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Synthesis method and application of sialylated TF antigen and its fluorination derivatives

A technology of sialylation and synthesis method, applied in the direction of sugar derivatives, sugar derivatives, cancer antigen components, etc., can solve the problem of reducing the electron density of sugar rings

Active Publication Date: 2018-06-15
TIANJIN UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to its unique structure, the nine-carbon sugar sialic acid is not only easy to form intramolecular hydrogen bonds, but also the carboxyl group at the C1 position, the deoxygenation at the C3 position, and the nitrogen heteroatom substitution at the C7 position all reduce the electron density on the sugar ring, making The generation of sialyl glycosidic bonds has become a classic challenge in the field of sugar synthesis (Xi Chen., Ajit Varki., ACS Chem. Biol., 2010, 5, 2, 163–176)

Method used

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  • Synthesis method and application of sialylated TF antigen and its fluorination derivatives
  • Synthesis method and application of sialylated TF antigen and its fluorination derivatives
  • Synthesis method and application of sialylated TF antigen and its fluorination derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Synthesis of the compound 2-acetylamino-2-deoxy-D-galactose

[0071] The reaction equation is as follows:

[0072]

[0073] Into a 250mL round bottom flask, add galactosamine hydrochloride 8 (5g, 23mmol), CuSO 4 .5H 2 O (58mg, 0.23mmol), potassium carbonate (1.38g, 10mmol), TfN 3 (5.3g, 27.6mmol) and methanol (100mL), stirred at room temperature for 6h. After the completion of the reaction was detected by thin-layer chromatography, concentrated by rotary evaporation, added dilute hydrochloric acid solution (80 mL) and EtOAc (80 mL) for extraction, and repeated 3 times. The organic phases were combined and concentrated under reduced pressure to obtain an intermediate. Into a 100mL round bottom flask, the intermediate obtained in the previous step and 3-chloro-1-propanol (50mL) were added, acetyl chloride (2mL) was added dropwise, and reacted at room temperature for 3h to obtain compound 9 (4.4g, 67%).

[0074] In the 100mL round bottom flask, add compound 9 (920m...

Embodiment 2

[0076] Synthesis of 2,3,4-tri-acetyl-6-fluoro-α-D-galactosyltrichloroacetimidate 7

[0077] The reaction equation is as follows:

[0078]

[0079] Galactose (1, 10 g, 56 mmol) was dissolved in dry acetone (300 mL), and concentrated sulfuric acid (10 mL) was gradually added under ice-bath conditions. The ice bath was removed and stirred at room temperature for 3 h. After the reaction was complete, water (10 mL) and sodium carbonate (20 g, 189 mmol) were added to quench sulfuric acid to terminate the reaction. Filtrate with celite, concentrate by rotary evaporation, and flash column separation and purification (PE:EtOAc=1:5~1:10) to obtain compound 2 (13.0 g, 90%) as syrup.

[0080] Compound 2 (1.0g, 3.85mmol), diethylaminosulfur trifluoride (DAST, 0.81g, 5.04mmol), 2,4,6-collidine (1.12g, 9.24mmol) and dry 1, 2-Dichloroethane (5 mL) was added into a 10 mL microwave reaction tube, and reacted at 80° C. and 100 W for 1 hour. After cooling to room temperature, methanol was ...

Embodiment 3

[0086] Compound 3-Azidopropyl β-D-6-deoxy-6-fluoro-galactopyranosyl-(1–3)-2-acetamido-2-deoxy-α-D-galactopyranoside (Gal6Fβ1-3GalNAcProN 3 ,13) Synthesis of

[0087] The reaction equation is as follows:

[0088]

[0089] Compound 7 (386 mg, 0.85 mmol) and compound 10 (210 mg, 0.57 mmol) were dissolved in CH 2 Cl 2 (5mL), add Molecular sieves, under ice bath conditions, stirred for 15min, added TMSOTf (11uL, 0.114mmol). After reacting for 20 minutes, triethylamine was added dropwise to stop the reaction, filtered with diatomaceous earth, concentrated by rotary evaporation, and purified by rapid column separation (PE:EtOAc= 5:1) to obtain white solid compound 11 (290 mg, 77%).

[0090] Compound 11 (1.4g 2.0mmol) was dissolved in THF (35mL), acetic acid (16mL), acetic anhydride (5.6mL), zinc powder (11.2g) and reacted at room temperature for 1 hour. Heat to reflux for 24 hours. After the reaction was detected by thin-layer chromatography, it was concentrated by rotary ev...

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Abstract

The invention discloses a synthesis method and an application of a sialylated TF antigen and its fluorination derivatives. The method includes the following steps: (1) chemically synthesizing fluorogalactose and fluorogalactosamine analogues; (2) chemically synthesizing a fluorinated TF antigen; and (3) synthesizing the sialylated TF antigen and its fluorination derivatives through an enzyme technology. The flexibility of a chemical synthesis technology is combined with the high regioselectivity and the high efficiency of the enzyme synthesis technology, so the enzymatic synthesis of the fluorosialylated TF antigen is achieved for the first time, and the disadvantages of many synthesis steps, poor stereoselectivity, low yield and use of a heavy metal salt in existing chemical synthesis ofthe fluorosialylated TF antigen are overcome. A fluorotumor-associated carbohydrate antigen has a higher stability than natural carbohydrate antigen, so the sialylated TF antigen and its fluorinationderivatives have a broad application prospect in the development of novel antitumor vaccines.

Description

technical field [0001] The invention belongs to the field of carbohydrate drugs, and relates to a chemical enzyme synthesis method of carbohydrate substances, in particular to a chemical enzyme synthesis method of tumor-associated carbohydrate antigen and its fluorinated product, and also relates to the application of sialylated TF antigen and its fluorinated derivative in drug research and development applications in the field. technical background [0002] In various stages of cancer occurrence and development, incomplete glycosylation and malformed glycosylation of mucin on the surface of tumor cells make the sugar chain structure significantly different from that on the surface of normal cells. This difference is reflected in the overexpression of some oligosaccharide structures with shortened sugar chains and / or terminal sialylation on the surface of tumor cells. These sugar chain structures overexpressed on the surface of tumor cells are called tumor-associated carboh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/04C07H1/06C12P19/26C12P19/44A61K39/00A61P35/00
CPCA61K39/0011C07H1/06C07H15/04C12P19/26C12P19/44Y02P20/55
Inventor 孟欣郁彭朱涛苏超袁丁董佩杰李晓粱健美廉旭静
Owner TIANJIN UNIV OF SCI & TECH
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