Synthesis and Selectin-Blocking Activity of a Novel Analog of Sulfatide: 3-C-Carboxymethylgalactosyl Lipid

Article abstract of DOI:10.1081/CAR-120026455

The 3-C-carboxymethylgalactose derivative carrying the 2-(tetradecyl) hexadecyl residue, which was designed as a novel analog of sulfatide, was synthesized. A key intermediate, 3-C-carboxymethylgalactose, was prepared from the suitably protected galactose

Full text of DOI:10.1081/CAR-120026455

Journal of Carbohydrate Chemistry
ISSN: 0732-8303 (Print) 1532-2327 (Online) Journal homepage: http://www.tandfonline.com/loi/lcar20
Synthesis and Selectin‐Blocking Activity of a Novel
Analog of Sulfatide: 3‐C‐Carboxymethylgalactosyl
Lipid
Ai Ishihara , Hideharu Ishida , Takao Ikami , Noboru Tomiya , Hiromune
Ando & Makoto Kiso
To cite this article: Ai Ishihara , Hideharu Ishida , Takao Ikami , Noboru Tomiya , Hiromune
Ando & Makoto Kiso (2003) Synthesis and Selectin‐Blocking Activity of a Novel Analog of
Sulfatide: 3‐C‐Carboxymethylgalactosyl Lipid , Journal of Carbohydrate Chemistry, 22:7-8,
513-520, DOI: 10.1081/CAR-120026455
To link to this article: http://dx.doi.org/10.1081/CAR-120026455
Published online: 23 Feb 2007.
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Date: 20 June 2016, At: 15:30

JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 22, Nos. 7 & 8, pp. 513–520, 2003
Synthesis and Selectin-Blocking Activity
of a Novel Analog of Sulfatide:
3-C-Carboxymethylgalactosyl Lipidy,#
2
2
Ai Ishihara,1 Hideharu Ishida,1, Takao Ikami, Noboru Tomiya,
*
Hiromune Ando,1 and Makoto Kiso1,
*
1Department of Applied Bioorganic Chemistry, Gifu University, Gifu, Japan
2Drug Discovery Research Department, Sanwa Kagaku
Kenkyusho Co., Hokusei-cho, Mie, Japan
ABSTRACT
The 3-C-carboxymethylgalactose derivative carrying the 2-(tetradecyl)hexadecyl
residue, which was designed as a novel analog of sulfatide, was synthesized. A key
intermediate, 3-C-carboxymethylgalactose, was prepared from the suitably protected
galactose by Swern oxidation and Wittig-Horner carboxymethylenation, followed by
stereoselective reduction of the double bond. The compound obtained showed much
more potent activity as a selectin blocker than the 3-O-sulfogalactose derivative with
2-(tetradecyl)hexadecyl residue.
Key Words: Selectin; Sulfatide; Inflammation; 3-C-carboxymethylgalactose.
yThis paper is dedicated to Professor Ge´rard Descotes on the occasion of his 70th birthday.
[1]
.
#Synthetic studies on sialoglycoconjugates, Part 131. For Part 130, see Ref.
*
Correspondence: H. Ishida and M. Kiso, Department of Applied Bioorganic Chemistry, Gifu
University, Gifu 501-1193, Japan; E-mail: ishida@cc.gifu-u.ac.jp; E-mail: kiso@cc.gifu-u.ac.jp.
513
DOI: 10.1081/CAR-120026455
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright D 2003 by Marcel Dekker, Inc.

514
Ishihara et al.
INTRODUCTION
Cell adhesion molecules (CAMs) play a crucial role during inflammatory con-
ditions in several immune disorders by recruiting leukocytes to the injured area.[2]
The selectins are a family of CAMs composed of three structurally related carbo-
hydrate-binding proteins (E-, L-, and P-selectin).[3–6] E-and P-selectin are induced on
the endothelial surface in response to inflammatory signals, whereas L-selectin is
constitutively expressed on all circulating leukocytes and interacts with cognate ligands
on endothelial cells. It is now well-accepted that all three selectins can efficiently
recognize sialyl LeX [Neu5Aca2-3Galb1-4(Fuca1-3)GlcNAc].[7] However, sulfatide (I,
Figure 1), one of the major acidic glycosphingolipids in mammalian tissues, was found
to be a good ligand for L-and P-selectin.[8] It shows highly protective effects against
selectin-dependent inflammatory lung injury.[9,10]
In view of these facts, we describe herein the synthesis and selectin-blocking
activity of a novel sulfatide analog containing 3-C-carboxymethylgalactose as part of
our search for selectin inhibitors.[11]
RESULTS AND DISCUSSION
The target compound (III) (Figure 1) was designed based on previous results
indicating that the 2-(tetradecyl)hexadecyl group could serve as a ceramide subs-
titute,[12,13] and that 3-C-carboxymethyl Lex was much more potent than the corres-
ponding sialyl Lex derivative in the ligand-selectin competitive binding assay.[14]
Figure 1. Structures of sulfatide and its analogs.

3-C-Carboxymethylgalactosyl Lipid
515
Scheme 1. I: COCl2, DMSO, Et3N; ii: diethylphosphonoacetate, MeONa, iii: H2, Pd-C; iv:
benzoyl chloride, pyr.; v: TFA; vi: CCl3CN, DBU; vii: 2-(tetradecyl)hexadecan-1-ol, TMSOTf;
viii: MeONa and then H2O (NaOH).
For the synthesis of the required 3-C-carboxymethylgalactose moiety, 2-
(trimethylsilyl)ethyl 2,4,6-tri-O-benzyl-b-D-galactopyranoside (1)[15] was employed as
a suitable starting material (Scheme 1). Oxidation[16] of 1 with oxalyl chloride and
dimethyl sulfoxide gave the 3-ulose derivative 2, which, on treatment[17] with ethyl
diethylphosphonoacetate in the presence of sodium methoxide, afforded the methyl
ester of the 3-C-carboxymethylene derivative 3 (83% in two steps) as a 1:1 mixture of
E,Z-isomers. Transesterification from ethyl to methyl was observed during the course of
the reaction. Catalytic hydrogenation of 3 over 10% palladium-on-charcoal in 4:1
methanol-acetic acid at rt gave the desired 3-C-carboxymethylgalactoside 4 stereo-
1
selectively. Benzoylation of 4 gave 5 (73% from 3). In the H NMR spectrum of 5, H-2
(dd, J1,2 7.7 Hz, J2,3 11.2 Hz) was observed at d 5.54, indicating the configuration of
the substituent at C-3 to be equatorial. Compound 5 was converted into the a-
trichloroacetimidate donor 7 by selective removal of 2-(trimethylsilyl)ethyl group with

516
Ishihara et al.
Table 1. Selectin-blocking activity of sulfatide analogs.
% inhibition at 0.3 mM
Compound
P-selectin
L-selectin
E-selectin
III
II
sLex
79
6
3
3
6
92
13
0
3
3
5
12
0
8
5
4
3
0
Each value represents the mean S.E. of 5 wells.
trifluoroacetic acid (98%), and subsequent imidate formation (88%).[18–20] Glycosyl-
ation of 2-(tetradecyl)hexadecanol with 7 in dichloromethane in the presence of
trimethylsilyl trifluoromethanesulfonate gave only the desired b-glycoside 8 in 95%
yield, as indicated by the one-proton doublet at d 4.66 ppm (d, J1,2 7.7 Hz) assigned to
1
H-1 in the H NMR spectrum of 8. O-Debenzoylation of 8 with sodium methoxide in
methanol, and subsequent saponification of the methyl ester group by addition of water,
yielded the desired 3-C-carboxymethylgalactosyl lipid III in 85% yield.
The activity of the target compound in vitro was measured in adhesion assays in
terms of the inhibition of the binding of sialyl Lex expressing HL-60 cells to recom-
binant human selectin-IgG fusion proteins.[21,22] The synthesized glycolipid (III) was
significantly more potent than the sialyl Lex tetrasaccharide and 3-O-sulfogalactosyl
lipid (II) to block the adhesion to P-and L-selectin (Table 1). Taking into consideration
that the 3-C-carboxymethylgalactose residue is expected to be more stable to both
chemical and enzymatic degradations than the corresponding sialyl- or sulfo deriva-
tives, the glycolipid synthesized here is viewed as a promising therapeutic agent against
selectin-dependent inflammation.
EXPERIMENTAL
General procedures. Optical rotations were determined with a Union PM-201
polarimeter at 25°C, and IR spectra were recorded with a Jasco IRA-100 spec-
trophotometer. H NMR spectra were recorded at 400 or 200 MHz with a Varian Inova
1
400 or Varian Gemini-2000 spectrometer using deuterated solvents (CDCl3) with TMS
as the internal standard. TLC was performed on Silica Gel 60 (E. Merck), and column
chromatography on silica gel (Fuji Silysia Co., 300 mesh) was accomplished with the
specified solvent systems (v/v). Concentrations were conducted in vacuo.
2-(Trimethylsilyl)ethyl 2,4,6-tri-O-benzoyl-3-deoxy-3-C-(methoxycarbonyl-
methyl)- -D-galactopyranoside (5). Oxalyl chloride (174 mL, 2.0 mmol) and
dimethyl sulfoxide (283 mL, 3.99 mmol) were added to dichloromethane (3 mL) at
ꢀ50°C, and stirred under a nitrogen atmosphere for 10 min at ꢀ50°C. After the
addition of 1 (1.0 g, 1.82 mmol), the mixture was stirred for a further 30 min at ꢀ50°C.
Triethylamine (1.3 mL, 9.07 mmol) was added, and the mixture was washed with brine.
The organic layer was dried over Na2SO4, and concentrated to give the corresponding
ketone 2; IR (film): 3075ꢀ2850 (CH), 1725 (C O) and 710 (phenyl) cmꢀ1
.

3-C-Carboxymethylgalactosyl Lipid
517
A solution of ethyl diethylphosphonoacetate (329 mL, 2.36 mmol) and methanolic
sodium methoxide freshly prepared from sodium (200 mg, 8.9 mmol) and methanol
(4.4 mL), was stirred for 10 min at rt. After addition of 2, the mixture was stirred for
1 h at rt and washed with water. The organic layer was dried over Na2SO4 and con-
centrated to a syrup, which was chromatographed on a column of silica gel with 1:10
ethyl acetate-hexane to give 3 (911 mg, 83% in two steps) as a mixture of E,Z-isomers.
A solution of 3 (500 mg, 827 mmmol) in methanol (164 mL) and acetic acid (36
mL) was treated with hydrogen over 10% Pd-C (500 mg) for 6 h at rt. The insoluble
materials were removed by filtration and the filtrate was concentrated to give 4. The
residue was dissolved in pyridine (3 mL) and treated with benzoyl chloride (346 mL,
2.98 mmol) for 12 h at rt. The mixture was diluted with chloroform and washed with
2M HCl and water, dried over Na2SO4, and concentrated. The obtained syrup was
chromatographed on a column of silica gel with 1:4 ethyl acetate-hexane to give 5 (390
mg, 73%) as an amorphous mass; [a]D + 16 (c 4.5, CHCl3); IR (film): 3075ꢀ2850
1
(CH), 1750 (methyl ester), 1740 and 1240 (benzoate) and 710 (phenyl) cmꢀ1; H NMR
(CDCl3) d 1.03 (m, 2H, (CH3)3SiCH2CH2O), 2.55 (m, 2H, CH2COOCH3), 3.03 (m, 1H,
H-3), 3.52 (s, 3H, COOCH3), 3.66 (m, 1H, (CH3)3SiCH2CH2O), 4.15 (m, 1H, (CH3)3
SiCH2CH2O), 4.40 (t, 1H, J5,6b = 5.6 Hz, H-5), 4.53 (dd, 1H, Jgem = 11.3 Hz, H-6a),
4.64 (dd, 1H, H-6b), 4.90 (d, 1H, J1,2 = 7.7 Hz, H-1), 5.54 (dd, 1H, J2,3 = 11.2 Hz, H-
2), 5.87 (d, 1H, H-4), 7.34–8.24 (m, 15H, 3Ph).
Anal. Calcd for C35H40O10Si: C, 64.80; H, 6.21. Found: C, 64.56; H, 5.98.
2,4,6-Tri-O-benzoyl-3-deoxy-3-C-(methoxycarbonylmethyl)-D-galactopyranose
(6). To a solution of 5 (342 mg, 527 mmol) in dichloromethane, cooled to 0°C, was
added trifluoroacetic acid (5 mL), and the mixture was stirred for 1 h at rt. Ethyl
acetate was added at 0°C, and the mixture was concentrated at 20°C. The residue was
diluted with chloroform, washed with sat aq Na2CO3 and H2O, dried over Na2SO4, and
concentrated. The obtained syrup was chromatographed on a column of silica gel with
1:2 ethyl acetate-hexane to give 6 (284 mg, 98%) as an amorphous mass; [a]D + 67° (c
5.7, CHCl3); IR (film): 3600ꢀ3300 (OH), 3075–2850 (CH), 1750 (methyl ester), 1740
and 1240 (benzoate) and 710 (phenyl) cmꢀ1 1H NMR (CDCl3) d 2.78 (m, 2H,
;
CH2COOCH3), 3.67 (m, 1H, H-3), 3.85 (s, 3H, COOCH3), 4.68 (m, 2H, H-5, H-6a),
5.07 (t, 1H, J5,6b = 6.4 Hz, H-6b), 5.57 (t, J1b,2 = 8.2 Hz, H-2b), 5.69 (dd, H-2a), 6.02
(d, 1H, H-4), 7.67–8.46 (m, 15H, 3Ph).
Anal. Calcd for C30H28O10: C, 65.69; H, 5.15. Found: C, 65.69; H, 4.95.
2,4,6-Tri-O-benzoyl-3-deoxy-3-C-(methoxycarbonylmethyl)- -D-galactopyrano-
syl trichloroacetimidate (7). To a solution of 6 (282 mg, 514 mmol) in dichlorome-
thane (1 mL) were added trichloroacetonitrile (0.158 mL, 1.54 mmol) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU; 40 mL, 257 mmol) at 0°C, and the mixture was
stirred for 3 h at 0°C. Column chromatography (1:2 ethyl acetate-hexane) of the mixture
on silica gel afforded 7 (314 mg, 88%); [a]D + 50° (c 1.1, CHCl3); IR (film): 3350 (NH),
3075ꢀ2850 (CH), 1750 (methyl ester), 1740 and 1240 (benzoate), and 710 (phenyl)
1
cmꢀ1; H NMR (CDCl3) d 2.74 (m, 2H, CH2COOCH3), 3.71 (m, 1H, H-3), 3.86 (s, 3H,
COOCH3), 4.78 (m, 2H, H-6a,6b), 5.07 (t, 1H, H-5), 5.93 (dd, 1H, J1,2 = 3.5, J2,3 = 11.9
Hz, H-2), 6.02 (d, 1H, H-4), 7.04 (d, 1H, H-1), 7.67–8.46 (m, 15H, 3Ph), 8.92 (s, 1H, NH).
Anal. Calcd for C32H28NO10CCl3: C, 55.47; H, 4.07. Found: C, 55.42; H, 4.02.

518
Ishihara et al.
2-(Tetradecyl)hexadecyl 2,4,6-Tri-O-benzoyl-3-deoxy-3-C-(methoxycarbonyl-
methyl)- -D-galactopyranoside (8). To a solution of imidate 7 (111 mg, 163 mmol)
and 2-(tetradecyl)hexadecan-1-ol (113 mg, 244 mmol) in dichloromethane (4 mL) was
˚
added powdered MS 4A (200 mg), and the mixture was stirred for 5 h at rt under a
nitrogen atmosphere, and then cooled to 0°C. Trimethylsilyl trifluoromethanesulfonate
(2.6 mL, 13 mmol) was added and stirring was continued for 12 h at 0°C. Solids were
filtered off through a pad of Celite, and washed with chloroform. The combined filtrate
and washings were washed with M aq Na2CO3 and water, dried over Na2SO4, and
concentrated. Column chromatography (1:10 ethyl acetate-hexane) of the residue on
silica gel gave 8 (158 mg, 95%); [a]D + 14.0° (c 0.9, CHCl3); IR (film): 3075ꢀ2850
1
(CH), 1750 (methyl ester), 1740 and 1240 (benzoate), and 710 (phenyl) cmꢀ1; H NMR
(CDCl3) d 0.88 (t, 6H, 2CH3), 1.23 (s, 52H, 26CH2), 2.50 (m, 2H, CH2COOCH3), 2.86
(m, 1H, H-3), 3.26 (dd, 1H, OCH2CH), 3.44 (s, 3H, CH2COOCH3), 4.23 (m, 1H, H-5),
4.36 (t, 1H, Jgem = 11.2 Hz, H-6a), 4.53 (dd, 1H, H-6b), 4.66 (d, 1H, J1,2 = 7.7 Hz, H-1),
5.53 (dd, 1H, J2,3 = 11.5 Hz, H-2), 5.72 (d, 1H, H-4), 7.27–8.30 (m, 15H, 3Ph).
Anal. Calcd for C60H80O10: C, 74.35; H, 9.15. Found: C, 74.16; H, 9.10.
2-(Tetradecyl)hexadecyl 3-C-(carboxylmethyl)-3-deoxy- -D-galactopyranoside
(III). To a solution of 8 (170 mg, 175 mmol) in methanol (5 mL) were added 3
drops of 28% sodium methoxide in methanol, the reaction mixture was stirred for 24
h at 40°C, then water (a few drops) was added. After stirring for 7 h at rt, the mixture
was treated with Amberlite IR-120 (H+) resin. The resin was filtered off and washed
with methanol. The combined filtrate and washings were concentrated to a residue,
which was chromatographed on a column of Sephadex LH-20 (5:4:0.7 chloroform-
methanol-water) to give the title compound III (95 mg, 85%); [a]D + 61° (c 1.9,
1
CHCl3); H NMR (CDCl3) d 0.80 (t, 6H, 2CH3), 1.19 (s, 52H, 26CH2), 1.49 (m, 1H,
CH), 3.24 (t, 1H, J1,2 = J2,3 = 7.7 Hz, H-2), 3.29, 3.60 (2dd, 2H, Jgem = 9.6, Jvic = 6.0
Hz, OCH2 CH), 4.12 (d, 1H, H-1).
Anal. Calcd for C38H74O7: C, 70.98; H, 11.60. Found: C, 70.92; H, 11.49.
Biological Assay. In vitro inhibitory activity: The activity of the compounds in
vitro was measured in adhesion assays as the inhibition of binding promyelocytic
leukemia HL-60 cells to immobilized recombinant selectin-IgG proteins. Briefly, P-
selectin-IgG was immobilized onto microtiter plate wells (96 wells; Nunc Maxisorp) by
adding 20 ng of the purified protein to each well in a final volume of 100 mL PBS (+),
and incubated overnight at 4°C. The excess coating solution was removed by aspi-
rating, and non-specific binding sites were blocked by a 1 h incubation with PBS (+)
containing 1% BSA (w/v) at rt. After aspirating the blocking solution, 100 mL of the
test compound was dissolved in RPMI 1640, then 100 mL of HL-60 cells (106 cell/mL
suspended in the binding buffer) were added to each well. The plate was centrifuged at
500 rpm for 2 min at rt and the wells were carefully filled with the binding buffer. The
plate was sealed with acetate sealing tape, without trapping any air bubbles. Non-
adherent HL-60 cells were removed by inverting the plate, centrifuging at 500 rpm for
10 min, removing the acetate film, and aspirating the binding buffer. The amount of
bound cells was quantified by the WST-1 assay method (Dojin Chemicals, Japan).
Inhibition of L-or E-selectin binding was carried out as described above using
immobilized L-(100 ng) or E-selectin-IgG (40 ng).

3-C-Carboxymethylgalactosyl Lipid
ACKNOWLEDGMENT
519
This study was supported in part by a Grant-in-Aid (No. 12306007) for Scientific
Research from Japan Society for the Promotion of Science.
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Received March 6, 2003
Accepted July2, 2003