A process for the ring-opening polymerization of N-carboxylic anhydrides

Abstract

The application provides a ring-opening polymerization method of N-carboxylic anhydride, which uses N-carboxylic anhydride as a monomer, uses a dendrimer polyamide-amine (PAMAM) as an initiator, and performs a ring-opening polymerization reaction to obtain an amino acid polymer. The technical scheme provided by the application can effectively avoid the beta-folding of N-carboxylic anhydride monomers (including N-carboxylic anhydride with a beta-fold tendency) during ring-opening polymerization, and obtain a product with an alpha-helix configuration. Therefore, the reaction rate of the ring-opening polymerization of N-carboxylic anhydride is obviously accelerated; the molecular weight of the formed polymer is controllable, and the molecular weight distribution is more uniform; and the strategy of irreversible chemical modification of N-carboxylic anhydride monomers is avoided, the chemical nature of the N-carboxylic anhydride residue is retained to the maximum extent; the whole reaction process is simple, the monomer raw material is easy to obtain, and is very suitable for large-scale popularization and application.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of synthetic polypeptides, in particular to a ring-opening polymerization method of N-carboxyl anhydride. BACKGROUND

[0002] Polypeptides as a class of functional polymers with controllable sequence and secondary structure, show broad application prospects in biomedical (such as drug delivery, tissue engineering) and material science (such as biomimetic materials, nanodevices) and other fields. N-carboxyl anhydride (NCA) belongs to cyclic amino acid derivatives, and its general structure is: ; wherein the five-membered ring containing anhydride is formed by condensation of the carboxyl group (—COOH) and the amino group (—NH2) of the corresponding amino acid and its derivatives. At present, ring-opening polymerization (ROP) based on N-carboxyl anhydride (NCA) is the mainstream method for synthesizing polypeptides.

[0003] However, when N-carboxyl anhydride (NCA) formed by amino acids with β-sheet tendency (such as tyrosine, phenylalanine, etc.) is ring-opening polymerized to form polypeptides, the polypeptide chain is prone to form β-sheet secondary structure through hydrogen bonding during synthesis, leading to intermolecular aggregation and precipitation, thereby destroying the reaction homogeneity, forcing the chain growth rate to decrease, and the reaction time to be significantly prolonged (usually several days to several weeks); and the formed precipitate will wrap the active chain ends of the product, causing the sequence design freedom of the product to decrease, which not only limits the molecular weight of the synthetic polypeptide, but also makes it difficult to synthesize functional polypeptides with complex topological structures (such as blocks, gradients).

[0004] At the same time, the premature formation of β-sheet structure also affects the chain extension from the kinetic point of view, making the molecular weight polydispersity index of the product increase (PDI>1.5), making the consistency and molecular weight controllability of the polymer poor, thereby significantly reducing the mechanical properties and biological function programmability of the polypeptide, and seriously restricting its large-scale application in high-end biological material fields such as drug controlled release carriers and biomimetic tissue scaffolds. Therefore, how to inhibit the aggregation and precipitation effect caused by β-sheet initiation in the NCA ring-opening polymerization process has become a core scientific problem to break through the industrialization preparation and application barriers of functional polypeptides.

[0005] In the prior art, researchers try to inhibit the formation of β-sheet structure by chemically modifying the side chain of NCA. For example, by introducing polyethylene glycol (PEG) or sulfonic acid groups and other hydrophilic protecting groups into the side chain to enhance the steric hindrance and solvation effect to inhibit the interchain hydrogen bonding and β-sheet structure formation. However, these chemical modifications irreversibly change the chemical nature of the monomer residues, and such non-natural amino acid side chain modification will affect the biological effects of the final product polypeptide, such as loss of enzyme degradation responsiveness. SUMMARY

[0006] In view of the above-mentioned disadvantages of the prior art, the present application aims to provide a ring-opening polymerization method of N-carboxylic anhydride for solving the problems in the prior art.

[0007] To achieve the above-mentioned and other related purposes, the present application is obtained by the following technical solutions.

[0008] The present application provides a ring-opening polymerization method of N-carboxylic anhydride, which uses N-carboxylic anhydride as a monomer and dendrimer polyamide-amine (PAMAM) as an initiator to perform a ring-opening polymerization reaction to obtain an amino acid polymer.

[0009] Preferably, the amino acid polymer includes any one of a polypeptide and a block type amino acid copolymer.

[0010] Preferably, the dendrimer polyamide-amine (PAMAM) includes a core structure, a branched unit and a surface functional group; the core structure includes one or both of a monoamine and a diamine; the components of the branched unit include ethylenediamine and propionamide; and the surface functional group includes one or both of an amino group and a hydroxyl group.

[0011] Preferably, the monoamine includes ethylamine.

[0012] Preferably, the diamine includes ethylenediamine and butanediamine.

[0013] Preferably, the dendrimer polyamide-amine (PAMAM) is a third generation PAMAM (denoted as G3-PAMAM), the core structure of the third generation PAMAM is ethylenediamine, the components of the branched unit are ethylenediamine and propionamide, and the surface functional group is an amino group.

[0014] Preferably, the N-carboxylic anhydride includes N-carboxylic anhydride having a β-sheet tendency.

[0015] Preferably, the N-carboxylic anhydride includes one or more of N-carboxylic anhydride containing an aromatic ring structure, N-carboxylic anhydride containing a hydrophobic side chain structure, and N-carboxylic anhydride containing a polar group in the side chain.

[0016] Preferably, the N-carboxylic anhydride with a β-sheet tendency comprises: tyrosine N-carboxylic anhydride and its derivatives, serine N-carboxylic anhydride and its derivatives, cysteine N-carboxylic anhydride and its derivatives, phenylalanine N-carboxylic anhydride and its derivatives, tryptophan N-carboxylic anhydride and its derivatives, threonine N-carboxylic anhydride and its derivatives, valine N-carboxylic anhydride and its derivatives, isoleucine N-carboxylic anhydride and its derivatives, alanine N-carboxylic anhydride and its derivatives, and leucine N-carboxylic anhydride and its derivatives.

[0017] Preferably, the N-carboxylic anhydride comprises one or more of BLT-NCA, BLS-NCA, BLC-NCA, and Phe-NCA.

[0018] Preferably, the N-carboxylic anhydride comprises natural amino acid N-carboxylic anhydride and unnatural amino acid N-carboxylic anhydride.

[0019] Preferably, the N-carboxylic anhydride comprises one or more of α-NCA, β-NCA, and γ-NCA.

[0020] Preferably, the N-carboxylic anhydride comprises one or more of L-type N-carboxylic anhydride, D-type N-carboxylic anhydride, and DL-type N-carboxylic anhydride.

[0021] Preferably, the ring-opening polymerization reaction is performed in an organic solvent comprising one or more of dichloromethane, tetrahydrofuran, chloroform, and dichloroethane.

[0022] Preferably, the molar ratio of the monomer to the amino group on the surface of the initiator is 1-300:1. It can be 50-200:1, 50-300:1, 1-200:1, 100-200:1, or 50-100:1.

[0023] The second aspect of the present application provides a method for synthesizing an amino acid polymer, which comprises performing the ring-opening polymerization reaction as described above using an N-carboxylic anhydride as a monomer to obtain the amino acid polymer.

[0024] Preferably, when the ring-opening polymerization reaction is performed using the same N-carboxylic anhydride as a monomer, the amino acid polymer is a polypeptide.

[0025] Preferably, when the ring-opening polymerization reaction is performed using different N-carboxylic anhydrides as monomers, the amino acid polymer is a block-type amino acid copolymer.

[0026] The beneficial effects of the present application are as follows:

[0027] 1) The method for ring-opening polymerization of N-carboxylic anhydride provided by the application can effectively avoid the β-folding of N-carboxylic anhydride monomers (including N-carboxylic anhydride with β-folding tendency) during ring-opening polymerization, which not only effectively avoids the aggregation precipitation effect caused by β-folding, significantly accelerates the reaction rate of ring-opening polymerization of N-carboxylic anhydride, but also makes the molecular weight of the formed polymer controllable and more uniform, thereby laying a favorable foundation for the subsequent synthesis of functional polymers with complex topological structures (such as block and gradient).

[0028] 2) The method for ring-opening polymerization of N-carboxylic anhydride provided by the application also discards the strategy of irreversible chemical modification of the side chain of NCA commonly used in the prior art, thereby retaining the chemical nature of the N-carboxylic anhydride residue to the greatest extent, and thereby avoiding the influence of the biological effect of the final product to the greatest extent.

[0029] 3) The present application introduces dendrimer PAMAM with a specific structure as an initiator, and utilizes the unique three-dimensional steric hindrance effect, so that the N-carboxylic anhydride monomer with β-folding tendency can form a copolymer with α-helix as the dominant secondary structure during ring-opening polymerization, and the process is simple, the monomer raw material is easy to obtain, and is very suitable for large-scale popularization and application. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 A process diagram of ring-opening polymerization reaction in Example 1 and Comparative Example 1 of the present application is shown.

[0031] Figure 2 A UV-Vis spectrophotometer measurement transmittance result analysis diagram of the polymer in Example 1 and Comparative Example 1 of the present application is shown.

[0032] Figure 3 An infrared spectrum analysis diagram (left) and kinetic result diagram (right) of the polymer in Example 1 and Comparative Example 1 of the present application are shown.

[0033] Figure 4 A gel permeation chromatography result diagram of the polymer in Example 1-5 of the present application is shown.

[0034] Figure 5 An infrared spectrum analysis diagram (right) and kinetic result diagram (left) of the polymer in Example 6-9 of the present application are shown.

[0035] Figure 6 A specific process diagram of the final formation of α-helix configuration of the amino acid NCA with β-folding tendency in the present application is shown.

[0036] Figure 7Figure 2 is a schematic diagram showing the specific process of the amino acid NCA with a β-sheet tendency in the present application eventually forming an α-helix configuration. DETAILED DESCRIPTION

[0037] The present application will be described in more detail by the following specific examples, and other advantages and effects of the present application will be easily understood by those skilled in the art from the contents disclosed in the specification.

[0038] Before further describing the present application, it should be understood that the scope of the protection of the present application is not limited to the specific embodiments described below; it should also be understood that the terms used in the embodiments of the present application are used to describe specific embodiments and are not intended to limit the scope of protection of the present application. The test methods in the following examples are not specified, and are generally carried out under conventional conditions or under conditions recommended by the manufacturers.

[0039] When the embodiments give numerical ranges, it should be understood that, unless otherwise stated by the present application, both endpoints of each numerical range and any number between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present application have the same meaning as generally understood by those skilled in the art. In addition to the specific methods, devices, materials used in the embodiments, any method, device and material of the prior art similar or equivalent to those described in the embodiments of the present application can also be used to implement the present application according to the mastery of the prior art by those skilled in the art and the description of the present application.

[0040] The initiator used in the present application is a dendrimer PAMAM with a specific structure, which is a near-spherical nanoparticle with a plurality of amino functional groups distributed on the molecular surface, which can drive the ring-opening polymerization of NCA monomers as active initiation sites. When multiple amino groups simultaneously initiate the extension of multiple peptide chains, significant steric hindrance effects will occur between adjacent growing chains, thereby affecting the molecular conformation, so that the amino acid NCA originally with a β-sheet tendency eventually forms an α-helix configuration. Specifically, due to the significant steric hindrance effect between adjacent growing chains, each polypeptide chain tends to adopt an α-helix configuration with a more negative change in Gibbs free energy (i.e. the α-helix configuration is more likely to be spontaneously generated), and the specific process is shown in Figure 1. Figure 6 When the adjacent peptide chains are arranged in a certain degree of orientation to form an initial α-helix structure, the directional dipole moment of each polypeptide chain will produce a synergistic arrangement effect, thereby polarizing the surrounding monomers, reducing the energy barrier of the polymerization reaction, and accelerating the polymerization reaction, and the specific process is shown in Figure 2.

[0041] When the adjacent peptide chains are arranged in a certain degree of orientation to form an initial α-helix structure, the directional dipole moment of each polypeptide chain will produce a synergistic arrangement effect, thereby polarizing the surrounding monomers, reducing the energy barrier of the polymerization reaction, and accelerating the polymerization reaction, and the specific process is shown in Figure 2. Figure 7

[0042] ​Thus, the NCA monomer with high β-sheet tendency is ring-opening polymerized to form a polymer with α-helix as the dominant secondary structure.

[0043] Example 1

[0044] This example provides a specific ring-opening polymerization method of N-carboxylated cyclic anhydride, which specifically comprises the following steps:

[0045] 1) Take 14.86 mg of BLT-NCA and dissolve it in 1 mL of dichloromethane (DCM) to obtain a BLT-NCA solution with a concentration of 0.05 M.

[0046] 2) Take 50 μL of G3-PAMAM and dissolve it in 350 μL of DCM to obtain an initiator solution with a concentration of 3.126×10 -6 mmol / μL.

[0047] 3) Take 5 μL of the initiator solution and add it to the BLT-NCA solution in step 1) to obtain a polymer by stirring, so that the molar ratio of BLT-NCA monomer to amino group on the surface of G3-PAMAM initiator is 100:1. The degree of polymerization (DP) of the product is 100.

[0048] The specific reaction process is shown in the following figure: Figure 1 .

[0049] Comparative Example 1

[0050] This comparative example provides a specific ring-opening polymerization method of N-carboxylated cyclic anhydride, which specifically comprises the following steps:

[0051] 1) The same as Example 1.

[0052] 2) Take 100 μL of n-hexylamine and dilute it with 900 μL of DCM to obtain a diluent; take 100 μL of the diluent and dissolve it in 900 μL of DCM to obtain an initiator solution with a concentration of 7.7 mg / mL.

[0053] 3) Take 6.6 μL of the initiator solution and add it to the BLT-NCA solution in step 1) to obtain a polymer by stirring, so that the molar ratio of BLT-NCA monomer to n-hexylamine initiator is 100:1.

[0054] The specific reaction process is shown in the following figure: Figure 1 .

[0055] Application Example 1

[0056] The polymers prepared in Example 1 and Comparative Example 1 are subjected to permeability analysis.

[0057] The specific experimental steps are as follows:

[0058] The polymer samples prepared in Example 1 and Comparative Example 1, respectively, were prepared and placed in a cuvette, and the transmittance thereof was measured and analyzed using an ultraviolet-visible spectrophotometer (model Shimadzu UV2600i) with a wavelength of 660 nm.

[0059] The specific experimental results are shown in Figure 2 .

[0060] As can be seen from Figure 2 , the transmittance of the polymer prepared in Example 1 is much higher than that of the polymer prepared in Comparative Example 1. This indicates that almost no precipitation occurs in the polymer prepared in Example 1, while a large amount of precipitation occurs in the polymer prepared in Comparative Example 1, resulting in turbidity of the polymer. It is shown that, compared with the method in Comparative Example 1, the ring-opening polymerization method provided in Example 1 can effectively inhibit the generation of precipitation induced by the generation of β-sheet structure of monomers during the polymerization process. That is, the ring-opening polymerization system using G3-PAMAM as an initiator can effectively inhibit the generation of precipitation induced by the generation of β-sheet structure of monomers during the polymerization process.

[0061] Application Example 2

[0062] The kinetics of the ring-opening polymerization processes in Example 1 and Comparative Example 1 were measured and analyzed.

[0063] The specific experimental steps are as follows: using the kinetics monitoring mode of a Fourier infrared spectrometer (model Bruker, INVENIO-R), the reaction solution was placed in a kinetics monitoring cell, and sampling was performed every 2 minutes. By comparing the changes in the peak area at 1790 cm -1 , which is a characteristic peak of NCA monomers, the peak at this position will disappear after ring-opening, the ring-opening polymerization processes in Example 1 and Comparative Example 1 were monitored, respectively. After the reaction of each group of reaction systems was completed, the positions of the secondary structure infrared peaks of the products prepared in Example 1 and Comparative Example 1 were compared to compare the secondary structures of the products.

[0064] The specific experimental results are shown in Figure 3 .

[0065] As can be seen from Figure 3 , the left graph, the polymer ultimately obtained by the ring-opening polymerization reaction in Example 1 has a main peak at 1660 cm -1 , and thus is a polymer with an α-helix secondary structure; while the polymer ultimately obtained by the ring-opening polymerization reaction in Comparative Example 1 has a main peak at 1632 cm -1 , and thus is a polymer with a β-sheet secondary structure.

[0066] By Figure 3 As can be seen from the right graph, in Example 1, when G3 PAMAM is used as an initiator, the degree of polymerization increases rapidly with the increase of polymerization time, and the reaction is almost completed in about 30 minutes (the ordinate of 3 represents that the reaction is close to completion); while in Comparative Example 1, when n-hexylamine is used as an initiator, the degree of polymerization has little change with the increase of polymerization time, and slowly increases to 0. This shows that compared with Comparative Example 1, the technical solution provided in Example 1 of the application can significantly accelerate the ring-opening polymerization reaction process of N-carboxylated cyclic anhydride, and the reaction rate is high.

[0067] In summary, when G3 PAMAM is used as an initiator to participate in the ring-opening polymerization reaction of N-carboxylated cyclic anhydride, the reaction rate can be significantly accelerated, and even when N-carboxylated cyclic anhydride (BLT-NCA) with β-fold tendency is used as a reaction monomer, a polymer with α-helix secondary structure can still be prepared.

[0068] Example 2

[0069] This embodiment provides a specific ring-opening polymerization method of N-carboxylated cyclic anhydride, which specifically comprises the following steps:

[0070] 1) Take 7.43 mg of BLT-NCA and dissolve it in 1 mL of dichloromethane (DCM) to make the concentration of BLT-NCA 0.025 M, obtaining a BLT-NCA solution.

[0071] 2) The same as Example 1.

[0072] 3) Take 5 μL of initiator solution and add it to the BLT-NCA solution in step 1), stir to obtain a polymer, so that the molar ratio of BLT-NCA monomer to amino group on the surface of G3-PAMAM initiator is 50:1. And the DP of the product is 50.

[0073] Example 3

[0074] This embodiment provides a specific ring-opening polymerization method of N-carboxylated cyclic anhydride, which specifically comprises the following steps:

[0075] 1) Take 29.72 mg of BLT-NCA and dissolve it in 1 mL of dichloromethane (DCM) to make the concentration of BLT-NCA 0.1 M, obtaining a BLT-NCA solution.

[0076] 2) The same as Example 1.

[0077] 3) Take 5 μL initiator solution, add to the BLT-NCA solution in step 1), stir to obtain a polymer, so that the molar ratio of BLT-NCA monomer to amino group on the surface of G3-PAMAM initiator is 200:1. And the DP of the product is 200.

[0078] Example 4

[0079] The embodiment provides a specific amino acid polymer synthesis method, which specifically comprises the following steps:

[0080] 1) Take 14.86 mg of BLT-NCA, dissolve in 1 mL of dichloromethane (DCM), so that the concentration of BLT-NCA is 0.05 M, to obtain a BLT-NCA solution.

[0081] 2) Take 50 μL of G3-PAMAM, dissolve in 350 μL of DCM, so that the concentration of G3-PAMAM is 3.126×10 -6 mmol / μL, to obtain an initiator solution.

[0082] 3) Take 5 μL of the initiator solution, add to the BLT-NCA solution in step 1), stir to obtain a first polymer solution, wherein the molar ratio of BLT-NCA monomer to amino group on the surface of G3-PAMAM initiator is 100:1.

[0083] 4) Take 6.58 mg of BLG-NCA, add to the first polymer solution in 3) to react, to obtain a block type amino acid copolymer. The molar ratio of BLG-NCA to BLT-NCA is 1:1.

[0084] Example 5

[0085] The embodiment provides a specific amino acid polymer synthesis method, which specifically comprises the following steps:

[0086] 1) The same as in example 4.

[0087] 2) The same as in example 4.

[0088] 3) The same as in example 4.

[0089] 4) Take 3.29 mg of BLG-NCA, add to the first polymer solution in 3) to react, to obtain a block type amino acid copolymer. The molar ratio of BLG-NCA to BLT-NCA is 3:1.

[0090] Application Example 3

[0091] The applicant performs gel permeation chromatography analysis on the amino acid polymers prepared in examples 1-5.

[0092] Specifically, 5 mg of the products prepared in Examples 1-3 were dissolved in 1 mL of hexafluoroisopropanol and characterized by gel permeation chromatography (GPC) of the hexafluoroisopropanol phase. Specific experimental results are shown in [link to experimental results]. Figure 4 Left figure; 5 mg of the products prepared in Examples 4 and 5 were dissolved in DMF solution containing 0.1 M LiBr to prepare 5 mg / mL solutions, and characterized by gel permeation chromatography of the DMF phase. Specific experimental results are shown in [Figure number missing]. Figure 4 The image on the right.

[0093] Depend on Figure 4 As can be seen from the polystyrene standard curve provided by GPC, the molecular weight of the product prepared in Example 1 is 1.7 × 10⁻⁶. 5 The molecular weight of the product prepared in Example 2 was 5.5 × 10⁻⁶. 4 The molecular weight of the product prepared in Example 3 was 2.2 × 10⁻⁶. 6 The product obtained in Example 4 is G3-g-BLT. 50 -b-BLG 50 Its molecular weight is 4.45 × 10⁻⁶. 6 The product obtained in Example 5 is G3-g-BLT. 50 -b-BLG 150 Its molecular weight is 1.77 × 10⁻⁶. 7 .

[0094] This application demonstrates that the technical solution provided can not only prepare polypeptides of different molecular weights, but also block-type amino acid polymers with tunable sequences of different molecular weights; at the same time, the GPC results show that the chromatographic peaks of each sample are relatively narrow, indicating that the molecular weight distribution of the products prepared in Examples 1 to 5 is relatively uniform.

[0095] Therefore, the products obtained by the ring-opening polymerization method provided in this application are more controllable, with less limitation on molecular weight and a wider controllable range; moreover, the product has a low polydispersity index and good consistency; in addition, the ring-opening polymerization method can also be adapted to the preparation of various types of amino acid polymers.

[0096] Example 6

[0097] This embodiment provides a specific method for the ring-opening polymerization of N-carboxylic acid anhydrides, which includes the following steps:

[0098] 1) Take 11.05 mg of BLS-NCA and dissolve it in 1 mL of dichloromethane (DCM) to make the concentration of BLS-NCA 0.05 M, thus obtaining a BLS-NCA solution.

[0099] 2) Take 50 μL of G3-PAMAM, dissolve in 350 μL of DCM, so that the concentration of G3-PAMAM is 3.126 x 10 -6 mmol / μL, to obtain an initiator solution.

[0100] 3) Take 5 μL of the initiator solution, add to the BLT-NCA solution in step 1), stir to obtain a polymer, wherein the molar ratio of BLT-NCA monomer to amino groups on the surface of G3-PAMAM initiator is 100:1.

[0101] Example 7

[0102] This example provides a specific ring-opening polymerization method of N-carboxylated cyclic anhydride, specifically comprising the following steps:

[0103] 1) The same as in Example 6, except that 11.86 mg of BLC-NCA monomer is taken, and the rest is the same.

[0104] 2) The same as in Example 6.

[0105] 3) The same as in Example 6.

[0106] Example 8

[0107] This example provides a specific ring-opening polymerization method of N-carboxylated cyclic anhydride, specifically comprising the following steps:

[0108] 1) The same as in Example 6, except that 9.56 mg of Phe-NCA monomer is taken, and the rest is the same.

[0109] 2) The same as in Example 6.

[0110] 3) The same as in Example 6.

[0111] Example 9

[0112] This example provides a specific ring-opening polymerization method of N-carboxylated cyclic anhydride, specifically comprising the following steps:

[0113] 1) The same as in Example 6, except that 14.86 mg of BLT-NCA monomer is taken, and the rest is the same.

[0114] 2) The same as in Example 6.

[0115] 3) The same as in Example 6.

[0116] Application Example 4

[0117] The applicant analyzes the kinetics of the ring-opening polymerization in Examples 6-9.

[0118] The specific experimental procedure was as follows: using the kinetic monitoring mode of a Fourier transform infrared spectrometer (model Bruker, INVENIO-R), the reaction solution was placed in the kinetic monitoring cell, and samples were taken every 2 minutes. By comparing the 1790 cm⁻¹... -1 The change in peak area (the peak area is a characteristic peak of the NCA monomer, which disappears after the monomer is ring-opened) was monitored during the ring-opening polymerization process in Examples 6-9. After all reaction systems had completed their reactions, the secondary structures of the products prepared in Examples 6-9 were compared by comparing the positions of the infrared peaks in the secondary structure region.

[0119] For detailed experimental results, please see... Figure 5 .

[0120] Depend on Figure 5 As shown in the left figure, the reaction rates of the ring-opening polymerization processes in Examples 6-9 are all relatively fast, significantly faster than those using n-hexylamine as the initiator for ring-opening polymerization (Comparative Example 1). This indicates that the ring-opening polymerization method provided in this application is applicable to a variety of different types of NCAs with a tendency to β-sheet.

[0121] Depend on Figure 5 As shown in the right figure, the products obtained in Examples 6-9 all have a diameter of 1660 cm. -1 The dominant peak is at 1632 cm⁻¹, indicating a polymer with an α-helical secondary structure; while the peak at 1632 cm⁻¹ indicates a β-sheet secondary structure. -1 No peak was observed at that location.

[0122] Therefore, the technical solution of this application can be applied to different types of NCA with β-sheet tendency. This method can not only significantly improve the reaction rate of ring-opening polymerization, but also enable different types of NCA with β-sheet tendency to form α-helical structures during ring-opening polymerization.

[0123] In summary, the technical solution provided in this application effectively avoids the β-sheet formation of N-carboxylated intracyclic anhydride monomers (including N-carboxylated intracyclic anhydrides with β-sheet tendency) during ring-opening polymerization, resulting in products with an α-helical configuration. This significantly accelerates the reaction rate of N-carboxylated intracyclic anhydride ring-opening polymerization; makes the molecular weight of the formed polymer controllable and its molecular weight distribution more uniform; and avoids the strategy of irreversible chemical modification of N-carboxylated intracyclic anhydride monomers, preserving the chemical nature of the N-carboxylated intracyclic anhydride residues to the greatest extent. The entire reaction process is simple, and the monomer raw materials are readily available, making it highly suitable for large-scale application.

[0124] The above embodiments are only illustrative of the principles of the present application and its efficacy, and are not intended to limit the present application. Any modification or change made by any person skilled in the art without departing from the spirit and scope of the present application shall be covered by the claims of the present application.

Claims

1. A process for the ring-opening polymerization of N-carboxylic anhydride characterized in that, The method uses N-carboxylic anhydride as a monomer, dendrimer polyamide-amine as an initiator, and performs ring-opening polymerization to obtain an amino acid polymer; The N-carboxylic anhydride comprises N-carboxylic anhydride with a beta-fold tendency; The N-carboxylic anhydride with a beta-fold tendency comprises one or more of tyrosine N-carboxylic anhydride and derivatives thereof, serine N-carboxylic anhydride and derivatives thereof, cysteine N-carboxylic anhydride and derivatives thereof, phenylalanine N-carboxylic anhydride and derivatives thereof, tryptophan N-carboxylic anhydride and derivatives thereof, threonine N-carboxylic anhydride and derivatives thereof, isoleucine N-carboxylic anhydride and derivatives thereof, alanine N-carboxylic anhydride and derivatives thereof, and leucine N-carboxylic anhydride and derivatives thereof.

2. The ring-opening polymerization method according to claim 1, characterized by The amino acid polymer is a polypeptide, and the polypeptide comprises any one of a homopolypeptide chain and a copolypeptide chain.

3. The ring-opening polymerization method according to claim 1, characterized by, The dendrimer polyamide-amine comprises a core structure, a branched unit, and a surface functional group; The core structure comprises one or both of a monoamine and a diamine; The components of the branched unit comprise ethylenediamine and propionamide; The surface functional group comprises one or both of an amino group and a hydroxyl group.

4. The ring-opening polymerization method according to claim 3, characterized by The monoamine comprises ethylamine; The diamine comprises ethylenediamine and butanediamine; The dendrimer polyamide-amine is a third-generation polyamide-amine, the core structure of the third-generation polyamide-amine is ethylenediamine, the components of the branched unit are ethylenediamine and propionamide, and the surface functional group is an amino group.

5. The ring-opening polymerization method according to claim 1, characterized by The N-carboxylic anhydride comprises one or more of BLT-NCA, BLS-NCA, BLC-NCA, and Phe-NCA; The N-carboxylic anhydride comprises natural amino acid N-carboxylic anhydride and unnatural amino acid N-carboxylic anhydride; The N-carboxylic anhydride comprises one or more of alpha-NCA, beta-NCA, and gamma-NCA; The N-carboxylic anhydride comprises one or more of L-type N-carboxylic anhydride, D-type N-carboxylic anhydride, and DL-type N-carboxylic anhydride.

6. The ring-opening polymerization method according to claim 1, wherein The ring-opening polymerization is performed in an organic solvent, and the organic solvent comprises one or more of dichloromethane, tetrahydrofuran, chloroform, and dichloroethane; The molar ratio of the monomer to the amino group on the surface of the initiator is 1-300:

1.

7. A method of synthesizing an amino acid polymer, characterized by, The amino acid polymer is obtained by using N-carboxylic anhydride as a monomer and performing ring-opening polymerization by using the ring-opening polymerization method according to any one of claims 1-6.

8. The method of synthesis of claim 7, wherein, When the same N-carboxylic anhydride is used as a monomer to perform ring-opening polymerization, the amino acid polymer is a homopolypeptide chain; When different N-carboxylic anhydrides are used as monomers to perform ring-opening polymerization, the amino acid polymer is a copolypeptide chain.

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