Synthesis of sialic acid derivatives having a C{double bond, long}C double bond substituted at the C-5 position and their glycopolymers

Article abstract of DOI:10.1016/j.bmcl.2009.07.034

Glycomonomers of sialic acid in which the acetamide group at C-5 was converted into two kinds of C{double bond, long}C double bond substituents were prepared and the fully protected glycomonomers were directly polymerized before deprotection steps. Radical polymerization with acrylamide in DMF in the presence of ammonium persulfate and N,N,N',N'-tetramethylethylenediamine proceeded smoothly and gave corresponding sialopolymers. Interestingly glycomonomers had hemagglutination inhibitory activities not only for H1N1 but also for H3N2 of human influenza virus strains.

Full text of DOI:10.1016/j.bmcl.2009.07.034

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5105–5108
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of sialic acid derivatives having a C@C double bond substituted
at the C-5 position and their glycopolymers
Kaori Suzuki a, Jun-Ichi Sakamoto a, Tetsuo Koyama a, Sangchai Yingsakmongkon b, Yasuo Suzuki c,d
,
Ken Hatano a, Daiyo Terunuma a, Koji Matsuoka a,
*
a Division of Material Science, Graduate School of Science and Engineering, Saitama University, Sakura, Saitama 338-8570, Japan
b Department of Microbiology and Immunology, Faculty of Veterinary Medicine, Kasetsart University, Bangkok 10900, Thailand
c Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Aichi 487-8501, Japan
d Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Glycomonomers of sialic acid in which the acetamide group at C-5 was converted into two kinds of C@C
double bond substituents were prepared and the fully protected glycomonomers were directly polymer-
ized before deprotection steps. Radical polymerization with acrylamide in DMF in the presence of ammo-
nium persulfate and N,N,N’,N’-tetramethylethylenediamine proceeded smoothly and gave corresponding
sialopolymers. Interestingly glycomonomers had hemagglutination inhibitory activities not only for
H1N1 but also for H3N2 of human influenza virus strains.
Received 9 June 2009
Revised 30 June 2009
Accepted 2 July 2009
Available online 10 July 2009
Keywords:
Sialic acid
Ó 2009 Elsevier Ltd. All rights reserved.
Glycopolymers
Influenza viruses
HA inhibitory activities
The cell surface of a eukaryotic organism is covered with vari-
ous glycoconjugates, including glycolipids and glycoproteins. Car-
bohydrates are closely related to a wide range of biological
processes, such as growth and differentiation of cells, cell–cell
adhesions, immune responses, malignant alterations and oncogen-
esis.1 Sialic acids, which are usually located at the terminal posi-
tions of glycoconjugates, play a significant role in biological
systems. Influenza viruses are classified into types A, B and C on
the basis of the major internal proteins, such as nucleoprotein,
and each type of virus interacts with host cells through sialylated
oligosaccharides2 on the host cells. Hemagglutinin (HA) on the sur-
face of an influenza virus particle attaches to the terminal sialic
acid residues of glycoconjugates, allowing viruses to invade the
host cell. After budding, multiplied viruses interact with sialic acid
residues on the surface of the infected host cell. Then neuramini-
dase (NA), which is an alternative enzyme on the viral surface,
divides the interaction between sialic acid and HA, enabling the
multiplied viruses to spread to uninfected cells.
tamivir-resistant, and infection in humans with drug-resistant mu-
tant viruses has been reported. Several patients have died because
of the ineffectiveness of the drug.5 There have been many efforts to
develop an anti-influenza drug based on the sugar-clustering effect
of sialic acid.6 We have also explored potential agents against HA
and NA of influenza virus based on the naturally obtainable sialic
acid moiety.
A C-5-modified sialic acid derivative has been
reported by several groups,7 however no polymeric compound of
the C-5-modified sialic acid has been reported. Only a C-4-modi-
fied sialic acid derivative and the glycopolymer have been
reported.8 In this letter, the synthesis of novel sialic acid deriva-
tives modified at C-5 and polymerization of the sialic acid deriva-
tives are described. Since a monomeric carbohydrate does not have
strong inhibitory potency against carbohydrate-binding proteins,
glycoside clustering effect9 is used for enhancement of the weak
binding activity.10 One of the most effective and facile methods
to obtain this effect is polymerization with acrylamide11 in order
to construct a glycopolymer having a large number of glycoepi-
topes. Accordingly, we planned to prepare cluster compounds by
simple polymerization and we describe herein the synthesis of
novel sialic acid derivatives and the polymers.
Oseltamivir,3 one of the NA inhibitors, is a transition-state ana-
log of sialic acid in the course of hydrolysis of the sialyl glycoside
by NA, and it is known as an effective therapeutic agent for influ-
enza infection.4 However, its structure differs from that of natural
sialic acid. Due to its structure, influenza viruses have become osel-
Anomeric mixtures 2 were derivatized from neuraminic acid 1
by Sinaÿ’s protocol12 (Scheme 1). The acetate 2 gave anomeric mix-
ture of lauryl thioglycoside 3 by treatment with 1-dodecanthiol in
the presence of Lewis acid in dichloromethane, which was sepa-
* Corresponding author.
E-mail address: koji@fms.saitama-u.ac.jp (K. Matsuoka).
rated into 3a
and 3b by means of chromatographic purification.13
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.07.034

5106
K. Suzuki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5105–5108
OH
OAc
OAc
OAc
OH
OAc
O
COOH
OH
COOMe
COOMe
S(CH2)11CH3
i
ii
HO
AcHN
AcO
AcHN
AcO
AcHN
O
O
OAc
HO
AcO
AcO
1
3
2
OH
OH
OH
OH
COOMe
S(CH2)11CH3
COOMe
S(CH2)11CH3
iii
iv
HO
AcHN
HO
O
O
H3N+
-
MeSO3
HO
HO
4α
5α
OAc
OAc
OAc
COOMe
S(CH2)11CH3
OAc
OH
AcO
NH
AcO
NH
vi
O
v
O
COOMe
AcO
AcO
O
O
7
α
6
Scheme 1. Reagents and conditions: (i) Ac2O, Pyr., rt, overnight, then CH2N2, 0 °C (88%); (ii) CH3(CH2)11SH, BF3ꢂOEt2, CH2Cl2, 3 h (81%); (iii) MeONa, MeOH, rt, overnight; (iv)
MeSO3H, MeOH, 60 °C, overnight (88% in two steps); (v) acryloyl chloride, Et3N, MeOH, 0 °C, then DMAP, Ac2O, Pyr., rt, overnight (61%); (vi) NIS, H2O–(CH3)2CO (1:9), rt, 1 h
(quant.).
After deacetylation of 3
was treated with methanesulfonic acid14 to provide ammonium
salt 5 in 88% yield (two steps). The amino group of 5 was
N-acryloylated under Schotten–Baumann conditions and then
acetylated to give the fully protected derivative 6 in 61% yield
a
under Zemplén conditions, the acetamide
performed for the acetate 12b, giving the hemiketal 13 in 80% yield,
+1.9 (c 1.07, CHCl3).
After removal of protective groups of the glycomonomers, poly-
4a
½ ꢀ
a 3D1
a
a
merization of the monomers was carried out in aqueous media.17
The reaction proceeded, but all trials gave unsoluble gel-state
products. Consequently, we needed to change our methodology
of the polymerization in order to accomplish our research objec-
tive. Thus, the step of deprotection of the products was changed
after polymerization. Radical polymerizarion of glycomonomers
a
31
having a terminal C@C double bond, ½aꢀD ꢁ 25 (c 1.27, CHCl3), 1H
NMR (CDCl3) d 5.31 (dd, 1H, J6,7 = 2.1 Hz and J7,8 = 6.9 Hz, H-7),
4.95 (ddd, 1H, J3ax,4 = 11.0 Hz, J3eq,4 = 4.3 Hz and J4,5 = 11.0 Hz, H-4),
4.34 (dd, 1H, J8,9a = 2.6 Hz and J9a,9b = 12.5 Hz, H-9a), 4.12 (m, 1H,
H-9b), 2.75 (dd, 1H, J3ax,3eq = 12.8 Hz, H-3eq).15 To examine the effect
of the aglycon moiety, a hydroxyl group was introduced at an
6a, 7, 12a, 12b and 13 with varous ratios of acrylamide in DMF
in the presence of APS—TEMED as a radical initiator system pro-
anomeric position. The reaction of thioglycoside 6
a with NIS in
ceeded smoothly and produced the corresponding copolymers
14a, 15, 16a, 16b and 17, respectively (Scheme 3). When solubility
H2O–acetone (1:9)16 quantitatively produced the corresponding
30
hemiketal 7, ½aꢀD ꢁ 2.1 (c 1.13, CHCl3).
of the polymers in organic solvents was examined, the polymers
showed unique solubility dependent on the polymer compositions
based on the sugar–acrylamide unit ratio. Therefore, polymers that
are soluble in ethyl acetate were purified by gel filtration (Sepha-
dex LH-20) with ethyl acetate as the eluent, and transesterification
of the purified polymers, followed by saponification yielded corre-
sponding water-soluble glycopolymers. On the other hand, poly-
mers that are insoluble in ethyl acetate were directly treated
with 1 M NaOMe in MeOH without chromatographic purification.
After 3 h, 0.2 M NaOH aq was added to induce saponification,
and the mixture was further stirred overnight at room tempera-
ture. The solution containing sodium salts of carboxylic acid in sia-
lic acid residues was purified by dialysis against water and
As shown in Scheme 2, each anomer of the ammonium salts 5
was further treated with 6-bromohexanoyl chloride followed by
acetylation to give the alkyl halide 8a in 40% yield and 8b 51%
yield, respectively. A bromine atom of 8 was quantitatively dis-
placed by an azido group by the usual SN2 to yield the compound
9. After deacetylation of the azide 9, hydrogenation of 10 was car-
ried out in the presence of Pd(OH)2/C under H2 atomosphere fol-
lowed by Schotten–Baumann reaction and reacetylation to afford
the compound 12 having a longer aliphatic spacer-arm than that
of 6, 12
a
in 34% yield (two steps) from 10
a
; ½a 3D2
ꢀ
+ 20 (c 1.27,
CHCl3), 1H NMR (CDCl3) d 5.29 (dd, 1H, J6,7 = 1.8 Hz and J7,8
=
7.8 Hz, H-7), 4.88 (ddd, 1H, J3ax,4 = 11.0 Hz, J3eq,4 = 4.5 Hz and
J4,5 = 11.0 Hz, H-4), 4.34 (dd, 1H, J8,9a = 2.5 Hz and J9a,9b = 12.4 Hz,
lyophilized to furnish white powdery copolymer 18
20b or 21 as the sodium salt, 18 in 91% yield; x:y = 11:1, Mw
49 kDa, Mw/Mn ¼ 1:3, 19 in 80% yield; x:y = 13:1, Mw 300 kDa,
in 87% yield; x:y = 10:1, Mw 100 kDa, Mw/
a, 19, 20a,
H-9a), 4.11 (dd, 1H, J8,9b = 5.6 Hz, H-9b), 2.72 (dd, 1H, J3ax,3eq
=
a
12.5 Hz, H-3eq), 12b in 76% yield (two steps) from 10b; ½a D32
ꢁ42
ꢀ
(c 1.27, CHCl3), 1H NMR (CDCl3) d 5.42 (t, 1H, J6,7 = J7,8 = 2.3 Hz,
H-7), 5.29 (ddd, 1H, J3ax,4 = 11.0 Hz, J3eq,4 = 4.7 Hz and
J4,5 = 10.4 Hz, H-4), 4.83 (dd, 1H, J8,9a = 2.2 Hz and J9a,9b = 12.4 Hz,
H-9a), 4.19 (dd, 1H, J8,9b = 8.3 Hz, H-9b), 2.52 (m, 1H, H-3eq). The
same reaction as that described for the preparation of 7 was
Mw/Mn ¼ 2:0, 20
a
Mn ¼ 2:4, 20b in 35% yield; x:y = 10:1, Mw 50 kDa, Mw/Mn ¼ 1:5,
or 21 in 14% yield; x:y = 2:1, Mw 66 kDa, Mw/Mn ¼ 1:2.
Since the synthesis of sialic acid derivatives having a C@C dou-
ble bond substituent at C-5 position and their glycopolymers was
accomplished, our attention was directed to biological activities
of a series of novel sialic polymers and monomers for influenza
virus HA. In addition to the polymers, monomeric candidates for
All new compounds with the specific rotation data gave satisfactory results of
elemental analyses.
biological evaluations were prepared from 6a, 7 and 12a by means

K. Suzuki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5105–5108
5107
OAc
OAc
OAc
O
OAc
O
COOMe
S(CH2)11CH3
COOMe
S(CH2)11CH3
AcO
AcO
O
i
ii
H
N
H
N
5
Br
N3
AcO
AcO
O
9
8
OH
OH
OH
OH
COOMe
S(CH2)11CH3
COOMe
S(CH2)11CH3
HO
O
HO
O
iv
H
N
v
iii
H
N
O
O
H2N
N3
HO
HO
11
10
OAc
OAc
OAc
OAc
O
COOMe
S(CH2)11CH3
OH
COOMe
AcO
O
AcO
O
O
O
vi
H
H
O
N
N
N
H
N
H
AcO
AcO
12
13
Scheme 2. Reagents and conditions: (i) 6-bromohexanoyl chloride, Et3N, MeOH, 0 °C, then DMAP, Ac2O, Pyr., rt, overnight (5a?8a; 40%, 5b?8b; 51%); (ii) NaN3, DMF, 60 °C,
1 h (8 ?9 ; quant., 8b?9b; 97%); (iii) MeONa, MeOH, rt, overnight (9 ?10 ; quant., 9b?10b; 97%); (iv) H2, Pd(OH)2/C, MeOH, rt, overnight; (v) acryloyl chloride, Et3N,
a
a
a
a
MeOH, 0 °C, then DMAP, Ac2O, Pyr., rt, overnight (10
a
?12
a; 34% in two steps, 10b?12b; 76% in two steps); (vi) NIS, H2O–(CH3)2CO (1:9), rt, 1 h (12b?13; 80%).
14α: R1=Ac, R2=COOMe, R3=SLauryl, n=0
18α: R1=H, R2=COONa, R3=SLauryl, n=0
ii
O
H2N
15: R1=Ac, R2=COOMe or OH, R3=OH or COOMe, n=0
19: R1=H, R2=COONa or OH, R3=OH or COONa, n=0
ii
x
OR1
OR1
O
R2
R3
R1O
O
16α: R1=Ac, R2=COOMe, R3=SLauryl, n=5
i
O
H
+
6, 7, 12 or 13
N
NH2
16β: R1=Ac, R2=SLauryl, R3=COOMe, n=5
N
H
ii
R1O
n
O
y
20α: R1=H, R2=COONa, R3=SLauryl, n=5
ii
20β: R1=H, R2=SLauryl, R3=COONa, n=5
17: R1=Ac, R2=COOMe or OH, R3=OH or COOMe, n=5
21: R1=H, R2=COONa or OH, R3=OH or COONa, n=5
ii
Scheme 3. Reagents and conditions: (i) TEMED, APS, DMF, 60 °C; (ii) 1 M MeONa in MeOH, rt, 3 h, then 0.2 M aq NaOH, rt, 1 day.
OR1
R1O
OR1
R2
R3
R1O
i
O
H
O
6α, 7 or 12α
N
N
H
n
2
O
1
3
22α: R =H, R =COOH, R =SLauryl, n=0
23: R =H, R =COOH or OH, R =OH or COOH, n=0
1
2
3
1
2
3
24α: R =H, R =COOH, R =SLauryl, n=5
Scheme 4. Reagents and conditions: (i) 1 M MeONa in MeOH, rt, 3 h, then 0.05 M aq NaOH, rt, 1 day.
of a combination of transesterification and saponification to afford
22 in quantitative yield, 23 in 97% yield and 24 in 69% yield
(Scheme 4).
Inhibitory activities of the sialyl derivatives against hemaggluti-
nation of erythrocytes by various human influenza viruses and
avian influenza virus were examined18 and the results are summa-
rized in Figure 1. Sugar concentrations are corrected on the basis of
sialic acid unit, and polymer compositions used for the hemagglu-
tination inhibition assay (HAI) were x:y = ca. 10:1. Interestingly,
68(H3N2), while duck influenza virus was not strongly inhibited
in the concentration range used in this study. Glycopolymer 19
and its monomer 23 showed no interaction with various influenza
viruses at the concentration range used in this study because nei-
ther of these compounds had hydrophobic spacer-arms as the agly-
con and linker at C-5 of sialic acid residue. In addition to the
hydrophobicity, it is likely that the degree of freedom by sugar
moieties in the polymeric architecture was lower than that of other
a
a
glycopolymers, 18a, 20a and 20b, which had flexible longer
both the polymeric substrates (18
meric substrates (22 and 24 ) showed potent inhibitory activities
against human influenza viruses, A/PR/8/34(H1N1) and A/Aichi/2/
a
, 20
a
and 20b) and the mono-
spacer-arms from the pyranoid ring system.
In conclusion, we have successfully demonstrated the prepara-
tion of sialic acid derivatives having a polymerizable spacer-arm at
a
a

5108
K. Suzuki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5105–5108
6. (a) Roy, R.; Laferrière, C. A.; Gamian, A.; Jennings, H. J. J. Carbohydr. Chem. 1987,
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1000
>250μM
>250μM
N.D.: not detected
100
10
1
7. For examples, see: (a) Matsuoka, K.; Oka, H.; Terunuma, D.; Kuzuhara, H.
Carbohydr. Lett. 2001, 4, 123; (b) Schneider, R.; Freyhardt, C. C.; Schmidt, R. R.
Eur. J. Org. Chem. 2001, 1655; (c) Yu, C.-S.; Niikura, K.; Lin, C.-C.; Wong, C.-H.
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N.D.
N.D.
N.D.
18α 19 20α 20β 22α 23 24α
Compounds
8. Wu, W.-Y.; Jin, B.; Krippner, G. Y.; Watson, K. G. Bioorg. Med. Chem. Lett. 2000,
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199; (c) Lee, Y. C. Acc. Chem. Res. 1995, 28, 321.
Figure 1. Inhibitory activity of a series of sialopolymers and monomers against
hemagglutination of various human influenza viruses and avian influenza virus.
the C-5 position and their polymers. Some of the cluster-type sialo-
polymers as well as the monomers showed potent inhibitory activ-
ities against human influenza viruses, and the results suggested
hydrophobic-type compounds had biological potency for HA. Fur-
ther biological evaluation of these compounds against NA of
human influenza viruses19 is now in progress, and the results will
be reported in the near future.
10. (a) Miyagawa, A.; Kurosawa, H.; Watanabe, T.; Koyama, T.; Terunuma, D.;
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Acknowledgment
We are grateful to Snow Brand Milk Products Co., Ltd for provid-
ing the sialic acid used in this study.
14. Komba, S.; Galustian, C.; Ishida, H.; Feizi, T.; Kannagi, R.; Kiso, M. Angew. Chem.,
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