Synthesis of novel mimetics of CMP-sialic acid as the inhibitors of sialyltransferases

Article abstract of DOI:10.1055/s-2002-33518

Novel mimetics of CMP-sialic acid were designed as the inhibitors of sialyltransferases. They were synthesized in a short step from a cytosine carrying β-hydroxy-α-L-amino acid based on the knowledge that nikkomycin, a peptidic derivative of an uracil carrying amino acid, shows a potent inhibitory activity toward N-acetyl-D-glucosaminyltransferases that employ UDP-N-acetyl-D-glucosamine as the donor substrate. The cytosine carrying β-hydroxyl-α-L-amino acid, a key intermediate in our synthetic strategy, was easily prepared by the L-threonine aldolase (LTA) catalyzed reaction.

Full text of DOI:10.1055/s-2002-33518

LETTER
1487
Synthesis of Novel Mimetics of CMP-Sialic Acid as the Inhibitors of
Sialyltransferases
Synthesis of
No
o
vel Mimetic
r
of CM
u
T
Inhibitors of
S
a
ialyltransf
e
n
rases aka,a Machiko Ozawa,a Tsuyoshi Miura,b Toshiyuki Inazu,b Shuichi Tsuji,c Tetsuya Kajimoto*a
a
Department of Biotechnology, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei-shi, Tokyo 184-8588,
Japan
Fax +81(42)3887295; E-mail: kajimoto@cc.tuat.ac.jp
b
c
The Noguchi Institute, 1-8-1 Kaga, Itabashi-ku, Tokyo 173-0003, Japan
Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8555, Japan
Received 20 July 2002
NH2
Abstract: Novel mimetics of CMP-sialic acid were designed as the
inhibitors of sialyltransferases. They were synthesized in a short
step from a cytosine carrying -hydroxy- -L-amino acid based on
the knowledge that nikkomycin, a peptidic derivative of an uracil
carrying amino acid, shows a potent inhibitory activity toward
N-acetyl-D-glucosaminyltransferases that employ UDP-N-acetyl-D-
glucosamine as the donor substrate. The cytosine carrying -hy-
droxyl- -L-amino acid, a key intermediate in our synthetic strategy,
was easily prepared by the L-threonine aldolase (LTA) catalyzed
reaction.
N
O
O
N
O
O
P
O
O
HO
OH
O
HO
AcHN
CO2H
OH OH
HO
CMP-sialic acid (1)
Key words: aldol reactions, amino acids, stereoselective synthesis,
NH2
sialyltransferase, inhibitor
N
OH
HO
CO2H
O2C
O
O
N
HO
AcHN
O
O
N
H
Oligosaccharides expressed on cell surfaces are properly
functionalized by sialyltransferases at the final step of gly-
cosylation in the Golgi apparatus,1 and play important
roles in embryonic development, inflammatory reaction,
infection, and other biological events involved in intercel-
lular adhesion.2 Therefore, the inhibition of sialyltrans-
ferases that transfer sialic acid from CMP-sialic acid (1) to
immature oligosaccharide could control the cell-cell rec-
ognition and its related biological events.3 Hence, we have
designed novel mimetics of CMP-sialic acid (2a,b) to act
as inhibitors of sialyltransferases; based on the knowledge
that nikkomycin (3),4 a peptidic derivative of an uracil
carrying amino acid, shows potent inhibitory activities to
N-acetyl-D-glucosaminyltransferases that employ UDP-
N-acetyl-D-glucosamine (4:UDP-GlcNAc) as the donor
substrate (Figure 1).5
HO
OH
Peptide mimetic of CMP-sialic acid
(2a: α-isomer, 2b: β-isomer)
OH
O
O
HO
HO
NH
O
P
OH
P
O
N
AcHN
O
O
O
O
O
O
OH
OH
UDP-GlcNAc (4)
O
NH
O2C
H3C
O
N
In the present paper, we report the synthesis of the mimet-
ics of CMP-sialic acid (2a,b). The key intermediate, cy-
tosine carrying amino acid (5), was easily prepared on a
large scale using a LTA (from Candida humicola
AKU4586) catalyzed reaction.6,7 The enzymatic aldol re-
action is also suitable for the preparation of pyrimidine
base (cytosine and uracil) bearing -hydroxy- -L-amino
acids (5, 6), as well as the purine base (guanine and ade-
nine) carrying amino acids, which were used in our previ-
ous synthetic study of peptide RNA.8
O
HO
N
N
O
H
HO
NH2
OH
nikkomycin (3)
OH
Figure 1 Structures of sugar nucleotides and their mimetics
Cytosine (7) was first alkylated with 2-bromo-1,1-di-
ethoxyethane (8) in the presence of potassium carbonate
in N,N-dimethylformamide (DMF) at 115 °C to afford N1-
alkylated cytosine (9a)9 in 65% yield, and the dialkylated
cytosine (9b) in 15% yield.10 After acid hydrolysis of 9a
with 1 N hydrochloric acid at 100 °C, the aldehyde con-
taining acidic aqueous solution (9c) was diluted with one-
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1487,1490,ftx,en;U03302ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1488
T. Tanaka et al.
LETTER
fifth of its volume of 200 mM tris-buffer solution (pH
6.3). Tris-buffer solution containing LTA (20 mM, pH
6.5) and then glycine (80-fold molar equivalent to 9a)
were successively added to the 9c containing solution, and
the reaction mixture gently stirred at 30 °C. The consump-
tion of 9c was monitored by silica gel TLC
(CHCl3:MeOH:H2O, 6:4:1) and once the reaction had
reached completion the reaction mixture was heated (100
°C for a minimum of 30 min) to deactivate the LTA. The
amino acid generated (5) was roughly purified by activat-
ed charcoal11 column chromatography (H2O, MeOH) and
further purified by ODS column chromatography (H2O).
The mixture obtained consisted of diastereomers, threo-
and erythro-isomers of 5 (4: 1). This was esterified by re-
fluxing in benzene with benzyl alcohol in the presence of
p-toluenesulfonic acid to afford 10a and 10b,12 which
were then separated by silica gel column chromatography
(modified with an aminopropyl group; EtOAc:EtOH,
4:1).13
OEt
OEt
NHR1
Br
NH2
N
8
N
O
N
K2CO3
65 %
O
N
H
R2
9a : R1 = H, R2 = CH2CH(OEt)2
9b : R1 = R2 = CH2CH(OEt)2
9c : R1 = H, R2 = CH2CHO
7
NH2
L-Threonine
aldolase
BnOH
TsOH
N
O
NH2
CO2H
N
glycine
83 %
65 %
OH
5
J = 4.5 Hz
The relative configuration of the benzyl esters obtained
(10a,b) was confirmed by the transformation to oxazoli-
dones (11a,b)14,15 and observation of the coupling con-
stants between - and -protons in the 1H NMR
spectroscopy of 11a and 11b (4.5 and 9.0 Hz, respective-
ly).16 The absolute configuration was determined by the
enzymatic resolution using both L- and D- amino acid ox-
idases (Scheme 1).17
NH2
N
H
H
ClCO2Et
NaOH aq.
CO2H
NH
R
+
O
NH3
N
O
CO2Bn
O
OH
11a
10a
In addition, the same procedure (except that sodium car-
bonate was chosen as the base during alkylation with 8)
converted uracil (12) to uracil bearing -hydroxy- -L-
amino acids (6) as a diastereomer mixture of erythro- and
threo-isomers (1:1) (Scheme 2).
+
J = 9.0 Hz
NH2
N
ClCO2Et
NaOH aq.
N
H
H
CO2H
NH
+
O
NH3
R
Concurrently, the methyl ester of N-acetylneuraminic acid
(13) was treated with acetyl chloride in acetic acid to con-
vert it to methyl 2-chloro-4,7,8,9-tetra-O-acetyl-N-acetyl-
neuraminate (14). This was then reacted with allyl alcohol
[in the presence of silver trifluoromethanesulfonate
(AgOTf) in CH2Cl2 at r.t.] to afford methyl 2-O- -allyl-
4,7,8,9-tetra-O-acetyl-N-acetylneuraminate (15, 28%),
methyl 2-O- -allyl-4,7,8,9-tetra-O-acetyl-N-acetylneur-
aminiate (16, 28%), and methyl 4,7,8,9-tetra-O-acetyl-N-
acetylneuraminate-2,3-ene (17, 6%).18
O
CO2Bn
OH
O
11b
10b
Scheme 1 Preparation of cytosine bearing amino acid (5) and its
benzyl ester (10a,b)
O
O
L-Threonine
HN
1) 8, Na2CO3
In order to obtain 15 in a much higher yield (80%), 2-
chloro-sialic acid derivative (14) was treated with silver
salicylate in allyl alcohol.19 In the next step, the terminal
olefins of the allyl sialosides (15, 16) were oxidized with
ruthenium tetroxide, prepared from ruthenium dioxide hy-
drate and sodium periodate in situ,20 to give carboxylic
acid (18, 19) in 44% and 40%, respectively (Scheme 3).
aldolase
HN
O
N
NH2
CO2H
2) HCl
45 %
N
glycine
79 %
H
Scheme 2 Preparation of uracil bearing amino acid (6)
The benzyl ester of the threo-isomer (10a) and the fully
protected -isomer of sialoside (18) were coupled by a
conventional method (DCC/HOBt /NMM) to afford pro-
tected peptidic compounds (20)21 in 52% yield. In the
same way, -sialoside derivative (19) was coupled with
10a to give 2122 in 58% yield. Acetyl and benzyl groups
of 20 and 21 were deprotected with 0.02 N sodium meth-
oxide, and the methyl groups of the compounds saponi-
fied with 0.01 N aqueous sodium hydroxide. Successive
neutralization and desalting procedures were carried out
using Sephadex LH-20 column chromatography to afford
the target compounds, the peptide mimetics of CMP-sialic
acid (2a,b)23 (Scheme 4).
The inhibitory activity (IC50) of 2a and 2b toward sialyl-
transferases 6 Gal I24,25 is estimated at around 1,000 M,
Synlett 2002, No. 9, 1487–1490 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Mimetics of CMP-Sialic Acid as the Inhibitors of Sialyltransferases
1489
RO
OR
References
X
OH
(1) For a review of glycosylation in the Golgi apparatus, see:
Tsuji, S. J. Biochem. 1996, 120, 1.
RO
AcHN
+
15
+
16
O
CO2Me
RO
AgOTf
(2) For a review of intercellular adhesion , see: Glycoscience:
Chemistry and Chemical Biology; Fraiser-Reid, B.; Tatsuta,
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Ed. 1998, 37, 2893. (b) Compain, P.; Martin, O. R. Bioorg.
Med. Chem. 2001, 9, 3077.
AcO
OAc
13 : R = H, X = OH
14 : R = OAc, X = Cl
AcO
AcHN
O
CO2Me
AcO
17
(4) Dahn, U.; Hagenmaier, H.; Hohne, H.; Konig, W. A.; Wolf,
G.; Zahner, H. Arch. Microbiol. 1976, 107, 143.
(5) Calib, E. Antimicrob. Agents Chemother. 1991, 35, 170.
(6) (a) Vassilev, V. P.; Uchiyama, T.; Kajimoto, T.; Wong,
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Uchiyama, T.; Kajimoto, T.; Wong, C.-H. Tetrahedron Lett.
1995, 36, 5063. (c) Uchiyama, T.; Vassilev, V. P.;
Kajimoto, T.; Wong, W.; Huang, H.; Lin, C.-C.; Wong, C.-
H. J. Am. Chem. Soc. 1995, 117, 5395. (d) Uchiyama, T.;
Woltering, T. J.; Wong, W.; Lin, C.-C.; Kajimoto, T.;
Takebayashi, M.; Weitz-Schmidt, G.; Asakura, T.; Noda,
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(e) Shibata, K.; Shingu, K.; Vassilev, V. P.; Nishide, K.;
Fujita, T.; Node, M.; Kajimoto, T.; Wong, C.-H.
AcO
OAc
AcO
AcO
AcO
CO2Me
OAll
OAc
AcO
RuO2
NaIO4
CO2Me
O
AcO
AcHN
O
O
AcHN
CO2H
44 %
15
18
AcO
AcO
OAc
AcO
AcO
OAc
RuO2
NaIO4
O
CO2H
CO2Me
OAll
O
AcHN
O
AcHN
CO2Me
AcO
40 %
Tetrahedron Lett. 1996, 37, 2791. (f) Miura, T.; Kajimoto,
T. Chirality 2001, 13, 577. (g) Fujii, M.; Miura, T.;
Kajimoto, T.; Ida, Y. Synlett 2000, 1046.
AcO
19
16
(7) (a) Yamada, H.; Kumagai, H.; Nagate, T.; Yoshida, H.
Biochem. Biophys. Res. Commun. 1970, 39, 53.
Scheme 3 Preparation of sialic acid carboxylates (18, 19)
(b) Yamada, H.; Kumagai, H.; Nagate, T.; Yoshida, H.
Agric. Biol. Chem. 1971, 35, 1340. (c) Kumagai, H.;
Nagatae, T.; Yoshida, H.; Yamada, H. Biochim. Biophys.
Acta 1972, 258, 779. (d) Herbert, R. B.; Wilkinson, B.;
Ellames, G. J.; Kunec, E. K. J. Chem. Soc., Chem. Commun.
1993, 205. (e) Liu, J.-G.; Nagata, S.; Dairi, T.; Misono, H.;
Shimizu, S.; Yamada, H. Eur. J. Biochem. 1997, 245, 289.
(f) Kataoka, M.; Wada, M.; Nishi, K.; Yamada, H.; Shimizu,
S. FEMS Microbiol. Lett. 1997, 151, 245. (g) Liu, J.-Q.;
Dairi, T.; Kataoka, M.; Shimizu, S.; Yamada, H. J.
Bacteriol. 1997, 179, 3555. (h) Liu, J.-Q.; Dairi, T.; Itoh, N.;
Kataoka, M.; Shimizu, S.; Yamada, H. Eur. J. Biochem.
1998, 255, 220. (i) Liu, J.-G.; Ito, S.; Dairi, T.; Itoh, N.;
Shimizu, S.; Yamada, H. Appl. Microbiol. Biotechnol. 1998,
in spite of the assay condition not having been accurately
optimized yet. Further structural modification of 2a and
2b to increase their inhibitory activity is in progress.
Acknowledgement
We appreciate Prof. Toshiro Hamamoto (Jichi Medical School,
3311-1 Yakushiji, Minami-kawachi gun, Tochigi 239-0498, Japan)
for measuring the inhibitory assay of our compounds toward the
sialyltransferase, and thank Ms. Junko Takizawa (Tokyo Univ. of
A&T) for her kind technical support in measuring 1H NMR spectra.
NH2
N
1) 0.02
N NaOMe
in MeOH
AcO
AcO
OAc
AcO
O
10a
BnO2C
N
CO2Me
O
18
O
2a
DCC, HOBt, NMM
in DMF
O
2) 0.01
N
NaOH
AcHN
N
H
quant.
OH
52 %
20
NH2
N
1) 0.02
N NaOMe
O
in MeOH
N
BnO2C
10a
O
2b
19
AcO
AcO
OAc
O
DCC, HOBt, NMM
in DMF
N
H
2) 0.01
N
NaOH
OH
O
quant.
AcHN
CO2Me
21
58 %
AcO
Scheme 4 Synthetic route of peptide CMP-sialic acid (2a,b)
Synlett 2002, No. 9, 1487–1490 ISSN 0936-5214 © Thieme Stuttgart · New York

1490
T. Tanaka et al.
LETTER
49, 702. (j) Liu, J.-G.; Ito, S.; Dairi, T.; Itoh, N.; Kataoka,
M.; Shimizu, S.; Yamada, H. Appl. Environ. Microbiol.
1998, 64, 549.
(19) (a) Roy, R.; Laferriere, C. A. Can. J. Chem. 1990, 68, 2045.
(b) Miura, T.; Aonuma, M.; Kajimoto, T.; Ida, Y.; Kawase,
M.; Kawase, Y.; Yoshida, Y. Synlett 1997, 650.
(8) Miura, T.; Fujii, M.; Shingu, K.; Koshimizu, I.; Naganoma,
J.; Kajimoto, T.; Ida, Y. Tetrahedron Lett. 1998, 39, 7313.
(9) 9a: 1H NMR (CDCl3) = 1.16 (t, 6 H, J = 7.0 Hz), 3.50 (dq,
2 H, J = 9.5, 7.0 Hz), 3.73 (dq, 2 H, J = 9.5, 7.0 Hz), 3.80 (d,
2 H, J = 5.5 Hz), 4.68 (t, 1 H, J = 5.5 Hz), 5.74 (d, 1 H,
J = 7.5 Hz), 7.32 (d, 1 H, J = 7.5 Hz).
(10) (a) Martinez, A. P.; Lee, W. W. J. Org. Chem. 1965, 30,
317. (b) Lawley, P. D. J. Chem. Soc. 1962, 1348.
(11) Charcoal, activated for chromatography (>300 m 40%,
300–63 m 50%, <63 m 10%, purchased from Wako Pure
Chemical Industries, Ltd.).
(20) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936.
(21) 20: 1H NMR (CD3OD) = 1.87, 1.97, 1.98, 2.02, 2.11 (s,
each 3 H, 5Ac), 2.71 (dd, 1 H, J = 5.0, 13.0 Hz, H-3eq), 3.55
(dd, 1 H, J = 8.5, 13.5 Hz, H- ), 3.83 (s, 3 H, -CO2Me), 3.98
(dd, 1 H, J = 4.0, 13.5 Hz, H- ), 4.01 (t, 1 H, J = 11.0 Hz,
H-5), 4.07 (dd, 1 H, J = 5.5, 12.5 Hz, H-9), 4.09, 4.36 (d,
each 1 H, J = 15.0 Hz, -CH2CO2H), 4.18 (dd, 1 H, J = 2.0,
11.0 Hz, H-6), 4.23 (dd, 1 H, J = 2.5, 12.5 Hz, H-9 ), 4.54
(m, 1 H, H- ), 4.70 (d, 1 H, J = 2.5 Hz, H- ), 4.89 (m, 1 H,
H-4), 5.17, 5.22 (d, each 1 H, AB type, J = 12.0 Hz,
PhCH2-), 5.30 (dd, 1 H, J = 2.0, 9.0 Hz, H-7), 5.44 (m, 1 H,
H-8), 5.80 (d, 1 H, J = 7.5 Hz, cytosine H-5), 7.33 (m, 5 H,
Ph), 7.47 (d, 1 H, J = 7.5 Hz, cytosine H-6)
(12) 10a: 1H NMR (CD3OD) = 3.48 (d, 1 H, J = 4.5 Hz, H- ),
3.59 (dd, 1 H, J = 9.0, 13.5 Hz, H- ), 4.09 (dd, 1 H, J = 3.5,
13.5 Hz, H- ), 4.30 (m, 1 H, H- ), 5.10, 5.18 (d, each 1 H,
AB type, J = 12.5 Hz, PhCH2), 5.78 (d, 1 H, J = 7.0 Hz,
cytosine H-5), 7.30 (m, 5 H, Ph), 7.49 (d, 1 H, J = 7.0 Hz,
cytosine H-6). 10b: 1H NMR (CD3OD) = 3.50 (d, 1 H,
J = 5.0 Hz, H- ), 3.55 (dd, 1 H, J = 8.5, 14.0 Hz, H- ), 4.05
(m, 1 H, H- ), 4.11 (dd, 1 H, J = 3.0, 14.0 Hz, H- ), 5.16 (s,
2 H, PhCH2), 5.75 (d, 1 H, J = 7.5 Hz, cytosine H-5), 7.32
(m, 6 H, cytosine H-6, and Ph).
(22) 21: 1H NMR (CD3OD) = 1.85, 2.00, 2.09 (s, each 3 H,
3Ac), 1.97 (s, 6 H, 2Ac), 1.90 (dd, 1 H, J = 11.0, 13.0 Hz, H-
3ax), 2.53 (dd, 1 H, J = 5.0, 13.0 Hz, H-3eq), 3.62 (dd, 1 H,
J = 8.5, 14.0 Hz, H- ), 3.75 (s, 3 H, -CO2Me), 3.95 (br t, (1
H, J = 10.5 Hz, H-5), 4.01 (dd, 1 H, J = 7.0, 12.5 Hz, H-9),
4.02 (dd, 1 H, J = 3.5, 14.0 Hz, H- ), 4.12, 4.20 (d, each 1
H, AB type, J = 15.0 Hz, -CH2CO2H), 4.51 (m, 1 H, H- ),
4.70 (dd, 1 H, J = 2.0, 12.5 Hz, H-9 ), 4.71 (d, 1 H, J = 2.0
Hz, H- ), 5.15, 5.23 (d, each 1 H, AB type, J = 12.0 Hz,
PhCH2), 5.24 (m, 1 H, H-8), 5.30 (dt, 1 H, J = 5.0, 11.0 Hz,
H-4), 5.39 (dd, 1 H, J = 2.0, 5.0 Hz, H-7), 5.83 (d, 1 H,
J = 7.5 Hz, cytosine H-5), 7.32 (m, 5 H, Ph), 7.55 (d, 1 H,
J = 7.5 Hz,cytosine H-6).
(13) Chromatrex NH (100–200mesh, purchased from Fuji Silysia
Chemical Ltd.).
(14) Kaneko, T.; Inui, T. J. Chem. Soc. Jpn. 1961, 82, 1075.
(15) 11a: 1H NMR (D2O) = 4.00 (d, 1 H, J = 4.5 Hz, H- ), 4.04
(m, 2 H, H- ), 4.75 (dt, 1 H, J = 4.5, 7.0 Hz, H- ), 5.83 (d, 1
H, J = 7.0 Hz, cytosine H-5), 7.43 (d, 1 H, J = 7.0 Hz,
cytosine H-6).
(23) 2a: 1H NMR (D2O) = 1.68 (t, 1 H, J = 13.0 Hz, H-3ax),
1.86 (s, 3 H, Ac), 2.57 (dd, 1 H, J = 4.5, 13.0 Hz, H-3eq),
3.35–4.30 (m, 13 H), 5.89 (d, 1 H, J = 7.5 Hz, cytosine H-5),
7.54 (d, 1 H, J = 7.5 Hz, cytosine 6 H).
11b: 1H NMR (D2O) = 3.49 (dd, 1 H, J = 10.5, 14.5 Hz, H-
), 4.19 (dd, 1 H, J = 2.5, 14.5 Hz, H- ), 4.34 (d, 1 H, J = 9.0
Hz, H- ), 4.96 (m, 1 H, H- ), 5.81 (d, 1 H, J = 7.0 Hz,
cytosine H-5), 7.39 (d, 1 H, J = 7.0 Hz, cytosine H-6).
(16) Saeed, A.; Young, D. W. Tetrahedron 1992, 48, 2507.
(17) Compounds were subjected to the reaction with D- and L-
amino acid oxidases [12 mM substrate in 1 mL of tris buffer
(10 mM, pH 8.5), 5 units of amino acid oxidase, 30 °C, 3 d]
and it was found that both compounds were substrates of L-
amino acid oxidase but reacted just as strongly with D-amino
acid oxidase as they had done in the beginning, according to
TLC monitoring of the reaction.
2b: 1H NMR (D2O) = 1.58 (t, 1 H, J = 13.0 Hz, H-3ax),
1.85 (s, 3 H, Ac), 2.32 (dd, 1 H, J = 5.0, 13.0 Hz, H-3eq),
3.40–4.35 (m, 13 H), 5.91 (1 H, J = 7.5 Hz, cytosine H-5),
7.55 (d, 1 H, J = 7.5 Hz, cytosine H-6).
(24) Weinstein, J.; de Souza-e-Silva, U.; Paulson, J. C. J. Biol.
Chem. 1982, 257, 13835.
(25) Hamamoto, T.; Tsuji, S. In Handbook of
Glycosyltransferases and Their Related Genes; Taniguchi,
N.; Fukuda, M., Eds.; Springer-Verlag: Tokyo, 2001, 295–
300.
(18) Kuhn, R.; Lutz, P.; MacDonald, D. L. Chem. Ber. 1966, 99,
611.
Synlett 2002, No. 9, 1487–1490 ISSN 0936-5214 © Thieme Stuttgart · New York