Synthesis of new fucose-containing carbohydrate derivatives
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A fucose and fucose-based technology, which is applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problems of failure of separation technology and failure to provide fucoidal oligosaccharides, etc.
Inactive Publication Date: 2013-12-11
GLYCOM AS (DK)
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[0007] Due to the wide variety of oligosaccharides present in libraries from natural sources such as human milk, isolation techniques have not been able to provide large quantities of fucoidal oligosaccharides
In addition, the presence of regioisomers characterized by closely similar structures makes separation techniques unsuccessful
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Embodiment 1
[0182] Example 1. Production of fucosyl acceptors
[0183] A) General procedure: Lactose (5 g, 14.6 mmol) and TsOH·H 2 O (0.2 g, 1.05 mmol) was added in one portion to a mixture of DMF (20 ml) and benzaldehyde dimethyl acetal (5.5 ml, 35.4 mmol, 2.4 eq.). The reaction mixture was stirred vigorously at 70° C. for 1 hour with the exclusion of moisture. After cooling, triethylamine (0.15ml) was added and the volatile components (MeOH, triethylamine, residual benzaldehyde dimethyl acetal) were removed in vacuo. Benzyl bromide derivative (1.5 eq.) was added to the reaction mixture (predissolved in 5ml-10ml of DMF if the reagent was solid), and the mixture was cooled to 0°C for 20 minutes. Continue to add NaH (0.8 g of 55% mineral oil dispersion, 1.3 eq.) in one portion under cooling, and stir the mixture under cooling until hydrogen gas formation ceases, and then stir at room temperature for 2-3 hours. Methanol (2ml) was added carefully and the reaction was stirred for an addi...
Embodiment 2
[0216] Example 2. Preparation of Fucosyl Donors of Formula 2A
[0217] a) 2,3,4-Tris-O-(4-methoxybenzyl)-L-fucopyranose trichloroacetimide ester (α / β mixture, from 85 mmol of 2,3,4-Tri-O-(4-methoxybenzyl)-L-fucopyranose and trichloroacetonitrile (prepared in the presence of NaH) in diethyl ether (100ml) were added to -14 C in a mixture of 2,5-dimethyl 4-hydroxy 3-oxo-(2H)-furan (85mmol) and TMS-trifluoromethanesulfonate (1.2ml) in ether (200ml). After 3 hours the cooling bath was removed and stirring was continued for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO 3 solution (3x150ml) and brine (150ml) extracted. Organic phase with Na 2 SO 4 Dry and evaporate. The resulting slurry was purified by column chromatography to yield 23.27 g of 2,5-dimethyl-3-oxo-(2H)-furan-4-yl 2,3,4-tri-O-(4-methoxy benzyl)-α-L-fucopyranoside as a 1:1 mixture of diastereoisomers in the form of a viscous yellow syrup. CDCl 3 Selected NMR chemic...
Embodiment 3
[0219] Example 3. Transfucosylation reaction
[0220] General procedure: Add an appropriate fucosyl donor (e.g., p-nitrophenyl α-L-fucopyranoside, α-L-fucosyl fluoride, 2,5-dimethyl 3-oxo Generation-(2H)-furan-4-yl α-L-fucopyranoside or 2'-O-fucosyllactose) and acceptor (10mmol to 500mmol, donor acceptor ratio of 5:1 to 1:5) solution was incubated with recombinant α-fucosidase, α-transfucosidase or α-fucose synthase in degassed incubation buffer at pH 5.0 to 9.0. The reaction mixture was stirred at a temperature of 20 to 70°C for 24 hours. Samples were taken at different times of the reaction and 1M NaHCO at pH=10 was added 3 solution to terminate the reaction and analyze by TLC and / or HPLC. After completion, the enzyme was denatured and centrifuged. The resulting solution was evaporated under reduced pressure. After lyophilization, the dried residue was dissolved in water and purified by biogel chromatography (P-2 Biogel, 16x900 mm) with water or by reverse phase chrom...
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Abstract
A method for the synthesis of a compound of formula (1) or a salt thereof, wherein A is a carbohydrate linker which is a lactosyl moiety or which consists of a lactosyl moiety and at least one monosaccharide unit selected from the group consisting of: glucose, galactose, N-acetylglucosamine, fucose and N-acetyl neuraminic acid; and wherein R1 is one of the following anomeric protecting groups: a) -OR2, wherein R2 is a protecting group removable by catalytic hydrogenolysis; b) -SR3, wherein R3 is an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted benzyl; c) -NH- C(R")=C(R')2, wherein each R' independently is one of the following electron withdrawing groups: -CN, -COOH, -COO-alkyl, -CO-alkyl, -CONH2, -CONH- alkyl or -CON(alkyl)2, or wherein the two R'-groups are linked together and form -CO-(CH2)2-4-CO- and thus form, together with the carbon atom to which they are attached, a 5-7 membered cycloalkan-1,3-dione, in which dione any of the methylene groups is optionally substituted with 1 or 2 alkyl groups, and R" is H or alkyl, in which a fucosyl donor of formula (2) wherein X is selected from the group consisting of: a guanosine diphosphatyl moiety, a lactose moiety, azide, fluoride, optionally substituted phenoxy-, optionally substituted pyridinyloxy-, optionally substituted 3-oxo-furanyloxy- of formula (A), optionally substituted 1,3,5-triazinyloxy- of formula (B), 4-methylumbelliferyloxy-group of formula (C), and a group of formula (D) wherein Ra is independently H or alkyl, or two vicinal Ra groups represent a=C(Rb)2 group, wherein Rb is independently H or alkyl, Rc is independently selected from the group consisting of alkoxy, amino, alkylamino and dialkylamino, Rd is selected from the group consisting of H, alkyl and -C(=O)Re, wherein Re is OH, alkoxy, amino, alkylamino, dialkylamino, hydrazino, alkylhydrazino, dialkylhydrazino or trialkylhydrazino, is reacted with an acceptor of formula H-A-R1 or a salt thereof, wherein A and R1 are as defined above, under the catalysis of an enzyme capable of transferring fucose. A compound of formula 1', its use in manufacture of human milk oligosaccharides, a method of manufacture of human milk oligosaccharides, and a fucosyl donor are also provided.
Description
technical field [0001] The present invention relates to the enzymatic synthesis of fucooligosaccharide glycosides. Background technique [0002] Human milk oligosaccharides (HMOs) are of great interest as they are directly associated with unique biological activities such as antibacterial, antiviral, immune system and cognitive development enhancing activities. HMOs were found to act as prebiotics within the human intestinal system, helping to develop and maintain the intestinal flora. Furthermore, they have also been shown to be anti-inflammatory substances, so they are used in the nutritional industry for the production of e.g. infant formula, infant cereals, clinical infant nutrition, toddler formula, etc., or as a Dietary supplements or health functional foods for women or breastfeeding women are attractive ingredients, whether as synthetically manufactured or naturally occurring compounds and their salts. HMOs are also of interest in the pharmaceutical industry for th...
Claims
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