Design and synthesis of 16-membered cyclopeptides active against vancomycin-resistant Enterococci (VRE)

Article abstract of DOI:10.2533/chimia.2013.916

The design, synthesis and antibiotic activities of the modified carboxylate binding pocket (D-O-E ring) of vancomycin (1) are summarized in this short account. The preliminary structure-activity relationship (SAR) studies indicated that both the structure

Full text of DOI:10.2533/chimia.2013.916

916 CHIMIA 2013, 67, Nr. 12
doi:10.2533/chimia.2013.916
PePtide Science in Switzerland
Chimia 67 (2013) 916–920 © Schweizerische Chemische Gesellschaft
Design and Synthesis of 16-Membered
Cyclopeptides Active Against
Vancomycin-resistant Enterococci (VRE)
Jieping Zhu*
Abstract: The design, synthesis and antibiotic activities of the modified carboxylate binding pocket (D-O-E ring)
of vancomycin (1) are summarized in this short account. The preliminary structure–activity relationship (SAR)
studies indicated that both the structure of the 16-membered macrocycle including the absolute configuration
of the modified AA4 unit and the presence of a hydrophobic chain were important for anti-VRE activities of these
series of synthetic analogues. Compounds 9c and 9d in which the central amino acid (AA4) of vancomycin was
replaced by (2R,3R)-α-hydroxy-β-amino acid and (2R,3R)-α,β-diamino acid, respectively, were found to be
useful templates in searching for active compounds against both vancomycin-sensitive and -resistant strains.
Two of these compounds (16d and 16n) having an elongated peptide chain at the C-terminal were found to be
active against a broad spectrum of both vancomycin-sensitive (Staphylococcus aureus) and -resistant strains
(E. faecium, E. faecalis).
Keywords: Antibiotic · Cyclopeptide · Macrocycle · SNAr reaction · Vancomycin
to methicillin-resistant Staphylococcus
aureus (MRSA) and other Gram-positive
organisms in patients allergic to β-lactam
antibiotics.[1] Unfortunately, resistance to
vancomycin appeared in the late 1980s and
1. Introduction
HO
NH2
OH
O
OH
Vancomycin (1) is a glycosylated
non-ribosomal peptide produced by the
Actinobacteria species Amycoplatopsis
O
OH
O
O
Cl
the frequency of resistance has increased
orientalis. The side chain of haptapep-
O
O
significantly over the past decades. Since
vancomycin-resistant enterococci (VRE)
carries resistance to virtually all other
known antibiotics, it represents a serious
tide aglycon was oxidatively linked via
two endo aryl-aryl ether and one endo
aryl-aryl bond creating an interconnected
strained tricyclic ring system.[1] It is a rare
halogen-containing natural product that
contains three elements of chirality: cen-
tral chirality, planar chirality and axial
chirality. Isolated in 1953 by scientists at
Eli Lilly, vancomycin was marketed in
1958 long before its structure and mode
of action had been fully determined. For
many years since its initial use, vancomy-
cin was one of the few antibiotics of last
resort for the treatment of infections due
C
D
E
OH
O
HO
Cl
O
O
H2
N
H
N
O
N
H
N
H
N
O
N
H
H
O
O
NH
threat to public health.[2] To make things
B
NH2
O2C
even worse, in vitro experiment has shown
1
A
H
N
O
O
OH
OH
that such resistance is transferable to
Staphylococci.[3]
N
H
O
HO
O
Vancomycin acts by binding to d-al-
anyl-d-alanine (d-Ala-d-Ala) of the pep-
tidoglycan precursors, blocking therefore
the final stages of the peptidoglycan syn-
Fig. 1. Hydrogen bonding network of vancomy-
cin (1) and N-Ac-d-Ala-d-Ala.
thesis. This mode of action takes place at
the cell surface avoiding therefore some tance provided an incentive for the discov-
common cellular resistance mechanisms ery and development of new antibiotics that
such as efflux pumps and bacterial modi- would be active against both sensitive and
fication. Bacteria become resistant to van- resistant strains of enterococci. Since van-
comycin by reprogramming of the pepti- comycin is readily available by fermenta-
doglycan termini from d-Ala-d-Ala dipep- tion technology, many efforts have been
tide to d-Ala-d-Lact (d-alanyl-d-lactate) dedicated to the structural modification
depsipeptide that binds only weakly to the of natural glycopeptides. Extensive struc-
drug.[4] In fact, in vitro binding studies have ture–activity relationship (SAR) studies of
shown that the affinity of vancomycin for semisynthetic derivatives led to the devel-
N-Ac-d-Ala-d-Lact is about 1000 times opment of one marketed drug (telavancin,
weaker than its affinity for N-Ac-d-Ala-d- 2)[6] and two drug candidates, oritavancin
Ala, due to one missing hydrogen bond and (LY333328, 3)[7] and the dalbavancin (4,
the ground state repulsion between the two Fig. 2).[8] In addition, other structurally un-
oxygen lone-pairs in the former complex. related compounds such as Synercid (a 3/7
The reduced binding affinity translated
mixture of quinopristin 5 and dalfopristin
*Correspondence: Prof. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fédérale de Lausanne
EPFL-SB-ISIC-LSPN, CH-1015 Lausanne
E-mail: jieping.zhu@epfl.ch
into about 1000-fold reduced sensitivity of 6),[9] linezolide (7),[10] and daptomycin (8,
vancomycin-resistant bacteria to this drug Fig. 3)[11] have been developed and mar-
(Fig. 1).[5]
keted for the treatment of vancomycin-re-
The emergence of vancomycin resis- sistant infections.

PePtide Science in Switzerland
CHIMIA 2013, 67, Nr. 12 917
Fig. 3. Drugs active
against VRE.
Synercid: a3/7 mixture of quin
opristin and dalfopristin
N
H
O
N
Me
N
O
H
2
H
O
OH
O
N
N
N
OH
OH
N
H
O
O
O
O
O
H
O
N
HN
O
O
N
S
H
N
O
O
N
H N
2
O
O
O
O
O
HO
O
O S
2
Cl
O
NH
O
O
O
Cl
O
O
H
OH
H
N
H
Me N
2
H
O
H
O
O
NH2CH3
N
N
N
O
5 Quino
pristin
6 Dalfopristin
N
N
O
H
O
O
H
NH2
N
H
O
N 2
H
O
O
O
O
H
N
O
H
O
O
H
N
2 Telav
ancin
O
H2NO
C
H
P(O)(OH)2
H
H
N
Me
O
O
O
H
HN
Me
N
CO2H
N
N
HC1 H
Cl
0 21
OH
N
H
N
O
O
N
H
H
O
HN
HO
O
O
O
F
NH
OH
H
O
O
CO2H
N
HO2C
HO2C
OH
N
O
O
O
NH
O
H
H
O
N
N
H
H N
2
N
O
N
O
HO
H
H
Cl
Me O
O
O
O
Cl
8 Daptomycin
7 Linezolid
NH2
O
O
H
H
H
H
O
H
N
O
O
O
NH2CH3
N
N
O
N
N
O
H
O
H
NH
O
not impossible, to chemically modify the
carboxylate-binding pocket (D-O-E ring)
of natural glycopeptides to include new
hydrogen bond contacts with the modified
peptidoglycan termini.[17]
sugar moiety at the appropriate position
of the modified D-O-E ring. It is known
that introducing a hydrophobic chain into
the sugar part of vancomycin can produce
compounds that are capable of reversing
the drug-resistance (cf telavancin (2) and
NH2
O
OH
O
H
3 Oritavancin (LY333328)
H
O
O
HN
H
O
O
H
O
O
O
HOOC
O
the oritavancin (3), Fig. 2). This is sur-
H
O
Cl
O
O
H
N
H
H
3. Synthesis of the Modified
Carboxylate-binding Pocket
prising at first glance since this subunit is
not directly involved in substrate binding.
Indeed, in vitro activity of oritavancin did
not parallel with its binding affinity with
H
N
N
N
N
H
H
O
O
O
Cl
O
N
H
H
N
N
HO
NHMe
Synthesis of 16-membered macrocy-
O
OH
O
O
H
O
cles 9a and 9b was accomplished as shown
d-Ala-d-Lact. Two theories have been pro-
O
HO
OH
H
O
in Scheme 1. Coupling of the suitably pro-
posed to account for oritavancin’s bioactiv-
ity against VRE.[1] Williams hypothesized
that the presence of a lipid chain in the
disaccharide part of vancomycin enhanced
avidity for d-Ala-d-Lact by facilitating
membrane anchoring and/or by promot-
ing dimerization.[14] Kahne advanced that
oritavancin acts against VRE by direct in-
teraction with the transglycosylase without
O
H
OH
4 Dalbavancin
tected (2S,3R)-α-hydroxy-β-amino acid
10[18] with tripeptide 11 (EDC, HOBt) af-
Fig. 2. Semi-synthetic glycopeptide antibiotics.
forded tetrapeptide 12 in excellent yield.
Treatment of 12 with BCl led to the si-
multaneous deprotection of3 the isopropyl
ether, the tert-butyldimethylsilyl ether and
the N-Boc function. Re-protection of the
terminal amine in the form of N-Boc fur-
nished phenol 13 in 81% yield over two
2. Molecule Design Aiming at
Reversing Vancomycin Resistance
substrate binding.[15] It is worth noting that
The 16-membered D-O-E ring is the
steps. The key intramolecular SNAr-based
cycloetherification of 13 was best per-
structural modification of the vancomy-
cin-type glycopeptide is particularly chal-
lenging due to its structure complexity.[16]
binding pocket of vancomycin since at-
tractive electrostatic interactions (charged
ammonium salt and carboxylate) and four
out of five H-bonds formed between van-
comycin and N-Ac-D-Ala-D-Ala reside in
the peptide backbone of this m,p-cyclo-
formed in DMSO (c 0.01 M) in the pres-
ence of CsF at room temperature.[19] Under
Therefore, most of the chemical transfor-
these conditions, the desired 16-membered
m,p-cyclophane was formed as a mixture
of two separable atropisomers 9a and 9b
mations reported to date have been local-
ized on the periphery of the macrocycles
relying on simple chemical reactions.
phane. To evaluate the minimum struc-
in 72% overall yield (ratio 9a/9b = 3/1).
Indeed, it would be extremely difficult, if
tural requirement of vancomycin against
both sensitive and resistant strains of en-
terococci, we became interested in the
general structure 9[12] (Fig. 4) in which
the carboxylate binding pocket of vanco-
mycin is modified following two guide-
lines: a) replacing the carbonyl group of
central amino acid (AA4) of vancomycin
by OHCHCOR or PHNCHCOR. It was
expected that this structural modification
can, a priori, lead to a modified D-O-E
ring with increased affinity toward N-Ac-
d-Ala-d-Lact by restoring the missing
hydrogen bond and by avoiding the unfa-
vorable electronic repulsion found in the
Fig. 4. Modified
vancomycin carbox-
ylate-binding pocket:
restoring the missing
H-bond with d-Ala-
d-Lact.
Glycosidation
acylation
Effect of planar chirality
and nature of substituents
OR4
Y
R3O
O
C-terminal
functionalizaiton
X
O
O
O
H
N
NH2
*
R2
N
H
N
H
R5
O
WH
OH or NHR1 as
H-bond donnor
9
vancomycin/d-Ala-d-Lact
b) introducing a hydrophobic chain or a
complex;[13]
Effect of stereochemistry

918 CHIMIA 2013, 67, Nr. 12
PePtide Science in Switzerland
Scheme 1. Synthesis
of 16-membered
The linear tetrapeptide 14 containing a
(2R,3R)-α-hydroxy-β-amino acid unit was
synthesized following the same synthetic
route as described for 13. Interestingly,
intramolecular SNAr reaction of 14 (CsF,
DMSO, 25 °C, 16 h) afforded only one at-
ropdiastereomer 9c in 65% yield (Eqn. 1,
F
N 2
O
O
Me
OiPr
O
Me
OiPr
F
O
Pri
O
Pri
N 2
O
macrocycles 9a and
9b: a) EDC, HOBt,
CH2Cl2, 25 °C, 12 h,
89%; b) BCl3, CH2Cl2,
0 °C, 1 h; then MeOH;
c) Boc2O, NaHCO3,
dioxane/H2O (2/1),
25 °C, 12 h, 81% (2
a
O
O
+
H
N
O
O
O
H
N
H
O
NHBoc
NHBoc
H
O
N
TBSO
Me
O
N
N
H
N 2
CO2Me
H
O
H
TB
S
O
10
1
1
12
OMe
F
Y
OMe
HO
O
Scheme 2). The high diastereoselectivity
observed in the cycloetherification of 14
H
O
OH
NO2
X
b,c
d
O
O
O
Hc
O
O
O
H
H
N
N
NH
Boc steps); d) CsF, DMSO, relative to13wasdifficulttorationalize,but
NHBoc
N
MeO
N
Me
O
N
N
H
H
H
H
H
O
25 °C, 16 h, 72%.
O
O
wasinaccordwiththepreviousobservation
O
H
that the atropdiastereoselectivity of this
9
a X=N 2
O ,Y=H
13
reaction is highly substrate-dependent.[20]
9
b X=H,Y=N 2
O
The macrocycle 9d having an amino func-
tion was similarly synthesized (Eqn. 2,
Scheme 2). It is worth noting that in the
latter case, the alternative cyclization mode
Scheme 2. Synthesis
of 16-membered
macrocycles 9c and
9d: a) CsF, DMF, 25
°C, 16 h.
O
Me
O
F
O
Me
H
O
HO
OH
with primary amine acting as nucleophile
N 2
O
O N
2
a
was not observed.[21]
O
O
O
eq 1
O
O
O
H
N
H
NHBoc
N
N Boc
H
From compounds 9a–9d, a series of
derivatives 16 were synthesized and some
N
MeO
N
MeO
N
N
H
H
H
H
H
O
O
O
65%
OH
representative examples are shown in
1
4
9C
F
O
Me
O
Fig. 5.
O
Me
H
O
HO
OH
The synthesis of compound 16d is rep-
N 2
O
O N
2
a
resentative and is summarized in Scheme 3.
Selective glycosylation of phenol was real-
ized by reaction of 9c with freshly prepared
3,4,6-tri-O-acetyl-2-N-lauroyl-2-amino-2-
deoxy-α-d-glucopyranosyl bromide (17)
O
O
O
O
O
O
eq 2
H
N
H
N
H
O
NHBoc
NHBoc
N
H
MeO
N
Me
O
H N
N
N
H
85%
H
O
H N
2
2
15
9D
O
H
O
H
H
O
O
O
Me
H
O
O
H
O
O
O
Me
O
O
H
O
N
H
O
O
O
N
H
C H
O
11 2
3
O N
2
C H
O
O
11 2
3
O N
O
O
O
2
H
N
O N
2
.
HCl
NH2
O
O
O
O N
H
N
2
O
H
Cl
H
O
N
N
.
H
O N
2
N 2
O
O
H
H
H
O
N
N
H
N
OH
O
.
TFA
H
H
H
N 2
Ph
OH
O
H
O
N
N
Ph
H
H
O
16b
H
O
Ph
16a
16c
O
Me
OR
Y
O
H
O
Me
H
O
O
O
O
H
O
O
O
O
HO
X
O
O N
2
O
N
H
O
11 2
O N
2
O N
H
Cl
O
O
O
O
2
C H
H
H
3
.
NH2
.
O
O
O
H
Cl
N
N 2
H
N
TFA
H
.
NH2
H
O
N
N
H
H
O
O
N
N
N
H
H
Ph
H
N
N
N
N
O
NH
O
NH
O
H
O
H
H
R
O
H
O
O
Ph
C H
C H
11 23
11 2
3
N
H
N
H
16e X=N 2
16f X=H,Y=N 2
16g X=Y=H, R=Ph
16h X=NO2,Y=H, R=CONH2
O ,Y=H, R=Ph
16i R=H
16j R= Me
O ,R=Ph
16d
O
H
O
Me
O
H
H
O
O
HO
O
OMe
H
O
H
O
O
N
H
O
O
O
H
O
O N
2
C H
O
NH
11 2
3
O
TFA
O
O
O
O N
2
H
N
C H
.
NH2
O
O
11 2
3
H
Cl
.
H
O
O
O
H
N
N
N
N
N
N 2
H
O
H
H
O N
O
2
O
N
H
O
H
O
N
N
O N
2
O
Ph
O
O
TFA
.
NH2
H
H
H
O
NH
O
NH
N
Ph
C H
11 2
3
N
H
H
O
N
N
R
H
H
O
NH
O
Ph
16l R=C 3
16m R=C H
11 23
H
16n
C H
11 2
16k
3
Fig. 5. Structures of macrocycles 16a–16n.

PePtide Science in Switzerland
CHIMIA 2013, 67, Nr. 12 919
inhibited the growth of E faecalis Van A at
O
Me
O
O
Ac
O
Me
O
reasonably low MIC values (Table 1, en-
try 1). More interestingly, O-glycosylated
derivatives 16b and especially 16c dis-
played potent activities against VRE (en-
tries 2, 3). Furthermore, compound 16d
having an elongated peptide chain at the
C-terminal was active not only against
VRE, but also against vancomycin-sensi-
H
O
Ac
O
O
O
O
O
Ac
Ac
O
O N
2
N
H
O
Ac
O
O N
2
O
O
O
O
b
a
Ac
O
C H
11 23
H
N
O
O
NHBoc
O
N
H
H
N
N
MeO
N
Br
N
H
Boc
C H
11 23
H
H
Me
O
N
N
O
OH
H
H
O
H
O
9c
17
18
O
O
H
O
H
OMe
OMe
H
O
H
O
O
O
O
H
O
O
O
H
O
O
N
H
O
NH
tive Staphylococcus aureus (entry 4).
O N
2
c
O N
2
O
C H
11 23
C H
11 23
O
O
O
O
O
O
H
N
The bioactivity of compounds derived
from 9d depended very much on the na-
ture of the functional group attached to the
H
H
N
NHBoc 20
N
NHBoc
HO
N
N
N
N
N
N
N
H
H
H
H
H
H
O
H
O
O
O
H
O
1
9
21
Cα amino group. Thus, neither the parent
OH
O
Me
H
O
O
compounds, nor its N,N-dimethylated de-
rivative (structure not shown), were active
against VRE. Whereas N-acetyl derivative
16l is poorly active (entry 12), the lauroyl
(N-dodecanoyl) amides 16e and 16f dis-
played interesting activities against VRE
(entries 5, 6), indicating the important
role of a hydrophobic chain. Compound
16h (entry 8) having an asparagine unit in
the i+2 position, was slightly less active
than 16e having a phenylalanine (entry
O
O
H
O
O
NH
O
H
O N
2
N
C H
11 23
N
N
NH2
d
O
O
O
O
H
H
H
O
N
N
NH2
N
N
H
N
N
N
H
H
H
O
OH
O
20
16d
Scheme 3. Synthesis of compound 16d: a) (nBu)4NHSO4, 10% aqueous Na2CO3/CH2Cl2 (1/1),
25 °C, 4 h, 76%; b) LiOH, THF/H2O (3:1), 0 °C, 4 h, 62%; c) 20, EDC, HOBt, CH2Cl2, 25 °C, 12 h,
34%; d) TFA, CH2Cl2, 0 °C, 1 h, 75%.
under mild phase-transfer conditions (10% cin-sensitive and -resistant strains, regard- 5). Planar chirality plays only a minor ef-
aqueous Na2CO , nBu NHSO4, CH Cl2, less of the absolute configuration of the fect on the bioactivity since the potency of
rt).[22] Treatment3 of 184 with lithium2 hy-
planar chirality of the m,p-cyclophane. On 16e and 16f is comparable (entries 5 vs 6).
droxide (LiOH, THF-H O) removed both
the other hand, compounds derived from However, the presence of the nitro group
the methyl ester and three2 acetate functions 9c with an external R-configured second- at the E ring is beneficial since 16g, be-
to provide the hydroxy acid 19. Coupling ary hydroxy group displayed interesting ing devoid of this group, was much less
of 19 with amine 20 (EDC, HOBt, CH Cl2) bioactivities. The parent compound was
active (entry 7). The activity against VRE
provided 21, which upon N-deprotec2tion, inactive, but its O-arylated derivatives 16a remained essentially unchanged upon ben-
afforded the desired compound 16d in 75%
yield. Compound 16d having an elongated
C-terminal was designed with the aim to
Table 1. MICs (mg/mL) of selected macrocycles and reference compoundsa
introduce an additional hydrogen bond
with the peptidoglycan termini (Fig. 6).
Entry Cmpd.
E. faecium
sensitiveb resistantc sensitived
E. faecalis
resistante
Staph.
aureusf
>128
>128
128
1
2
3
4
5
6
7
16a
16b
16c
16d
16e
16f
128
128
64
128
128
32
8
16
64
8
16
32
8
4. Antibiotic Activities of Synthetic
Compounds 16
Minimum inhibitory concentrations
for these compounds as well as reference
compounds (vancomycin, teicoplanin,
Synercid®, and daptomycin) are measured
using a standard microdilution assay.[23]
16
16
4
8
32
128
128
>128
8
4
64
16
128
8
8
>128
>128
16g
128
128
Selected results are summarized in Table 1.
8
16h
>128
128
128
>128
1024
128
8
128
128
128
>128
1024
32
16
8
64
Compounds derived from 9a and 9b
having an external S-configured secondary
hydroxy group (structure not shown) were
found to be inactive against both vancomy-
9
16i
4
4
>128
>128
10
11
12
13
14
15
16
17
18
16j
4
2
16k
8
8
16l
64
64
8
>1024
OMe
HO
O
O
16m
8
>256
O2N
O
16n
8
8
8
16
1
O
H
N
NH2
N
N
N
H
N
H
vancomycin
teicoplanin
synercid
daptomycin
2
>128
>128
4
1
0.125
4
>128
64
8
H
O
N
O
H
O
O
Ph
O
0.5
4
1
N
C11H23
N
H
H
8 1
2
O
O
32
16
4
8
N
O
H
O
aMICs = Minimum Inhibitory Concentrations; bBacterial strain L568 (isogenic of L569); Bacterial
strain L2215 clin. isolate Van-A; dBacterial strain L559 (isogenic of L560); eBacterial strain L560;
fBacterial strain L613 clin. isolate Met-R.
c
Fig. 6. Hypothetic H-bond network between
16d and N-Ac-d-Ala-d-Lact.

920 CHIMIA 2013, 67, Nr. 12
PePtide Science in Switzerland
Kahne, Science 1999, 284, 507; b) U. S. Eggert,
N. Ruiz, B. V. Falcone, A. A. Branstrom, R.
C. Goldman, T. J. Silhavy, D. Kahne, Science
2001, 294, 361.
zylation and glucosylation of the phenol acid as the C-terminal component of the
function. As in the case of the OH series, 16-membered cyclopeptide; b) the pres-
compound 16n (entry 14) having an elon- ence of a hydrophobic chain or lipidated
gated peptide chain at the C-terminal is aminoglucose at the appropriate position.
[16] Modification of vancomycin type glycopeptide
antibiotics by reprogramming the biosynthesis
active against a broad spectrum of both The SAR studies indicated that a combi-
pathway, see: a) S. Weist, C. Kittel, D. Bischoff,
B. Bister, V. Pfeifer, G. J. Nicholson, W.
Wohlleben, R. D. Süssmuth, J. Am. Chem.
Soc. 2004, 126, 5942; b) P. C. Schmartz, K.
vancomycin-sensitive
aureus) and -resistant strains.
(Staphylococcus nation of a modified binding pocket with
a suitably positioned hydrophobic chain
It is noteworthy that some of these constitutes a viable approach in the search
simple macrocycles are more active, in for compounds active against VRE.
vitro, against VRE than most of the vanco-
Wölfel, K. Zerbe, E. Gad, E. S. El Tamany, H.
K. Ibrahim, K. Abou-Hadeed, J. A. Robinson,
Angew. Chem. Int. Ed. 2012, 51, 11468.
Received: September 14, 2013
mycin and teicoplanin derivatives reported
in the literature and are almost as active
as Synercid®, a clinically used drug for
[17] By total synthesis, see: J. Xie, J. G. Pierce, R.
C. James, A. Okano, D. L. Boger, J. Am. Chem.
Soc. 2011, 133, 13946.
[1] a) D. H. Williams, Nat. Prod. Report 1996, 469;
b) J. Zhu, Expert. Opin. Ther. Pat. 1999, 9, 1005;
[18] Z. Liu, N. Ma, Y. Jia, M. Bois-Choussy, A.
combating VRE. The generic structure 9
c) K. C. Nicolaou, C. N. C. Boddy, S. Bräse, N.
Winssinger, Angew. Chem. Int. Ed. 1999, 38,
2096; d) R. D. Süssmuth, ChemBioChem. 2002,
3, 295; e) D. Kahne, C. Leimkuhler, W. Lu, C.
Malabarba, J. Zhu, J. Org. Chem. 2005, 70,
was originally designed with the hope to
restore the missing hydrogen bond with
the d-Ala-d-lact depsipeptide by switch-
ing the amide carbonyl (hydrogen-bond
acceptor) of vancomcyin’s fourth amino
acid into a hydroxy group (hydrogen-bond
donor). Although interesting activities
against VRE were indeed found for some
of these derivatives, substrate binding can-
not account for their antibiotic activities
for the following reasons: a) attempts to
measure the binding affinity between 16c
and N-Ac-d-Ala-d-Ala as well as 16c and
N-Ac-d-Ala-d-Lact by either UV absorp-
tion or by NMR titration (in DMSO) failed
to provide any exploitable results, most
probably due to the low receptor–substrate
affinities; b) the observed hydrophobic
effect is apparently not due to the simple
increase of effective molarity resulting
from membrane anchoring. Rather it was
specific, as no beneficial effect was ob-
served when the same aliphatic chain was
introduced to the E-ring of the molecule
2847.
[19] a) R. Beugelmans, G. P. Singh, M. Bois-
Choussy, J. Chastanet, J. Zhu, J. Org. Chem.
T. Walsh, Chem. Rev. 2005, 105, 425.
1994, 59, 5535; b) b) J. Zhu, R. Beugelmans,
[2] B. K Hubbard, C. T. Walsh, Angew. Chem. Int.
S. Bourdet, J. Chastanet, G. Roussi, J. Org.
Ed. 2003, 42, 730.
[3] M. N. Swartz, Proc. Natl. Acad. Sci. USA 1994,
91, 2420.
[4] D. H. Williams, B. Bardsley, Angew. Chem. Int.
Ed. 1999, 38, 1172.
Chem. 1995, 60, 6389; c) J. Zhu, J. P. Bouillon,
G. P. Singh, J. Chastanet, R. Beugelmans,
Tetrahedron Lett. 1995, 36, 7081; d) R.
Beugelmans, A. Bigot, M. Bois-Choussy, J.
Zhu, J. Org. Chem. 1996, 61, 771; e) K. Burgess,
[5] a) R. K. Jain, J. Trias, J.A. Ellman, J. Am. Chem.
D. Lim, M. Bois-Choussy, J. Zhu, Tetrahedron
Soc. 2003, 125, 8740; b) C. C. McComas, B. M.
Crowley, D. L. Boger, J. Am. Chem. Soc. 2003,
125, 9314; c) J.-G. Lee, C. Sagui, C. Roland, J.
Am. Chem. Soc. 2004, 126, 8384; d) X. Jie, A.
Okano, J. G. Pierce, R. C. James, S. Stamm, C.
M. Crane, D. L. Boger, J. Am. Chem. Soc. 2012,
134, 1284.
Lett. 1997, 38, 3345; f) P. Cristau, J. P. Vors, J.
Zhu, Org. Lett. 2001, 3, 4079; g) P. Cristau, J.
P. Vors, J. Zhu, Tetrahedron 2003, 59, 7859; h)
P. Cristau, J. P. Vors, J. Zhu, Tetrahedron Lett.
2003, 44, 5575; i) M. Bois-Choussy, P. Cristau,
J. Zhu, Angew. Chem. Int. Ed. 2003, 42, 4238; j)
Y. Jia, M. Bois-Choussy, J. Zhu, Angew. Chem.
Int. Ed. 2008, 47, 4167; k) Z. H. Wang, M. Bois-
Choussy, Y. Jia, J. Zhu, Angew. Chem. Int. Ed.
2010, 49, 2018; l) Q. Wang, J. Zhu, Chimia
2011, 65, 168.
[6] C. S. Lunde, S. R. Hartouni, J. W. Janc, M.
Mammen, P. P. Humphrey, B. M. Benton,
Antimicrob. Agents Chemother. 2009, 53, 3375.
[7] http://ir.themedicinescompany.com/phoenix.
zhtml?c=122204&p=irol-newsArticle
&id=1834647
[8] http://en.wikipedia.org/wiki/Dalbavancin
[9] B. Pavan, Curr. Opin. Investig. Drugs 2000, 1,
173.
[20] a) For temperature-controlled atropdiastereo-
selective cycloetherification, see: R. Beugel-
mans, M. Bois-Choussy, C. Vergne, J.-P.
Bouillon, J. Zhu, Chem. Commun. 1996,
1029; b) For designed substrate-controlled
atropdiastereoselective cycloetherification, see:
K. C. Nicolaou, C. N. C. Boddy, J. Am. Chem.
[10] M. R. Barbachyn, C. W. Ford, Angew. Chem.
Int. Ed. 2003, 42, 2010.
(structure not shown). This result can be
[11] R. H. Baltz, Curr. Opin. Chem. Biol. 2009, 13,
144.
Soc. 2002, 124, 10451; c) For an example of
enantioselective cycloetherification, see: G.
Islas-Gonzalez, M. Bois-Choussy, J. Zhu, Org.
Biomol. Chem. 2003, 1, 30; d) For an earlier
account, see: J. Zhu, Synlett 1997, 133.
better explained on the basis of a specific
interaction between the macrocycle and
the target enzymes. Overall and in accord
with Kahne’s observation,[15] we hypoth-
esize that these compounds might have a
direct interaction with proteins critical for
VRE cell-wall biosynthesis although a de-
tailed mechanism of action remains to be
investigated.
[12] a) N. Ma, Y. Jia, Z. Liu, E. Gonzalez-Zamora,
M. Bois-Choussy, A. Malabarba, C. Brunati, J.
Zhu, Bioorg. Med. Chem. Lett. 2005, 15, 743;
b) Y. Jia, E. Gonzalez-Zamora, N. Ma, Z. Liu,
M. Bois-Choussy, A. Malabarba, C. Brunati, J.
Zhu, Bioorg. Med. Chem. Lett. 2005, 15, 4594;
c) Y. Jia, M. Bois-Choussy, A. Malabarba, C.
Brunati, J. Zhu, J. Antibiot. 2006, 59, 543; d)
Y. Jia, N. Ma, Z. Liu, M. Bois-Choussy, E.
Gonzalez-Zamora, A. Malabarba, C. Brunati, J.
Zhu, Chem. Eur. J. 2006, 12, 5334.
[21] Synthesis of cyclopeptide alkaloids having an
endo aryl–alkyl ether bond by intramolecular
SNAr reaction, see: a) T.
Temal-Laïb, J.
Chastanet, J. Zhu, J. Am. Chem. Soc. 2002,
124, 583; b) P. Cristau, T. Temal-Laïb, M. Bois-
Choussy, M. T. Martin, J. P. Vors, J. Zhu, Chem.
Eur. J. 2005, 11, 2668.
In conclusion, a modified vancomycin
binding pocket (D-O-E ring) has been de-
[22] G. Islas-Gonzalez, J. Zhu, J. Org. Chem. 1999,
[13] M. Bois-Choussy, L. Neuville, R. Beugelmans,
J. Zhu, J. Org. Chem. 1996, 61, 9309.
64, 914.
[23] The antibiotic activities of these compounds
signed and synthesized. The key structural
[14] D. H. Williams, A. J. Maguire, W. Tsuzuki, M.
were measured by scientists at Vicuron
Pharmaceuticals, Italy Research Center.
features of this biaryl ether-containing
macrocycle are: a) the incorporation of
β-amino-α-hydroxy acid or α,β-diamino
S. Westwell, Science 1998, 280, 711.
[15] a) M. Ge, Z. Chen, H. R. Onishi, J. Kohler, L. L.
Silver, R. Kerns, S. Fukuzawa, C. Thompson, D.