CN114907428A - Two uridine diphosphate-2-deoxysugars and preparation method and application thereof - Google Patents
Two uridine diphosphate-2-deoxysugars and preparation method and application thereof Download PDFInfo
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- uridine diphosphate
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- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 title claims abstract description 88
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 title claims abstract description 44
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 229940045145 uridine Drugs 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 235000000346 sugar Nutrition 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 9
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 9
- 229940079593 drug Drugs 0.000 claims abstract description 7
- 229920001542 oligosaccharide Polymers 0.000 claims abstract description 6
- 150000002482 oligosaccharides Chemical class 0.000 claims abstract description 6
- 108700023372 Glycosyltransferases Proteins 0.000 claims abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 4
- 229940097217 cardiac glycoside Drugs 0.000 claims abstract description 4
- 239000002368 cardiac glycoside Substances 0.000 claims abstract description 4
- 229930002534 steroid glycoside Natural products 0.000 claims abstract description 4
- 239000000758 substrate Substances 0.000 claims abstract description 4
- 102000051366 Glycosyltransferases Human genes 0.000 claims abstract description 3
- 150000008143 steroidal glycosides Chemical class 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- UGJBHEZMOKVTIM-UHFFFAOYSA-N N-formylglycine Chemical compound OC(=O)CNC=O UGJBHEZMOKVTIM-UHFFFAOYSA-N 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 150000003536 tetrazoles Chemical class 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 230000003115 biocidal effect Effects 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 14
- -1 L-fucosyl Chemical group 0.000 abstract description 6
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 abstract description 5
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052799 carbon Inorganic materials 0.000 abstract description 4
- PNNNRSAQSRJVSB-BXKVDMCESA-N aldehydo-L-rhamnose Chemical compound C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O PNNNRSAQSRJVSB-BXKVDMCESA-N 0.000 abstract description 3
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 229940088710 antibiotic agent Drugs 0.000 abstract description 2
- 230000026030 halogenation Effects 0.000 abstract 1
- 238000005658 halogenation reaction Methods 0.000 abstract 1
- 230000026731 phosphorylation Effects 0.000 abstract 1
- 238000006366 phosphorylation reaction Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000000203 mixture Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 235000011180 diphosphates Nutrition 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- MEJLHDUXDMCALH-SELJRJPRSA-N UDP-2-deoxyglucose Chemical compound C1[C@@H](O)[C@H](O)[C@@H](CO)OC1OP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 MEJLHDUXDMCALH-SELJRJPRSA-N 0.000 description 3
- 229940045799 anthracyclines and related substance Drugs 0.000 description 3
- 239000001177 diphosphate Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- SHZGCJCMOBCMKK-PQMKYFCFSA-N L-Fucose Natural products C[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O SHZGCJCMOBCMKK-PQMKYFCFSA-N 0.000 description 2
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 2
- XCCTYIAWTASOJW-XVFCMESISA-N Uridine-5'-Diphosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 XCCTYIAWTASOJW-XVFCMESISA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 102000045442 glycosyltransferase activity proteins Human genes 0.000 description 1
- 108700014210 glycosyltransferase activity proteins Proteins 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/12—Disaccharides
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/18—Preparation of compounds containing saccharide radicals produced by the action of a glycosyl transferase, e.g. alpha-, beta- or gamma-cyclodextrins
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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- Y02P20/00—Technologies relating to chemical industry
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Abstract
The invention belongs to the field of medicines and discloses two uridine diphosphate-2-deoxysugars and a preparation method and application thereof, wherein L-rhamnose and L-fucosyl are respectively used as starting raw materials and subjected to anomeric carbon halogenation, phosphorylation and UMP-morpholinoate reaction to obtain the uridine diphosphate-2-deoxy-L-rhamnose and the uridine diphosphate-2-deoxy-L-fucose. The product obtained by the invention can be used for chemically synthesizing or biologically synthesizing oligosaccharides, glycoconjugates and the like, can also be used as a substrate of glycosyltransferase for synthesizing glycoconjugates and the like, and can be used as a sugar chain part in anti-cancer drugs, cardiac glycosides, antibiotics and other drugs in the field of medicine.
Description
Technical Field
The invention belongs to the field of medicines, relates to two uridine diphosphate-2-deoxysugars and preparation methods and applications thereof, and particularly relates to a preparation method and an application of uridine diphosphate-2-deoxy-L-rhamnose and uridine diphosphate-2-deoxy-L-fucose.
Background
Nucleoside diphosphate sugars are sugar donors for the synthesis of oligosaccharides, glycoconjugates, and also are necessary substrates for glycosyltransferases. Researches show that sugar chains in the glycoconjugates play an important role in drug metabolism, drug action targets, pharmacodynamics and the like, for example, Anthracyclines (Anthracyclines) compounds are one of anticancer drugs which are widely used clinically and have the best curative effect, and the sugar chain part of the drugs plays an important role in fixing the insertion of Anthracyclines into DNA molecular structures, and in the aspects of drug efficacy and toxicity. 2-deoxy sugars, in which the hydroxyl group at the 2-position of the sugar is replaced by hydrogen, have important physiological functions in vivo, and are frequently found in cardiac glycosides, antibiotics, and anticancer drugs. However, 2-deoxy sugar is contained in a small amount in natural products and exists in a complex mixture, so that the synthesis of 2-deoxy sugar glycoside by chemical synthesis is very important.
Hindsgaul et al (Carbohydr. Res.1993,245: 137-.
Disclosure of Invention
In order to make up for the defects of the prior art, the invention provides two uridine diphosphate-2-deoxysugars and a preparation method and application thereof, and the invention relates to a method which is different from the literature reports and is used for glycosylation by using L-rhamnose and L-fucose as starting materials, and uridine diphosphate-2-deoxy-L-rhamnose (UDP-2-deoxy-L-rhamnose) and uridine diphosphate-2-deoxy-L-fucose (UDP-2-deoxy-L-fucose) are obtained by halogenating and phosphorylating an anomeric carbon and then reacting with UMP-morpholinote. At present, no chemical synthesis of the two substances is reported.
Based on this, the present invention provides a process for the preparation of uridine diphosphate-2-deoxy-L-rhamnose and uridine diphosphate-2-deoxy-L-fucose.
The above purpose of the invention is realized by the following technical scheme:
a uridine diphosphate-2-deoxy sugar, named uridine diphosphate-2-deoxy-L-rhamnose, has a structure shown in the following structural formula:
R 1 ＝H，R 2 ＝OH。
a uridine diphosphate-2-deoxy sugar, named uridine diphosphate-2-deoxy-L-fucose, has a structure represented by the following structural formula:
R 1 ＝OH，R 2 ＝H。
another object of the present invention is to claim the above process for the preparation of uridine diphosphate-2-deoxy-L-rhamnose (I) and uridine diphosphate-2-deoxy-L-fucose (II) represented by the following formulae:
the preparation method comprises the following steps:
firstly, introducing dry HCl gas into acetylated glycal 1, taking benzene as a solvent, and reacting for 20 minutes to 1 hour at room temperature to prepare 1-chloro-2-deoxy sugar 2;
second, Bu is added 4 NH 2 PO 4 Dissolving in anhydrous acetonitrile, dropwise adding into the anhydrous acetonitrile solution of the 1-chloro-2-deoxy sugar 2 obtained in the first step, and reacting at room temperature for 2-5 hours under the protection of nitrogen to obtain 2-deoxy sugar-1-phosphoric acid 3;
thirdly, reacting the obtained 2-deoxysugar-1-phosphoric acid 3 with UMP-morpholinoate, adding tetrazole into reaction liquid, and reacting for 36-50 hours at room temperature under the protection of nitrogen by using pyridine as a solvent to obtain UDP-2-deoxyacetyl sugar 4;
in the fourth step, UDP-2-deoxyacetyl sugar 4 is added to CH 3 OH/H 2 O/Et 3 And reacting for 2-5 hours at room temperature in the N mixed solvent to obtain the target product UDP-2-deoxysugar 5.
Further, in the first step, the acetylated glycal 1 is acetylated-L-rhamnose or acetylated-L-fucosyl.
Further, the UDP-2-deoxy sugar 5 in the fourth step is uridine diphosphate-2-deoxy-L-rhamnose (I) or uridine diphosphate-2-deoxy-L-fucose (II).
Further, the structures of the uridine diphosphate-2-deoxy-L-rhamnose (I) and uridine diphosphate-2-deoxy-L-fucose (II) obtained in the fourth reaction step are shown in the specification 1 H NMR、 13 C NMR and 31 PNMR confirmed that the configuration of the glycosidic bond of the C-1 sugar ring in the structures I and II was alpha configuration by NMR data analysis.
Furthermore, the dosage of the acetylated glycal 1 in the first step is 0.5-5 g, and the dosage of the benzene is 2-50 mL.
Further, the second step of Bu 4 NH 2 PO 4 The dosage of the anhydrous acetonitrile solution is 0.5-5 g, and the dosage of the anhydrous acetonitrile solution is 5-50 mL.
Furthermore, in the third step, the dosage of the 2-deoxysugar-1-phosphoric acid 3 is 0.01-5 g, the dosage of the UMP-morpholinoate is 0.01-5 g, the dosage of the tetrazole is 0.01-5 g, and the dosage of the pyridine is 0.2-5 mL.
Further, the fourth step is that the dosage of the UDP-2-deoxyacetyl sugar 4 is 0.01 to 5g, and the CH 3 OH/H 2 O/Et 3 The dosage of the N mixed solvent is 0.5-25 mL, and CH 3 OH、H 2 O and Et 3 N is mixed according to the volume ratio of 7:3: 1.
An application of uridine diphosphate-2-deoxysugar in chemical synthesis or biological synthesis of oligosaccharide, glycoconjugate, etc, or as the substrate of glycosyltransferase in synthesizing glycoconjugate, etc, or as the sugar chain part in anticancer medicine, cardiac glycoside, antibiotic, etc is disclosed.
Compared with the prior art, the invention has the beneficial effects that:
in the prior art, because 2-position of 2-deoxysugar is lack of hydroxyl, the configuration of anomeric carbon cannot be controlled through an ortho-group, so that the configuration of the generated 2-deoxyglycoside is difficult to control; in addition, the electron cloud density on the anomeric carbon is increased due to the deletion of the hydroxyl at the 2-position, the 2-deoxyglycosidic bond has poor stability, is very sensitive to acid and is easy to hydrolyze or isomerize at the anomeric position, and the synthesis of the 2-deoxyglycosidic compound is difficult to a certain extent. Therefore, the invention starts from L-rhamnose and L-fucose, synthesizes uridine diphosphate-2-deoxy-L-rhamnose and uridine diphosphate-2-deoxy-L-fucose through four steps, lays a foundation for synthesizing nucleoside diphosphates of other types of 2-deoxy sugars, indicates directions, and does not have chemical synthesis reports about the two substances at present.
Drawings
FIG. 1 is an example of the application of UDP-2-deoxyglucose to synthetic oligosaccharides;
FIG. 2 is an example of the use of uridine diphosphate sugars in plants for the synthesis of various substances.
Detailed Description
The invention is described in more detail below with reference to specific examples, without limiting the scope of the invention. Unless otherwise specified, the experimental methods adopted by the invention are all conventional methods, and experimental equipment, materials, reagents and the like used in the experimental method can be purchased from chemical companies.
EXAMPLE 1 general procedure for the first Synthesis step
In a 25mL round bottom flask, 1g of acetylated glycal 1 was repeatedly dissolved and rotary-distilled with an appropriate amount of benzene 3 times, finally dissolved in 12mL of benzene, dried HCl (g) was added to the reaction solution, the reaction was stirred at room temperature for 30min, the progress of the reaction was checked by TLC (petroleum ether: ethyl acetate 1:1), after completion of the glycal reaction, HCl (g) and benzene were distilled off under reduced pressure to obtain a pale yellow syrupy mixture 2, which was directly subjected to the next reaction.
EXAMPLE 2 general Synthesis of the second step
In a 50mL round-bottom flask, the 2 mixture obtained above was dissolved in 25mL anhydrous CH 3 In CN, with Et 3 Adjusting pH of the solution to be approximately equal to 9 by N, and adding the solution which is activated at high temperature
Molecular sieves, the mixture was cooled in an ice-water bath. 1.5g of Bu 4 NH 2 PO 4 Dissolved in 12mL of anhydrous CH 3 In CN, in N 2 Under the protection of (2), Bu 4 NH 2 PO 4 The solution was added dropwise to the above mixture 2, and the mixture was reacted at room temperature for about 3 hours. TLC check of reaction progress (with CH) 2 Cl 2 :CH 3 OH:H 2 O:Et 3 N is 16:8:0.2:0.3), and after the reaction is finished, the residual liquid is added with CH 2 Cl 2 /CH 3 OH/H 2 O/Et 3 The system of N-24/6/0.2/0.3 was used as an eluent, and the acetylated 2-deoxy sugar-tetrabutylammonium phosphate salt 3 was obtained by silica gel column chromatography.
EXAMPLE 3 third Synthesis general procedure
Dissolving 0.05g of acetylated 2-deoxy sugar-1-tetrabutylammonium phosphate salt 3 in a 25mL pear-shaped bottle by using a small amount of anhydrous pyridine and performing rotary evaporation, repeating the dissolving and the rotary evaporation for 3 times, adding 0.05g of UMP-morpholinodate, adding 0.01g of tetrazole, and finally adding 0.5mL of anhydrous pyridine as a reaction solvent, wherein the whole reaction system is N 2 Reacting for 48h under the protection of gas, detecting the reaction by TLC, and taking CHCl as a developing agent 3 :CH 3 OH:25％NH 4 OH:H 2 O ═ 3.5:2:0.2:0.2, and after the reaction was complete, pyridine was distilled off and subjected to silica gel column chromatography (using CHCl) 3 :CH 3 OH:25％NH 4 OH:H 2 Gradient elution of the O system) to yield pure uridine diphosphate acetylated-2-deoxysugar 4.
EXAMPLE 4 Synthesis of the fourth step
40.02g of acetylated uridine diphosphate-2-deoxy sugar was dissolved in 2mL of CH 3 OH/H 2 O/Et 3 N (7/3/1) mixed solvent, reacting for 3h under stirring at room temperature, and detecting the reaction progress by TLC (with CHCl) 3 :CH 3 OH:25％NH 4 OH:H 2 O ═ 1:1:0.2:0.2 system as a developing solvent), after the reaction was completed, the solvent was dried by spinning, and uridine diphosphate 2-deoxysugar 5 in the form of triethylammonium salt was obtained by silica gel column chromatography. Or 25% NH at 4 ℃ 4 OH/H 2 And continuously reacting for 48 hours in an O (1/5) solution system to remove acetyl.
Example 5
The structures of uridine diphosphate-2-deoxy-L-rhamnose 5a (I) and uridine diphosphate-2-deoxy-L-fucose 5b (II) prepared according to examples 1-4 were subjected to 1 H NMR、 13 C NMR and 31 p NMR confirms that the configuration of the glycosidic bond of the C-1 sugar ring in the structures I and II is alpha configuration by NMR data analysis.
The specific data are as follows:
5a:yield 52％,R f 0.60(1:1:0.2:0.2CHCl 3 :CH 3 OH:25％NH 4 OH:H 2 O) 1 H NMR(400MHz,D 2 O)δ7.81(d,J＝8.1Hz,1H),5.81(dd,J＝10.8,6.0Hz,2H),5.15(d,J＝3.8Hz,1H),4.22(d,J＝3.4Hz,2H),4.08(m,3H),3.79–3.65(m,1H),3.56(m,3H),3.50(ddd,J＝11.6,9.1,5.0Hz,1H),3.34–3.15(m,1H),2.99–2.83(m,1H),2.09(dd,J＝12.3,3.3Hz,1H),2.01–1.85(m,1H),1.63–1.47(m,1H),1.34(dd,J＝22.0,12.1Hz,1H),1.20–0.95(m,3H)； 13 C NMR(100MHz,D 2 O)δ:174.42,174.26,,167.01,152.63,142.54,103.52,93.65,89.35,84.08,75.68,74.56,71.82,70.43,69.00,66.51,55.54,37.57,35.74,35.48,21.17,21.07,. 31 P NMR(162MHz,D 2 O)δ-10.50,-12.56.
5b:yield 50％,R f 0.56(1:1:0.2:0.2CHCl 3 :CH 3 OH:25％NH 4 OH:H 2 O) 1 H NMR(400MHz,D 2 O)δ7.98(d,J＝7.8Hz,1H),6.00(s,2H),5.35(d,J＝3.8Hz,1H),5.17(m,4H),4.38(s,2H),4.31–4.15(m,3H),4.06–3.90(m,3H),3.36(s,3H),3.18(d,J＝5.5Hz,1H),2.95–2.86(m,1H),2.27–1.99(m,1H),1.95–1.68(m,2H),1.61(d,J＝7.0Hz,1H),1.52(s,1H),1.39–1.06(m,3H)； 13 C NMR(100MHz,D 2 O)δ:174.92,173.91,142.40,103.55,103.11,95.31,89.19,84.08,84.01,74.66,74.59,69.89,65.74,65.71,55.15,49.71,39.86,36.29,32.64,26.24,24.09,19.88,16.39,16.27,15.78； 31 P NMR(162MHz,D 2 O)δ-11.60,-13.40.
from 1 In the H NMR spectrum, it can be seen that the chemical shifts of H on the 5a and 5b sugar rings C-1 are 5.15(d, J ═ 3.8Hz,1H) and 5.35(d, J ═ 3.8Hz,1H), respectively, and the coupling constant values are all within 3 to 5Hz, indicating that C-1H is on the e bond, and thus it can be inferred that 5a and 5b exist mainly as α -configuration isomers. When synthesizing uridine diphosphate-2-deoxysugar, not only UDP-2-deoxyrhamnose 5a and UDP-2-deoxyfucose 5b are synthesized, but also UDP-2-deoxyglucose and UDP-2-deoxygalactose are synthesized by the same method, and the nuclear magnetic resonance data confirms that the nuclear magnetic data of the two structures are consistent with the data reported in the Miyagawa (Synthetic Commun, 2016,46:1790 and 1795) literature, thereby proving that 5a and 5b are alpha-structure. In addition, 5a and 5b 31 PNMR is a doublet indicating the presence of pyrophosphate bonds in the target product.
Example 6
There are no examples of the use of UDP-2-deoxy-L-rhamnose and UDP-2-deoxy-L-fucose, but many other sugars have been used as nucleoside diphosphates, as shown in FIG. 1, for example, the application of UDP-2-deoxyglucose to the synthesis of oligosaccharides is reported in Carbohydr. Res.1993,245: 137-144.
As shown in FIG. 2, Frontiers in Plant Science, 2019,9,1822(doi.org/10.3389/fpls.2018.01822) reviews the use of various uridine diphosphate sugars in plants for the synthesis of various substances.
These examples indirectly illustrate the use of uridine diphosphate-2-deoxysugar in biosynthesis or in the pharmaceutical field.
The above description is only for the purpose of creating a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can substitute or change the technical solution and the inventive concept of the present invention within the technical scope of the present invention.
Claims (10)
1. The uridine diphosphate-2-deoxysugar is characterized by being named as uridine diphosphate-2-deoxy-L-rhamnose and having a structure shown in the following structural formula:
2. a uridine diphosphate-2-deoxy sugar, named uridine diphosphate-2-deoxy-L-fucose, having a structure represented by the following structural formula:
3. a preparation method of uridine diphosphate-2-deoxysugar is characterized by comprising the following steps:
firstly, introducing dry HCl gas into acetylated glycal 1, taking benzene as a solvent, and reacting for 20 minutes to 1 hour at room temperature to prepare 1-chloro-2-deoxy sugar 2;
second, Bu is added 4 NH 2 PO 4 Dissolving in anhydrous acetonitrile, dropwise adding into the anhydrous acetonitrile solution of the 1-chloro-2-deoxy sugar 2 obtained in the first step, and reacting at room temperature for 2-5 hours under the protection of nitrogen to obtain 2-deoxy sugar-1-phosphoric acid 3;
thirdly, reacting the obtained 2-deoxy sugar-1-phosphoric acid 3 with UMP-morpholino, adding tetrazol into reaction liquid, and reacting for 36-50 hours at room temperature under the protection of nitrogen by using pyridine as a solvent to obtain UDP-2-deoxy acetyl sugar 4;
in the fourth step, UDP-2-deoxyacetyl sugar 4 is added to CH 3 OH/H 2 O/Et 3 And reacting for 2-5 hours at room temperature in the N mixed solvent to obtain the target product UDP-2-deoxysugar 5.
4. The process of claim 3, wherein in the first step the acetylated glycal 1 is acetylated-L-rhamnose or acetylated-L-fucose.
5. The process for the preparation of uridine diphosphate-2-deoxy sugar according to claim 3, wherein said UDP-2-deoxy sugar 5 of said fourth step is uridine diphosphate-2-deoxy-L-rhamnose (I) or uridine diphosphate-2-deoxy-L-fucose (II).
6. The process according to claim 3, wherein the amount of acetylated glycal 1 in the first step is 0.5-5 g, and the amount of benzene is 2-50 mL.
7. The process for producing uridine diphosphate-2-deoxy sugar according to claim 3, wherein said Bu in the second step is 4 NH 2 PO 4 The dosage of the anhydrous acetonitrile solution is 0.5-5 g, and the dosage of the anhydrous acetonitrile solution is 5-50 mL.
8. The method for preparing uridine diphosphate-2-deoxysugar according to claim 3, wherein the amount of said 2-deoxysugar-1-phosphate 3 used in the third step is 0.01 to 5g, the amount of said UMP-morplate used is 0.01 to 5g, the amount of said tetrazole used is 0.01 to 5g, and the amount of said pyridine used is 0.2 to 5 mL.
9. The process for producing uridine diphosphate-2-deoxy sugar according to claim 3, wherein said UDP-2-deoxyacetyl sugar 4 in the fourth step is used in an amount of 0.01 to 5g, and said CH is 3 OH/H 2 O/Et 3 The dosage of the N mixed solvent is 0.5-25 mL, and CH 3 OH、H 2 O and Et 3 N is mixed according to the volume ratio of 7:3: 1.
10. The application of uridine diphosphate-2-deoxysugar is characterized in that the uridine diphosphate-2-deoxysugar is used for chemically synthesizing or biologically synthesizing oligosaccharides and glycocomplexes, or is used as a substrate of glycosyltransferase for synthesizing glycocomplexes, or is used as a sugar chain part in anticancer drugs, cardiac glycosides and antibiotic drugs.
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| AU2008269585A1 (en) * | 2007-06-27 | 2008-12-31 | The Chancellor, Masters And Scholars Of The University Of Oxford | Substrate reduction therapy |
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| EP2051708A2 (en) * | 2006-07-27 | 2009-04-29 | ISIS Innovation Limited | Epitope reduction therapy |
| AU2008269585A1 (en) * | 2007-06-27 | 2008-12-31 | The Chancellor, Masters And Scholars Of The University Of Oxford | Substrate reduction therapy |
Non-Patent Citations (1)
| Title |
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| VAGHEFI, MORTEZA M.ET AL.: ""Synthesis of glycopyranosylphosphonate analogs of certain natural nucleoside diphosphate sugars as potential inhibitors of glycosyltransferases"", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 30, no. 8, pages 1383 - 1391 * |
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