Synthesis of Novel Mimetics of CMP-Sialic Acid as the Inhibitors of Sialyltransferases

Toru  Tanaka; Machiko  Ozawa; Tsuyoshi  Miura; Toshiyuki  Inazu; Shuichi  Tsuji; Tetsuya  Kajimoto

doi:10.1055/s-2002-33518

LETTER

Synthesis of Novel Mimetics of CMP-Sialic Acid as the Inhibitors of
Sialyltransferases

Toru Tanaka^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 The Noguchi Institute, 1-8-1 Kaga, Itabashi-ku, Tokyo 173-0003, Japan
^c Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8555, Japan

Abstract

All articles of this category

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

Full Text

References

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

9

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).

10a Martinez AP. Lee WW. J. Org. Chem. 1965, 30: 317

10b Lawley PD. J. Chem. Soc. 1962, 1348

11

Charcoal, activated for chromatography (>300 µm 40%, 300-63 µm 50%, <63 µm 10%, purchased from Wako Pure Chemical Industries, Ltd.).

12

10a: 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).

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) 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).

16 Saeed A. Young DW. 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.

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

21

20: 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)

22

21: 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).

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 Genes Taniguchi N. Fukuda M. Springer-Verlag; Tokyo: 2001. p.295-300