring) of natural glycopeptides to in-
clude new hydrogen bond contacts with the modified
Cl
NH
HO
OH
OH
O
O
OH
O
2
H N
O
HO
Cl
7
O
peptidoglycan termini. Therefore, the minimum struc-
O
O
Cl
O
OH
O
H
H
N
H O
H
O
N
N
NH
CH
NO2
O
2
3
N
H
N
OMe
F
O
O
H
NH
O
PriO
OiPr
a
O
NH2
+
O
O
O
H
OH
N
NHBoc
OH
MeOOC
N
HO
HO
NH2
H
O
Oritavancin (LY333328)
OTBS
O
3
4
HN
NO
2
OCH3
HO
O
F
HO
PriO
OiPr
O
b,c
HOOC
O
O
O
O
O
HO
H
H
Cl
N
NHBoc
H
O
O
MeO
N
H
H
N
N
H
N
N
H
N
H
O
NH
O
OTBS
O
O
Cl
O
NH
H
5
N
N
NO2
HO
OCH3
OH
NHMe
O
O OH
O
F
HO
OH
O
d
HO
OH
HO
OH
O
O
O
OH
H
N
NHBoc
MeO
N
H
Dalbavancin
N
H
O
OH
Figure 2. Second-generation semi-synthetic lipoglycopeptides in clinic
development.
6
OCH3
Y
O
HO
Extensive structure–activity relationship studies per-
formed by both academic and industrial researchers
indicated that the incorporation of a hydrophobic chain
into the natural product is highly beneficial for activities
against VRE. Indeed, two semi-synthetic analogues of
glycopeptides: oritavancin (LY333328) and dalbavancin
X
O
O
O
H
N
NHBoc
N
MeO
N
H
H
O
OH
(
Fig. 2) that entered into late-stage clinical trials contain
6
7 X = NO2, Y = H
a hydrophobic group. However, given the architectural
complexity of vancomycin family glycopeptide, the
structural modification of the natural products is partic-
8
X = H, Y = NO2
OCH3
O
HO
O
O N
2
O
Glycosidation
Planar chirality
Effect of substituents
O
H
NHBoc
N
N
MeO
N
H
H
O
3
OH
OR
X
E
2
R O
O
10
D
CH3
O
H
O
H
1
R
Scheme 1. Synthesis of 16-membered meta,para-cyclophane with an
endo aryl–aryl ether bond. Reagents and conditions: (a) EDC, HOBT,
CH Cl , room temperature, 89%; (b) BCl , CH Cl , 0 °C, then MeOH;
N
NH2
N
N
H
H
4
O
O
R
2
2
3
2
2
H
(
3 2 2
c) NaHCO , Boc O, dixoane–H O (1:1), room temperature, 81%
Stereochemistry
(over two steps); (d) CsF, DMSO, room temperature, 72%. TBS =
tert-butyldimethylsilyl, Boc = tert-butoxycarbonyl, EDC = N-(3-di-
2
0
Figure 3. Generic structure of modified carboxylate-binding pocket of
glycopeptides.
methylaminopropyl)-N -ethylcarbodiimide hydrochloride, HOBT =
1-hydroxybenzotriazole, DMSO = dimethyl sulfoxide.

4596
Y. Jia et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4594–4599
ture required to carry the hydrophobic substituent re-
8
for the active compounds against both vancomycin-
sensitive strains and VRE.
mained unknown. A notable exception is the work of
Ellman who has synthesized a combinatorial library of
1
appendage at the C-terminal and identified synthetic
receptors that bind to the N-Ac -L-Lys-D-Ala-D-Ala.
2
6-member macrocycles having different tripeptide
Synthesis of the parent compounds 7, 8 and 10 is sum-
marized in Scheme 1. Coupling of a-hydroxy-b-amino
acid (3) with tripeptide 4 under standard conditions
9
12
We have recently described the synthesis and biological
activity evaluation of modified D–O–E ring bearing a
afforded tetrapeptide 5. Treatment of 5 with BCl caused
3
deprotection of isopropyl ether, the tert-butyldimethyl-
silyl ether and the N-Boc function. Re-protection of
the primary amine by tert-butoxycarbonlyation fur-
nished the phenol 6 in 81% overall yield. The key
SNAr-based cycloetherification of 6 was performed in
DMSO (concentration of substrate: 0.05 M) in the pres-
ence of CsF at room temperature to provide two separa-
ble atropisomers 7 and 8 in 87% overall yield (ratio
1
0,11
NHCOR group at AA4 position.
As a logical
extension of this work, we report herein an efficient
synthesis of a modified carboxylate-binding pocket of
vancomycin (Fig. 3, generic structure 2) in which the
fourth amino acid was replaced by an a-hydroxy-b-
amino acid and demonstrate that both the structure
of the macrocycle and the presence of a lipidated
aminoglucose are important for anti-VRE activity.
We also document that compound 2f can serve as a
useful template, to a certain degree even more effective-
ly than the entire glycopeptide framework, in searching
1
3
7/8 = 3/1). The absolute configuration of the planar
4
1
chirality of 7 and 8 was deduced by NOE studies.
Concurrently, starting from (2R,3R) methyl 2-tert-
0
0
butyldimethylsilyoxy-3-amino-3-(3 ,5 -diisopropyloxy-
OMe
2
O N
OMe
D
OMe
D
R
HO
O
O
HO
O
O
HO
O
O
O
D
E
E
E
R
OH
O
O
O
H
O
H
N
NH .HCl
2
H
N
NH
2
.HCl
CH
CH3
N
NH
2
.HCl
CH3
CH3
N
N
HO
N
N
HO
N
N
H
O
H
H
O
H
H
H
OH
CH
3
O
OH
3
OH
CH
3
2
a, R = NO2
2c, R = NO2
2d, R = C11H23CONH
2b, R = C11H23CONH
2e
OMe
D
OR
O
O
HO
O
O
E
D
E
2
O N
O N
2
O
O N
O
2
O
O
O
H
H
2
NH . HCl
N
NH . HCl
2
N
N
H
N
H
HO
N
H
HO
N
O
H
O
OH
OH
2
g, R = H
2f
2h, R = Me
HO
OH
OMe
D
O
NH
2
.TFA
HO
HO
O
HO
HO
O
O
O
O
O
O N
2
NH
E
O
O
2
N
O
NH
NH
O
O
H
N
O
HN
O
O
O
NH .HCl
2
N
HO
N
H
H
O
O
NH
OH
OH
O N
HO
2
2i
2j
HO
OMe
OH
HO
HO
O
OMe
D
O
O
HO
HO
O
O
O
E
O
D
NH
O
2
N
E
O N
O
2
NH
O
O
O
O
O
O
H
N
H
NH .HCl
2
N
2
NH .TFA
O
N
HO
N
N
N
N
H
O
H
O
H
H
O
H
OH
OH
NH
N
N
H
2k
2l
Figure 4. Structures of macrocycles.

Y. Jia et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4594–4599
4597
0
4
-methoxyphenyl)propionate 9, the macrocycle 10 was
H-bond following the vancomycin/N-Ac-D-Ala-D-Ala
binding model.
synthesized following the same synthetic scheme as de-
tailed for 7 and 8. From compounds 7, 8 and 10, a series
of derivatives were synthesized and their structures are
enlisted in Figure 4. While most of these compounds
have been prepared without event, the access to com-
pound 2l was more demanding and was detailed in
Scheme 2. Glycosylation of phenol was best realized
with the freshly prepared N-acyl glucosaminyl bromide
Minimum inhibitory concentrations for compounds 2a–
l as well as reference compounds: vancomycin and tei-
coplanin, are measured using a standard microdilution
assay and part of these results are summarized in Table
1. Regardless of the absolute configuration of the sec-
ondary alcohol (2a vs 2f), the planar chirality (2a vs
2c and 2b vs 2d) of the cyclophane, macrocycles 2a–f
were inactive against both vancomycin-sensitive and
vancomycin-resistant enterococci (VRE), with MICs
being higher than 256 mg/mg (data not shown). The
introduction of a hydrophobic chain at the E-ring did
not improve the activities of these compounds neither
1
5
(
11) under mild phase transfer conditions. Saponifica-
tion of 12 followed by coupling with polyamine (14) fur-
nished 15, which upon N-deprotection under mild acidic
conditions provided 2l in good overall yield. Compound
2
l was designed with the hope to introduce an additional
(
2a vs 2b and 2c vs 2d). Upon arylation of the free phe-
nol of the D-ring, weak antibiotic activities against VRE
were observed for compounds 2g and h, but remained
insignificant. On the other hand, the O-glycosylated
derivatives of 2a and f displayed interesting and
disparate results. While compound 2i remained inactive,
2j and k became active against VRE. Furthermore,
compound 2l having an elongated peptide chain at the
C-terminal displayed a broad spectrum of activity
against both vancomycin-sensitive (S. aureus) and resis-
tant-strains.
1
0
AcO
NH
AcO
AcO
O
a
O
Br
1
1
11 23
C H
AcO
OCH
3
AcO
AcO
O
O
O
O
NH
2
O N
C H
11 23
O
O
O
H
NHBoc
From these preliminary structure–activity relationship
studies, we assumed that both the structure of the mac-
rocycle (carrier) and the hydrophobic substituent con-
tributed to the activity of compounds 2k and 2l.
Glycosylation of 2a with a lipidated aminoglucose did
N
N
H
MeO
N
H
O
OH
1
0
12
not provide the active compound. On the other hand,
2f became active against VRE only upon attachment
b
HO
OCH3
of the lipidated aminoglucose. Both phenoxy group
can be served as anchoring points for the lipidated
aminoglucose leading to active compounds (2j and k).
Attaching a polyamide chain to the C-terminal of 2k
improved significantly its activity against vancomycin-
sensitive strains, although its potency against VRE
remained almost unchanged.
HO
HO
O
O
O
O
NH
O N
2
C11H23
O
O
O
H
N
NHBoc
N
HO
N
H
H
O
OH
13
O
O
NH
2
The very interesting anti-VRE activity of macrocycles
2k and l is intriguing. Indeed in vitro, it is more active
N
NH
N
H
c
against VRE than most of the vancomycin and teicopl-
anin derivatives reported to date. The generic structure 2
was designed with the hope to restore the missing hydro-
gen bond with the D-Ala-D-lact depsipeptide by switch-
ing the amide carbonyl (hydrogen-bond acceptor) of
vancomcyinÕs fourth amino acid into a hydroxy group
1
4
HO
OMe
HO
O
O
O
HO
O
NH
O
2
N
(hydrogen-bond donor). However, attempt to measure
O
H
N
O
O
O
H
the binding affinity between 2k and N-Ac-D-Ala-D-Ala
as well as 2k and N-Ac-D-Ala-D-lactate by either UV
absorption technique or by NMR titration (in DMSO)
failed to provide any exploitable results due most prob-
ably to the low receptor–substrate affinities. Overall and
in accord with Kahne and co-workers seminal contribu-
N
NHBoc
N
N
H
N
N
N
O
H
H
H
OH
O
15
d
8
,16,17
tion,
we hypothesized that compounds 2k and 2l
2l
might have a direct interaction with proteins critical
for VRE cell-wall biosynthesis. The role of the lipidated
aminoglucose may be attributed to its ability to anchor
the molecule to membrane in the vicinity of both lipid II
and the trans-glycosylases, blocking consequently more
Scheme 2. Synthesis of compound 2l. Reagents and conditions: (a) 11,
0% aqueous Na CO –CH Cl (1:1), (n-Bu) NHSO , room tempera-
ture, 76%; (b) LiOH, THF–H
O (3:1), 0 °C, 62%; (c) 14, EDC, HOBT,
CH Cl , room temperature, 25%; (d) CF CO H, CH Cl
, 0 °C, 75%.
1
2
3
2
2
4
4
2
2
2
3
2
2
2

4598
Y. Jia et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4594–4599
a
Table 1. MICs (mg/mL) of macrocycles 2g–l and reference compounds
Entry
Microorganism
2a
2f
2g
2h
2i
2j
2k
2l
Teico
Vanco
1
2
3
4
5
6
7
8
9
819 S. aureus Smith MSSA
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>1024
>128
>128
64
>128
>128
16
>128
>128
>128
>128
>128
>128
32
>128
>128
32
512
128
128
256
—
64
32
32
32
8
256
32
32
16
—
16
8
1
1
613 S. aureus clin. isolate Met-R
3797 S.aureus clin. isolate VISA
3798 S. aureus clin. isolate VISA
1400 S. aureus clin. isolate Met-R
147 S. epidermidis ATCC 12228
49 S. pyogenes C203
1
16
1
8
>128
>128
>128
64
>128
128
128
16
>128
>128
>128
32
4
8
1
1
2
1
60125
60.125
>128
60.125
128
60125
2
1139 E. faecalis teico–vanco-sensitive
2981 E. faecalis clin. Isolate Van-A
559 E. faecalis (isogenic of L 560)
560 E. faecalis Van-A
>128
—
64
64
>128
>128
>128
>128
>128
>128
>128
32
32
32
16
8
—
—
>128
1
10
11
12
13
14
16
16
8
64
8
64
8
>128
2
568 E. faecium (isogenic of L569)
569 E. faecium clin. isolate Van-A
2215 E. faecium clin. isolate Van-A
>128
>128
—
128
128
—
64
32
32
16
8
60.125
>128
>128
32
>128
>128
—
32
a
MICs = minimum inhibitory concentrations.
efficiently the last stages of peptidoglycan assembly.
Importantly, such a hydrophobic effect seems to be spe-
cific as no beneficial effect is observed when the same ali-
phatic chain was introduced to E-ring of the molecule
Int. Ed. 1999, 38, 2096; (d) S u¨ ssmuth, R. D. ChemBio-
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2
. Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed. 1999,
8, 1172.
3
(
2b and d). The efficiency of the inhibitory interaction
3
. (a) Walsh, C. T.; Fisher, S. L.; Park, I.-S.; Prahalad, M.;
Wu, Z. Chem. Biol. 1996, 3, 21; (b) Hubbard, B. K.;
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with trans-glycosylases will in turn depend on the struc-
ture of the carrier, in our case, the 16-membered macro-
cycle. The macrocycle 2f with an external R-configured
secondary alcohol being more active than 2a, we sur-
mised that either the hydroxy group was involved in
the interaction with the trans-glycosylases or the stereo-
chemistry of the secondary alcohol modified the overall
conformation of the molecule making it more or less
efficient in interacting with the enzymes.
4
6
. Malabarba, A.; Nicas, T. I.; Thompson, R. C. Med. Res.
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7
. For selected examples of controlled degradation of glyco-
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In conclusion, we demonstrated in the present study that
a combination of a modified binding pocket with a suit-
ably positioned hydrophobic chain constitutes a viable
approach in the searching for compound active against
VRE and that these two structural elements contribute
synergistically the activity of a given compound. While
the positive hydrophobic effect is well known in the field,
we demonstrated that a simple macrocycle (2f) can serve
as a useful template for the development of agents active
against VRE as well as against vancomycin-sensitive
strains. We also documented that the stereochemistry
of the peptide backbone can significantly influence the
efficiency of the macrocycle as a carrier of the hydropho-
bic chain, which is understandable if the enzyme–sub-
strate interaction was to be considered.
1
997, 50, 70; (e) Malabarba, A.; Nicas, T. I.; Ciabatti, R.
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Acknowledgments
Financial support from Vicuron Pharmaceuticals (Post-
Doctoral Fellowships to Drs. Y. Jia, N. Ma and Z. Liu),
CONACYT, Mexico (Pr. E. Gonzalez-Zamora) and
CNRS is gratefully acknowledged.
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