Synthesis of conjugates between oxazolidinone antibiotics and a pyochelin analogue

Article abstract of DOI:10.1016/j.bmcl.2017.09.039

Pseudomonas aeruginosa is a Gram-negative pathogenic bacterium responsible for severe infections, and it is naturally resistant to many clinically approved antibiotic families. Oxazolidinone antibiotics are active against many Gram-positive bacteria, but

Full text of DOI:10.1016/j.bmcl.2017.09.039

Accepted Manuscript
Synthesis of conjugates between oxazolidinone antibiotics and a pyochelin an-
alogue
Aurélie Paulen, Françoise. Hoegy, Béatrice. Roche, Isabelle J. Schalk,
Gaëtan.L.A. Mislin
PII:
S0960-894X(17)30935-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.09.039
BMCL 25303
Reference:
Bioorganic & Medicinal Chemistry Letters
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Revised Date:
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29 August 2017
15 September 2017
16 September 2017
Please cite this article as: Paulen, A., Hoegy, Franccediloise., Roche, Beacuteatrice., Schalk, I.J., Mislin,
Gaeumltan.L.A., Synthesis of conjugates between oxazolidinone antibiotics and a pyochelin analogue, Bioorganic
& Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.09.039
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Synthesis of conjugates between
oxazolidinone antibiotics and a pyochelin
analogue
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Aurélie Paulen, Françoise Hoegy, Béatrice Roche, Isabelle J. Schalk, Gaëtan L. A. Mislin∗
UMR7242 CNRS/University of Strasbourg, Illkirch (France)

Bioorganic & Medicinal Chemistry
journal homepage: www.els evier.com
Synthesis of conjugates between oxazolidinone antibiotics and a pyochelin analogue†
Aurélie Paulena,b, Françoise. Hoegya,b, Béatrice. Rochea,b, Isabelle J. Schalka,b and Gaëtan. L. A. Mislina,b,
∗
a CNRS Equipe Transport Membranaire Bactérien, Biotechnologie et Signalisation Cellulaire, UMR7242, Pole API, 300 boulevard Sébastien Brant, CS10413,
67412 Illkirch Cedex, France.
bUniversity of Strasbourg. Ecole Supérieure de Biotechnologie de Strasbourg (ESBS), F-67413, Illkirch Cedex. France
ARTICLE INFO
ABSTRACT
Article history:
Received
Pseudomonas aeruginosa is a Gram-negative pathogenic bacterium responsible for severe
infections, and it is naturally resistant to many clinically approved antibiotic families.
Oxazolidinone antibiotics are active against many Gram-positive bacteria, but are inactive
against P. aeruginosa. Increasing the uptake of oxazolidinones through the bacterial envelope
could lead to an increased antibiotic effect. Pyochelin is a siderophore of P. aeruginosa which
delivers external iron to the bacterial cytoplasm and is a potential vector for the development of
Trojan Horse oxazolidinone conjugates. Novel pyochelin-oxazolidinone conjugates were
synthesized using an unexpectedly regioselective peptide coupling between an amine
functionalized pyochelin and oxazolidinones functionalized with a terminal carboxylate.
Received in revised form
Accepted
Available online
Keywords:
Pyochelin
Siderophore
Oxazolidinone antibiotic
Linezolid
2009 Elsevier Ltd. All rights reserved
.
Trojan Horse strategy
∗ Corresponding author. Tel.: +33-3-68854727; fax: +33-3-68854683; e-mail: mislin@unistra.fr
†This article is dedicated to the late Pr. Dieter Haas, in memory of its outstanding contributions to molecular microbiology on Pseudomonas
aeruginosa.

Bacterial resistance is one of the major health threats of the
near future and there is an urgent need for new and effective
antibiotic agents. The ESKAPE (Enterococcus faecium,
Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter
baumannii, Pseudomonas aeruginosa, and Enterobacteria
species) group is a “shady club” of microorganisms causing
serious anxiety among health authorities.1-3 This group is
composed of Gram-positive and Gram-negative pathogenic
bacteria which can cause antibiotic-resistant infections with
potentially fatal outcomes. After several decades of big
pharmaceutical companies showing less interest in anti-infective
drug research, innovative molecules are once again in the
pipelines. However, very few of the biological targets validated
and the leads investigated are relevant to the treatment of
infections due to Gram-negative bacteria in general and P.
aeruginosa in particular.2,3 The low permeability of the P.
aeruginosa cell envelope provides natural resistance to many
antibiotic families currently approved for use against Gram
positive bacteria.
This siderophore forms complexes with iron(III) with a 2:1
stoichiometry.20,21 Ferric pyochelin is recognized and transported
through the outer membranes by a specific OMT called FptA and
through the inner membrane by a proton motive force permease
called FptX.22,23 The molecular mechanism involved in iron
release from pyochelin in the bacterial cytoplasm remains
unclear. Ferric pyochelin has been described to be the effector of
the PchR protein responsible for the regulation of the expression
of the enzymes involved in pyochelin biosynthesis, and of fptA
and fptX.24,25 These observations strongly suggest that pyochelin
enters the cytoplasm as a ferric complex, although this has not
been formally proved. Nothing is known about the ferric
pyochelin dissociation mechanism or the recycling, if any, of the
Nutrient uptake systems are gates through the bacterial
envelope and therefore could be exploited by Trojan horse
strategies to allow, or improve, the delivery of antibiotics into
bacteria. Iron-uptake systems are promising candidates, and
could be used as gates for antibiotic conjugates with siderophores
as vectors.4-6 Siderophores are low molecular weight secondary
metabolites secreted by bacteria into the extracellular medium to
scavenge iron(III).7 The ferric siderophore complexes formed are
recognized by specific outer membrane transporters (OMT) and
imported into the periplasm using energy supplied by the TonB
machinery.8,9 The subsequent fate of the ferric siderophore
complexes is very different according to the siderophore and the
microorganism: some siderophores deliver iron to the periplasm
whereas others cross the inner membrane and deliver the metal to
the bacterial cytoplasm.10 Import across the inner membrane
involves ABC transporters or proton motive force-dependent
permease. The siderophores selected for Trojan horse strategies
for antibiotics need to deliver the drug payload to the appropriate
bacterial compartment for antibacterial activity.4
siderophore (Figure 1).
Figure 1. Structure of pyochelin 1 and the pyochelin-dependent iron uptake
pathway in P. aeruginosa. Iron(III) is represented as orange balls and
pyochelin as blue arch.
Oxazolidinones are antibiotics active against many Gram-
positive bacteria but have only weak or moderate activity against
Gram-negative bacteria.26 For example, linezolid, the first
oxazolidinone approved has no activity against P. aeruginosa.27
The target of these drugs is the 50S subunit of bacterial
ribosomes in the cytoplasm; the difference in activity against
Gram-positive and -negative bacteria seems to be related to both
impermeability of the Gram-negative outer membrane (Gram-
positives have no such membrane) and efflux processes.
Vectorisation of linezolid analogues with a monocatechol vector
Siderophore-based antibiotic vectorization was once
considered to be a pipedream of academic scientists. However,
recent work by the groups of Elizabeth Nolan and Marvin J.
Miller show that this approach could be valuable to improve the
activity of β-lactam antibiotics against Gram-negative
bacteria.11,12 Moreover, several molecules developed by
pharmaceutical companies are currently in clinical trials. MC-1,
BAL30072 and cefiderocol (formerly S-649266) are conjugates
between β-lactam antibiotics from various families and catechol,
or isoster, vectors.13 These compounds were specifically
developed for the treatment of infections due to Gram-negative
bacilli in general and P. aeruginosa in particular. Thus, it is
evident that siderophore-based Trojan horse strategies are now
plausible for vectorisation of antibiotics with periplasmic targets.
The next challenge is to vectorise antibiotics with a cytoplasmic
target.14 In this context, the group of Marvin J. Miller proved
recently that the Trojan horse strategy could extend efficiently
the antibiotic spectrum of daptomycin.15 The siderophore
derived from aminochelin,
a siderophore of Azotobacter
vinelandii, seems to improve the antibiotic activities against P.
aeruginosa.27 These oxazolidinone conjugates were amongst the
most active described against this microorganism, but the MICs
were nevertheless much higher than those of antibiotics currently
approved against P. aeruginosa. There is evidence that catechol
siderophores, like enterobactin and azotochelin, deliver iron to
the periplasm of P. aeruginosa.28,29 The iron-uptake system used
by aminochelin-oxazolidinone conjugates has not been
determined, but it is likely that our conjugates accumulate in the
periplasm. The MICs of vectorised oxazolidinones against P.
aeruginosa may be improved using pyochelin because it passes
into the cytoplasm where the ribosomes are located. We have
already described the synthesis of functionalized pyochelin 2 and
of the corresponding free amine analogue 3 (Figure 2).30
pyochelin is a promising candidate for such innovative
therapeutic approach.
Pyochelin 1 is an endogenous siderophore produced, and used,
by Pseudomonas aeruginosa and some species of the cepacia
complex.16,17 The biosynthesis of pyochelin has been described
exhaustively,18,19 but the secretion process remains unknown.

O
O
tBuO
tBuO
tBuO
OH
OC6F5
i
O
O
O
4
6
5
O
O
O
tBuO
O
Cl
OH
OH
O
O
ii
O
7
O
O
OC6F5
9
BocHN
BocHN
iii
8
Figure 2. Structures of pyochelin analogues 2 and 3.
O
The ferric form of molecule 2 binds FptA with nearly the
same affinity as the natural siderophore.31 Analogue 3 is able to
promote iron(III) accumulation in bacteria using the pyochelin-
dependent iron-uptake system. Analogues 2 and 3 thus mimic
natural pyochelin 1, and efficiently vectorise NBD fluorophores
into P. aeruginosa.30 Therefore, siderophore analogue 3 has
properties making it a promising vector for antibiotic Trojan
horse strategies. Preliminary data based on the vectorization of
fluoroquinolones were disappointing: antibiotic activities were
poor, mainly due to the poor solubility of the conjugates in
physiological media and to the hydrolysis of the spacer arm in
culture broth.31 Here, we report the synthesis of conjugates
between pyochelin 3 and oxazolidinone antibiotics connected by
succinic and more water-soluble PEG-derived linkers. The
oxazolidinone payloads were connected to functionalized
pyochelin through a direct peptide bond between the amine
function of vector 2 and oxazolidinones bearing a terminal
carboxylate.
O
NR
N
N
H
N
O
F
10 : R = Boc
11 : R = H
iv
O
O
O
N
N
N
H
N
O
iv,v
tBuO
F
12
13
O
O
O
O
O
O
N
N
N
H
N
tBuO
O
iv, vii
iv, vi
O
O
F
O
O
O
O
O
O
O
N
N
N
H
N
tBuO
O
HN
O
F
15
O
iv, vi
O
O
N
N
N
H
N
BocHN
O
F
14
Scheme 1. Synthesis of oxazolidinone-linker building blocks 12, 13 and 15. i.
C6F5OH, DCC, CH2Cl2, 20°C. ii. Cl3COCOOCCl3, pyridine, THF, 5°C. iii.
C6F5OH, DCC, CH2Cl2, 25°C. iv. TFA/CH2Cl2 20%, 25°C. v. 5, DIPEA,
CH2Cl2, 25°C. vi. 7, DIPEA, CH2Cl2, 25°C. vii. 9, DIPEA, CH2Cl2, 25°C.
The synthesis of pyochelin vectors 2 and 3 has been
described.30,31 Pyochelin vector
3 was conjugated with
oxazolidinone-spacer arm building blocks bearing a terminal
carboxylate. The functionalization of oxazolidinones can deeply
modify the antibiotic activity. However, the morpholine moiety,
present in linezolid, was shown to be replaced by many other
functional groups without impairing drastically neither the
binding to the target nor the antibiotic properties.32,33
The conjugation of pyochelin analogue 2 to oxazolidinones
building blocks 12, 13 and 15 requires preliminary cleavage of
Boc or tert-butyl protecting groups on these molecules. The best
results were obtained with an ethereal hydrogen chloride
solution. In these conditions, the free reactive functions were
cleanly deprotected and the corresponding amine and carboxylate
compounds were used without any further purification. However,
in this coupling, the concomitant presence of carboxylates
functions on both the two reactants, namely pyochelin 3 and
oxazolidinone building blocks, might lead to a mixture of
compounds when reacted with the free amine. For this purpose,
in a previous work, the carboxylate function of a fluorescent
The synthesis of oxazolidinones 12, 13 and 15 with terminal
carboxylates started with the production of the structural
elements of three spacer arms selected: these three linkers of
different lengths and chemical properties were selected to avoid
the solubility problems encountered with pyochelin-
fluoroquinolone conjugates described previously.31 For the
shortest linker, the synthesis started with mono-tButyl-succinate
4.30 The free carboxylate was then activated in the presence of
pentafluorophenol and DCC. The expected pentafluorophenyl
ester 5 was obtained at 50% yield. A longer spacer arm was
prepared from commercially available tert-butyl-2-(2-(2-
hydroxyethoxy)ethoxy)acetate 6: it was treated with triphosgene
in the presence of pyridine leading to the corresponding
chloroformate 7, which was isolated in 94% yield. An third linker
fragment 9 was obtained at 95% yield by the treatment of Boc-
glycine 8 with pentafluorophenol in the presence of DCC as a
coupling agent. These linkers were then connected to an
oxazolidinone antibiotic: the Boc protecting group of this
linezolid analogue 1027 was cleaved using 20% TFA in
dichloromethane; the resulting free secondary amine 11 was then
reacted with each of compounds 5, 7 and 9 in the presence of
Hünig base in dichloromethane. The expected building blocks 12,
13 and 14 were isolated, at yields of 65%, 75% and 87%,
respectively, over the two steps combined. The synthesis of
building block 15 bearing the longer spacer arm was based on the
compound 14: it was treated with TFA 20% in dichloromethane
and the resulting amine was treated directly with chloroformate 7
in the presence of Hünig base. The third oxazolidinone-spacer
arm building block 15 was thereby obtained, at a yield of 57%
over the three steps from oxazolidinone 10 (Scheme 1).
payload was first activated under the form of pentafluorophenyl-
ester in order to discriminate the two carboxylates and avoid
therefore the formation of pyochelin 3 auto-condensation
products.30
Unfortunately,
in
our
hands,
neither
pentafluorophenyl- nor N-hydroxysuccinimidyl esters of building
blocks 12, 13, 15 were obtained in yields and purities compatible

with further reactions. Direct peptidic coupling was then tested
with several coupling agent. Intriguingly, expected conjugates
16, 17 and 18 were soles product isolated and pyochelin 3 auto-
condensation products were never detected in the crude mixtures.
Best results for this last step were obtained using 1-
[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5b] pyridi-
nium 3-oxid hexafluorophosphate (HATU), in the presence of
Hünig base in dichloromethane at 20°C. Using these conditions
the corresponding conjugates 16, 17 and 18 were isolated in 30,
34 and 62% yield over two steps (Scheme 2).
technological obstacle to the development of efficient Trojan
horse conjugates between siderophores and antibiotic with
cytoplasmic targets.
Acknowledgments
Authors warmly thank “Vaincre la Mucoviscidose” and the
“Association Grégory Lemarchal” (French associations against
cystic fibrosis) for repeated financial support. AP acknowledges
the Ministère de l’Education National, de l’Enseignement
supérieur et de la Recherche (MENESR) for a PhD fellowship.
BR would like to thank Roche Pharmaceutical Research and
Early Development Basel for their financial support via the
Roche Postdoctoral Fellowship (RPF) Program. Authors
acknowledge also the Centre National de la Recherche
Scientifique (CNRS) for general financial support. Finally, the
research leading to these results was conducted as part of the
Translocation consortium (www.translocation.com) and has
received support from the Innovative Medicines Joint
Undertaking under Grant Agreement n°115525, resources which
are composed of financial contribution from the European
Union’s seventh framework programme (FP7/2007-2013) and
EFPIA companies in kind contribution.
Scheme 2. Synthesis of pyochelin-oxazolidinone conjugates 16, 17 and 18. i.
HCl, Et2O, 20°C. ii. HATU,DIPEA, CH2Cl2, 20°C.
The regioselectivity observed during the conjugation reaction
could be both due to steric hinderance around the carboxylate of
pyochelin 3 and to the presence of a complex hydrogen bond
involving the carboxylate of the siderophore vector. Indeed, a
complex intramolecular hydrogen bond network was suggested
by previous physical-chemistry data obtained on natural
pyochelin 1.20,21 We hypothesize that these properties could be
extrapolated to the functionalized pyochelins 2 and 3.
References and Notes
Conjugates 16, 17 and 18 were then tested for their
antibacterial activity against P. aeruginosa PAO1. Using a disk
diffusion assay in Petri dishes in iron deplete conditions, none of
these three conjugates exhibited evident antibiotic activity in the
range of the concentrations tested. This absence of activity could
have several origins. On one hand the functionalization of
pyochelin with oxazolidinones can impairs the uptake, especially
across to the inner membrane. On the other hand, even peptide
bonds could be cleaved by endogenous bacterial hydrolases,
these enzymes are substrate-specific. In this context, the
oxazolidinone is probably not released and the presence of the
vector can impact the recognition and the inhibition of the target.
As previously observed for fluoroquinolone conjugates,31 this
absence of activity could be also related to the low solubility of
these conjugates in physiological media. The preparation of salts
of conjugates 16, 17 and 18 was explored. However, the acidic
and basic conditions tested proved to be deleterious for
conjugates.
1.
2.
3.
Pendleton, J.N.;. Gorman and, S.P; Gilmore, B.F. Expert
Rev. Anti Infect.Ther. 2013, 11, 297.
Bassetti, M.; Merelli, M.; Temperoni, C.; Astilean, A.
Ann. Clin. Microbiol. Antimicrob. 2013, 12, 1.
Tommasi, R.; Brown, D.G.: Walkup, G.K.; Manchester
J.I.; Miller, A.A. Nat. Rev. Drug Discovery 2015, 14,
529.
Mislin, G.L.A., Schalk, I.J. Metallomics 2014, 6, 408.
Page, M.G.P. Ann. New York, Acad. Sci., 2013, 1277,
115.
4.
5.
6.
Górska, A.; Sloderbach, A.; Marszałł, M.P. Trends
Pharmacol. Sci. 2014, 35, 442.
7.
8.
Hider, R.C.; Kong, X. Nat. Prod. Rep. 2010, 27, 637.
Schalk, I.J.; Mislin, G.L.A.; Brillet, K. Curr Top Membr.
2012, 69, 37.
9.
Schauer, K.; Rodionov, D.A., de Reuse, H. Trends
Biochem. Sci., 2008, 33, 330.
Schalk, I.J; Guillon, L. Amino Acids 2013, 44, 1267.
Ji, C.; Miller, P.A.; Miller, M. J. J. Am. Chem. Soc.,
2012, 134, 9898.
10.
11.
12.
13.
Chairatana, P.; Zheng, T.; Nolan, E.M. Chem. Sci., 2015,
6, 4458.
We describe the synthesis of three unprecedented conjugates
between the pyochelin siderophore and oxazolidinone antibiotics.
These compounds were isolated thanks to an unexpectedly
regioselective reaction of conjugation. However, these
compounds did not present any antibiotic activity. This result
could be partly due to the low solubility of compounds 16, 17
and 18 in physiological medium. Spacer arms bearing PEG units
in conjugates 17 and 18 did not substantially increase the
solubility in aqueous media. The length of the PEG spacer cannot
be increased without impairing iron chelation properties or
recognition and uptake by FptA. These same constraints prevent
any large modification of the hydrophobicity of the
siderophore.34. The lack of antibiotic activity could be also
related to an impaired uptake process through the bacterial
envelop. Previous data, proved that pyochelin conjugates are
recognized by the specific outer membrane transporter,30,31 but
the fate of such compounds at the inner membrane level remains
to be addressed in order to design conjugates with optimal
biological properties. Finally, our results highlighted again the
necessity to develop new linkers able to release the antibiotic
from the vector in the required bacterial compartment. In the
struggle against P. aeruginosa, this specific point remains a
a. Han, S.; Zaniewski, R. P; Marr, E. S.; Lacey, B. M.;
Tomaras, A. P.; Evdokimov, A.; Miller, J. R., V.
Shanmugasundaram, V. Proc. Natl. Acad. Sci 2010 , 107,
22002. b. van Delden, C.; Page, M.G.P; Köhler, T.
Antimicrob. Ag. Chemother., 2013, 57, 2095. c. Ito, A.;
Kohira, N.; Yoshizawa, H.; Nakamura, R.; Tsuji,
M.;Yamano, Y.; Bouchillon, S.K.; West, J.; Rittenhouse,
S.; Sader, H.S.; Rhomberg, P.R.; Jones, R.N. J.
Antimicrob. Chemother. 2016, 71, 670.
14.
15.
Isabelle, J. Schalk; Mislin, G.L.A. J. Med. Chem. 2017,
60, 4573-4576.
Gosh, M.; Miller, P.A.; Möllman, U.; Claypool, W.D.;
Schroeder, V.A.; Wolter, W.R.; Sucknow, M.; Yu, H.;
Li, S.; Huang, W.; Zajicek, J.; Miller, M.J. J. Med.
Chem. 2017, 60, 4577-4583.
16.
Cox, C. D.; Rinehart, K. L.; Moore, M. L.; Cook, J.C.
Proc. Natl. Acad. Sci. USA., 1981, 78, 4256.
Thomas, M.S. Biometals, 2007, 20, 431.
17.
18.
Reimmann, C.; Patel, H.M.; Serino, L.; .Barone, M.;
Walsh, C.T.; Haas, D. J. Bacteriol., 2001, 183, 813.
Cunrath, O.; Gasser, V.; Hoegy, F.; Reimmann, C.;
Guillon, L.; Schalk, I.J. Environ Microbiol. 2015, 17,
171.
19.

20.
21.
Tseng, C.F.; Burger, A.; Mislin, G.L.A; Schalk, I.J.; Yu,
S.S.; Chan, S.I.; Abdallah M.A. J. Biol. Inorg.
Chem.2006, 11, 419.
31.
32.
Noël, S.; Gasser, V.; Pesset, B.; Hoegy, F.; Rognan, D.;
Schalk, I.J.; Mislin, G.L.A. Org. Biomol. Chem. 2011, 9,
8288.
Brandel, J.; Humbert, N.; Elhabiri, M.; Schalk, I.J.;
Mislin, G.L.A.; Albrecht-Gary, A.-M., Dalton Trans.,
2012, 41, 2820.
Phetsang, W.; Blaskovich, M.A.T.; Butler, M.S.; Huang,
J.X.; Zuegg, J.; Mamidyala, S.K.; Ramu, S.; Kavanagh,
A.M.; Cooper, M.A. Bioorg. Med. Chem. 2014, 22,
4490.
22.
23.
Cobessi, D.; Célia, H.; Pattus, F. J. Mol. Biol. 2005, 352,
893.
33.
Ang, W.; Ye, W.; Sang, Z.; Liu, Y.; Yang, T.; Deng, Y.;
Luo, Y.; Wei, Y. Bioorg. Med. Chem. Lett. 2014, 24,
1496.
O’Cuiv, P.; Clarke, P.; Lynch, D.; O’Connell, M. J.
Bacteriol. 2004, 186, 2996.
24.
25.
Heinrichs, D.E; Poole, K. J. Bacteriol. 1996, 178, 2586.
Michel, L.; Gonzalez, N.; Jagdeep, S.; Nguyen-Ngoc, T.;
Reimmann, C. Mol. Microbiol. 2005, 58, 495.
a. Rybak, M.J.; Cappelletty, D.M.; Moldovan, T.;
Aeschlimann, J.R.; Kaatz, G.W. Antimicrob Agents
Chemother. 1998, 42, 721. b. Brickner, S. J.; Barbachyn,
M.R.; Hutchinson, D.K.; Manninen, P.R. J. Med. Chem.
2008, 51, 1981.
34.
35.
Mislin, G.L.; Hoegy, F.; Cobessi, D.; Poole, K.; Rognan,
D.; Schalk, I.J. J. Mol. Biol., 2006, 357, 1437.
Hennard, C.; Truong, Q. C.; Desnottes ,J.-F.; Paris, J.-
M.; Moreau, N.J.; Abdallah, M.A. J. Med. Chem., 2001,
44, 2139.
26.
27.
36.
Mills, A.D.; Yoo, C.; Choong, J.D. ; Butler, B. Yang,
Verkman, A.S.; Kurth, M.J. Bioorg. Med. Chem. Lett.,
2010, 20, 87.
Paulen, A.; Gasser, V.; Hoegy, F.; Perraud, Q.; Pesset,
B.; Schalk, I.J.; Mislin. G.L.A. Org. Biomol. Chem.,
2015, 13, 11567.
37.
38.
Yan, S.; Miller, M.J.; Wencewicz, T.A.; Möllmann, U.
MedChemComm 2010, 1, 145.
Youard, Z.A.; Mislin, G.L.; Majcherczyk, P.A.; Schalk,
I.J.; Reimmann, C. J. Biol. Chem. 2007, 282, 35546.
28.
29.
Dean, C.R.; Poole, K. Mol. Microbiol. 1993, 8, 1095.
Gasser, V.; Baco, E.; Cunrath, O.; Saint-August, P.;
Perraud, Q.; Zill, N.; Schleberger, C.; Schmidt, A.;
Paulen, A.; Bumann, D.; Mislin, G.L.A.; Schalk, I.J.
Environ. Microbiol., 2016, 18, 819.
Supplementary Material
Protocols and analytical data for compounds 5, 7, 9 and 12 to
18 are provided. LC-HRMS analyses of conjugates 16, 17 and 18
are also provided. Supplementary data associated with this article
can be downloaded in an online version at DOI:http://xxxxxxx
30.
Noël,S.; Guillon, L.; Schalk, I.J.; Mislin, G.L.A. Org.
Lett., 2011, 13, 844.