CN112940162B - Synthetic method of highly-ordered dendritic heterogeneous sugar-containing polymer containing multiple glycosyl groups - Google Patents

Synthetic method of highly-ordered dendritic heterogeneous sugar-containing polymer containing multiple glycosyl groups Download PDF

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CN112940162B
CN112940162B CN202011425485.0A CN202011425485A CN112940162B CN 112940162 B CN112940162 B CN 112940162B CN 202011425485 A CN202011425485 A CN 202011425485A CN 112940162 B CN112940162 B CN 112940162B
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王星又
刘美娜
王梦彤
周志
叶飞
何子怡
杨玉莹
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Shanghai Institute of Technology
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    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
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    • C08F2438/00—Living radical polymerisation
    • C08F2438/03—Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX]
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Abstract

The invention relates to a synthesis method of a highly ordered dendritic heterogeneous sugar-containing polymer containing multiple sugar groups, which comprises the following steps: (1) Adding anhydrous triethylamine into a dichloromethane solution of pentafluorophenol under an ice bath condition, adding acryloyl chloride for reaction, and after the reaction is finished, washing, drying and purifying to obtain a compound PFPA; (2) Taking a compound PFPA to perform a polymerization reaction with a chain transfer agent and an initiator to obtain a polymer pPFPA; (3) Mixing the polymer pPFPA with dendritic glycosylamine to carry out ammonolysis reaction to obtain a saccharide-containing polymer; (4) And then putting the sugar-containing polymer into a sodium methoxide/methanol solution for reaction, and purifying after the reaction is finished to obtain the dendritic heterogeneous sugar-containing polymer containing multiple glycosyl groups. Compared with the prior art, the invention combines the advantages of RAFT polymerization and post-modification to obtain the sugar-containing polymer with an ordered structure, particularly obtain a regular heterogeneous sugar polymer, provide a universal platform for the preparation of the functional sugar-containing polymer, and the like.

Description

Synthetic method of highly-ordered dendritic heterogeneous sugar-containing polymer containing multiple glycosyl groups
Technical Field
The invention belongs to the technical field of synthesis of sugar-containing polymers, and relates to a synthesis method of a highly ordered dendritic heterogeneous sugar-containing polymer containing multiple glycosyl groups.
Background
The high binding affinity of multivalent sugars to lectins is referred to as the "glycocluster effect". The carbohydrate cluster effect is widely researched, and because the complexity of natural polysaccharide is not beneficial to direct synthesis and replication, a series of quasi-natural polysaccharide scaffolds based on the carbohydrate cluster effect are developed to research the specific recognition of carbohydrates and lectin. These controllable, nature-like polysaccharide scaffolds not only facilitate large-scale synthesis, but can also be adapted to the desired biological activities and explore specific biological processes by human adaptation. The sugar-containing polymer has a large adjustable range on the chain sugar group price, the binding group distance, the connecting group function and the integral framework, and has outstanding advantages on the influence of a systematic research sugar cluster structure on the biological function, so the sugar-containing polymer has wide application in biology. The activity of carbohydrate clusters such as carbohydrate-containing polymers is often influenced by structure, and it is ascertained that these influencing factors play an important role in extending the biological function of carbohydrate-containing polymers.
With the wide application of click reaction in synthesizing sugar-containing polymer and the development of polymerization technologies such as controllable/active free radical polymerization and the like, the sugar-containing polymer can realize the direct polymerization of functional sugar-containing monomers while meeting the multifunctionality, but still has wide side chain functions which can not be introduced by the direct polymerization of any existing controllable polymerization technology, and the functional groups can completely prevent the controllable polymerization and can also participate in side reactions to cause the polymerization reaction to lose control. Post-polymerization modification methods can overcome these disadvantages and can generate libraries of different functional saccharide-containing polymers with the same average chain length and chain length distribution, greatly facilitating the establishment of structure-property relationships. By adding different glycosyl groups on the pre-synthesized polymer precursor scaffold, a carbohydrate-containing polymer library with the same macromolecular structure can be conveniently and quickly generated, the tendency of self-polymerization of some carbohydrate monomers is eliminated, and the method is more suitable for modification after polymerization compared with a larger functional carbohydrate group in practical application.
The limited functionality of saccharide-containing monomers and the difficult achievement of high yields, the current direct polymerization of saccharide-containing monomers to obtain high purity heterosaccharide polymers does not meet the demand for diversity and functionalization of saccharide-containing polymers. Many of these synthetic carbohydrate-containing polymers contain only one type of carbohydrate residue, which is quite different from the inherent heterogeneity of biological systems, resulting in carbohydrate-containing polymers that do not accurately mimic the strong recognition capabilities of natural polysaccharides.
Disclosure of Invention
The invention aims to provide a synthesis method of a highly ordered dendritic heterogeneous sugar-containing polymer containing multiple glycosyl groups, which combines the advantages of RAFT polymerization and post-modification to obtain the sugar-containing polymer with an ordered structure, especially obtain a regular heterogeneous sugar polymer, provide a general platform for the preparation of a functional sugar-containing polymer, and is suitable for the preparation of a branched sugar-containing side chain polymer.
The purpose of the invention can be realized by the following technical scheme:
a method for synthesizing a highly ordered dendritic heterogeneous sugar-containing polymer containing multiple sugar groups comprises the following steps:
(1) Adding anhydrous triethylamine into a dichloromethane solution of pentafluorophenol under an ice bath condition, adding acryloyl chloride for reaction, and after the reaction is finished, washing, drying and purifying to obtain a compound PFPA;
(2) Taking a compound PFPA to perform a polymerization reaction with a chain transfer agent and an initiator to obtain a polymer pPFPA;
(3) Mixing the polymer pPFPA with the dendritic glycosylamine to perform ammonolysis reaction to obtain a sugar-containing polymer;
(4) And then putting the sugar-containing polymer into a sodium methoxide/methanol solution for reaction, and purifying after the reaction is finished to obtain light brown powder, namely the target product of the dendritic heterogeneous sugar-containing polymer containing multiple glycosyl groups.
Further, in the step (1), the molar ratio of anhydrous triethylamine, pentafluorophenol and acryloyl chloride is (1.0-1.4): 1.0: (1.0-1.4), preferably about 1.2.
Further, in the step (2), the chain transfer agent is trithiocarbonate (DDMAT), the initiator is Azobisisobutyronitrile (AIBN), and the solvent is anhydrous 1, 4-dioxan.
Further, in the step (2), the molar ratio of the chain transfer agent, the initiator and the compound PFPA is (180-220): (8-12): 1, preferably 204.
Further, in the step (2), the polymerization reaction process specifically comprises: the temperature was 80 ℃ and the reaction was stirred under nitrogen atmosphere for 24h.
Further, in the step (3), the dendronized glycosylamine is NH 2 -αMan-αMan-αMan-OAc(S1,AAA)、NH 2 -αMan-αMan-βGal-OAc(S2,AAB)、NH 2 -αMan-αMan-βGlu-OAc(S3,AAC)、NH 2 -αMan-βGal-βGal-OAc(S4,ABB)、NH 2 -αMan-βGlu-βGlu-OAc(S5,ACC)、NH 2 -αMan-βGal-βGlu-OAc(S6,ABC)、NH 2 - α Man- α Man-yne-OAc (S7, AAX) and NH 2 -one or more of-alpha Man-yne-yne-OAc (S8, AXX). The chemical structural formula of each specific dendronized sugar amine is shown as the following table:
Figure BDA0002824642660000031
Figure BDA0002824642660000041
Figure BDA0002824642660000051
further, in the step (3), the molar ratio of the polymer pPFPA to the branched sugar amine to the 4-dimethylaminopyridine is (1.8-2.4): (2.5-3.5): 1.0, preferably 2.1:3.0:1.0.
further, in the step (3), the temperature of the ammonolysis reaction is 65 ℃ and the time is 24 hours.
Further, in the step (4), the reaction temperature is room temperature, and the reaction time is 1h.
Further, in the step (4), the molar ratio of the sugar-containing polymer to sodium methoxide is 1: (10-15).
Further, in the step (4): the purification method is dialysis purification in methanol (MWCO 3500 Da).
The invention attaches the branched glycosylamine containing a plurality of glycosyl groups on the main chain of the polymer through modification (PPM) after polymerization, and prepares the similar/heterogeneous branched sugar-containing polymer with highly ordered structure and definite definition. The method is simple, efficient and convenient to operate, and provides a method for synthesizing the dendronized polymer containing multiple glycosyl groups.
According to the invention, reversible-addition fragmentation chain transfer radical polymerization (RAFT) is firstly utilized to synthesize a polymer precursor poly-pentafluorophenyl acrylate (pPFPA) with controllable molecular weight, and then the dendronized glucosamine and the polymer precursor pPFPA are subjected to aminolysis reaction to introduce a plurality of different glycosyl groups. Then removing the protection of OAc group on glycosyl by sodium methoxide/methanol solution to obtain the branched sugar-containing polymer with controllable molecular weight and high order. The invention combines the advantages of RAFT polymerization and post-modification to obtain the saccharide-containing polymer with an ordered structure, particularly obtain a regular heterogeneous saccharide polymer, provide a universal platform for preparing the functional saccharide-containing polymer, and is suitable for preparing the branched saccharide-containing side chain polymer.
Compared with the prior art, the invention has the following advantages:
(1) The invention utilizes RAFT polymerization to synthesize a linear polymer precursor with ordered structure and controllable molecular weight in advance.
(2) The invention utilizes ammonolysis reaction for modification after polymerization, and overcomes the difficulty that some macromolecular sugar-containing monomers are not beneficial to direct polymerization.
(3) The method for preparing the branched heterogeneous sugar-containing polymer can also be suitable for preparing other functional materials, such as heterogeneous sugar-containing polymers containing silicon materials and fluorine materials.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of Compound 1;
FIG. 2 is a nuclear magnetic hydrogen spectrum of Compound 2;
FIG. 3 is a nuclear magnetic hydrogen spectrum of compound P1;
FIG. 4 is a nuclear magnetic hydrogen spectrum of compound P2;
FIG. 5 is a nuclear magnetic hydrogen spectrum of Compound P3;
FIG. 6 is a nuclear magnetic hydrogen spectrum of Compound P7;
FIG. 7 is a nuclear magnetic hydrogen spectrum of Compound P6;
FIG. 8 is a nuclear magnetic hydrogen spectrum of Compound P4;
FIG. 9 is a nuclear magnetic hydrogen spectrum of compound P5;
FIG. 10 is a nuclear magnetic hydrogen spectrum of Compound P8;
FIG. 11 is a nuclear magnetic hydrogen spectrum of Compound P9;
FIG. 12 is a nuclear magnetic hydrogen spectrum of Compound P10;
FIG. 13 is a nuclear magnetic hydrogen spectrum of Compound P11;
FIG. 14 is a nuclear magnetic hydrogen spectrum of Compound P15;
FIG. 15 is a nuclear magnetic hydrogen spectrum of Compound P14;
FIG. 16 is a nuclear magnetic hydrogen spectrum of Compound P12;
FIG. 17 is a nuclear magnetic hydrogen spectrum of Compound P13;
FIG. 18 is a nuclear magnetic hydrogen spectrum of Compound P16;
FIG. 19 is a graph showing the turbidity assay for the change in absorbance between branched sugar-containing polymers and Con A recognition;
FIG. 20 is a schematic diagram of a manufacturing process according to the present invention.
Detailed Description
The invention is described in detail below with reference to the figures and the specific embodiments. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.
In the following examples, the sources of the reagents used are specifically as follows:
pentafluorophenol, a product of shanghai hadamard reagents ltd; acryloyl chloride, a product of shanghai hadamard reagents ltd; triethylamine, a product of shanghai hadamard reagent ltd; azobisisobutyronitrile, a product of Shanghai Adamax reagent, inc.; trithiocarbonate, a product of Haicha Adama reagents, inc.; 1, 4-dioxane, a product of Shanghai Adamax reagent, inc.; trifluoroacetic acid, a product of Haicha Adama reagents, inc.; anhydrous diethyl ether, a product of shanghai hadamard reagent ltd; 4-dimethylaminopyridine, available from Haemardish reagents, inc. of Shanghai; sodium methoxide, a product of hadamard reagent limited, shanghai; (H) Ion exchange resins, products of Hakka Adama reagents, inc. The other raw materials were all commercially available analytical reagents, wherein anhydrous methanol, anhydrous Dichloromethane (DCM) and anhydrous N, N-Dimethylformamide (DMF) (containing molecular sieves, water content. Ltoreq.0.05%) were purchased from Shanghai Michelin Biochemical Co., ltd.
Furthermore, dendronized glycosylamine NH 2 -αMan-αMan-αMan-OAc(S1,AAA)、NH 2 -αMan-αMan-βGal-OAc(S2,AAB)、NH 2 -αMan-αMan-βGlu-OAc(S3,AAC)、NH 2 -αMan-βGal-βGal-OAc(S4,ABB)、NH 2 -αMan-βGlu-βGlu-OAc(S5,ACC)、NH 2 -αMan-βGal-βGlu-OAc(S6,ABC)、NH 2 - α Man- α Man-yne-OAc (S7, AAX) and NH 2 - α Man-yne-yne-OAc (S8, AXX) was prepared specifically by itself, as follows:
1. a solution of di-tert-butyl dicarbonate (23.4g, 107.3mmol) in t-BuOH (100 mL) was added to a solution of tris (hydroxymethyl) aminomethane (10.0g, 82.6 mmol) in MeOH/t-BuOH (MeOH, 75mL of t-BuOH,75 mL) at room temperature, followed by reaction for 18h at room temperature. The reaction solution was evaporated to remove the solvent, the residue was recrystallized from ethyl acetate and dried by suction filtration to give Boc group-protected white powdery product one (16.4 g, 90% yield).
2. The white powder product one (10.0 g,45.2 mmol) prepared above was dissolved in 50mL of DMF and stirred at 0 ℃ for 10min, 3-bromopropyne (11.0 mL,140.1 mmol) was added dropwise, and then powdered potassium hydroxide (7.9 g,140.1 mmol) was added and stirring was continued at 0 ℃ for 1h. The reaction was then allowed to warm to room temperature for 18h. TLC (PE: EA =6 f = 0.55) upon completion of the reaction, the reaction mixture was diluted with 100mL of ethyl acetate and washed with water (3 × 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the product was obtained as a yellow oil by silica gel column chromatography (PE: EA =9 1) (9.9 g, yield 65%).
3. The above yellow oily product (4.4g, 13.1mmol) and azidomannose (. Alpha.Man-OAc-N) were mixed 3 I.e., azido sugar A) (4.9 g, 13.1mmol) was dissolved in t-BuOH/H 2 O (60mL, 1. The reaction was stirred at room temperature for 3h, tlc (PE: EA =1, compound 11R f =0.5; compound No. 12, R f =0.25; compound No. 13, R f = 0.7) detection reaction completion, 100mL of dichloromethane was added to dilute the reaction solution, and the reaction solution was washed with water (2 × 50 mL) and saturated brine (2 × 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the product Boc- α Man-OAc (i.e., AAA pre-AAA =6Driver) (2.7g, 42%), boc- α Man-yne-OAc (i.e. AAX precursor) (2.2g, 30%) and Boc- α Man-yne-OAc (i.e. AXX precursor) (1.6g, 17%).
4. AAX precursor (0.5g, 0.4mmol) and azidogalactose (beta Gal-OAc-N) 3 ) (0.2g, 0.5mmol) the same procedure as in step 3 above was followed (except for the AAX precursor,. Beta.Gal-OAc-N 3 The molar ratio of copper sulfate pentahydrate and sodium ascorbate was adjusted to approximately 1.0 f ＝0.47)。
5. With AAX precursor (0.5g, 0.4mmol) and azido glucose (beta Glu-OAc-N) 3 ) (0.2g, 0.5mmol) the same procedure as in step 3 above was followed (except for AAX precursor,. Beta.Glu-OAc-N 3 The molar ratio of copper sulfate pentahydrate and sodium ascorbate was adjusted approximately to 1.0 f ＝0.47)。
6. AXX precursor (0.8g, 1.1mmol) and azidogalactose (beta Gal-OAc-N) 3 ) (0.3g, 0.8mmol) the same procedure as in step 3 above (AXX precursor,. Beta.Gal-OAc-N) 3 The molar ratio of copper sulfate pentahydrate and sodium ascorbate was adjusted to approximately 1.5 f ＝0.4；R f ＝0.12)。
7. Synthesis of the compound Boc- α Man- β Gal- β Glu-OAc (ABC precursor):
the same procedures as in Compounds 4,5 and 6 were carried out using ABX precursor (0.3g, 0.3mmol) and azidoglucose (. Beta.Glu-OAc-N3) (c) (0.1g, 0.3mmol) (except for ABX precursor and. Beta.Glu-OAc-N) 3 (C) The molar ratio of copper sulfate pentahydrate and sodium ascorbate was adjusted to approximately 1.0.
8. Synthesis of Compound Boc-alpha Man-beta Glu-OAc (ACC precursor)
Using AXX precursor (0.5g, 0.4mmol) and azido glucose (beta Glu-OAc-N) 3 ) (0.2g, 0.5mmol) the same procedure as in step 3 above was followed (except for AXX precursor,. Beta.Glu-OAc-N 3 Copper sulfate pentahydrate and sodium ascorbate in a molar ratio of 1.0 f ＝0.47)。
9. Trifluoroacetic acid (0.6 mL) in DCM (0.6 mL) was added dropwise to a solution of the above precursor (0.3 mmol) in DCM (1 mL) at 0 ℃ and stirred, the reaction was stirred at 0 ℃ for 1h, then continued at room temperature for 3h, tlc (DCM/MeOH = 10) checked reaction completion, the reaction was concentrated to dryness, the residue was redissolved in DCM (20 mL), and saturated NaHCO was added 3 The solution (2x 20mL) was washed, then with H 2 O (2x 20mL). The organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is removed by rotary evaporation to obtain the corresponding desired dendrimeric glycoamine S1-S8.
In the above preparation, three azido sugars (. Alpha.Man-OAc-N) 3 、βGal-OAc-N 3 、βGlu-OAc-N 3 ) Prepared according to the following references: document 1 is a.bianchi and a.bernardi, j.org.chem.,2006,71, 4565-4577; document 2 is v.percec, p.leowanawat, h.j.sun, o.kulikov, c.d.nusbaum, t.m.tran, a.bertin, d.a.wilson, m.peterca, s.zhang, n.p.kamat, k.vargo, d.moock, e.d.johnston, d.a.hammer, d.j.pochan, y.chen, y.m.charbe, t.c.shiao, m.bergron-Brlek, s.andr, r.roy, h.j.gabius and p.a.heiney, j.am.chem.soc, 2013,135, 55-9077.
And the rest of the raw material reagents or treatment techniques which are not particularly specified indicate that the raw materials are conventional commercial products or conventional techniques in the field.
The present invention is described in more detail below with reference to the following examples and the process scheme of FIG. 20.
Example 1
1. Synthesis of Compound 1
Redistilled triethylamine (0.6mL, 4.0 mmol) was added dropwise to an anhydrous DCM solution (6 mL) of pentafluorophenol (0.62g, 3.37mmol) at 0 deg.C, followed by stirring for 15min, addition of acryloyl chloride (0.3mL, 4.0 mmol) dropwise, and reaction at 0 deg.C for 30min, followed by 2h at room temperature. After the reaction was completed, the reaction solution was diluted with DCM, filtered, and the residue was washed with DCM, and the filtrate was washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the product PFPA (Compound 1,0.6g, 70% yield) was obtained as a colorless oily product by silica gel column chromatography (PE).
The nuclear magnetic hydrogen spectrum of the prepared compound 1 is shown in figure 1.
1 H NMR(500MHz,CDCl 3 ):δ＝6.72(d,J＝17.0Hz,1H),6.37(dd,J＝17.5,10.5Hz,1H),6.18(d,J＝10.5Hz,1H). 19 F NMR(470MHz,CDCl 3 ):δ＝-152.52(m,2F,ortho),-158.08(t,1F,para),-162.26(m,2F,meta).
2. Synthesis of Compound 2
In a glove box filled with nitrogen, the obtained pentafluorophenol acrylate (PFPA) (779mg, 3.27mmol), trithiocarbonate (DDMAT) (59.6mg, 0.164mmol) and AIBN (2.7mg, 0.016mmol) were charged into a glass bottle, and then 2mL of an anhydrous 1, 4-dioxan solution was added. The mixture was stirred at 80 ℃ for 24h in a nitrogen-filled glove box. After the polymer solution was cooled to room temperature, it was settled in methanol three times and then dried in a vacuum oven at 40 ℃ for 24h. The product was obtained as a pink powder (Compound 2, pPFPA,0.49g, 63% yield).
The nuclear magnetic hydrogen spectrum of the prepared compound 2 is shown in figure 2.
1 H NMR(500MHz,CDCl 3 ):δ＝3.09(s,1H),2.49(s,1H),2.10(s,1H).M n,NMR ＝4651g/mol(by end-group analysis),M n,GPC (DMF)＝3318g/mol,
Figure BDA0002824642660000101
(M w /M n )＝1.16. 19 F NMR(470MHz,CDCl 3 ):δ＝-153.21(bs,2F,ortho),-156.76(bs,1F,para),-162.22(bs,2F,meta).FT-IR(KBr,cm –1 ):1785(C＝O stretching of PFP ester),1521(C＝C stretching of aryl).
Example 2
1. Synthesis of Compound 1 (PFPA) and Compound 2 (pPFPA) As in example 1
2. Preparation of sugar-containing polymers P1 to P8
In a nitrogen-filled glove box, compound 2 (50mg, 0.21mmol), and dendronized sugar amine (S1-S8, 0.30 mmol), DMAP (12.8mg, 0.10mmol) were charged into a glass bottle, followed by addition of anhydrous DMF (4 mL) for dissolution, and the mixture was stirred at 65 ℃ in a nitrogen-filled glove box for 24 hours. After completion, the reaction was precipitated three times in ether, centrifuged, and dried under vacuum at 40 ℃ overnight to give OAc protected sugar-containing polymers (P1-P8 according to S1-S8, respectively) as brown powders in 55% -58% yield.
The nuclear magnetic hydrogen spectra of the prepared sugar-containing polymers P1-P8 are shown in FIGS. 3-10, respectively.
3. Preparation of branched sugar-containing polymers P9-P16
A solution of MeONa (0.48 mmol) in 0.5mL DCM was added dropwise to a solution of the OAc group-protected saccharide-containing polymers P1-P8 (0.04 mmol) in MeOH/DCM (2mL, 1. The reaction was stirred at room temperature for 1h, then the solvent was removed under reduced pressure. The crude product was dissolved in water (1 mL) and Dowex H was added + The resin was neutralized to pH 7. The aqueous solution was filtered and purified by dialysis in methanol (MWCO 3500 Da). After vacuum drying, light brown powdery sugar-containing polymers (P9-P16) are obtained, and the Gel Permeation Chromatography (GPC) is characterized as the following table 1, a series of prepared sugar-containing polymers have the molecular weight dispersion width of between 1.26 and 1.30,
Figure BDA0002824642660000102
the values were small, and the resulting sugar-containing polymers P9-P11 and P13-P15 had molecular weights (9.6-9.8 kDa) close to the expected set molecular weight of about 10.9kDa, P12 close to the expected set molecular weight of about 8.4kDa, and P16 close to the expected set molecular weight of about 5.9kDa, indicating that heterogeneous and homogeneous sugar-containing polymers with ordered structures and controllable molecular weights were successfully synthesized.
The nuclear magnetic hydrogen spectra of the prepared sugar-containing polymers P9-P16 are shown in FIGS. 11-18, respectively.
TABLE 1
Figure BDA0002824642660000111
Example 3
1. Synthesis of Compound 1 (PFPA) and Compound 2 (pPFPA) As in example 1
2. Preparation of sugar-containing polymers P1 to P8 and P9 to P16 As in example 2
3. Turbidity method for detecting specific recognition effect of branched carbohydrate-containing polymer P9-P16 and canavalin A (Con A)
Experiments were performed with Con a and sugar-containing polymer dissolved in HEPES buffer pH = 7.4. 238mg of HEPES were first dissolved in 10mL of deionized water, pH =7 was adjusted with aqueous NaOH, and 62.5mg of MnCl were added 2 ，55.5mg CaCl 2 480mg NaCl was dissolved in 15mL deionized water, and added to the HEPES aqueous solution with adjusted pH to mix well, and then added to a 100mL volumetric flask for constant volume, and filtered with a filter before use to prepare 0.01M HEPES buffer. Then, 1mg/mL of Con A solution and 1mg/mL of sugar-containing polymer solution were prepared using the prepared buffers. After 0.40mL of Con A solution (1 mg/mL) was added to the cuvette and placed in an ultraviolet spectrometer at 25 deg.C, 0.1mL of 1mg/mL sugar-containing polymer solution was quickly added using a pipette and the absorbance of the solution was quickly recorded at 420nm every 3 seconds until 10 min. Each sample was tested three times and then the steepest fraction of the initial aggregation rate was fitted to determine the rate of interaction.
Figure 19 shows that although a high density of glycosyl groups is not necessary and a large number of glycosyl groups are not involved in the binding process, the turbidimetric results show that the more mannosyl groups, the higher the final absorbance, and the combination of pfpa backbone and loose branches seems to be more suitable for the interaction of high epitope density carbohydrate-containing polymers with Con a.
The embodiments described above are intended to facilitate a person of ordinary skill in the art in understanding and using the invention. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.

Claims (8)

1. A method for synthesizing a highly ordered dendritic heterogeneous sugar-containing polymer containing multiple sugar groups is characterized by comprising the following steps:
(1) Adding anhydrous triethylamine into a dichloromethane solution of pentafluorophenol under an ice bath condition, adding acryloyl chloride for reaction, washing, drying and purifying after the reaction is finished to obtain a compound PFPA;
(2) Taking a compound PFPA to perform a polymerization reaction with a chain transfer agent and an initiator to obtain a polymer pPFPA;
(3) Mixing the polymer pPFPA with dendritic glycosylamine to carry out ammonolysis reaction to obtain a saccharide-containing polymer;
(4) Then putting the sugar-containing polymer into sodium methoxide/methanol solution for reaction, and purifying after the reaction is finished to obtain light brown powder, namely the target product of the dendritic heterogeneous sugar-containing polymer containing multiple glycosyl groups;
in the step (2), the chain transfer agent is trithiocarbonate, the initiator is azobisisobutyronitrile, and the solvent used in the polymerization reaction process is anhydrous 1, 4-dioxane;
in the step (3), the dendronized glycosylamine is NH 2 -αMan-αMan-βGal-OAc、NH 2 -αMan-αMan-βGlu-OAc、NH 2 -αMan-βGal-βGal-OAc、NH 2 - α Man- β Glu- β Glu-OAc or NH 2 One or more of-alpha Man-beta Gal-beta Glu-OAc and NH 2 -αMan-αMan-βGal-OAc、NH 2 -αMan-αMan-βGlu-OAc、NH 2 -αMan-βGal-βGal-OAc、NH 2 -αMan-βGlu-βGlu-OAc、NH 2 The chemical structural formula of-alpha Man-beta Gal-beta Glu-OAc is as follows:
Figure FDA0003953421920000011
Figure FDA0003953421920000021
2. the method for synthesizing the highly ordered branched heterogeneous sugar-containing polymer containing multiple sugar groups according to claim 1, wherein the molar ratio of anhydrous triethylamine, pentafluorophenol and acryloyl chloride in step (1) is (1.0-1.4): 1.0: (1.0-1.4).
3. The method for synthesizing a highly ordered dendrimeric heterogeneous sugar-containing polymer containing multiple sugar groups according to claim 1, wherein in step (2), the molar ratio of the compound PFPA, the chain transfer agent and the initiator is (180-220): (8-12): 1.
4. the method for synthesizing a highly ordered dendrimeric heterogeneous sugar-containing polymer containing multiple sugar groups according to claim 1, wherein the polymerization reaction process in step (2) is specifically as follows: the temperature was 80 ℃ and the reaction was stirred under nitrogen atmosphere for 24h.
5. The method for synthesizing highly ordered dendrimeric heterogeneous sugar-containing polymers containing multiple sugar groups according to claim 1, wherein in step (3), the molar ratio of the polymers pPFPA, dendrimeric sugar amine and 4-dimethylaminopyridine is (1.8-2.4): (2.5-3.5): 1.0.
6. the method for synthesizing a highly ordered dendrimeric heterogeneous sugar-containing polymer containing multiple sugar groups according to claim 1, wherein the temperature of the ammonolysis reaction in step (3) is 65 ℃ for 24h.
7. The method for synthesizing a highly ordered branched heterogeneous sugar-containing polymer containing multiple sugar groups according to claim 1, wherein the reaction temperature in step (4) is room temperature and the reaction time is 1 hour.
8. The method for synthesizing a highly ordered dendrimeric heterogeneous sugar-containing polymer containing multiple sugar groups according to claim 1, wherein the molar ratio of sugar-containing polymer to sodium methoxide in step (4) is 1: (10-15).
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