Squaryl group modified phosphoglycolipid analogs as potential modulators of GPR55

Article abstract of DOI:10.1039/c8cc04467h

Lysophosphatidyl glucoside (LPGlc) is a structurally unique glycolipid that acts as a guidance cue for extending axons during central nervous system development by activating the class A G protein coupled receptor (GPR) 55 of spinal cord sensory axons. GPR55 not only plays an important role during development, but is also implicated in many disease states, rendering molecules that target GPR55 of widespread interest. In this study, we developed synthetic access to a novel class of LPGlc analogues featuring a squaryl diamide group as surrogate for the phosphodiester. We report the facile synthesis of a series of LPGlc analogues, their GPR dependent biological activity and a systematic analysis of the structure-activity relationship in regards to GPR55 modulation. The lead compound featuring identical configuration at all stereocenters compared to natural LPGlc exhibits an activity to repel axons of dorsal root ganglion (DGR) nociceptive neurons.

Full text of DOI:10.1039/c8cc04467h

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first methanofullerene derivatives of Sc
3
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Squaryl Group Modified Phosphoglycolipid Analogs as Potential
Modulators of GPR55
Received 00th January 20xx,
Accepted 00th January 20xx
a,†
b,†
b
c
*b
Feiqing Ding, Adam T. Guy, Peter Greimel, Yoshio Hirabayashi, Hiroyuki Kamiguchi, and
*a
Yukishige Ito
DOI: 10.1039/x0xx00000x
www.rsc.org/
8
a structurally unique cannabinoid receptor but more recently lysophosphatidyl
Lysophosphatidyl glucoside (LPGlc) is
9
5
glycolipid that acts as a guidance cue for extending axons during inositol and LPGlc have been reported as its endogenous
central nervous system development by activating the class A G ligands. It has been shown that GPR55 plays important roles in
5
protein coupled receptor (GPR) 55 of spinal cord sensory axons. development and is implicated in many disease states such
,6
1
0
11
12
GPR55 not only plays an important role during development, but as neuropathic pain, cancer, and inflammation. To-date a
is also implicated in many disease states, rendering molecules that number of GPR55 agonists and antagonists have been
1
3,14
target GPR55 of widespread interest. In this study, we developed developed,
but the need for new specific GPR55 ligands
1
synthetic access to a novel class of LPGlc analogues featuring a remains, for both clinical and research needs.
5
OH
squaryl diamide group as surrogate for the phosphodiester. We
report the facile synthesis of a series of LPGlc analogues, their GPR
dependent biological activity and a systematic analysis of the
structure-activity relationship in regards to GPR55 modulation.
The lead compound featuring identical configuration at all
stereocenters compared to natural LPGlc exhibits an activity to
repel axons of dorsal root ganglion (DGR) nociceptive neurons.
OH
OH
OR
R
H
N
H
N
O
O
HO
HO
S
S
(CH2)16CH3
HO
HO
O
O
O
2 3
(CH )16CH
P
OH
OH
Oꢀ
O
O
O
O
1
A
OH
OH
PtdGlc CO(CH2)18CH3
LPGlc
H
N
H
N
O
HO
HO
(CH2)16CH3
H
OH
2+
ꢀ
ꢀ
O
O
Scheme 1 Structures of PtdGlc, LPGlc, and a squaryl analogue 1A
.
Phosphatidyl-β-
D-glucoside (PtdGlc) is a structurally unique
glycolipid (Scheme 1) which was identified in mammalian cells
To develop a new class of GPR55 modulators, we sought an
approach based on the recently identified native ligand
structure. LPGlc degradation is expected to proceed either via
the phosphodiester (PDE) or the fatty acid (FA) ester group.
The PDE links the carbohydrate head group with the sn-3
position of the glycerol backbone, while the FA ester attached
to the sn-1 position. Consequently, we envisaged to replace
1
in 2001. The proposed structure was rigorously confirmed by
2
3
chemical synthesis. Mammalian PtdGlc exhibits a strikingly
homogeneous fatty acid composition and is enriched in lipid
4
rafts. More recently, we revealed that PtdGlc is locally
converted to lyso-phosphatidyl-β-
D-glucoside (LPGlc, Scheme
1), released from radial glia in the developing spinal cord and
regulates sensory axon wiring by specifically repelling nerve
growth factor (NGF)-responsive dorsal root ganglion (DRG)
5
axons. Extensive screening of G-protein coupled receptors
16
them with appropriate bioisosteres. As a suitable PDE
surrogate, we identified the squaryl (SQ) group, which has
been exploited as a bidirectional electrophile suitable for
identified GPR55 as a receptor of LPGlc.
17
18
glycan conjugation and protein labeling. The migration
prone FA ester was planned to be replaced by a thioether to
not only increase the stability but also to satisfy the demand
for ease and economy of production. In this context, LPGlc FA
ester to ether exchange did not abrogate the activity of LPGlc,
while the amide analogue was completely inactive (Guy,
Greimel, et al., unpublished). Additionally, the mannose and
GPR55 is a class A G-protein coupled receptor first identified
6
7
in 1999. It is expressed in various organs including central
and peripheral nervous systems, gastrointestinal tract, bone,
and immune systems. Initially it was considered as
a
5
galactose analogues of LPGlc are also inactive, strongly
suggesting to preserve the equatorial configuration of the C-2
and -4 hydroxy group of the glucose residue. Based on the
above rationale, compound 1A (Scheme 1) was envisaged as
our lead compound. Sekine and co-workers reported that
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Journal Name
analogue, a considerable number of potential energy minima
is observed, with no obvious rotational barrier present in the
anomeric linkage between the pyranose analogue and the
squaryl group. The conformational space of
against representative conformations of each of the identified
potential energy minima in , based on their ability to
reproduce one of the carbonyl oxygen and the methyl group
positions in . This revealed that can mimic each of the three
identified potential energy minima conformations of
3 was ranked
2
2
3
2
adequately without the need to attain energetically
unfavourable conformations. Superimposition of the lowest
energy conformer of
I
2
minima and an equivalent conformation of
associated with potential energy
, less than 3
3
kcal/mol above its respective lowest energy, reveals their high
degree of similarity (Figure 1b). Equally matching
conformations of
3 with conformations of 2 associated with
potential energy minima II and III exhibited similar energy
penalties (Supporting information Figure S5). This suggests
that the envisaged glucose residue in combination with the
Figure 1 (a) Energy landscape and conformational similarity of equatorial phosphate 2
with equatorial squarate 3 on a pyranose ring, based on QM free energy calculations.
(
b) The lowest energy conformation of compound 2 is superimposed on the most
closest matching conformation of compound 3. Carbon, cyan or iceblue; oxygen, red or squaryl aglycon is able to attain highly similar conformations
magenta; hydrogen, white or grey; nitrogen, blue; phosphorous, tan.
compared to LPGlc and thus exhibits a high potential to fit into
(a)
squaryl diamides are polarizable and mimic PDE linkage in DNA
9
oligomers.
O
1) DTBAD
PPh3
O
TBSCl
imidazole
O
1
OH
OTBS
Br
KSAc
O
NH
+
HO
N
Br
N
N
2)
HBr
DCM
94%
THF
92%
To better understand the conformational characteristics of
the squaryl group compared to an anomeric phosphate we
performed quantum mechanics calculation of model
O
O
O
O
(
S)ꢀglycidol 80% for 2 steps
9s
10s
O
OTBS
O
O
Br
OTBS
SAc
NaOMe
OTBS
16
S
N
N
SH
MeOH
94%
16
NaH
90%
O
O
13s
compounds
2
and
3
(Figure 1a). The analysis revealed the
11s
12s
OH
presence of three potential energy minima (Figure 1a, labeled
I, II and III) in case of an anomeric PDE and a clear rotational
1) TBAF
H2N
S
2
)
hydrazine
16
6A
8
5% for 2 steps
O
OTBS
OH
O O
1
3s
O
O
1) TBAF
barrier of the anomeric bond between -45
º
<
φ
good agreement with reported NMR results of the LPGlc
< 45º. This is in
H2
N
S
64%
N
S
2) hydrazine
88% for 2 steps
1
6
6
Oxone
O
1
6
6B
1
4s
DCM
O
OTBS
OH
O
S
O
1) TBAF
N
S
H2N
(
a)
2) hydrazine
1
30%
16
G
NH2
L
NH2
OEt
O
15s
85% for 2 steps
6C
(
b)
H
N
H
N
H
N
EtO
O
OEt
O
G
G
L
OH
O
OH
6A
H
N
H
N
HO
S
OH
O
HO
76%
OH
O
O
O
O
OH
16
6D
HO
HO
H
N
H
S
DES
O
O
O
1A
72%
OH
16
X
L
X
OH
O
O
H
N
H
N
H
N
OH
OH
O
O
O
O
NH2
H2N
S
(CH2)nCH3
S
(CH2)nCH3
H
N
6B
1D
HO
HO
S
OH
16
OH
O
OH
O
O
71%
H
N
G
NH2
NH2
6E
H
N
O
O
O
O
1B
HO
HO
S
5
(
b)
1
OH
O
OH
16
76%
O
S
R
H
N
H
N
6C
O
O
/6/8
HO
HO
OH
OH
1E
OH
O
H
N
H
OH
16
61%
OH
O
HO
HO
N
R
OH
O
A
S
(CH2)16CH3
(CH2)16CH3
O
H
N
H
N
HO
HO
O
O
1C
6F
NH2
HO
HO
S
OH
OH
OH
OH
16
OH O
O
O
H
N
H
63%
O
O
HO
HO
N
S
B
C
D
6G
O
O
S
1
4
6
OH
16
1F
8
3%
OH
O
S
O
O
1G
OH
OH
O
H
(CH2)16CH3
(CH2)16CH3
(CH2)16CH3
HO
HO
OEt
N
OH
OH
H
H
N
6A
O
S
OH
HO
HO
N
H2N
R
OH
16
76%
6D
H
N
H
N
OH
OH
S
O
O
HO
HO
O
S
S
O
O
8
A
78%
OH
16
16
5
OH O O
S
E
F
H
H
N
O
O
O
O
O
6B
H
N
H
N
H
N
HO
HO
N
S
7
O
O
8D
HO
HO
OEt HO
HO
R
16
OH
75%
O
O
OH
O
S
OH
OH
6
E
O
H
N
H
N
O
O
8B
HO
HO
(CH2)16CH3
(CH2)16CH3
O
O
O
O
70%
OH
O
H
N
H
N
S
6G
HO
HO
O
O
G
S
7
8
OH
16
8E
8
0%
O
O
8G
Scheme 2 (a) Synthetic strategy, X = -OH (S), -OH (R) or H. (b) Structures of
synthetic blocks and LPGlc analogues.
Scheme 3 Syntheses of (a) chiral building blocks and (b) LPGlc analogues.
2
parent compound phosphatidylglucoside. Interestingly, all
0
the GPR55 binding pocket.
+
–
potential energy minima of
conformation of the second inner dihedral of the PDE
Supporting information Figure S4). In case of the squaryl
2 exhibit either gauch or gauch
Our synthetic strategy for the envisaged LPGlc analogues is
outlined in Scheme 2a. It is based on three fragments, namely
(
2
glycosylamine (G-NH ), squaryl diester (DES), and lipid
2
| J. Name., 2012, 00, 1-3
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component (L-NH
2
). As the sequential coupling of these homochiral forms, they were synthesized from (S)- or (R)-
gave
-xylose analogues 8A-
components can be achieved without additional protection- glycidol as starting materials. Subsequent reaction with
deprotection, facile synthesis of various analogues is 1A (Scheme 3b). In a similar manner,
were prepared from
To confirm the relevance of our design of LPGlc analogues,
5
a
-G
D
possible. This strategy also enables access to an array of
molecules differing in chain length, stereochemistry, and
E
7.
functional groups. In addition, further diversification is activity of 1A to initiate axon turning was evaluated in
possible by oxidation of the thioether to sulfoxide or sulfone, comparison with its diastereomer 1D and the xylose analogue
to allow a broader characterization of the GPR55 binding 8A, along with sulfones 1B and 1E (Figure 2a). Assay was
5
conducted as previously reported with some modifications.
pocket.
To begin with, glucosylamine
2
4
1
readily available from Glc Exploratory experiments (Figure 2b) conducted at in-pipette
was reacted with diethyl squarate to give mono amide
5
concentration of 10 µM (approximately 10 nM near the tip of
axons) (Figure 2b) indicated that the compound 1A has the
most favourable activity to repel axons of DRG nociceptive
neurons. Higher chemorepulsive response was observed when
(
a)
OH
6
OH
H
N
H
N
OH
OH
O O
O
HO
HO
S
(CH2)16CH3
2′
S
2 3
(CH )16CH
OH
the in-pipette concentration was increased to 20 µM (Figure
2c,d), comparable to the native LPGlc . On the other hand, no
O
O
5
1
A
1B
OH
O
O
significant activity was observed for other compounds
22,23
S
(CH2)16CH3
OH
S
(CH2)16CH3
including the diastereomer 1D and the xylose analogue 8A
.
1
D
1E
These results indicate the importance of C-6 and C-2’ hydroxy
groups in order for LPGlc analogues to activate GPR55. The
potent analogue 1A did not affect axon extension (Figure S-2),
O
H
N
H
N
HO
HO
S
(CH2)16CH3
OH
O
O
8
A
14c
and was blocked by the specific GPR55 inhibitor ML193,
(b)
(c)
indicating that it indeed acts on GPR55.
In conclusion, we developed a facile and modular strategy to
create novel class of LPGlc analogues. Compound 1A
,
exhibiting identical stereoconfiguration of its hydroxy groups
as native LPGlc, showed the expected LPGlc-like activity to
repel DRG nociceptive axons. This confirmed our initial
hypothesis that the squaryl group can act as a bioisostere of
anomeric phosphodiesters. Failure of the xylose analogue 8A
to stimulate GPR55, similar to the Gal and Man analogues
reported previously, further augments the high preference of
the GPR55 binding pocket towards glucose head groups. The
inactivity of the sulfone analogues, such as 1B, suggests the
presence of spatial constraints close to the FA ester position.
Based on this strategy, systematic synthesis of LPGlc analogues
as potential modulators of GPR55 is possible and a more
comprehensive structure-activity relationship study along this
line is underway.
(d)
This work was supported by Grants-in Aid for Scientific
Research 16H0629 (YI), 17K14970 (ATG), and 16K08259 (PG)
from Japan Society for the Promotion of Science, AMED-CREST
Grant JP18gm0910006 (HK), Special Postdoctoral Program (FD)
and Integrated Lipidology Program (PG, YH) of RIKEN. We
Figure 2 (a) LPGlc analogues used for axon turning assay. (b) Biological activity of thank Dr. Hiroyuki Koshino for NMR measurements, Dr.
squaryl group modified analogues assessed by axon turning assay. Compounds
Takemichi Nakamura for mass spectroscopy measurements,
were tested at an in-pipette concentration of 10 µM. Bars show mean turning
angle ± SEM, numbers in parentheses indicate the number of axons tested. (c) and Akemi Takahashi for technical assistance. The computing
Effect of GPR55 inhibitor on chemorepulsive response to compound 1A
Compound 1A was used at an intrapipette concentration of 20 µM. Treating
axons with bath-applied ML193, a specific inhibitor of GPR55, abolished 1A
.
resources were provided in part by the HOKUSAI-GreatWave
system at RIKEN. We are indebted to Dr. Atsushi Miyawaki and
-
induced chemorepulsion. Bars show mean turning angle ± SEM, numbers in Dr. Yasushi Sako for their support.
parentheses indicate the number of axons tested. **P<0.01, Kruskal-Wallis test.
d) Representative images of axon turning assays using compound 1A. Numbers
(
in each panel show the minutes after onset of concentration gradient, arrows
indicate the source of the gradient. Scale bar, 10 µm. Assay conditions are Conflicts of interest
further described in the supporting information.
There are no conflicts to declare.
(Scheme 2b). On the other hand, a small library of the lipid
component (6A-G) was created (see Supporting Information)
as exemplified for 6A (Scheme 3a). To obtain 6A-F in
Notes and references
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DOI: 10.1039/C8CC04467H
Squaryl Group Modified Phosphoglycolipid Analogs as
Potential Modulators of GPR55
Feiqing Ding,a,† Adam T. Guy,b,† Peter Greimel,b Yoshio Hirabayashi,c Hiroyuki
Kamiguchi,*b and Yukishige Ito*a
We report the facile synthesis of a series of LPGlc analogs, their GPR dependent
biological activity and a systematic analysis of the structure-activity relationship in
regards to GPR55 modulation.