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Sialic acid (α-(2→6))-d-pyranose derivative and its synthesis method and application

A technology of sialic acid and derivatives, which is applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problem of ineffective tumor antigens, and achieve effective immune response, IgG/IgM improvement, and good activity Effect

Active Publication Date: 2011-12-14
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

and The difficulties encountered are similar. The common problem encountered by anti-tumor sugar vaccines is that the vaccine cannot produce a satisfactory immune response in vivo. The most common method currently used is to couple the sugar antigen to the carrier protein, but this method is for Tumor antigens are not very effective, is an example of this

Method used

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  • Sialic acid (α-(2→6))-d-pyranose derivative and its synthesis method and application
  • Sialic acid (α-(2→6))-d-pyranose derivative and its synthesis method and application
  • Sialic acid (α-(2→6))-d-pyranose derivative and its synthesis method and application

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Experimental program
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Embodiment 1

[0039] The synthesis of embodiment 1 compound 2

[0040] Compound 48 (see Example 42 for its synthesis) (100 mg, 0.119 mmol) was dissolved in 10 mL of methanol, NaOMe / MeOH solution (30%, 0.02 g, 0.11 mmol) was added, and stirred at room temperature for 0.5 hours. After adjusting the pH of the reaction system to 3 with 1N HCl / MeOH, the reaction solution was concentrated in vacuo. The primary product was passed through a P-2 column and eluted with water. Get pure. Yield 95%.

[0041] 1 H-NMR (400MHz, D 2 O) δ5.90-5.77 (m, 1H), 5.22 (dd, 1H, J 1 = 1.6Hz,J 2 = 17.6Hz), 5.14 (d, 1H, J = 10.4Hz), 4.75 (d, 1H, J = 3.6Hz, anomeric H of GalNAc), 4.15 (dd, 1H, J 1 = 4.0Hz,J 2 = 13.6Hz), 4.05(dd, 1H, J 1 = 4.0Hz,J 2 =10.8Hz), 3.96-3.87(m, 3H), 3.82-3.74(m, 5H), 3.60-3.48(m, 4H), 3.46(dd, 1H, J 1 = 1.6Hz,J 2 =8.8Hz), 2.59(dd,1H,J 1 = 4.4Hz,J 2 = 12.4Hz, siaH-3eq), 1.91(s, 6H), 1.56(t, 1H, J=12.4Hz, siaH-3ax); 13 C-NMR (75MHz, D 2 O) 175.59, 175.16, 173.99, 134.221, 118.64,...

Embodiment 2

[0042] The synthesis of embodiment 2 compound 3

[0043] Compound 14 (allyl 4-O-(5-amino-3,5-dideoxy-α-D-pyranoneuraminyl)-2-acetylamino-2-deoxy-α-D- Galactopyranoside, its synthesis see Example 13) as reaction raw material 10mg, be dissolved in 1mL methanol, add 2-3mg NaHCO 3 , add a drop of the corresponding acid anhydride (propionic anhydride, about 5 μl) under ice-cooling, after stirring for one hour, add another drop of acid anhydride, TLC shows that most of the raw materials are converted. The reaction was overnight and gradually warmed to room temperature. TLC showed the reaction was complete. Strengthen the acidic resin to neutralize NaOH, filter with suction, concentrate the solvent, pass through a Biogel-P2 column, and elute with water. Then pass through a C18 column and elute with water-water / methanol. 8-9 mg of product was obtained. (Yield 75-85%).

[0044] 1 H-NMR (500MHz, D 2 O) δ6.02-5.96 (m, 1H), 5.35 (dq, 1H, J = 1.5Hz, 16.5Hz), 5.29-5.24 (m, 1H), 4.93...

Embodiment 3

[0045] The synthesis of embodiment 3 compound 4

[0046] It is prepared from compound 14 and n-butyric anhydride, and the specific operation steps are the same as those of compound 3. (Yield 75-85%).

[0047] 1 H-NMR (500MHz, D 2 O) δ6.02-5.96 (m, 1H), 5.35 (ddd, 1H, J 1 = 1.5Hz,J 2 = 3.0Hz,J 3 =17.0Hz), 5.26(dd,1H,J 1 = 1.0Hz,J 2 = 3.0Hz,J 3 = 10.5Hz), 4.92 (d, 1H, J = 3.5Hz, anomeric H of GalNAc), 4.22 (ddt, 1H, J 1 =J 2 = 1.5Hz,J 3 =5.5Hz,J 4 =13.0Hz), 4.15(dd,1H,J 1 = 3.5Hz,J 2 =11.0Hz), 4.06(dd,1H,J 1 = 4.0Hz,J 2 =8.0Hz), 4.04-4.00(m, 2H), 3.93-3.80(m, 5H), 3.71-3.61(m, 4H), 3.56(dd, 1H, J 1 =1.5,J 2 =9.0Hz), 2.73(dd,1H,J 1 = 4.5Hz,J 2 =12.5Hz, siaH-3eq), 2.26(t, 2H, J=7.5Hz), 2.03(s, 3H), 1.68(t, 1H, J 1 =J 2 =12.5Hz, siaH-3ax), 1.60(hexad, 2H, J=7.5Hz), 0.91(t, 3H, J=7.5Hz); 13 C-NMR (75MHz, D 2 O) δ178.88, 175.31, 174.08, 134.40, 118.81, 101.08, 96.98, 73.36, 72.47, 70.26, 69.45, 69.22, 69.10, 68.80, 68.29, 64.46, 63.35, 51.50, 50.56, 39.5 13.56...

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Abstract

The invention discloses an N-acyl group modified sialic acid (alpha-(2-6))-D-amino pyranose derivative and its synthetic method and use. The sialic acid (alpha-(2-6))-D-amino pyranose derivative shown in the formula (I) is synthesized from raw materials of D-galactosamine (glucose) and sialic acid and is coupled with a carrier protein or a polypeptide to form a glycoprotein (glycopeptide) conjugate. In a structure of the N-acyl group modified sialic acid (alpha-(2-6))-D-amino pyranose derivative, a derivative acyl group replaces an acetyl group and thus the structure is novel. The N-acyl group modified sialic acid (alpha-(2-6))-D-amino pyranose derivative has good activity in anti-tumor vaccines. A result of an experiment on mice shows that through structural derivatization, a carbohydrate antigen based vaccine can produce an effective immune response and a mass of antibodies and IgG / IgM is improved obviously. The antibodies can identify specifically tumor cells expressing STn and thus anti-tumor effects are realized. STn antigens can be expressed on multiple tumors and thus the N-acyl group modified sialic acid (alpha-(2-6))-D-amino pyranose derivative has a wide application scope.

Description

technical field [0001] The present invention relates to carbohydrate conjugates, in particular to sialic acid (α-(2→6))-D-aminopyranose derivatives, conjugates formed by the derivatives and proteins or polypeptides, and combinations of the above compounds The synthesis method, and the invention also relates to the application of these compounds in the preparation of antitumor drugs, belonging to the field of antitumor sugar vaccines. Background technique [0002] In recent years, anti-tumor vaccines based on carbohydrate antigens have become a research hotspot (Keding, S. Carbohydrate vaccines. Chem. Eng. News. 2004, 82, 31-35.). Among them, the antigen STn is a disaccharide structure containing sialic acid, which is mostly expressed in human breast cancer, colorectal cancer, ovarian cancer, and prostate cancer, but rarely expressed in normal tissues (Holmberg, L.ExpertRev.Vaccines 2004, 3 , 655-663.), thus becoming an important target for tumor immunotherapy. Based on thi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H5/06C07H15/04C07H1/00C07K2/00A61K31/7008A61K31/7028A61K38/02A61P35/00A61K31/385
CPCA61K39/00C07H13/00C07K1/1077A61K47/48092C07H15/04A61K47/48284A61K39/0011C07H17/04C07H15/10C07K2/00A61K2039/585A61K2039/6081A61K47/549A61K47/643A61P35/00
Inventor 叶新山郑秀静杨帆
Owner PEKING UNIV
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