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DOI: 10.1055/s-2002-33518
Synthesis of Novel Mimetics
of CMP-Sialic Acid as the Inhibitors of
Sialyltransferases
Publication History
Publication Date:
17 September 2002 (online)
![](https://www.thieme-connect.de/media/synlett/200209/lookinside/thumbnails/10.1055-s-2002-33518-1.jpg)
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 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.
Key words
aldol reactions - amino acids - stereoselective synthesis - sialyltransferase - inhibitor
- 1 For a review of glycosylation in
the Golgi apparatus, see:
Tsuji S. J. Biochem. 1996, 120: 1 - 2 For a review of intercellular adhesion
, see:
Glycoscience: Chemistry and Chemical
Biology
Fraiser-Reid B.Tatsuta K.Thiem J. Springer-Verlag; Tokyo: 2001. -
3a
Müller B.Schaub C.Schmidt RR. Angew. Chem. Int. Ed. 1998, 37: 2893 -
3b
Compain P.Martin OR. Bioorg. Med. Chem. 2001, 9: 3077 - 4
Dahn U.Hagenmaier H.Hohne H.Konig WA.Wolf G.Zahner H. Arch. Microbiol. 1976, 107: 143 - 5
Calib E. Antimicrob. Agents Chemother. 1991, 35: 170 -
6a
Vassilev VP.Uchiyama T.Kajimoto T.Wong C.-H. Tetrahedron Lett. 1995, 36: 4081 -
6b
Vassilev VP.Uchiyama T.Kajimoto T.Wong C.-H. Tetrahedron Lett. 1995, 36: 5063 -
6c
Uchiyama T.Vassilev VP.Kajimoto T.Wong W.Huang H.Lin C.-C.Wong C.-H. J. Am. Chem. Soc. 1995, 117: 5395 -
6d
Uchiyama T.Woltering TJ.Wong W.Lin C.-C.Kajimoto T.Takebayashi M.Weitz-Schmidt G.Asakura T.Noda M.Wong C.-H. Bioorg. Med. Chem. 1996, 4: 1149 -
6e
Shibata K.Shingu K.Vassilev VP.Nishide K.Fujita T.Node M.Kajimoto T.Wong C.-H. Tetrahedron Lett. 1996, 37: 2791 -
6f
Miura T.Kajimoto T. Chirality 2001, 13: 577 -
6g
Fujii M.Miura T.Kajimoto T.Ida Y. Synlett 2000, 1046 -
7a
Yamada H.Kumagai H.Nagate T.Yoshida H. Biochem. Biophys. Res. Commun. 1970, 39: 53 -
7b
Yamada H.Kumagai H.Nagate T.Yoshida H. Agric. Biol. Chem. 1971, 35: 1340 -
7c
Kumagai H.Nagatae T.Yoshida H.Yamada H. Biochim. Biophys. Acta 1972, 258: 779 -
7d
Herbert RB.Wilkinson B.Ellames GJ.Kunec EK. J. Chem. Soc., Chem. Commun. 1993, 205 -
7e
Liu J.-G.Nagata S.Dairi T.Misono H.Shimizu S.Yamada H. Eur. J. Biochem. 1997, 245: 289 -
7f
Kataoka M.Wada M.Nishi K.Yamada H.Shimizu S. FEMS Microbiol. Lett. 1997, 151: 245 -
7g
Liu J.-Q.Dairi T.Kataoka M.Shimizu S.Yamada H. J. Bacteriol. 1997, 179: 3555 -
7h
Liu J.-Q.Dairi T.Itoh N.Kataoka M.Shimizu S.Yamada H. Eur. J. Biochem. 1998, 255: 220 -
7i
Liu J.-G.Ito S.Dairi T.Itoh N.Shimizu S.Yamada H. Appl. Microbiol. Biotechnol. 1998, 49: 702 -
7j
Liu J.-G.Ito S.Dairi T.Itoh N.Kataoka M.Shimizu S.Yamada H. Appl. Environ. Microbiol. 1998, 64: 549 - 8
Miura T.Fujii M.Shingu K.Koshimizu I.Naganoma J.Kajimoto T.Ida Y. Tetrahedron Lett. 1998, 39: 7313 -
10a
Martinez AP.Lee WW. J. Org. Chem. 1965, 30: 317 -
10b
Lawley PD. J. Chem. Soc. 1962, 1348 - 14
Kaneko T.Inui T. J. Chem. Soc. Jpn. 1961, 82: 1075 - 16
Saeed A.Young DW. Tetrahedron 1992, 48: 2507 - 18
Kuhn R.Lutz P.MacDonald DL. Chem. Ber. 1966, 99: 611 -
19a
Roy R.Laferriere CA. Can. J. Chem. 1990, 68: 2045 -
19b
Miura T.Aonuma M.Kajimoto T.Ida Y.Kawase M.Kawase Y.Yoshida Y. Synlett 1997, 650 - 20
Carlsen PHJ.Katsuki T.Martin VS.Sharpless KB. J. Org. Chem. 1981, 46: 3936 - 24
Weinstein J.de Souza-e-Silva U.Paulson JC. J. Biol. Chem. 1982, 257: 13835 - 25
Hamamoto T.Tsuji S. In Handbook of Glycosyltransferases and Their Related GenesTaniguchi N.Fukuda M. Springer-Verlag; Tokyo: 2001. p.295-300
References
9a: 1H NMR (CDCl3) δ = 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).
11Charcoal, activated for chromatography (>300 µm 40%, 300-63 µm 50%, <63 µm 10%, purchased from Wako Pure Chemical Industries, Ltd.).
1210a: 1H NMR (CD3OD) δ = 3.48 (d, 1 H, J = 4.5 Hz, H-α), 3.59 (dd, 1 H, J = 9.0, 13.5 Hz, H-γ), 4.09 (dd, 1 H, J = 3.5, 13.5 Hz, H-γ), 4.30 (m, 1 H, H-β), 5.10, 5.18 (d, each 1 H, AB type, J = 12.5 Hz, PhCH 2), 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) δ = 3.50 (d, 1 H, J = 5.0 Hz, H-α), 3.55 (dd, 1 H, J = 8.5, 14.0 Hz, H-γ), 4.05 (m, 1 H, H-β), 4.11 (dd, 1 H, J = 3.0, 14.0 Hz, H-γ), 5.16 (s, 2 H, PhCH 2), 5.75 (d, 1 H, J = 7.5 Hz, cytosine H-5), 7.32 (m, 6 H, cytosine H-6, and Ph).
13Chromatrex NH (100-200mesh, purchased from Fuji Silysia Chemical Ltd.).
15
11a: 1H
NMR (D2O) δ = 4.00 (d, 1 H, J = 4.5 Hz,
H-α), 4.04 (m, 2 H, H-γ), 4.75 (dt, 1 H, J = 4.5, 7.0
Hz, H-β), 5.83 (d, 1 H, J = 7.0
Hz, cytosine H-5), 7.43 (d, 1 H, J = 7.0
Hz, cytosine H-6).
11b: 1H
NMR (D2O) δ = 3.49 (dd, 1 H, J = 10.5,
14.5 Hz, H-γ), 4.19 (dd, 1 H, J = 2.5,
14.5 Hz, H-γ), 4.34 (d, 1 H, J = 9.0 Hz,
H-α), 4.96 (m, 1 H, H-β), 5.81 (d, 1 H, J = 7.0 Hz, cytosine
H-5), 7.39 (d, 1 H, J = 7.0
Hz, cytosine H-6).
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.
2120: 1H NMR (CD3OD) δ = 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-γ), 3.83 (s, 3 H, -CO2Me), 3.98 (dd, 1 H, J = 4.0, 13.5 Hz, H-γ′), 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, -CH 2CO2H), 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-β), 4.70 (d, 1 H, J = 2.5 Hz, H-α), 4.89 (m, 1 H, H-4), 5.17, 5.22 (d, each 1 H, AB type, J = 12.0 Hz, PhCH 2-), 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)
2221: 1H NMR (CD3OD) δ = 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-γ), 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-γ′), 4.12, 4.20 (d, each 1 H, AB type, J = 15.0 Hz, -CH2CO2H), 4.51 (m, 1 H, H-β), 4.70 (dd, 1 H, J = 2.0, 12.5 Hz, H-9′), 4.71 (d, 1 H, J = 2.0 Hz, H-α), 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).
23
2a: 1H
NMR (D2O) δ = 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).
2b: 1H
NMR (D2O) δ = 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).