Ring-opening polymerization method of N-carboxyl anhydride

Abstract

The invention provides a ring-opening polymerization method of N-carboxyl intracyclic anhydride, which comprises the following step: by taking N-carboxyl intracyclic anhydride as a monomer and taking dendritic macromolecular polyamide-amine (PAMAM) as an initiator, carrying out ring-opening polymerization reaction to obtain an amino acid polymer. According to the technical scheme provided by the invention, beta-folding of N-carboxyl intracyclic anhydride monomers (including N-carboxyl intracyclic anhydride with beta-folding tendency) during ring opening polymerization can be effectively avoided, and a product with alpha-helical configuration is obtained. Therefore, the reaction rate of ring-opening polymerization of the N-carboxyl anhydride is obviously accelerated; the molecular weight of the formed polymer is controllable, and the molecular weight distribution is more uniform; the strategy of irreversible chemical modification on the N-carboxyl intracyclic anhydride monomer is avoided, and the chemical nature of the N-carboxyl intracyclic anhydride residue is retained to the greatest extent; the whole reaction process is simple, monomer raw materials are easy to obtain, and the method is very suitable for large-scale popularization and application.

Description

Technical Field

[0001] The present invention relates to the field of synthetic polypeptides, and in particular to a ring-opening polymerization method of an N-carboxyl intracyclic acid anhydride. Background Art

[0002] Polypeptides, as a class of functional polymers with controllable sequences and secondary structures, have shown broad application prospects in biomedicine (such as drug delivery, tissue engineering) and materials science (such as biomimetic materials, nanodevices). N-carboxycyclic anhydride (NCA) is a cyclic amino acid derivative with the general structural formula: The five-membered ring containing anhydrides is formed by the condensation of the carboxyl (—COOH) and amino (—NH2) groups of the corresponding amino acids and their derivatives. Currently, ring-opening polymerization (ROP) based on N-carboxyl intracyclic anhydrides (NCA) is the mainstream method for synthesizing polypeptides.

[0003] However, when N-carboxycyclic anhydrides (NCAs) formed by amino acids with β-folding tendencies (such as tyrosine and phenylalanine) are ring-opening polymerized to form polypeptides, the polypeptide chains easily form β-folding secondary structures through hydrogen bonds during the synthesis process, resulting in intermolecular aggregation and precipitation, which in turn destroys the homogeneity of the reaction, forcing the chain growth rate to decrease and the reaction time to be significantly prolonged (usually taking several days to several weeks); and the formed precipitates will wrap around the active chain ends of the product, resulting in a decrease in the freedom of sequence design of the product, which not only limits the molecular weight of the synthesized polypeptides, but also makes it difficult to synthesize functionalized polypeptides with complex topological structures (such as blocks and gradients).

[0004] At the same time, the premature formation of β-sheet structures also kinetically affects chain extension, increasing the product molecular weight polydispersity index (PDI>1.5), resulting in poor polymer consistency and molecular weight controllability, significantly reducing the mechanical properties and biofunctional programmability of polypeptides, and severely restricting their large-scale application in high-end biomaterials such as drug controlled release carriers and biomimetic tissue scaffolds. Therefore, how to inhibit the aggregation and precipitation effect caused by β-sheets during the ring-opening polymerization of NCA has become a core scientific issue that has overcome the barriers to the industrial preparation and application of functional polypeptides.

[0005] Prior art attempts have attempted to inhibit β-sheet formation by chemically modifying NCA side chains. For example, hydrophilic protecting groups such as polyethylene glycol (PEG) or sulfonic acid groups have been introduced into the side chains to enhance steric hindrance and solvation effects, thereby inhibiting interchain hydrogen bonding and β-sheet formation. However, these chemical modifications irreversibly alter the chemical nature of the monomer residues. Such non-natural amino acid side chain modifications can compromise the biological effects of the final polypeptide, such as loss of responsiveness to enzymatic degradation. Summary of the Invention

[0006] In view of the above-mentioned shortcomings of the prior art, the object of the present invention is to provide a ring-opening polymerization method of N-carboxyl intracyclic anhydride to solve the problems in the prior art.

[0007] To achieve the above-mentioned purpose and other related purposes, the present invention is achieved through the following technical solutions.

[0008] The first aspect of the present invention provides a ring-opening polymerization method for N-carboxyl intracyclic acid anhydride. The method uses N-carboxyl intracyclic acid anhydride as a monomer and dendritic macromolecule polyamidoamine (PAMAM) as an initiator to carry out a ring-opening polymerization reaction to obtain an amino acid polymer.

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

[0010] Preferably, the dendrimer polyamidoamine (PAMAM) comprises a core structure, branching units and surface functional groups; the core structure comprises one or both of monoamine and diamine; the components of the branching units comprise ethylenediamine and propionamide; and the surface functional groups comprise one or both of amino groups and hydroxyl groups.

[0011] Preferably, the monoamine comprises ethylamine.

[0012] Preferably, the diamines include ethylenediamine and butanediamine.

[0013] Preferably, the dendrimer polyamidoamine (PAMAM) is a third-generation PAMAM (denoted as G3-PAMAM), the core structure of the third-generation PAMAM is ethylenediamine, the components of the branching units are ethylenediamine and propionamide, and the surface functional groups are amino groups.

[0014] Preferably, the N-carboxyl intracyclic acid anhydride includes an N-carboxyl intracyclic acid anhydride having a β-sheet tendency.

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

[0016] Preferably, the N-carboxyl ring anhydride with β-folding tendency includes: tyrosine N-carboxyl ring anhydride and its derivatives, serine N-carboxyl ring anhydride and its derivatives, cysteine N-carboxyl ring anhydride and its derivatives, phenylalanine N-carboxyl ring anhydride and its derivatives, tryptophan N-carboxyl ring anhydride and its derivatives, threonine N-carboxyl ring anhydride and its derivatives, valine N-carboxyl ring anhydride and its derivatives, isoleucine N-carboxyl ring anhydride and its derivatives, alanine N-carboxyl ring anhydride and its derivatives and leucine N-carboxyl ring anhydride and its derivatives.

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

[0018] Preferably, the N-carboxyl intracyclic anhydride includes natural amino acid N-carboxyl intracyclic anhydride and non-natural amino acid N-carboxyl intracyclic anhydride.

[0019] Preferably, the N-carboxyl cyclic anhydride includes one or more of α-NCA, β-NCA and γ-NCA.

[0020] Preferably, the N-carboxyl intracyclic anhydride includes one or more of L-type N-carboxyl intracyclic anhydride, D-type N-carboxyl intracyclic anhydride and DL-type N-carboxyl intracyclic anhydride.

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

[0022] Preferably, the molar ratio of the monomer to the amino groups on the surface of the initiator is 1-300:1, such as 50-200:1, 50-300:1, 1-200:1, 100-200:1, or 50-100:1.

[0023] The second aspect of the present invention provides a method for synthesizing an amino acid polymer, wherein the amino acid polymer is obtained by performing the above-mentioned ring-opening polymerization reaction using N-carboxyl intracyclic acid anhydride as a monomer.

[0024] Preferably, when the same N-carboxylic intracyclic anhydride is used as a monomer for the ring-opening polymerization reaction, the amino acid polymer is a polypolypeptide.

[0025] Preferably, when different N-carboxyl intracyclic anhydrides are used as monomers to carry out the ring-opening polymerization reaction, the amino acid polymer is a block-type amino acid copolymer.

[0026] Beneficial effects of the present invention: 1) The method for the ring-opening polymerization of N-carboxylic acid anhydrides provided in this application can effectively prevent N-carboxylic acid anhydrides (including N-carboxylic acid anhydrides with a β-folding tendency) from forming β-folds during the ring-opening polymerization. This not only effectively avoids the aggregation and precipitation effect caused by β-folding and significantly accelerates the reaction rate of the ring-opening polymerization of N-carboxylic acid anhydrides; it also makes the molecular weight of the formed polymer controllable and the molecular weight distribution more uniform, laying a favorable foundation for the subsequent synthesis of functionalized polymers with complex topological structures (such as blocks and gradients).

[0027] 2) The method for the ring-opening polymerization of N-carboxylic anhydride provided in this application also abandons the strategy of irreversible chemical modification of the side chain of NCA commonly used in the prior art, so as to retain the chemical nature of the N-carboxylic anhydride residue to the greatest extent, thereby avoiding the impact on the biological effect of the final product to the greatest extent.

[0028] 3) The present invention introduces a dendritic macromolecule PAMAM with a specific structure as an initiator and utilizes its unique three-dimensional steric effect, so that the N-carboxyl ring anhydride monomer with a β-folding tendency can form a copolymer with an α-helix as the dominant secondary structure during ring-opening polymerization. The process is simple and the monomer raw materials are easily obtained, making it very suitable for large-scale promotion and application. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Shown is a schematic diagram of the process of the ring-opening polymerization reaction in Example 1 of the present invention and Comparative Example 1.

[0030] Figure 2 Shown is an analysis chart of the transmittance results of the polymers in Example 1 of the present invention and Comparative Example 1 measured using a UV-visible spectrophotometer.

[0031] Figure 3 Shown are the infrared spectrum analysis diagram (left figure) and kinetic result diagram (right figure) of the polymers in Example 1 of the present invention and Comparative Example 1.

[0032] Figure 4 Shown are the gel permeation chromatography results of the polymers in Examples 1 to 5 of the present invention.

[0033] Figure 5 Shown are infrared spectrum analysis diagrams (right) and kinetic results diagrams (left) of the polymers in Examples 6 to 9 of the present invention.

[0034] Figure 6 It shows one of the schematic diagrams of the specific process of the amino acid NCA with β-sheet tendency finally forming an α-helical structure in the present invention.

[0035] Figure 7The second schematic diagram shows the specific process of the amino acid NCA with β-sheet tendency in the present invention finally forming an α-helical structure. DETAILED DESCRIPTION

[0036] The following describes the implementation of the present invention through specific embodiments. People skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification.

[0037] Before further describing the specific embodiments of the present invention, it should be understood that the scope of the present invention is not limited to the specific embodiments described below. It should also be understood that the terminology used in the examples is intended to describe specific embodiments and is not intended to limit the scope of the present invention. The experimental procedures in the following examples, where specific conditions are not specified, were generally performed under conventional conditions or according to the conditions recommended by the respective manufacturers.

[0038] When the embodiments provide numerical ranges, it should be understood that, unless otherwise specified in the present invention, both endpoints of each numerical range and any numerical value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those generally understood by those skilled in the art. In addition to the specific methods, equipment, and materials used in the embodiments, according to the understanding of the prior art by those skilled in the art and the description of the present invention, any methods, equipment, and materials of the prior art similar or equivalent to the methods, equipment, and materials described in the embodiments of the present invention may also be used to implement the present invention.

[0039] The initiator used in this application is a dendritic macromolecule PAMAM with a specific structure. The PAMAM is a nearly spherical nanoparticle with multiple amino functional groups distributed on its molecular surface. These amino functional groups can drive the ring-opening polymerization of NCA monomers as active initiation sites. When multiple amino groups simultaneously trigger the extension of multiple peptide chains, there will be a significant steric effect between adjacent growing chains, which will affect the molecular conformation, so that the amino acid NCA that originally had a β-folding tendency will eventually form an α-helical configuration. Specifically, due to the significant steric effect generated between adjacent growing chains, each polypeptide chain tends to adopt an α-helical configuration with a more negative Gibbs free energy change (that is, the α-helical configuration is easier to spontaneously generate). The specific process is shown in the attached figure. Figure 6 shown.

[0040] When adjacent peptide chains are arranged in a certain orientation to form the initial α-helical structure, the directional dipole moment of each peptide chain will produce a cooperative arrangement effect, thereby polarizing the surrounding monomers, reducing the energy barrier of the polymerization reaction, and accelerating the polymerization reaction. The specific process is shown in the attached figure. Figure 7 As shown; As a result, the NCA monomer with a high β-sheet tendency undergoes ring-opening polymerization to form a polymer with α-helix as the dominant secondary structure.

[0041] Example 1 This embodiment provides a specific ring-opening polymerization method of N-carboxyl intracyclic acid anhydride, which specifically includes the following steps: 1) Dissolve 14.86 mg of BLT-NCA in 1 mL of dichloromethane (DCM) to a concentration of 0.05 M to obtain a BLT-NCA solution.

[0042] 2) Take 50 μL of G3-PAMAM and dissolve it in 350 μL of DCM to make the concentration of G3-PAMAM 3.126×10 -6 mmol / μL to obtain the initiator solution.

[0043] 3) Add 5 μL of the initiator solution to the BLT-NCA solution from step 1) and stir to obtain a polymer such that the molar ratio of BLT-NCA monomer to amino groups on the surface of the G3-PAMAM initiator is 100:1. The product has a degree of polymerization (DP) of 100.

[0044] The specific reaction process is shown in the attached Figure 1 .

[0045] Comparative Example 1 This comparative example provides a specific ring-opening polymerization method of N-carboxyl intracyclic anhydride, which specifically comprises the following steps: 1) Same as Example 1.

[0046] 2) Dilute 100 μL of n-hexylamine with 900 μL of DCM to obtain a diluent. Dissolve 100 μL of the diluent in 900 μL of DCM to a n-hexylamine concentration of 7.7 mg / mL to obtain an initiator solution.

[0047] 3) Take 6.6 μL of the initiator solution and add it to the BLT-NCA solution in step 1) and stir to obtain a polymer such that the molar ratio of BLT-NCA monomer to n-hexylamine initiator is 100:1.

[0048] The specific reaction process is shown in the attached Figure 1 .

[0049] Application Example 1 The transmittance of the polymers prepared in Example 1 and Comparative Example 1 was analyzed.

[0050] The specific experimental steps are: The polymer samples prepared in Example 1 and Comparative Example 1 were respectively prepared and placed in cuvettes, and their transmittances were measured and analyzed using an ultraviolet-visible spectrophotometer (model: Shimadzu UV2600i), wherein the wavelength was set to 660 nm.

[0051] Specific experimental results can be found in Figure 2 .

[0052] Depend on Figure 2 It can be seen that the transmittance of the polymer prepared in Example 1 is much higher than that of the polymer prepared in Comparative Example 1. This shows that the polymer prepared in Example 1 has almost no precipitation, while the polymer prepared in Comparative Example 1 has a large amount of precipitation, resulting in polymer turbidity. This shows that compared with the method in Comparative Example 1, the ring-opening polymerization method provided in Example 1 can effectively inhibit the formation of precipitation induced by the formation of β-pleated structure in the monomer during the polymerization process. That is, the ring-opening polymerization system using G3-PAMAM as the initiator can effectively inhibit the formation of precipitation induced by the formation of β-pleated structure in the monomer during the polymerization process.

[0053] Application Example 2 The ring-opening polymerization processes of Example 1 and Comparative Example 1 were subjected to kinetic measurement analysis.

[0054] The specific experimental steps are as follows: using the kinetic monitoring mode of a Fourier transform infrared spectrometer (Bruker, INVENIO-R), the reaction solution was placed in a kinetic monitoring cell and sampled every 2 minutes. -1 The ring-opening polymerization processes in Example 1 and Comparative Example 1 were monitored by measuring changes in the peak area at π (this peak is characteristic of the NCA monomer and disappears after the monomer is ring-opened). After completion of each reaction system, the secondary structures of the products prepared in Example 1 and Comparative Example 1 were compared by comparing the positions of the infrared peaks in the secondary structure region.

[0055] Specific experimental results can be found in Figure 3 .

[0056] Depend on Figure 3 As shown in the left figure, the polymer finally obtained by the ring-opening polymerization reaction in Example 1 has a wavelength of 1660 cm -1 The main peak is at 1632 cm -1 The main peak is at , which indicates that the polymer has a β-sheet secondary structure.

[0057] Depend on Figure 3As shown in the right figure, in Example 1, when G3 PAMAM was used as the initiator, the degree of polymerization increased rapidly with increasing polymerization time, and the reaction was almost complete around 30 minutes (the vertical axis is 3, indicating that the reaction was nearly complete). In contrast, in Comparative Example 1, when n-hexylamine was used as the initiator, the degree of polymerization remained essentially unchanged with increasing polymerization time, rising slowly to near zero. This indicates that, compared to Comparative Example 1, the technical solution provided in Example 1 of the present application can significantly accelerate the ring-opening polymerization process of N-carboxylic intracyclic anhydride, resulting in a high reaction rate.

[0058] In summary, when G3 PAMAM is used as an initiator to participate in the ring-opening polymerization reaction of N-carboxyl intracyclic anhydride, the reaction rate can be significantly accelerated. Even if N-carboxyl intracyclic anhydride (BLT-NCA) with a β-folding tendency is used as a reaction monomer, a polymer with an α-helical secondary structure can still be prepared.

[0059] Example 2 This embodiment provides a specific ring-opening polymerization method of N-carboxyl intracyclic acid anhydride, which specifically includes the following steps: 1) Dissolve 7.43 mg of BLT-NCA in 1 mL of dichloromethane (DCM) to a BLT-NCA concentration of 0.025 M to obtain a BLT-NCA solution.

[0060] 2) Same as Example 1.

[0061] 3) Add 5 μL of the initiator solution to the BLT-NCA solution from step 1) and stir to obtain a polymer such that the molar ratio of BLT-NCA monomer to amino groups on the surface of the G3-PAMAM initiator is 50:1. The product has a DP of 50.

[0062] Example 3 This embodiment provides a specific ring-opening polymerization method of N-carboxyl intracyclic acid anhydride, which specifically includes the following steps: 1) Dissolve 29.72 mg of BLT-NCA in 1 mL of dichloromethane (DCM) to a concentration of 0.1 M to obtain a BLT-NCA solution.

[0063] 2) Same as Example 1.

[0064] 3) Add 5 μL of the initiator solution to the BLT-NCA solution from step 1) and stir to obtain a polymer with a molar ratio of BLT-NCA monomer to amino groups on the surface of the G3-PAMAM initiator of 200:1. The product has a DP of 200.

[0065] Example 4 This embodiment provides a specific method for synthesizing an amino acid polymer, which specifically includes the following steps: 1) Dissolve 14.86 mg of BLT-NCA in 1 mL of dichloromethane (DCM) to a concentration of 0.05 M to obtain a BLT-NCA solution.

[0066] 2) Take 50 μL of G3-PAMAM and dissolve it in 350 μL of DCM to make the concentration of G3-PAMAM 3.126×10 -6 mmol / μL to obtain the initiator solution.

[0067] 3) Take 5 μL of the initiator solution and add it to the BLT-NCA solution in step 1) and stir to obtain a first polymer solution, wherein the molar ratio of the BLT-NCA monomer to the amino groups on the surface of the G3-PAMAM initiator is 100:1.

[0068] 4) Add 6.58 mg of BLG-NCA to the first polymer solution from 3) to react and obtain a block amino acid copolymer. The molar ratio of BLG-NCA to BLT-NCA is 1:1.

[0069] Example 5 This embodiment provides a specific method for synthesizing an amino acid polymer, which specifically includes the following steps: 1) Same as Example 4.

[0070] 2) Same as Example 4.

[0071] 3) Same as Example 4.

[0072] 4) Add 3.29 mg of BLG-NCA to the first polymer solution in 3) to react and obtain a block amino acid copolymer. The molar ratio of BLG-NCA to BLT-NCA is 3:1.

[0073] Application Example 3 The applicant performed gel permeation chromatography analysis on the amino acid polymers prepared in Examples 1 to 5.

[0074] Specifically, 5 mg of the products prepared in Examples 1 to 3 were taken, dissolved in 1 mL of hexafluoroisopropanol, and characterized by gel permeation chromatography (GPC) of hexafluoroisopropanol phase. The specific experimental results are shown in Figure 4 Left: 5 mg of the products prepared in Examples 4 and 5 were respectively dissolved in a DMF solution containing 0.1 M LiBr to prepare a 5 mg / mL solution, and characterized by gel permeation chromatography of the DMF phase. The specific experimental results are shown in Figure 4 Right picture.

[0075] Depend on Figure 4 It can be seen that the molecular weight of the product prepared in Example 1 is 1.7×10 5 The molecular weight of the product prepared in Example 2 is 5.5×10 4 The molecular weight of the product prepared in Example 3 is 2.2×10 6 The product prepared in Example 4 is G3-g-BLT 50 -b-BLG 50 The molecular weight is 4.45×10 6 The product prepared in Example 5 is G3-g-BLT 50 -b-BLG 150 The molecular weight is 1.77×10 7 .

[0076] It shows that the technical solution provided in this application can not only prepare polypeptides of different molecular weights, but also prepare sequence-controllable block amino acid polymers 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.

[0077] Therefore, the product obtained by the ring-opening polymerization method provided in this application is more controllable, with a small molecular weight limit and a large controllable range; and the product molecular weight polydispersity index is low and the consistency is good; in addition, the ring-opening polymerization method can also be adapted to the preparation of various types of amino acid polymers.

[0078] Example 6 This embodiment provides a specific ring-opening polymerization method of N-carboxyl intracyclic acid anhydride, which specifically includes the following steps: 1) Dissolve 11.05 mg of BLS-NCA in 1 mL of dichloromethane (DCM) to a concentration of 0.05 M to obtain a BLS-NCA solution.

[0079] 2) Take 50 μL of G3-PAMAM and dissolve it in 350 μL of DCM to make the concentration of G3-PAMAM 3.126×10 -6 mmol / μL to obtain the initiator solution.

[0080] 3) Take 5 μL of the initiator solution and add it to the BLT-NCA solution in step 1) and stir to obtain a polymer in which the molar ratio of the BLT-NCA monomer to the amino groups on the surface of the G3-PAMAM initiator is 100:1.

[0081] Example 7 This embodiment provides a specific ring-opening polymerization method of N-carboxyl intracyclic acid anhydride, which specifically includes the following steps: 1) The same as Example 6, except that 11.86 mg of BLC-NCA monomer was used, and the rest was the same.

[0082] 2) Same as Example 6.

[0083] 3) Same as Example 6.

[0084] Example 8 This embodiment provides a specific ring-opening polymerization method of N-carboxyl intracyclic acid anhydride, which specifically includes the following steps: 1) The same as Example 6, except that 9.56 mg of Phe-NCA monomer was used, and the rest was the same.

[0085] 2) Same as Example 6.

[0086] 3) Same as Example 6.

[0087] Example 9 This embodiment provides a specific ring-opening polymerization method of N-carboxyl intracyclic acid anhydride, which specifically includes the following steps: 1) The same as Example 6, except that 14.86 mg of BLT-NCA monomer was used, and the rest was the same.

[0088] 2) Same as Example 6.

[0089] 3) Same as Example 6.

[0090] Application Example 4 The applicant conducted kinetic measurement analysis on the ring-opening polymerization process in Examples 6 to 9.

[0091] The specific experimental steps are as follows: using the kinetic monitoring mode of a Fourier transform infrared spectrometer (Bruker, INVENIO-R), the reaction solution was placed in a kinetic monitoring cell and sampled every 2 minutes. -1 The ring-opening polymerization processes of Examples 6-9 were monitored by measuring the change in the peak area at (this peak is characteristic of the NCA monomer and disappears after the monomer is ring-opened). After completion of each reaction system, 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.

[0092] Specific experimental results can be found in Figure 5 .

[0093] Depend on Figure 5As 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 ring-opening polymerization initiator (Comparative Example 1). This demonstrates that the ring-opening polymerization method provided in this application is applicable to a variety of different NCAs with β-sheet tendencies.

[0094] Depend on Figure 5 As shown in the figure on the right, the products obtained in Examples 6 to 9 all have a wavelength of 1660 cm -1 The main peak is at 1632 cm, indicating that the polymer has an α-helical secondary structure; -1 No peak appears.

[0095] Therefore, the technical solution of the present application can be applied to different types of NCA with β-folding tendency. This method can not only significantly improve the reaction rate of ring-opening polymerization, but also enable different types of NCA with β-folding tendency to form α-helical structures during ring-opening polymerization.

[0096] In summary, the technical solution provided in this application effectively prevents β-folding of N-carboxylic anhydride monomers (including those with β-sheet tendencies) during ring-opening polymerization, resulting in products with α-helical configurations. This significantly accelerates the reaction rate of ring-opening polymerization of N-carboxylic anhydride monomers, allows for controllable molecular weight and a more uniform molecular weight distribution of the resulting polymers, and avoids irreversible chemical modification of the N-carboxylic anhydride monomers, preserving the chemical properties of the N-carboxylic anhydride residues to the greatest extent possible. The overall reaction process is simple, and the monomer raw materials are readily available, making it highly suitable for large-scale application.

[0097] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the present invention. Anyone skilled in the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by one of ordinary skill in the art without departing from the spirit and technical principles disclosed herein are intended to be covered by the claims of the present invention.

Claims

1. A method for the ring-opening polymerization of an N-carboxyl intracyclic acid anhydride, characterized in that: The method uses N-carboxyl intracyclic acid anhydride as a monomer and dendritic macromolecular polyamide-amine as an initiator to carry out a ring-opening polymerization reaction to obtain an amino acid polymer.

2. The ring-opening polymerization method according to claim 1, wherein The amino acid polymer includes any one of a polypolypeptide and a block amino acid copolymer; And / or, the N-carboxyl intracyclic acid anhydride includes an N-carboxyl intracyclic acid anhydride having a β-sheet tendency.

3. The ring-opening polymerization method according to claim 1, wherein The dendrimer polyamidoamine comprises a core structure, branching units and surface functional groups; The core structure includes one or both of a monoamine and a diamine; The components of the branching unit include ethylenediamine and propionamide; The surface functional groups include one or both of amino groups and hydroxyl groups.

4. The ring-opening polymerization method according to claim 3, wherein The monoamine includes ethylamine; and / or, the diamines include ethylenediamine and butanediamine; And / or, 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 branching units are ethylenediamine and propionamide, and the surface functional groups are amino groups.

5. The ring-opening polymerization method according to claim 1 or 2, characterized in that The N-carboxyl intracyclic acid anhydride includes one or more of an N-carboxyl intracyclic acid anhydride containing an aromatic ring structure, an N-carboxyl intracyclic acid anhydride containing a hydrophobic side chain structure, and an N-carboxyl intracyclic acid anhydride having a polar group in the side chain.

6. The ring-opening polymerization method according to claim 2, characterized in that The N-carboxyl ring anhydride with β-folding tendency includes: tyrosine N-carboxyl ring anhydride and its derivatives, serine N-carboxyl ring anhydride and its derivatives, cysteine N-carboxyl ring anhydride and its derivatives, phenylalanine N-carboxyl ring anhydride and its derivatives, tryptophan N-carboxyl ring anhydride and its derivatives, threonine N-carboxyl ring anhydride and its derivatives, valine N-carboxyl ring anhydride and its derivatives, isoleucine N-carboxyl ring anhydride and its derivatives, alanine N-carboxyl ring anhydride and its derivatives and leucine N-carboxyl ring anhydride and its derivatives.

7. The ring-opening polymerization method according to claim 1 or 2, characterized in that The N-carboxyl intracyclic anhydride includes one or more of BLT-NCA, BLS-NCA, BLC-NCA, and Phe-NCA; and / or, the N-carboxyl intracyclic anhydride comprises a natural amino acid N-carboxyl intracyclic anhydride and a non-natural amino acid N-carboxyl intracyclic anhydride; and / or, the N-carboxyl cyclic anhydride comprises one or more of α-NCA, β-NCA and γ-NCA; And / or, the N-carboxyl intracyclic acid anhydride includes one or more of L-type N-carboxyl intracyclic acid anhydride, D-type N-carboxyl intracyclic acid anhydride and DL-type N-carboxyl intracyclic acid anhydride.

8. The ring-opening polymerization method according to claim 1, wherein Carrying out the ring-opening polymerization reaction in an organic solvent, wherein the organic solvent comprises one or more of dichloromethane, tetrahydrofuran, chloroform, and dichloroethane; And / or, the molar ratio of the monomer to the amino groups on the surface of the initiator is 1-300:

1.

9. A method for synthesizing an amino acid polymer, characterized in that: The amino acid polymer is obtained by using N-carboxyl intracyclic acid anhydride as a monomer and carrying out a reaction by the ring-opening polymerization method according to any one of claims 1 to 8.

10. The synthesis method according to claim 9, characterized in that When the same N-carboxyl intracyclic acid anhydride is used as a monomer for the ring-opening polymerization reaction, the amino acid polymer is a polypolypeptide; And / or, when different N-carboxyl intracyclic acid anhydrides are used as monomers for the ring-opening polymerization reaction, the amino acid polymer is a block-type amino acid copolymer.

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