Fucosylated chondroitin sulfate oligosaccharide glycocluster and preparation method thereof

A chondroitin sulfate and fucosylation technology, which can be used in pharmaceutical formulations, medical preparations containing active ingredients, and extracellular fluid diseases, etc.

Active Publication Date: 2018-11-13
YANTAI DONGCHENG PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, all current research results are based on oligosaccharides obtained by extraction or degradation methods, and their structures are microscopically heterogeneous, so it is impossible to draw definite conclusions and clear structure-activity relationships.

Method used

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  • Fucosylated chondroitin sulfate oligosaccharide glycocluster and preparation method thereof
  • Fucosylated chondroitin sulfate oligosaccharide glycocluster and preparation method thereof
  • Fucosylated chondroitin sulfate oligosaccharide glycocluster and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0130] Example 1: (2,3,4-tri-O-acetyl-β-D-glucopyranosyl-methyl)-(1→3)-(1,4,6-tri-O-acetyl Synthesis of 2-deoxy-N-acetylamino-β-D-galactopyranose

[0131] Dissolve chondroitin sulfate A sodium salt (20.0g) in 200mL deionized water, add IR-120 cation exchange resin to adjust the pH to 1.6 (pH meter), filter, wash the resin 3 times with deionized water, combine the filtrates, and adjust the volume to 390mL, slowly add concentrated sulfuric acid (18M, 11.1mL, final concentration 0.5M) dropwise, heat reaction at 100°C for 6 hours, cool to room temperature, add barium hydroxide octahydrate to adjust pH to 3.5 under vigorous stirring, and leave overnight. Diatomaceous earth was filtered to remove the precipitate, and the precipitate was washed 3 times with deionized water to obtain a yellow filtrate, which was concentrated to about 200mL, slowly passed through a section of IR-120 cationic resin column (column volume about 200mL), and then deionized water (400mL) , acetic acid / water...

Embodiment 2

[0135] Example 2: (2,3,4-tri-O-acetyl-β-D-glucopyranosyl-methyl)-(1→3)-2-methyl-(4,6-di- Synthesis of O-acetyl-1,2-dideoxy-α-D-galactopyranosyl)[2,1,d]2-oxazoline

[0136] Under argon protection, (2,3,4-tri-O-acetyl-β-D-glucopyranosyl-methyl)-(1→ 3)-(1,4,6-tri-O- Acetyl-2-deoxy-N-acetylamino-β-D-galactopyranose (5.00 g, 7.54 mmol) was dissolved in anhydrous CH 2 Cl 2 (180mL), trimethylsilyl trifluoromethanesulfonate (2.73mL, 15.08mmol, 2.0eq) was slowly added dropwise under ice-bath conditions, and moved to room temperature for reaction. After TLC showed that the starting material disappeared, Et was added under ice-cooling 3 N quenching. The reaction solution was evaporated to dryness and purified by direct column chromatography (PE / EtOAc=1:1.7~1:2.0, 0.1%EtOAc 3 N), concentrated under reduced pressure to obtain a white solid (4.55 g, 79%). R f =0.50(CH 2 Cl 2 / MeOH 30:1).

[0137] 1 H NMR (400MHz, CDCl 3 ,TMS)δ5.93(1H,d,H A -1, J=6.5Hz), 5.40 (1H, d, H A -4,J=3...

Embodiment 3

[0140] Example 3: 6-Azidohexyl-O-(2,3,4-tri-O-acetyl-β-D-glucopyranosyl-methyl)-(1→3)-(4,6 -Synthesis of Di-O-acetyl-2-deoxy-N-acetylamino-β-D-galactopyranose

[0141] Under argon protection, (2,3,4-tri-O-acetyl-β-D-glucopyranosyl-methyl)-(1→3)-2-methyl-(4,6-di -O-acetyl-1,2-dideoxy-α-D-galactopyranosyl)[2,1,d]2-oxazoline (3.564g, 5.91mmol) was dissolved in anhydrous chloroform and added- 6-Azidohexanol (6.623g, 46.3 mmol, 7.8eq) and anhydrous copper chloride (874mg, 6.50mmol, 1.1eq) were heated to reflux and reacted overnight. Add saturated sodium bicarbonate solution to quench the reaction, remove the solid by diatomaceous earth filtration, wash the filtrate with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography (PE / EtOAc=1:1.5~1:2.0,0.1 %Et 3 N), concentrated under reduced pressure to obtain a white solid (4.142 g, 94%). R f =0.30(CH 2 Cl 2 / MeOH 40:1).

[0142] 1 H NMR (400MHz, CDCl 3 , TMS) δ5.80 (1H, d, NH, J...

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Abstract

The invention discloses a fucosylated chondroitin sulfate oligosaccharide glycocluster with a structure show in general formula Q in the description. Definitions of substituent groups are detailed inthe description. The glycocluster compound is synthesized from chondroitin sulfate A salt as a raw material by acidolysis, protecting group operation and glycosylation in sequence on the basis of molecules of multifunctional groups as molecular skeletons. The glycocluster can simulate activity of natural glycosaminoglycan based on glycocluster effect, and can be applied to the medical field due tostructural certainty.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, more specifically, to a fucosylated chondroitin sulfate oligosaccharide cluster, a preparation method thereof, a key intermediate, and an application of the multivalent cluster compound. Background technique [0002] Fucosylated chondroitin sulfate is a kind of glycosaminoglycan extracted from sea cucumber. Its structure uses chondroitin sulfate as the backbone, and at the same time, there is a branch of fucose at the 3-position of the aldonic acid sugar, and has different Degree of sulfation, thus forming a trisaccharide repeating unit (J.Biol.Chem.1988,263,18176). [0003] [0004] Fucosylated chondroitin sulfate has biological functions such as anticoagulation, anti-inflammation, anti-HIV, and wound repair (Carbohydr. Polym. 2014, 112, 173). Among them, the anticoagulant activity has a different mechanism from that of heparin drugs, which greatly reduces the risk of bleeding (P...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/08A61P7/02A61K31/737
CPCA61K31/737A61P7/02C08B37/0069
Inventor 李中军张肖姚望沙勐孟祥豹李树春李庆娄清华
Owner YANTAI DONGCHENG PHARMA GRP
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