Synthesis and biological properties of thiazole-analogues of pyochelin, a siderophore of Pseudomonas aeruginosa

Article abstract of DOI:10.1016/j.bmcl.2013.11.054

Pyochelin is a siderophore common to all strains of Pseudomonas aeruginosa utilized by this Gram-negative bacterium to acquire iron(III). FptA is the outer membrane transporter responsible of ferric-pyochelin uptake in P. aeruginosa. We describe in this Letter the synthesis and the biological properties ( ⁵⁵Fe uptake, binding to FptA) of several thiazole analogues of pyochelin. Among them we report in this Letter the two first pyochelin analogues able to bind FptA without promoting any iron uptake in P. aeruginosa.

Full text of DOI:10.1016/j.bmcl.2013.11.054

Bioorganic & Medicinal Chemistry Letters 24 (2014) 132–135
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological properties of thiazole-analogues
of pyochelin, a siderophore of Pseudomonas aeruginosa
Sabrina Noël a, Françoise Hoegy a, Freddy Rivault a, Didier Rognan b, Isabelle J. Schalk a,
Gaëtan L. A. Mislin a,
⇑
a Team ‘Transports Membranaires Bactériens’, UMR 7242 CNRS-Université de Strasbourg, 300 Boulevard Sébastien Brant, BP 10413, F-67412 Illkirch-Graffenstaden Cedex, France
b Team ‘Chémogénomique Structurale’ Laboratoire d’Innovation Thérapeutique (LIT), UMR 7200 CNRS-Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67400
Illkirch-Graffenstaden, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyochelin is
a siderophore common to all strains of Pseudomonas aeruginosa utilized by this
Received 24 October 2013
Revised 22 November 2013
Accepted 23 November 2013
Available online 4 December 2013
Gram-negative bacterium to acquire iron(III). FptA is the outer membrane transporter responsible of
ferric-pyochelin uptake in P. aeruginosa. We describe in this Letter the synthesis and the biological
properties (55Fe uptake, binding to FptA) of several thiazole analogues of pyochelin. Among them we
report in this Letter the two first pyochelin analogues able to bind FptA without promoting any iron
uptake in P. aeruginosa.
Keywords:
Pyochelin
Ó 2013 Elsevier Ltd. All rights reserved.
Siderophore
FptA
Pseudomonas aeruginosa
Outer membrane transporter
Iron is a crucial element for almost all forms of life, and bacteria
are no exception. Despite iron being one of the most common ele-
ments in the earth’s crust, its bioavailability is very limited because
of the poor solubility of iron(III) at physiological pHs under aerobic
conditions. The human body contains substantial amounts of iron,
all tightly associated with transport and storage proteins; conse-
quently, iron is not freely available to pathogenic bacteria. The con-
centration of free iron(III) in physiological fluids is estimated to be
10ꢀ9 to 10ꢀ18 M, whereas bacteria generally require iron concen-
trations in the micromolar range for optimal proliferation.1 Thus,
there has been a strong evolutionary pressure for microorganisms
to develop efficient iron uptake systems to acquire this essential
element either from the environment or from a host.2 One of the
more efficient and prevalent iron uptake system is based on low
molecular weight chelators called siderophores.3,4 Under condi-
tions of iron depletion, microorganisms synthesize siderophores
and secrete them into the extracellular medium where they che-
late iron(III).3,4 Gram-negative bacteria express outer membrane
transporters (OMTs) that each recognize, bind and transport a spe-
cific ferric-siderophore. Siderophore–iron(III) complexes are then
translocated through the membranes, by a multiprotein system.5
This uptake process is driven by the proton motive force of the
inner membrane via an inner membrane complex composed of
TonB, ExbB and ExbD proteins.6 All the proteins involved in sider-
ophore-dependent iron acquisition systems are promising, and
widely untapped, targets for the design of new antibiotics.7,8
Siderophore OMTs are the best studied proteins of bacterial iron
uptake systems, and the three-dimensional structures of several
siderophore OMTs have been reported over the last 10 years.5,9
The study of structure–activity relationships between siderophores
and their specific OMTs could contribute to the development of
new antibiotic strategies (particularly the design of OMTs inhibi-
tors, and the development of siderophore-based Trojan horse strat-
egies, for example).10
Pseudomonas aeruginosa is an opportunistic Gram-negative bac-
terium responsible for severe lung infections in cystic fibrosis
patients.11 These patients are treated regularly with antibiotics
leading to a progressive and unavoidable increase of bacterial
resistance.11,12 The emergence of antibiotic-resistant strains has
been exacerbated by the almost complete lack of new classes of
clinically useful antibiotics reaching the market over the last
decades.7,13 The discovery of new biological targets for innovative
inhibitors would make an enormous contribution to regain the
upper hand against these human pathogens. Under conditions of
iron starvation, P. aeruginosa produces two siderophores:
pyochelin (Pch) 1 and pyoverdin.14–16 Pch 1 is recognized by FptA,
a specific OMT expressed in P. aeruginosa.17 Therefore, the Pch-
dependent iron uptake system is a promising potential target for
⇑
Corresponding author. Tel.: +33 (0) 68 85 47 27; fax: +33 (0) 68 85 48 29.
E-mail address: mislin@unistra.fr (G.L.A. Mislin).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.11.054

S. Noël et al. / Bioorg. Med. Chem. Lett. 24 (2014) 132–135
133
antibiotic strategies dedicated to the treatment of chronic lung
infection in cystic fibrosis patients.
compound 11 with a fluoride on the C5 position of the phenol ring,
12 bearing a hydroxyl group, and 13 and 14 bearing a nitro group
in the C4 and C5 positions, respectively (Scheme 1).
Pch is a tricyclic siderophore bearing three chiral centres at
positions C40, C200 and C400.18 Pch chelates iron(III) with a stoichiom-
etry of 2:1.19 One of the Pch is tetradently bound to the metal ion
and the second Pch is necessary for octahedral hexacoordination.20
The three-dimensional structure of a ternary complex between
FptA and Pch-iron(III) was solved a few years ago.9a The structure
of the FptA transporter revealed that only the iron(III) tetradently
bound to Pch is necessary for the recognition by the binding site
of the FptA transporter:21 the Pch binding pocket is located on
the extracellular face of FptA and is mostly constituted of hydro-
phobic and aromatic residues (Phe114, Leu116, Leu117) in the api-
cal loop of the plug domain. The ferric Pch is stabilized in the
binding site by several van der Waals interactions and by one
hydrogen bond between its carboxylate group and the main chain
of FptA.21,9a This three-dimensional structure was exploited for a
structure–activity relationship study, unprecedented in the field
of siderophores chemistry.21,9a First, the significance of the config-
uration of the three chiral centres was investigated. To do this, sev-
eral stereoisomers and analogues of Pch were synthesized and
tested for their biological properties.21,22 This work demonstrated
that the configuration of the C4’’ chiral centre is determinant for
the stereospecific recognition of the siderophore by its trans-
porter.9a However, the configuration of the C40 chiral centre seems
to have only a small effect on Pch recognition.21 Thus, the Pch thi-
azole analogue HPTBT 2,23 loaded with iron(III) binds the FptA
receptor with an affinity in the same range as ferric Pch
(Ki = 2.2 0.5 nM for Pch2-Fe(III), Ki = 9.8 3.5 nM for HPTBT2–
Fe(III)) and also promotes iron(III) uptake in P. aeruginosa through
the Pch-dependent pathway (Fig. 1).21
Docking experiments showed that in the FptA binding site, the
aromatic ring of Pch 1 and HPTBT 2 is surrounded by several polar
residues (Y356, Q395) and peptide bonds of the main chain.21 We
mapped these interactions because they may be relevant to in-
crease affinity of Pch analogs: modifications of these structures
may allow the development of specific FptA inhibitors. In this con-
text thiazole analogues of Pch, modified at the C4 and C5 positions
of the aromatic ring by the addition of polar organic functions
(fluoride, hydroxyl and amine functions) were synthesized. In
addition, the synthesis of thiazole analogues of Pch with methyl-
ated phenol functions, and unable to complex iron(III), was also
attempted. Syntheses and biological properties of these analogues
are reported in the present Letter. HPTBT was selected as a lead
compound in this approach since the biological properties of this
molecule and those of Pch are very similar. Moreover, the chemical
synthesis of Pch leads usually to a mixture of four stereoisomers
due to the partial epimerization of the C40 chiral centre.18 The
absence of this chiral centre in HPTBT limit the number of stereo-
isomers and lead only to a single ferric complex after the chelation
of iron(III).
Starting materials 10 and 11 are available commercially. Com-
pounds 12–14 were synthesized according to published proce-
dures as follows: 2,4-dihydroxy-benzonitrile 12 was synthesized
in one step with a yield of 88% from the commercially available
2,4-dihydroxybenzaldehyde;25 2-hydroxy-4-nitro-benzonitrile 13
was prepared from benzo[1,3]dioxole with an overall yield of
60% over two steps.26 2-hydroxy-5-nitro-benzonitrile 14 was syn-
thesized quantitatively from the 1,2-benzodioxazole in two
steps.27 The nitro function of compounds 13 was then reduced
by catalytic hydrogenation over 10% Pd/C in ethanol leading to
the expected amine 15 isolated in quantitative yield. To avoid
side-reactions during the further synthetic steps, the amine func-
tion of 15 was protected under the form of a carbamate as follows:
the crude amine 15 was reacted with benzyl-chloroformate in the
presence of sodium hydrogeno-carbonate leading to the expected
carbamate 16 (95% yield). The Boc-protected compound 17 was
obtained from the nitro compound 14 in two steps, with an overall
yield of 58%, by the procedure described previously by our team
(Scheme 2).28
2-Hydroxybenzonitrile 10, 12 and 17 were then converted to
thiazoline derivatives 18–20 by condensation with L-cysteine in a
hydromethanolic medium buffered at pH 6.4.29 In these conditions
the expected thiazolines were obtained with good yields (63–90%).
However, this protocol failed to produce the expected thiazolines
from compounds 16 to 11. Therefore, harsher conditions (e.g. L-cys-
teine, DIPEA, iPrOH, 90 °C)30 were used and allowed the production
of the expected thiazolines 21 and 22 at yields of 88% and 75%,
respectively. Thiazolines 18–22 were further converted into their
corresponding Weinreb amides 23–27 which were obtained at
poor to acceptable yields (32–76%) (Scheme 3).
The synthesis of Pch analogs 3, 5 and 8 requires methylation of
the phenol function. Various conditions were tested to introduce a
methyl group onto the phenol ring of compounds 23–25, but the
desired methylated compounds were never isolated; this appeared
to be due to the strong hydrogen bond between the phenol proton
and the nitrogen atom of thiazoline ring. Analysis by NMR indi-
cated that the phenol proton exchangeability was significantly
enhanced when the thiazoline was oxidized to a thiazole. This
property was used to protect the dihydroxyl compound 24 selec-
tively. The hydroxyl function in position 4 of compound 24 reacted
selectively when treated with p-methoxybenzyl bromide in the
presence of potassium carbonate. The expected PMB phenoxide
28 was isolated with a yield of 93%. Thiazolines 23–28 were then
further oxidized into the corresponding thiazoles 29–34 by
R
R1
R2
O
We previously reported an improved protocol for the synthesis
of Pch 1 and of its thiazole analogue HPTBT 2, using 2-hydrox-
ybenzonitrile 10 as starting material.23,24 The same protocol was
used to build the tricyclic core of thiazole analogues 3–9 of Pch
starting from adequately functionalized 2-hydroxybenzonitriles:
R
O
CN
COOH
H
R1
R2
10 : R = H, R1 = H, R2 = H
11 : R = CH3, R1 = H, R2 = F
N
N
R1
OH
S
S
R2
CN
3
: R = CH3, R1 = H, R2 = H
4 : R = H, R1 = OH, R2 = H
5 : R = CH3, R1 = OH, R2 = H
6 : R = H, R1 = NH2, R2 = H
7 : R = H, R1 = H, R2 = NH2
8 : R = CH3, R1 = H, R2 = NH2
COOH
H
12 : R1 = OH, R2 = H
13 : R1 = NO2, R2 = H
14 : R1 = H, R2 = NO2
COOH
H
OH
S
OH
S
4"
S
4"
S
N
2"
N
N
4'
N
2"
H
H
H
9
: R = CH3, R1 = H, R2 = F
1
2
Scheme 1. Retrosynthesis of pyochelin analogs 3–9 starting from the functional-
ized 2-hydroxybenzonitrile 10 to 14.
Figure 1. Structures of pyochelin 1 and HPTBT 2.

134
S. Noël et al. / Bioorg. Med. Chem. Lett. 24 (2014) 132–135
O2N
OH
CN
HO
OH
S
H2N
OH
CN
CbzHN
OH
CN
PMBO
OH
S
O
N
O
i
i
N
ii
OMe
24
13
14
15
16
17
N
OMe
N
28
OH
OH
CN
R1
R2
OR
R1
R2
OR
2 steps
Ref 28
BocHN
CN
O2N
O
O
N
N
ii
OMe
OMe
N
S
S
N
Scheme 2. Synthesis of functionalized 2-hydroxybenzonitrile 16 and 17 starting
from nitro compounds 13 and 14. Reagents and conditions: (i) H2, Pd/C 10%, EtOH,
20 °C (quant.); (ii) CbzCl, NaHCO3, MeOH, 0–20 °C (95%).
29 : R = H, R1 = H, R2 = H
30 : R = H, R1 = OH, R2 = H
(75 %)
(67%)
23 : R = H, R1 = H, R2 = H
24 : R = H, R1 = OH, R2 = H
25 : R = H, R1 = H, R2 = NHBoc
26: R = H, R1 = NHCbz, R2 = H
27 : R= CH3, R1 = H, R2 = F
28 : R = H, R1 = OPMB, R2 = H
31: R = H, R1 = H, R2 = NHBoc (76 %)
32 R = H, R1 = NHCbz, R2 = H (70 %)
R1
R2
OH
CN
33: R= CH3, R1 = H, R2 = F
(93 %)
34 : R = H, R1 = OPMB, R2 = H (92 %)
i
R1
OH
R1
O
S
10 : R1 = H, R2 = H
12 : R1 = OH, R2 = H
17 : R1 = H, R2 = NHBoc
R1
R2
OR
S
O
O
N
N
R2
R2
iii
N
OMe
OMe
N
S
N
COOH
R1
R2
OR
CN
29 : R = H, R1 = H, R2 = H
31 : R = H, R1 = H, R2 = NHBoc
34 : R = H, R1 = OPMB, R2 = H
35 : R = CH3, R1 = H, R2 = H
36 : R = CH3, R1 = H, R2 = NHBoc (80 %)
37 : R = CH3, R1 = OPMB, R2 = H (92 %)
(79 %)
18 : R = H, R1 = H, R2 = H
19 : R = H, R1 = OH, R2 = H
(90 %)
(67 %)
20 : R = H, R1 = H, R2 = NHBoc (63 %)
21 : R = H, R1 = NHCbz, R2 = H (88 %)
ii
Scheme 4. Synthesis of thiazoles compounds 29–37. Reagents and conditions: (i)
PMBBr, K2CO3, acetone reflux (93%); (ii) CBrCl3, DBU, CH2Cl2, 20 °C; (iii) CH3I, K2CO3,
acetone reflux.
11 : R = CH3, R1 = H, R2 = F
16 : R = H, R1 = NHCbz, R2 = H
22 : R= CH3, R1 = H, R2 = F
(75 %)
iii
23 : R = H, R1 = H, R2 = H
24 : R = H, R1 = OH, R2 = H
(75 %)
(32 %)
R1
R2
OR
S
COOH
R1
R2
OR
R1
R2
OR
S
25 : R = H, R1 = H, R2 = NHBoc (76 %)
26: R = H, R1 = NHCbz, R2 = H (59 %)
H
O
N
H
O
N
N
N
i,ii
OMe
O
S
N
N
27 : R= CH3, R1 = H, R2 = F
(70%)
S
Me
30 : R = H, R1 = OH, R2 = H
3
4
: R = CH3, R1 = H, R2 = H
: R = H, R1 = OH, R2 = H
(55%)
(41%)
Scheme 3. Synthesis of Weinreb amides 23–27 starting from the functionalized
2-hydroxybenzonitriles 10, 11, 12, 16 and 17. Reagents and conditions: (i)
Cysteine, phosphate buffer 0.1 M pH 6.4, MeOH, 60 °C; (ii) -Cysteine, DIPEA, iPrOH,
90 °C; (iii) EDCIꢁHCl, DIPEA, MeNHOMeꢁHCl, CH2Cl2, 0–20 °C.
31: R = H, R1 = H, R2 = NHBoc
32 R = H, R1 = NHCbz, R2 = H
33: R= CH3, R1 = H, R2 = F
L-
38 : R = CH3, R1 = OPMB, R2 = H (70%)
iii
iv
L
5
: R = CH3, R1 = OH, R2 = H
39 : R = H, R1 = NHCbz, R2 = H (71%)
: R = H, R1 = NH2, R2 = H
(82%)
40 : R = H, R1 = H, R2 = NHBoc (65%)
: R = H, R1 = H, R2 = NH2
(78%)
(82%)
35 : R = CH3, R1 = H, R2 = H
36 : R = CH3, R1 = H, R2 = NHBoc
37 : R = CH3, R1 = OPMB, R2 = H
6
v
v
treatment with a mixture of bromotrichloromethane and DBU.31
Finally, the reaction of phenol compounds 29, 31 and 34 with
methyl iodide in the presence of potassium carbonate led to the
expected methyl phenoxides 35–37 (Scheme 4).
Weinreb amides 30–37 were then reduced to their correspond-
ing aldehydes using LiAlH4.32 These aldehydes were not stable and
were therefore directly condensed with (R)-N-methylcysteine in
hydroethanolic medium. The thiazole analogues 3, 4 and 9 of Pch
were obtained directly and isolated (yields of 55%, 41% and 45%,
respectively) over two steps. However, an additional deprotection
step under acidic conditions was required to convert compounds
38–41 into the expected Pch analogues 5–8, over three steps from
the corresponding Weinreb amides (Scheme 5).
7
41 : R = CH3, R1 = H, R2 = NHBoc (51%)
8
9
: R = CH3, R1 = H, R2 = NH2
: R = CH3, R1 = H, R2 = F
(80%)
(45%)
Scheme 5. Synthesis of thiazole analogues 3–9 of pyochelin. Reagents and
conditions: (i) LiAlH4, THF, ꢀ40 to ꢀ10 °C; (ii) (R)-N-methylcysteineꢁHCl, AcOK,
EtOH/H2O, 20 °C; (iii) TFA/CH2Cl2 10%, TIS, 20 °C; (iv) HBr/AcOH 45%, 20 °C; (v) TFA/
CH2Cl2 10%, 20 °C.
hydrazone) at 0 °C, to confirm that the uptake process was depen-
dent of the TonB protein and distinct from passive diffusion. The
detailed procedure for these iron-uptake experiments has been de-
scribed previously.34 Inhibition constants (Ki) were determined by
assessing competition between compounds
3 and 9 and
Thiazole analogues 3–9 of Pch and Pch 1 and HPTBT 2 for refer-
ences, were then tested for their ability to transport iron and to
bind FptA, the Pch-specific OMT. PAD07, a P. aeruginosa mutant
deficient for production of both Pch and pyoverdine, was used
for these experiments.33 Using this strain, the endogenous sidero-
phores do not interfere with analyses of iron uptake and binding.
Iron uptake assays were carried out on PAD07 P. aeruginosa cells
(OD600nm = 1) incubated at 37 °C in the presence of 100 nM of
Pch 1-55Fe(III) or of Pch thiazole analogues-55Fe(III). At different
time of incubation, an aliquot was removed, centrifuged to pellet
the cells as a measure of the amount of 55Fe(III) transported into
the bacteria. These uptake experiments were repeated in the pres-
ence of the protonophore CCCP (carbonyl cyanide m-chlorophenyl
Pch-55Fe(III) according to methods published previously.34 PAD07
P. aeruginosa cells (OD600nm = 0.3) cells were incubated at 0 °C for
1 h in 50 mM Tris–HCl (pH 8.0), in the presence of 200 lM CCCP,
to prevent iron uptake, 1 nM of Pch 1-55Fe(III) and various concen-
trations (0.1–1 mM) of Pch 1-Fe(III) or Pch analogues-Fe(III)
(Table 1).
In iron uptake experiments, Pch analogues 3, 5, 8 and 9 bearing
a methylated phenol function were not able to transport iron(III).
This result is consistent with the phenol function being a major
contributor in the coordination of iron(III).20 However, compound
7, in which the phenol function is free, was also unable to mediate
iron uptake. This is probably because analogue 7 failed to bind to

S. Noël et al. / Bioorg. Med. Chem. Lett. 24 (2014) 132–135
135
Table 1
Supplementary data
Biological properties of Pch 1, HPTBT 2 and compounds 3–9
Compound tested
55Fe uptakea
Kib (nM)
Supplementary data (HRMS spectra for compounds 4, 6, 8 and
9) associated with this article can be found, in the online version,
at http://dx.doi.org/10.1016/j.bmcl.2013.11.054.
Pch 1
HPTBT 2
+
+
2.2 0.5
9.8 3.5
NBc
3
4
5
6
7
8
9
ꢀ
+
6.5 2.3
References and notes
ꢀ
+
ꢀ
ꢀ
ꢀ
NBc
11.3 9.6
NBc
460 150
1440 430
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24. Zamri, A.; Abdallah, M. A. Tetrahedron 2000, 56, 249.
25. Karmarkar, S. N.; Kelkar, S. L.; Wadia, M. S. Synthesis 1985, 21, 510.
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FptA. The reason for this behaviour is unclear but may involve
conjugation between the amino and the phenol groups which
can both impair the chelation of the metal and the recognition
by the receptor. Compounds 4 and 6 transported iron(III) and
bound to the Pch OMT (Ki of 6.5 2.6 and 11.3 9.6 nM, respec-
tively) with affinities in the same range as HPTBT 2 (Ki of
9.8 3.5 nM) used as the reference in these experiments. Thus,
the functionalization of the aromatic ring of HPTBT with polar
functions did not significantly improve its affinity for the Pch
OMT. However, when a polar function (e.g. F or NH2) was present
on position 4 of the aromatic ring, the negative contribution of the
methylated phenol was partially reversed; indeed, the correspond-
ing Pch thiazole analogues 8 and 9 bound to FptA albeit with a
much weaker affinity (Ki of 460 150 and 1440 430 nM, respec-
tively) than the reference molecules. These analyses lead to three
main conclusions. First, alkylation of the phenol function prevents
binding to the FptA transporter. Secondly, for analogues bearing an
ionizable phenol function, the presence of polar functions on posi-
tion 5 on the aromatic ring did not significantly improve the affin-
ity for the Pch OMT. Finally, the presence of such polar chemical
functions on position 4 partly restores the affinity of Pch analogues
bearing a methylated phenol. Compounds 8 and 9 are the first Pch
analogues described that are unable to chelate iron(III) but have an
affinity for FptA, the Pch OMT. These affinities could probably be
further improved through modelling and docking experiments
using the structure of FptA. Optimization of the structure–activity
relationships of such compounds could lead to the development of
both molecular tools for the investigation of iron-uptake mecha-
nisms in P. aeruginosa, and innovative therapeutic approaches to
struggle against infections involving this pathogenic bacterium.
28. Rivault, F.; Liebert, C.; Burger, A.; Hoegy, F.; Abdallah, M. A.; Schalk, I. J.; Mislin,
G. L. A. Bioorg. Med. Chem. Lett. 2007, 17, 640.
29. Bergeron, R. J.; Wiegand, J.; Dionis, J. B.; Egli-Kamarkka, M.; Frei, J.; Huxley-
Tencer, A.; Peter, H. J. Med. Chem. 1991, 34, 2072.
Acknowledgments
30. Mathur, K. B.; Iyer, R. N.; Dhar, M. L. J. Sci. Ind. Res. 1962, 21B, 34.
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331.
Authors thank Vaincre la Mucoviscidose (the French cystic
fibrosis association) for the PhD fellowship awarded to S.N. and
to the postdoctoral fellowship awarded to F.R. The authors also
thank the Centre National de la Recherche Scientifique (CNRS)
and the Agence National pour la Recherche (ANR) for general finan-
cial support.
32. Fehrentz, J. A.; Castro, B. Synthesis 1983, 676.
33. Takase, H.; Nitanai, H.; Hoshino, K.; Otani, T. Infect. Immun. 2000, 1834, 68.
34. Hoegy, F.; Lee, X.; Noël, S.; Rognan, D.; Mislin, G. L. A.; Reimmann, C.; Schalk, I.
J. J. Biol. Chem. 2009, 284, 14949.