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

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Synlett 2002(9): 1487-1490
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

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Publication History

Received 20 July 2002
Publication Date:
17 September 2002 (online)

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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

References

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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).

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.).

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).

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.

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).