Synthesis and in vitro evaluation of bisphosphonated glycopeptide prodrugs for the treatment of osteomyelitis

Article abstract of DOI:10.1016/j.bmcl.2010.01.006

As therapeutic agents of choice in the treatment of complicated infections, glycopeptide antibiotics are often preferentially used in cases of osteomyelitis, an infection located in bone and notoriously difficult to successfully manage. Yet frequent and heavy doses of these systemically administered antibiotics are conventionally prescribed to obtain higher antibiotic levels in the bone and reduce the high recurrence rates. Targeting antibiotics to the bone after systemic administration would present at least three potential advantages: (i) greater efficacy, by concentrating the therapeutic agent in bone; (ii) greater convenience, through a reduction in the frequency of administration; and (iii) greater safety, by reducing the levels of systemic drug exposure. We present here the design, synthesis and in vitro evaluation of eight prodrugs of the glycopeptide antibacterial agents vancomycin and oritavancin taking advantage of the affinity of the bisphosphonate group for bone for delivery to osseous tissues.

Full text of DOI:10.1016/j.bmcl.2010.01.006

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1355–1359
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and in vitro evaluation of bisphosphonated glycopeptide prodrugs
for the treatment of osteomyelitis
Kelly S. E. Tanaka , Evelyne Dietrich, Stéphane Ciblat à, Claude Métayer, Francis F. Arhin, Ingrid Sarmiento,
*
Gregory Moeck, Thomas R. Parr Jr., Adel Rafai Far
The Medicines Company, 7170 Avenue Frederick Banting, St. Laurent, Québec, Canada H4S 2A1
a r t i c l e i n f o
a b s t r a c t
Article history:
As therapeutic agents of choice in the treatment of complicated infections, glycopeptide antibiotics are
often preferentially used in cases of osteomyelitis, an infection located in bone and notoriously difficult
to successfully manage. Yet frequent and heavy doses of these systemically administered antibiotics are
conventionally prescribed to obtain higher antibiotic levels in the bone and reduce the high recurrence
rates. Targeting antibiotics to the bone after systemic administration would present at least three poten-
tial advantages: (i) greater efficacy, by concentrating the therapeutic agent in bone; (ii) greater conve-
nience, through a reduction in the frequency of administration; and (iii) greater safety, by reducing the
levels of systemic drug exposure. We present here the design, synthesis and in vitro evaluation of eight
prodrugs of the glycopeptide antibacterial agents vancomycin and oritavancin taking advantage of the
affinity of the bisphosphonate group for bone for delivery to osseous tissues.
Received 27 November 2009
Revised 29 December 2009
Accepted 4 January 2010
Available online 11 January 2010
Keywords:
Glycopeptides
Prodrugs
Osteomyelitis
Ó 2010 Elsevier Ltd. All rights reserved.
Osteomyelitis is an inflammatory process accompanied by bone
necrosis which results from an underlying microbial infection,1
primarily caused by gram-positive microorganisms.2 It is a chal-
lenging disease, routinely treated by a combination of surgical
debridement and a prolonged course of parenterally administered
high doses of antibiotics. It is characterized by frequent relapses3,4
and sometimes a need for amputations.5 None of the antibiotics
marketed in the United States have been approved for gram-posi-
tive osteomyelitis and treatments are devised through practice.
The difficulty in treating osteomyelitis is often attributed to the
sheltered environment provided by necrotic bone and the likely
quiescent state of bacteria found in such sequestra. Antibacterial
agents are therefore administered in large doses to provide a suffi-
cient level in the bone. In order to avoid the potential side effects
associated with the systemic administration of such large doses,
polymeric or mineral beads impregnated with antibiotics6–10 have
been proposed to concentrate the therapeutic agent at the site of
infection. Unfortunately, surgical intervention is required to insert
the beads, a significant hurdle in the context of a disease where
recurrences are common and repeat treatments are often required.
Targeting antibacterial drugs to bone after systemic administra-
tion would clearly provide a more convenient form of treatment.
Bisphosphonates,11–13 pyrophosphate analogs with high, near-irre-
versible affinity for hydroxyapatite, the calcium phosphate bone
mineral, have been used to deliver therapeutics,14–29 including
antibacterial agents,26–29 to bone.
While efficient bone delivery through conjugation with bis-
phosphonates is expected, our previous work26,28 has demon-
strated the near irreversible binding of bisphosphonates to
calcium mineral requires subsequent release of the free antibiotic
in order for it to freely exert its activity. The bisphosphonated en-
tity must therefore act as a prodrug.
Glycopeptide antibacterial agents are naturally occurring or
semisynthetic compounds, several members of which are currently
used clinically or are under clinical evaluation.30,31. They are active
only against gram-positive microorganisms. The archetypical gly-
copeptide antibiotic is vancomycin (1, Fig. 1), the discovery of
which triggered the isolation of a large number of related com-
pounds, including teicoplanin.30
Given its low potential for the selection of resistant microorgan-
isms, vancomycin is the primary agent for the treatment of meth-
icillin resistant gram-positive bacterial infections.32,33 As such, it is
very frequently used for the treatment of osteomyelitis, adminis-
tered by infusion twice daily.34
The clinical relevance of these naturally occurring glycopeptides
and, to some extent, the emergence of vancomycin resistance, in
particular in enterococci, spurred programs for the development
of second generation semisynthetic glycopeptides. This effort re-
sulted in the discovery of three drug candidates: dalbavancin, orit-
avancin (2, Fig. 1) and telavancin.35 Oritavancin demonstrates
substantial potency in vitro,36 displays rapid bactericidal activity
* Corresponding author. Tel.: +1 514 3321008; fax: +1 514 3326033.
E-mail addresses: adel.far@themedco.com, arafai@gmail.com (A.R. Far).
Present address: NutriAg Ltd.
à
Present address: Bellus Health Inc.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.006

1356
K. S. E. Tanaka et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1355–1359
Figure 1. The structures and schematic representations for vancomycin (1) and oritavancin (2). The arrows indicate the relevant amino and carboxylate groups depicted
schematically.
against planktonic bacteria,37 and, unlike vancomycin, is active
against cells both in stationary phase and in biofilms.38 It therefore
has the potential to be an attractive alternative to vancomycin for
the treatment of osteomyelitis. From this perspective, we present
herein the synthesis and in vitro evaluation of bisphosphonated
derivatives of vancomycin and oritavancin.
The lability of glycolamide esters under physiological condi-
tions,39 probably as a result of cleavage by acetylcholinesterases
and other esterases, provides a convenient strategy for the design
of prodrugs based on drugs possessing free carboxylates. The con-
cept has been successfully transposed to the use of bisphospho-
nates,14,15 in particular with fluoroquinolone antibiotics.27 Thus
the preparation of bisphosphonated glycolamide esters of glyco-
peptides appeared to be particularly attractive. Bisphosphonated
vancomycin glycolamides 8 and 11 were prepared by the treat-
ment of Fmoc protected vancomycin 5 with bromoacetamides
318 and 427 under basic conditions followed by deprotection reac-
tions (Scheme 1). The same procedure was not able to provide the
parent oritavancin prodrugs after deprotection, and therefore the
preparation was performed with allyl protected bromoacetamides
15 and 18 prepared from tetraallyl methylenebisphosphonate by a
sequence of either electrophilic amination or alkylation and reduc-
tion, followed by acylation with bromoacetyl bromide (Scheme 2).
The alkylation of allyloxycarbamate protected oritavancin 19 with
either 15 or 18, and subsequent global deprotection by palladium
catalyzed deallylation, furnished bisphosphonated oritavancin gly-
colamides 21 and 23, respectively (Scheme 3).
Simple PEGylated amides of vancomycin, formed by derivatiza-
tion on the N-methyl-leucyl residue, were shown, albeit unexpect-
Scheme 1. (a) N-(9H-fluorenylmethoxycarbonyloxy) succinimide, NaHCO3, Diox-
ane/H2O (Quant.); (b) 3 (for 6) or 4 (for 9), NaHCO3, DMF (56% for 6, 61% for 9); (c)
Piperidine, DMF (82% for 7, 95% for 10); (d) TMSBr, 2,6-lutidine, DMF, then
HF.pyridine, pyridine DMF (44% for 8, 42% for 11).
edly, to be labile under physiological conditions, and as such
useful as prodrugs.40 Therefore simple bisphosphonated amides of
oritavancin were prepared by selective acylation on the N-methyl-
leucyl nitrogen41 with the N-hydroxysuccinimide esters of bis-
phosphonated acids 2428 and 2528 (Scheme 4).
ethylmercapto group with chlorine and acylation of N-hydroxy-
succinimide with the resulting chloroformates 35 and 36. The acti-
vated carbonates 37 and 38 were then used with 2 in a sequence of
acylation and deprotection to furnish the bisphosphonated orita-
vancin derivatives 41 and 42. It should be noted that attempts to
prepare the same type of prodrug with the shorter bisphosphonat-
ed acid 24 did not succeed, possibly as a result of its greater
lability.
The antibacterial activities (as minimum inhibitory concentra-
tions—MICs) for vancomycin 1, oritavancin 2 and the bisphospho-
nated derivatives against S.aureus ATCC13709 were determined
(Table 1). This bioactivity provides a useful if only indirect means
by which to evaluate the behaviour of the prodrugs in solution. In-
Substituted acyloxyalkyl esters and carbamates are frequently
used as prodrugs,42–44 and this strategy has been successfully com-
bined with the use of bisphosphonates for delivery to bone.28 Acy-
loxyalkyl carbamates are generally prepared by treatment of a
chloromethyl carbamate with an acid. In this case, treatment of 2
with chloromethyl chloroformate or N-(chloromethoxyformyloxy)
succinimide as a first step resulted in a mixture of formylated
derivatives and no sign of product. The bisphosphonated deriva-
tives were therefore prepared by assembling the bisphosphonated
acyloxyalkyl formylating agent prior to acylation (Scheme 5). This
was performed by treatment of acids 25 and 3228 with S-ethyl O-
iodomethyl carbonothionate,45 electrophilic substitution of the

K. S. E. Tanaka et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1355–1359
1357
Scheme 4. (a) N-Hydroxysuccinimide, DCC, CH3CN (quant for 26, 93% for 26); (b) 2,
NaHCO3, H2O/dioxane (12% for 28, 22% for 29); (c) TMSBr, 2,6-lutidine, DMF, then
HF/pyridine, DMF (14% for 30, 15% for 31).
Scheme 2. (a) Allyl alcohol, pyridine, PhMe (69%); (b) NaH, DMF then
Ph2P(O)ONH2, THF (59%); (c) bromoacetyl bromide, pyridine, CH2Cl2 (74% for 15,
76% for 18); (d) NaH, DMF, 4-nitrobenzyl bromide (39%). (e) Zn, NH4Cl, MeCN (86%).
Scheme 3. (a) N-(allyloxycarbonyloxy)succinimide, NaHCO3, DMF/H2O (93%); (b)
15 (for 20) or 18 (for 22), NaHCO3, DMF; (c) Pd(PPh3)4, DMF, morpholine (24% over
two steps for 21, 43% over two steps for 23).
Scheme 5. (a) Tetrabutylammonium hydrogensulfate, NaHCO3, S-ethyl O-iodo-
methyl carbonothionate, H2O, CH2Cl2 (76% for 33, 83% for 34); (b) Neat SO2Cl2; (c)
N-hydroxysuccinimide, NaHCO3, H2O/dioxane (quant over two steps for 37, 70%
over two steps for 38); (d) 2, NaHCO3, H2O/dioxane (44% for 39, 32% for 40); (e)
TMSBr, 2,6-lutidine, DMF, then HF/pyridine, DMF (54% for 41, 44% for 42).
deed, while the potency of the parent glycopeptides in the absence
of serum is evident, the bisphosphonated conjugates were 16–64-
fold less active in this assay. This suggests that the addition of the
bisphosphonate moiety is detrimental to the antibacterial activity
associated with the glycopeptide scaffold. It confirms that a strat-
egy requiring the bisphosphonated group to be released under
physiological conditions is necessary for the compounds to bring
about a satisfactory therapeutic outcome.
The activity of the bisphosphonated conjugates of oritavancin
was greatly enhanced in the presence of mouse and rat serum,
which infers that under these conditions, these compounds are
converted back to oritavancin. This conclusion is supported by
the rapid bactericidal activity of oritavancin,37 which is able to ex-
ert its activity immediately upon reaching a satisfactory concentra-
tion in the medium. If the same effect is not observed with the
bisphosphonated vancomycin conjugates, it is likely the result of
the slower kinetics of bacterial killing associated with this antibi-
otic. Thus, one can compare compounds 8 and 21 or 11 and 23,
which would be expected to release the parent drugs to a similar
extent in plasma, but yet yield different outcomes in this assay.
The exceptions amongst the oritavancin derivatives are com-
pounds 31 and 42 which did not display any significant antibacte-
rial activity even in the presence of sera, and which are therefore
expected to be stable in the presence of serum hydrolytic enzymes
and unable to release oritavancin under these conditions.
An estimation of the affinity of the prodrugs for osseous tissues
can be obtained by measuring the amount of prodrug bound to
bone powder in phosphate buffered saline (PBS) at 37 °C over 1h.
This was ascertained by measuring antibacterial activity remaining
in the supernatant to determine the unbound fraction (Table 1).
The release of the parent glycopeptide from these prodrugs immo-

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K. S. E. Tanaka et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1355–1359
Table 1
Susceptibility of S.aureus to selected compounds (minimum inhibitory concentrations [MICs] in lg/mL)
Compds
S.aureus ATCC 13709
CAMHBa + 50% HSc
CAMHBa
CAMHBa + 50% MSb
CAHMBa + 50% RSd
Vancomycin (1)
1
2
1
2
8
11
16
16
0.5
16
>32
32
>32
8
16
16
2
2
8
8
16
1
32
>32
32
>32
4
32
32
0.25
2
8
4
>32
1
32
Oritavancin (2)e
21
23
30
31
41
42
4
>32
0.5
32
32
>32
a
b
c
Cation adjusted Mueller–Hinton broth.
Mouse serum.
Human serum.
d
e
Rat serum.
Measured in the absence of polysorbate-80.46
Table 2
bilized on bone powder can similarly be determined by measuring
the appearance of antibacterial activity in the supernatant over
time, as determined by an agar diffusion bioassay using, as the
indicator strains, Bacillus subtilis 1A754 for vancomycin derivatives
Bone binding and conversion of bisphosphonated glycopeptide prodrugs to parent
drugs after binding to bone (expressed as % prodrug converted after 24 h incubation)
Compounds
% Bone binding
% Conversion
50% RSb
PBSa
(vancomycin MIC 0.5
lg/mL) and Streptococcus pneumoniae ATCC
700902 for oritavancin derivatives (oritavancin MIC 0.001
l
g/
Vancomycin (1) derivatives
8
11
96.5
96.7
2.1
3.5
2.6
4.1
mL). To evaluate the potential for enzymatic cleavage, conversion
was assessed both in PBS and in 50% rat and human sera in PBS
after 24 h (Table 1). Compound 23 was not soluble under the con-
ditions of the assay and was therefore not investigated further.
As shown in this assay, bisphosphonated glycopeptide prodrugs
displayed very high affinity for bone powder, with >95% binding
over an hour. In fact, since the determination of binding affinity re-
lies on a bioassay monitoring antibacterial activity, it is quite likely
that at least a portion of the unbound material is the free parent
drug, thereby underestimating the true affinity of the prodrugs
for bone mineral.
Oritavancin (2) derivatives
21
30
31
41
42
97.6
0.18
0.01
0.01
0.2
4.09
0.05
0.9
26.4
0.05
99.9
99.8
96.9
99.9
<lodc
a
b
c
Phosphate buffered saline.
Rat serum in phosphate buffered saline.
Below the limit of detection.
As was demonstrated with other classes of compounds,14,15,27
bisphosphonated glycolamide prodrugs of vancomycin and orita-
vancin were readily converted to the parent drugs. In addition,
while there is a definite acceleration of the process in the presence
of serum, presumably as a result of the presence of serum hydro-
lytic enzymes, the conversion still occurs to a significant extent
in phosphate buffered saline. Therefore it at least does not require
the participation of any hydrolytic enzymes.
drug to a significant extent even in the absence of serum (13.4%
conversion over 24 h in PBS, 25.4% in 50% rat serum). This contrast
between the oritavancin prodrug and the gatifloxacin prodrug par-
allels the differences between the bisphosphonated vancomycin
prodrugs 8 and 11, for which conversion is relatively independent
of the presence of serum, and the parent oritavancin prodrug 21,
for which the presence of serum results in significant rate acceler-
ation. It is in fact quite likely that the greater dependence of the
oritavancin prodrugs on serum for conversion is an experimental
artifact due to the poor solubility of oritavancin in saline and its
greater solubility in plasma,46 and therefore poorer recovery in
the former medium. This would result in a lower concentration
of oritavancin in the supernatant in PBS and a greater concentra-
tion in 50% serum. Indeed spiking naïve rabbit bone powder and
extracting with PBS containing 0.002% polysorbate 80 at 0.25, 1
Simple bisphosphonated amides of oritavancin (compounds 30
and 31) failed to significantly regenerate the parent drug in buf-
fered saline. This was in agreement with our observations regard-
ing bisphosphonated fluoroquinolone amides.28 However, while
the conversion of compound 30 to oritavancin remains insignifi-
cant in the presence of serum, there is a marked acceleration for
compound 31 (0.01% over 24 h in the absence of serum as opposed
to 0.9% over 24 h in the presence of serum, Table 2). This unex-
pected result somewhat mirrors the lability of simple PEGylated
vancomycin amides.40 The role of serum in this rate acceleration
implies the possibility of enzymatic cleavage, and certainly the
structural dependence suggested by the contrast between 30 and
31 indicates a selectivity generally associated with enzymes.
A similar comparison can be performed with compounds 41 and
42. Indeed, while compound 42 is not converted back to oritavan-
cin to any significant level either in PBS or in the presence of ser-
um, compound 41 significantly decomposes to the parent drug in
the presence of serum. For this latter compound, the rate acceler-
ation in going from PBS to serum is spectacular. This stands in con-
trast with the parent gatifloxacin prodrug,28 which involved the
same prodrug strategy, but which was converted to the parent
and 4
lg/mL assuming full recovery after extraction resulted in
<1% recovery as measured by MIC using Enterococcus faecalis ATCC
29212 as the indicator strain.
Glycopeptides are important antibacterial agents in the treat-
ment of complicated gram-positive infections such as osteomyeli-
tis and the main recourse for infections caused by resistant gram-
positive pathogens. This study demonstrates that the use of bis-
phosphonates as a means to impart bone affinity can be extended
to the glycopeptide class. It also highlights the development of pro-
drug molecules around the glycopeptide scaffold and in particular
presents protection/deprotection strategies which are compatible
with both their complex molecular architecture and the chemically
labile bisphosphonated linkers. As was already highlighted with
other classes of molecules, the evaluation of these prodrugs

K. S. E. Tanaka et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1355–1359
1359
in vitro confirms the potential of glycolamides14,15,27 and acyl-
oxymethyl carbamates28 as efficient linkers for bisphosphonate
based bone delivery. But the results observed with prodrug 41 also
suggest that simple bisphosphonated amides are sufficiently labile
under physiological conditions to function as glycopeptide pro-
drugs. Further investigation of the efficacy and safety of these com-
pounds in accepted animal models is necessary to fully evaluate
their potential for the treatment of osteomyelitis.
ˇ
ˇ
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