New fluorinated agonists for targeting the sphingosin-1-phosphate receptor 1 (S1P1)

Article abstract of DOI:10.1016/j.bmcl.2015.10.026

The sphingosine-1-phosphate receptor type 1 (S1P₁) is involved in fundamental biological processes such as regulation of immune cell trafficking, vascular barrier function and angiogenesis. This Letter presents multistep syntheses of various fluorine substituted 12-aryl analogues of the drug fingolimod (FTY720) and a seven-steps route to 2-amino-17,17-difluoro-2-(hydroxymethyl)heptadecan-1-ol. In vitro and in vivo tests proved all these compounds as potent S1P₁ receptor agonists.

Full text of DOI:10.1016/j.bmcl.2015.10.026

Bioorganic & Medicinal Chemistry Letters 25 (2015) 5048–5051
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
New fluorinated agonists for targeting the sphingosin-1-phosphate
receptor 1 (S1P1)
Rizwan S. Shaikh a,b,y, Petra Keul c,y, Michael Schäfers d,e,f, Bodo Levkau c, Günter Haufe a,e,f,
a Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, D-48149 Münster, Germany
⇑
b NRW Graduate School of Chemistry, Westfälische Wilhelms-Universität Münster, Wilhelm-Klemm-Straße 10, D-48149 Münster, Germany
c Institute for Pathophysiology, Westdeutsches Herz- und Gefäßzentrum, University Hospital, Essen, University of Duisburg-Essen, Hufelandstraße 55, D-45122 Essen, Germany
d Klinik für Nuklearmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A1, D-48149 Münster, Germany
e European Institute for Molecular Imaging—EIMI, Westfälische Wilhelms-Universität Münster, Waldeyerstraße 15, D-48149 Münster, Germany
f Cells-in-Motion Centre of Excellence, Westfälische Wilhelms-Universität Münster, Waldeyerstraße 15, D-48149 Münster, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The sphingosine-1-phosphate receptor type 1 (S1P1) is involved in fundamental biological processes such
as regulation of immune cell trafficking, vascular barrier function and angiogenesis. This Letter presents
multistep syntheses of various fluorine substituted 12-aryl analogues of the drug fingolimod (FTY720)
and a seven-steps route to 2-amino-17,17-difluoro-2-(hydroxymethyl)heptadecan-1-ol. In vitro and
in vivo tests proved all these compounds as potent S1P1 receptor agonists.
Received 17 July 2015
Revised 9 October 2015
Accepted 10 October 2015
Available online 22 October 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Fluorine
FTY720 analogues
G protein-coupled receptors
Sphingosine-1-phosphate (S1P)
S1P1 receptor agonist
Sphingosine-1-phosphate (1) is a signalling lysophospholipid
that regulates pleiotropic biological functions including prolifera-
tion, inflammation and survival.1 Phosphate 1 has a high affinity
for five cognate G-protein coupled receptors (S1P1–5), that function
as key regulators in several biological processes such as cell
growth, angiogenesis, immune regulation, morphogenesis, and
cardiovascular functions.2 Among the S1P receptors S1P1 exhibits
wide tissue distribution3 and plays a key role in vascular matura-
tion,4 angiogenesis,4 immune cell trafficking,5 cell motility and
neurogenesis.3 S1P1 agonists such as the phosphate of FTY720 (2,
Fingolimod) FTY720-P (3) (Fig. 1) possess an immunosuppressive
effect that results from lymphocyte trapping in secondary lym-
phoid tissues due to S1P1 downregulation.4 The role of S1P recep-
tor modulation by its natural ligand S1P has been in the focus of
intense activities form research organizations and pharmaceutical
industries.2
phosphorylation to produce the active compound FTY720-P (3).
Binding of 3 to the S1P1 receptor results in internalization and
degradation of the receptor.7 This process causes the inhibition of
T- and B-lymphocyte exit from secondary lymphoid organs into
peripheral blood resulting in so-called ‘lymphopenia’. Effector
and memory
T
cells remain in lymph nodes and thymus.8
Phosphate 3 is also an agonist to other S1P receptors such as
S1P3, S1P4, and S1P5. S1P3 agonism of 3 results in side effects such
as bradycardia in rodents.9 S1P4 is mainly expressed hematopoi-
etic, in dendritic cells and lymphocytes, which play a significant
role in differentiation of TH cells.10 S1P5 bears limited expression
pattern in brain on oligodendrocytes. Upon activation it decreases
transendothelial monocyte migration and enhances barrier
integrity, respectively.11
Studying S1P receptor signalling and biology is an important
area of research12 and various structural analogues of S1P,
FTY720 and compounds with completely different scaffold have
been reported as S1P1 receptor agonists.13 Presence of five sub-
types (S1P1–5) makes it more complicated to design and synthesize
subtype-selective agonists. Wide structural features of S1P recep-
tors and the non-specific binding of currently known S1P receptor
agonists leaves space for the development of S1P receptor-
selective ligands, which can lead to better understanding in S1P
receptor signalling and physiological processes.
FTY720 (2) was originally discovered by Fujita et al. based on
structure activity relationship (SAR) studies on Myriocin (ISP-1).6
Its biological efficacy indicated S1P receptors as potential targets
for the treatment of autoimmune diseases and allograft rejection.
In cells 2 undergoes sphingosine kinase 1 (SphK1) catalysed
⇑
Corresponding author.
y
These two authors have contributed equally to this work.
http://dx.doi.org/10.1016/j.bmcl.2015.10.026
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

R. S. Shaikh et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5048–5051
5049
NH2
NH2
OH
OH
OP(O)(OH)2
OH
1
2
R
NH2
OR
R = H, 4-F, 4-CF3, 3-SF5, 4-SF5, 2,3,4,5,6-F
OH
NH2
F
OH
F
(R = H)
OH
3 (R = P(O)(OH)2
Figure 2. Structures of synthesized FTY720 analogues.
Figure 1. Structure of sphingosine-1-phosphate (1), FTY720 (2) and FTY720-P (3).
Recently, we have shown that monofluoro substitution of an OH
group or of a hydrogen in the vicinity of the head group of
saturated analogues of FTY720 caused a drop of potency, while a
fluorine in terminal position did not significantly affect the
In 2012, Hanson et al. dissolved the crystal structure of S1P1
with
a
bound antagonist, (R)-{3-amino-4-[(3-hexylphenyl)
amino]-4-oxobutyl}phosphonic acid (W146), which bears an
aminophosphonate head group. This study revealed the key inter-
actions affiliated with the binding of phospho-sphingolipids and
other class I ligands bearing the amino diol head group, which
undergoes in vivo phosphorylation to give the zwitterionic
aminophosphate prodrug. The binding site of the S1P1 receptor is
highly amphipathic, which reflects its nature towards hydrophobic
and hydrophilic agonists and antagonists.14 The crystal structure
also explains the interaction of the m-alkylphenyl part of W146
with the short aliphatic residues surrounded by the large aromatic
hydrophobic pocket. This gives brief information about the interac-
tion of phenyl alkyl chain of both agonist and antagonist S1P1
ligands with the hydrophobic pocket and the zwitterionic head
group with amino acid residues in the binding pocket.14,15
Medicinal chemistry research of the last two decades has
proved that the use of fluorine or fluorinated groups containing
compounds has advantageous effects.16,17 Fluorine can mimic
hydrogen because of similar van-der-Waals radii (H is 1.2 Å and
F 1.47 Å)18 and thus fulfils the steric requirements in enzyme
pocket. It can serve as well as bio-isosteric oxygen replacement.19
Generally, fluorine increases the lipophilicity, enhances the rate of
absorption, increases the metabolic stability and its high
electronegativity alters the chemical reactivity of neighbouring
functional groups as well as electronic and physical proper-
ties.16,17,20 As compared to a single fluorine substituent, the
trifluoromethyl (CF3) and pentafluorosulfanyl (SF5) groups are
more electron withdrawing, more lipophilic and generally more
inert to metabolic transformation. These properties all together
are expected to improve nonpolar interactions of regioisomeric
and substituted analogues of FTY720 with the membrane.
in vivo activity.21 Therefore, we also scheduled synthesis of an
x,
x
-difluoroalkyl analogue of the mentioned agonist. Moreover, we
designed structural analogues of FTY720 possessing 2-amino-1,3-
diol head group for the polar interaction but shifted the phenyl ring
at the end of a 10 carbon chain and introduced p-fluoro-, p-triflu-
oromethyl-, m- and p-pentafluorosulfanyl-, and perfluorinated
phenyl rings in order to get more information about the role of flu-
orinated groups in terminal position of this type of S1P agonists
(Fig. 2).
All the synthesized molecules were evaluated for biological
activity in vivo by measuring their ability to induce lymphopenia
as readout for their effectiveness as S1P1 receptor agonists.
The linear synthetic route started from nonane-1,9-diol (4) to
access the Wittig salt 11 as shown in Scheme 1. The commercially
available 4 was refluxed with 48% HBr in toluene22 to give 9-bro-
mononan-1-ol (5).23 Nucleophilic substitution of bromide 5 with
diethyl N-Boc-2-aminomalonate under basic conditions gave the
2-alkylmalonate 6. The ester groups of 6 were reduced to the cor-
responding 2-amino-1,3-diol
7 using lithium borohydride in
THF.24 The 1,3-diol was protected with dimethoxy propane
in the presence of a catalytic amount of p-toluenesulfonic acid
in DCM25 to afford the acetonide 8. Under standard Schotten–
Baumann conditions, the free terminal hydroxyl group of 8 was
tosylated to give 9. Finkelstein reaction of 9 using sodium iodide
in acetone26 afforded iodide 10. Substitution of the iodide with
triphenylphosphine (TPP) under standard conditions in toluene
gave the key Wittig salt 11 in 21% overall yield over 7 steps
(Scheme 1).
NHBoc
BocHN
NHBoc
a,b
60%
g
c
d,e,f
HO
X
a
HO
OH
HO
X
O
COOEt
COOEt
5
5
5
5
75%
63%
72%
4
5
(X = OH)
(X = Br)
O
OH
7
6
8 (X = OH)
9 (X = OTs)
10 (X = I)
BocHN
5
BocHN
5
NH2
BocHN
5
O
O
OH
IPh3P
O
j
h
i
5
O
O
OH
O
R
R
R
11
12 (R = 4-SF5), 83% 15
13 (R = 4-CF3), 72% 16
14 (R = 3-SF5), 87% 17
18 (R = 4-SF5), 75%
19 (R = 4-CF3), 73%
20 (R = 3-SF5), 76%
(R = 4-F), 75%
(R = 2,3,4,5,6-F), 85%
(R = H), 72%
(R = 4-F), 80%
(R = 2,3,4,5,6-F), 81%
(R = H), 73%
24 (R = 4-SF5), 63%
25 (R = 4-CF3), 53%
26 (R = 3-SF5), 49%
21
22
23
27
28
29
(R = 4-F), 65%
(R = 2,3,4,5,6-F), 38%
(R = H), 70%
Scheme 1. Synthesis of
x-aryl substituted analogues 24–29 of FTY720: Reagents and conditions: (a) 48% HBr, toluene, reflux, 6 h (80% of 5); (b) diethyl N-Boc-2-
aminomalonate, Cs2CO3, MeCN, reflux, 12 h (75% of 6); (c) LiBH4, THF, rt, 2 days (75% of 7); (d) dimethoxypropane, p-TsOH, DCM, 0 °C–rt, 12 h (98% of 8); (e) TsCl, DMAP, TEA,
DCM, 0 °C–rt, 12 h (71% of 9); (f) NaI, acetone, reflux, 2 h (91% of 10); (g) TPP, toluene, reflux, 12 h (72% of 11); (h) ArCHO, K2CO3, toluene, reflux, 12 h; (i) H2, Pd/C, EtOAc, rt,
1.5 h; (j) TFA, DCM, 0 °C–rt, 12 h.

5050
R. S. Shaikh et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5048–5051
The Wittig salt 11 was converted to various crucial intermedi-
and the acetonide groups with trifluoroacetic acid (TFA) gave 12-
ates required for the synthesis of FTY720 analogues as shown in
Scheme 1. Wittig reaction with substituted benzaldehydes in the
presence of potassium carbonate in toluene at 120 °C afforded
the olefins 12–17, which were hydrogenated with H2 over acti-
vated palladium on carbon to yield 18–23. Hydrolysis of the Boc
aryl analogues 24–29 of FTY720 in 26–42% yields over three steps.
A series of
x-monofluorinated analogues of FTY720 and its
shorter chain homologues have been synthesized and tested for
their immunosuppressive activity in our group earlier. These com-
pounds exhibited excellent potency to induce blood lymphopenia
resulting from lymphocyte trapping in secondary lymphoid
organs.27 Encouraged from the results obtained from these
monofluorinated ligands, we decided to synthesized an
orinated analogue. The complete synthetic pathway is depicted in
Scheme 2.
x,x-diflu-
O
a
b
O
Br
OH
HO
HO
12
12
97%
85%
The synthesis commenced with commercially available pen-
tadecanolide (30), which was reduced to diol 3128 using LAH in
THF, followed by a nucleophilic substitution using 48% HBr in
refluxing toluene22 to afford 15-bromopentadecanol (32).29 The
reaction of 32 with diethyl 2-acetamidomalonate in MeCN in the
presence of Cs2CO3 gave the diester 33 in moderate yield. Swern
oxidation of the terminal hydroxyl group gave the aldehyde 34,
12
30
31
NHAc
32
NHAc
O
d
c
HO
H
COOEt
COOEt
COOEt
COOEt
12
12
12
34
37%
82%
33
35
F
which was treated with DAST30 to give the
x,x-difluoro intermedi-
NHAc
OH
F
NHAc
e
f
ate 35. Reduction of the ester groups with LiBH4 in THF and subse-
quent hydrolysis of the amide 36 with LiOH in MeOH/H2O gave 2-
amino-17,17-difluoro-2-(hydroxymethyl)heptadecan-1-ol (37).
Having the new S1P ligands 24–29 and 37 in hand, their agonist
activities were tested in vitro in comparison to original S1P (1)
using Chinese Hamster Ovary (CHO) cells overexpressing the
human S1P1 (CHO-S1P1) and by means of the phosphorylation sta-
tus of the p44/42 mitogen activated kinases (MAPK) as the func-
tional (signalling) readout. Cells were stimulated with
F
F
F
COOEt
COOEt
12
36
53%
74%
OH
F
NH2
g
OH
12
38%
OH
37
Scheme 2. Synthesis of
x,x-difluorinated structural analogue of FTY720: Reagents
compounds 24–29, 37 and S1P (1) at 1 lm for different times
and conditions: (a) LAH, THF, 0 °C–rt, 2 h; (b) 48% HBr, toluene, reflux, 5 h; (c)
diethyl 2-acetamido-malonate, Cs2CO3, MeCN, reflux, 6 h; (d) oxalyl chloride,
DMSO, TEA, ꢀ78 °C to rt, DCM; (e) DAST, DCM, ꢀ78 °C to rt; (f) LiBH4, THF, 0 °C–rt;
(g) LiOH, 1:1 MeOH/H2O, reflux, 6 h.
and Western blotting was performed with cell lysates using a
phospho-specific antibody (Thr202/Tyr204) for the dually phos-
phorylated active form (Fig. 3).
Figure 3. Activation of p44/42 MAPK by 1 lm S1P, 24–29 and 37 in CHO-S1P1 cells. The phosphorylation status of p42/44 MAPK after stimulation with each compound was
determined by Western blotting and densitometric analysis by building the ratio of phosphorylated p42/44 (p42/44 phospho) to total p42/44 (p42/44 total) kinase signal in
arbitrary units (A.U.). Shown are the means of at least 3 independent experiments. Representative Western blots are shown at the bottom.

R. S. Shaikh et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5048–5051
5051
Table 1
References and notes
Immunosuppressive activity of 2 and 37
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Compound WBC (106/ CD4+
CD8+
B cells
Activity
(%)
mL)
(106/mL)
(106/mL)
(106/mL)
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Control
FTY720 (2) 3.69 0.63 0.02 0.00 0.04 0.01 0.61 0.12
37 1.67 0.33 0.03 0.00 0.04 0.01 0.29 0.07
8.94 0.59 0.73 0.07 0.48 0.05 4.72 0.53
97
95
3
3
Compounds were injected intraperitoneally and blood cells were measured after
24 h in peripheral blood. Data are expressed as mean SEM from experiments
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All synthesized compounds show agonist activity. However,
there are clear differences in both the kinetics and maximal
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2.5–5 min. The other compounds are less active than S1P at
2.5 min (all compounds) and 5 min (all but 37) and have their max-
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potent as S1P at 10 min (Fig. 3). It should be noted that the delay
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decan-1-ol (37) is as potent as S1P (1) it was also tested for
in vivo activity by measuring its effectiveness to induce lymphope-
nia in comparison with 2. Both compounds were injected at
1.25 mg/kg intraperitoneally into mice and peripheral blood was
analysed for CD4+ and CD8+ T-cells as well as B-cells. Biological
activity was expressed as percent inhibition of CD4+ lymphocyte
counts compared to control values (Table 1). The extent of lym-
phopenia induced by 37 (95%) was comparable to that induced
by FTY720 (97%). Since the in vitro potency of the fluorinated aryl
compounds 24–28 and 29 was less compared to the difluoride 37,
they were not tested in vivo.
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Various
x-aryl 24–29 and x,x-difluoro 37 analogues of FTY720
have been synthesized and tested in vitro for their agonist activity
towards S1P1. The m-pentafluorosulfanyl substituted aryl analogue
26, the first pentafluorosulfanyl derived S1P1 receptor agonist
showed higher in vitro potency as compared to its p-substituted
isomer 24 and the p-CF3 compound 25. The p-fluorophenyl ana-
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best active among the three. The 2-amino-17,17-difluoro-2-
(hydroxymethyl)heptadecan-1-ol (37), exhibited the highest
in vitro potency that was delayed but comparable in maximum
effectiveness to S1P. Therefore, compound 37 was further tested
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Acknowledgements
This work was supported in part by the Deutsche Forschungsge-
meinschaft, Germany (Collaborative Research Center, SFB 656, pro-
jects A06, and C06). R.S.S. is grateful to the NRW International
Graduate School of Chemistry, University of Münster (GSC-MS)
for a scholarship.
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Supplementary data
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Supplementary data (synthetic procedures, spectroscopic data
and copies of NMR spectra) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.bmcl.
2015.10.026.