CN115304508B - Bionic antibacterial and antioxidant nanoparticle based on pricklyash peel extract, and preparation method and application thereof - Google Patents

Bionic antibacterial and antioxidant nanoparticle based on pricklyash peel extract, and preparation method and application thereof Download PDF

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CN115304508B
CN115304508B CN202210945055.4A CN202210945055A CN115304508B CN 115304508 B CN115304508 B CN 115304508B CN 202210945055 A CN202210945055 A CN 202210945055A CN 115304508 B CN115304508 B CN 115304508B
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compound
antibacterial
antibacterial peptide
antioxidant
supercritical extraction
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CN115304508A (en
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蒋献
郭玲宏
李乙文
王天佑
顾志鹏
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West China Hospital of Sichuan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1767—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/20—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

Abstract

The invention provides bionic antibacterial and antioxidant nano particles based on a pricklyash peel extract, and a preparation method and application thereof, and belongs to the technical field of medicine preparation. The invention provides a compound shown in a formula I, or a salt or stereoisomer thereof. The invention also provides a nanoparticle prepared from the compound shown in the formula I and the antibacterial peptide. The invention carries out hydroformylation on the compound extracted from the pricklyash peel to obtain a novel compound which has antioxidant capacity. The antibacterial peptide-compound nano particles prepared by mixing the compound with the antibacterial peptide have good biocompatibility and synergistic antioxidation and antibacterial capability. The nano particles can controllably release the antibacterial peptide according to the microenvironment of the wound, can effectively remove bacteria brought by infection and regulate the oxidative stress state of the wound, can promote the rapid healing of the wound, simultaneously play a role in promoting the healing of the wound in a synergistic way, and have important application prospect for clinically promoting the healing of the wound.

Description

Bionic antibacterial and antioxidant nanoparticle based on pricklyash peel extract, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicine preparation, and in particular relates to bionic antibacterial and antioxidant nano particles based on pricklyash peel extract, and a preparation method and application thereof.
Background
The skin is the largest organ of human body, has important physiological functions, is directly contacted with the external environment, and is easily damaged and injured to a certain extent, thus forming a wound. And the wound can be in contact with the external environment, so that the wound is extremely easy to be affected by external micro-environment bacteria, and wound infection is caused. After the pathogen invades into blood vessels, the generated toxin can cause great damage and threat to the physiological state of human bodies, and bacterial infection can cause the wound microenvironment to present a higher oxidative stress state, so that the wound is difficult to heal, and long-term physiological damage and psychological pressure are brought to patients, so that a treatment scheme capable of effectively sterilizing and regulating the wound high-oxidative microenvironment is sought, and further the wound healing speed is necessary.
Antibiotics have been widely used as traditional antibacterial materials, and the mechanism of action mainly comprises the following four ways: inhibiting bacterial cell wall synthesis, enhancing bacterial cell membrane permeability, interfering with bacterial protein synthesis, and inhibiting bacterial nucleic acid replication transcription. The antibiotics are widely applied to clinic as effective antibacterial drugs, however, in recent years, side effects of the antibiotics are paid more and more attention, such as drug resistance brought by long-term administration, a certain degree of physiological toxicity, and in addition, most antibiotics cannot effectively regulate the oxidation state of the microenvironment of an affected part, so that functions are limited, and a certain obstruction exists in application of the antibiotics in treating bacterial infection wounds.
Antibacterial peptides are also an emerging antibacterial agent, which is of great interest because of its biological origin and antibacterial efficacy. The antimicrobial peptide has functions different from other antimicrobial agents, can target and concentrate on the cytoplasmic membrane of a pathogen, dislocates membrane proteins, blocks cell wall synthesis and cell respiration, and finally leads to pathogen death. Thus, antimicrobial peptides are widely used in anti-infective therapy, with relatively low risk of causing bacterial drug resistance mutations and cytotoxicity. However, the antibacterial peptide has little antioxidant effect, and as with most antibiotics, cannot effectively regulate the oxidation state of the microenvironment of the affected part.
The pricklyash peel contains various active ingredients. The antioxidant active ingredients such as polyphenol, flavone, alkaloid and the like in the pepper can play an antioxidant role by removing excessive free radicals and inhibiting the generation of free radicals. In addition, zanthoxylum bungeanum has a certain antibacterial effect. The amide compounds are common bioactive components in Zanthoxylum plants, and most of the amide compounds are chain unsaturated fatty acid amides. If an amide compound with excellent antibacterial and antioxidant effects can be extracted from the pricklyash peel, the preparation is beneficial to wound treatment. In addition, if the amide compound extracted from the pricklyash peel can be combined with the antibacterial peptide, the medicine with more excellent antibacterial and antioxidant effects can be obtained, and the method has more important significance for clinical wound healing.
Disclosure of Invention
The invention aims to solve the problem of bacterial infection wound treatment, and provides bionic antibacterial and antioxidant nano particles based on pricklyash peel extract, and a preparation method and application thereof.
The present invention provides a compound of formula I, or a salt thereof, or a stereoisomer thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 ～R 6 are independently selected from hydrogen, C 1 ～C 8 An alkyl group.
Further, the compound is the following compound:
the invention also provides a preparation method of the compound, which comprises the following steps:
in a solvent, the compound A and p-aldehyde benzoic acid react with an esterification catalyst under a closed condition to obtain the catalyst; the compound a is shown below:
preferably, the method comprises the steps of,
and/or the solvent is N, N-dimethylformamide;
and/or the esterification catalyst is 4-dimethylaminopyridine and N, N' -diisopropylcarbodiimide;
and/or, the reaction temperature is room temperature;
and/or the reaction time is 12-24 hours;
and/or, precipitating with deionized water, centrifuging, washing and drying after the reaction;
more preferably, the mass ratio of the compound A, the p-aldehyde benzoic acid, the 4-dimethylaminopyridine and the N, N' -diisopropylcarbodiimide is 1: (1-2): (0.1-1): (1-10).
Further, the preparation method of the compound A comprises the following steps: performing supercritical extraction on fructus Zanthoxyli with liquid carbon dioxide to obtain the final product;
preferably, the supercritical extraction of the pricklyash peel with liquid carbon dioxide is carried out for 2 times;
in the first supercritical extraction, the mass-volume ratio of the pricklyash peel to the liquid carbon dioxide is 1kg: (100-200) mL; the pressure of the supercritical extraction is 15-20 MPa; the temperature of the supercritical extraction is 40-50 ℃; and/or the supercritical extraction time is 30-60 min;
separating the extract after the first supercritical extraction to obtain a crude product, and performing the second supercritical extraction on the crude product; during the separation, the temperature is 40-60 ℃; the pressure is less than 6.5MPa; liquid carbon dioxide with the length of 100-150 m 3 Extracting at a speed of/h;
in the second supercritical extraction, the mass-volume ratio of the pepper fruit to the liquid carbon dioxide is 1kg: (100-200) mL; the pressure of the supercritical extraction is 20-30 MPa; the temperature of the supercritical extraction is 40-50 ℃; and/or the supercritical extraction time is 30-60 min;
more preferably, the pepper fruits are crushed to 50-100 meshes.
The invention also provides application of the compound, or salt or stereoisomer thereof in preparing antioxidant drugs and/or materials;
preferably, the medicament and/or material is a medicament and/or material that promotes wound healing.
The invention also provides a medicine which is a pharmaceutical preparation prepared by taking the compound, or the salt or the stereoisomer thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
The invention also provides an antibacterial and antioxidant nanoparticle, which is prepared from the following raw materials in parts by weight:
0.1 to 10 parts of the compound, or a salt or stereoisomer thereof, and 1 part of antibacterial peptide;
preferably, the feed additive is prepared from the following raw materials in parts by weight:
0.5 to 2 parts of the compound, or a salt or a stereoisomer thereof, and 1 part of antibacterial peptide;
more preferably, the feed additive is prepared from the following raw materials in parts by weight:
0.5 to 1.67 parts of the aforementioned compound, or a salt or stereoisomer thereof, and 1 part of an antibacterial peptide.
Further, the antibacterial peptide is antibacterial peptide KS26.
The invention also provides a preparation method of the antibacterial and antioxidant nanoparticle, which comprises the following steps:
(1) Dissolving the aforementioned compound, or a salt thereof, or a stereoisomer thereof in a solvent;
(2) Dissolving an antimicrobial peptide in a solvent;
(3) Adding the solution obtained in the step (1) into the solution obtained in the step (2), stirring for reaction, centrifuging the reaction solution, washing and drying to obtain the catalyst;
preferably, the method comprises the steps of,
in the step (1), the solvent is DMSO;
and/or, in step (1), the concentration of the aforementioned compound, or a salt thereof, or a stereoisomer thereof is from 10 to 25mg/mL;
and/or, in the step (2), the solvent is water;
and/or, in the step (2), the concentration of the antibacterial peptide is 0.5-1.5mg/mL;
and/or, in the step (3), the reaction time is 1-4h;
and/or, in the step (3), the centrifugation condition is 15000r/min for 10min;
more preferably, the process is carried out,
in the step (1), the concentration of the aforementioned compound, or a salt thereof, or a stereoisomer thereof is 20mg/mL;
and/or, in step (2), the concentration of the antibacterial peptide is 1.0mg/mL;
and/or, in the step (3), the reaction time is 2h.
The invention also provides application of the antibacterial and/or antioxidant nanoparticle in preparation of antibacterial and/or antioxidant drugs and/or materials;
preferably, the medicament and/or material is a medicament and/or material that promotes wound healing.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) The invention extracts a compound from pricklyash peel by a supercritical extraction method, and carries out hydroformylation on the compound to obtain a novel compound with an antioxidant effect.
(2) The invention takes the aldehyde compound and the antibacterial peptide as raw materials to prepare the nano particle, and the nano particle has good DPPH and ABTS free radical scavenging capability, plays a synergistic antioxidation role, and can be suitable for various oxidative stress microenvironments. The nanoparticle also has good oxidation resistance at the cell level, and can realize intrinsic free radical scavenging capability at the biological level.
(3) The nano particles prepared by the invention have good controllable release capability, and can adapt to microenvironment to realize the effect of release treatment.
(4) The nano particles prepared by the invention have good biocompatibility, and lay a solid foundation for biological application.
(5) The nano particles prepared by the invention have good bactericidal capability, can exert synergistic antibacterial activity, and have good killing effect on escherichia coli and staphylococcus aureus.
(6) The nano particles prepared by the invention have the capability of accelerating the healing of contaminated wounds, have better effect than the singly used aldehyde compound and antibacterial peptide, play the role of synergistic wound healing and have good biological application prospect.
In conclusion, the invention carries out hydroformylation on the compound extracted from the pricklyash peel to obtain a novel compound which has antioxidant capacity. The antibacterial peptide-compound nano particles prepared by mixing the compound with the antibacterial peptide have good biocompatibility and synergistic antioxidation and antibacterial capability. The nano particles can controllably release the antibacterial peptide according to the microenvironment of the wound, can effectively remove bacteria brought by infection and regulate the oxidative stress state of the wound, can promote the rapid healing of the wound, simultaneously play a role in promoting the healing of the wound in a synergistic way, and have important application prospect for clinically promoting the healing of the wound.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 is a nuclear magnetic pattern of compounds extracted from Zanthoxylum bungeanum fruit.
FIG. 2 is a nuclear magnetic resonance spectrum of the hydroformylation compound of the present invention.
FIG. 3 shows the reaction grafting rate at different amounts of paraaldehyde benzoic acid.
FIG. 4 is a graph showing the change in particle size of nanoparticles prepared with different amounts of aldehyde-based sanshool.
FIG. 5 shows DPPH radical scavenging ability of the antimicrobial peptide-compound nanoparticles of the invention in vitro.
FIG. 6 shows the ABTS radical scavenging ability of the antimicrobial peptide-compound nanoparticles of the present invention.
FIG. 7 is a graph showing the statistics of release efficiency of the antibacterial peptide-compound nanoparticles of the present invention.
FIG. 8 is a graph showing cell viability statistics of the antimicrobial peptide-compound nanoparticle PSA-1 of the present invention at various concentrations.
FIG. 9 shows the antioxidant capacity of the antibacterial peptide-compound nanoparticle PSA-1 of the present invention at various concentrations.
FIG. 10 shows the bactericidal capacity of the antibacterial peptide-compound nanoparticle PSA-1 of the present invention against E.coli and Staphylococcus aureus at various concentrations.
FIG. 11 is a chart showing the statistics of wound area of the antibacterial peptide-compound nanoparticle PSA-1 of the present invention accelerating the healing process of bacterial infection wounds.
Detailed Description
The materials and equipment used in the embodiments of the present invention are all known products and are obtained by purchasing commercially available products.
The starting materials used in the following examples and comparative examples were p-aldehyde benzoic acid (98.0%), 4-dimethylaminopyridine (DMAP, 98%), N' -diisopropylcarbodiimide (DIPC, 98%) available from shanghai An Naiji chemical company, inc; antibacterial peptide KS26 (95.0%) was purchased from Nanj dawski biotechnology Co., ltd.
Example 1 extraction of Compounds from Zanthoxylum bungeanum fruit and hydroformylation of the Compounds
1. Extraction of compounds from pricklyash peel
The specific steps of extracting the compound from the pricklyash peel are as follows:
(1) Preparing carbon dioxide: refrigerating and liquefying gaseous carbon dioxide in the storage tank; preparing pepper: screening the stem-removed pepper fruits and crushing the pepper fruits to 70 meshes.
(2) And (3) early-stage extraction: 2kg of crushed pepper is put into an extraction tank, 200mL of liquid carbon dioxide is introduced for supercritical extraction, the pressure is controlled to be 18MPa, the extraction temperature is set to be 45 ℃, and the extraction time is 60min, so that a pre-extraction liquid is obtained.
(3) And (3) separating the primary extract: the primary extract enters a separating tank, the temperature is increased to 50 ℃, the pressure is reduced to below 6.5MPa, liquid carbon dioxide is pumped out of the separating tank, and the flow rate of the carbon dioxide is 120m 3 And/h, obtaining a crude product.
(4) And (3) post-extraction: and (3) putting the crude product into an extraction tank again, increasing the pressure to 22MPa, reducing the temperature to 40 ℃, introducing 200mL of liquid carbon dioxide, performing supercritical extraction for 60min, and performing slag removal after extraction, so as to obtain the post-extraction compound. The structure of the post-extraction compound isThe nuclear magnetic pattern of the compound is shown in figure 1.
2. Hydroformylation of the extracted compounds
The compound obtained by the extraction is subjected to hydroformylation, and the specific steps are as follows:
(1) 1 part by mass of the compound obtained by the extraction was sufficiently dissolved in DMF at a concentration of 60mg/mL, followed by addition of 1.0, 1.3, 1.6, 2.0 parts by mass of p-aldehyde benzoic acid, 0.6 parts by mass of 4-Dimethylaminopyridine (DMAP), 5.5 parts by mass of N, N' -Diisopropylcarbodiimide (DIPC), and stirring at room temperature under a closed condition (with air isolated) for 24 hours.
(2) Precipitating the product obtained in the step (1) with deionized water, centrifuging, washing for three times to remove unreacted substances and a small amount of byproducts, and freeze-drying the precipitate to obtain light yellow powder, namely the hydroformylation compoundThe object has the structure ofThe nuclear magnetic spectrum of the compound is shown in figure 2 and is named as aldehyde-group sanshool. FIG. 2 is an example of an aldehyde sanshool prepared from 1.6 parts by mass of p-aldehyde benzoic acid.
The appearance of a benzene ring peak contained in the paraaldehyde benzoic acid is observed through nuclear magnetic resonance hydrogen spectrum characterization, and the grafting rate of the benzene ring peak and the compound before hydroformylation is calculated through integration, and the result is shown in a figure 3, and the result shows that the grafting rate is improved along with the improvement of the mass part of the paraaldehyde benzoic acid, and reaches nearly 100% when the mass part of the paraaldehyde benzoic acid reaches 1.6, and the feeding amount of the paraaldehyde benzoic acid is continuously increased without obvious change. Thus, 1 part by mass of the compoundThe hydroformylation was performed using 1.6 parts by mass of p-aldehyde benzoic acid.
Example 2 extraction of Compounds from Zanthoxylum bungeanum fruit and hydroformylation of the Compounds
1. Extraction of compounds from pricklyash peel
The specific steps of extracting the compound from the pricklyash peel are as follows:
(1) Preparing carbon dioxide: refrigerating and liquefying gaseous carbon dioxide in the storage tank; preparing pepper: screening the peduncles of the pricklyash peel and crushing the pricklyash peel to 50 meshes.
(2) And (3) early-stage extraction: 2kg of crushed pepper is put into an extraction tank, 200mL of liquid carbon dioxide is introduced for supercritical extraction, the pressure is controlled to be 15MPa, the extraction temperature is set to be 40 ℃, and the extraction time is 60min, so that a pre-extraction liquid is obtained.
(3) And (3) separating the primary extract: the primary extract enters a separating tank, the temperature is raised to 40 ℃, the pressure is reduced to below 6.5MPa, liquid carbon dioxide is pumped out of the separating tank, and the flow rate of the carbon dioxide is 100m 3 And/h, obtaining a crude product.
(4) And (3) post-extraction: and (3) putting the crude product into an extraction tank again, raising the pressure to 20MPa, reducing the temperature to 40 ℃, introducing 200mL of liquid carbon dioxide, performing supercritical extraction for 60min, and performing slag removal after extraction, so as to obtain a post-extraction compound, wherein the structure of the post-extraction compound is the same as that of example 1.
2. Hydroformylation of the extracted compounds
The compound obtained by the extraction is subjected to hydroformylation, and the specific steps are as follows:
(1) 1 part by mass of the compound obtained by the above extraction was sufficiently dissolved in DMF at a concentration of 40mg/mL, followed by addition of 1.6 parts by mass of p-aldehyde benzoic acid, 0.4 parts by mass of 4-Dimethylaminopyridine (DMAP), 4.0 parts by mass of N, N' -Diisopropylcarbodiimide (DIPC), and stirring at room temperature under closed conditions (air-insulated) for 16 hours.
(2) And (3) precipitating the product obtained in the step (1) by using deionized water, centrifuging and washing for three times to remove unreacted substances and a small amount of byproducts, and then freeze-drying the precipitate to obtain light yellow powder, namely the hydroformylation compound of the invention, wherein the structure of the hydroformylation compound is the same as that of the example 1.
Example 3 extraction of Compounds from Zanthoxylum bungeanum fruit
1. Extraction of compounds from pricklyash peel
The specific steps of extracting the compound from the pricklyash peel are as follows:
(1) Preparing carbon dioxide: refrigerating and liquefying gaseous carbon dioxide in the storage tank; preparing pepper: screening the stem-removed pepper fruits and crushing the pepper fruits to 70 meshes.
(2) And (3) early-stage extraction: 2kg of crushed pepper is put into an extraction tank, 200mL of liquid carbon dioxide is introduced for supercritical extraction, the pressure is controlled to be 20MPa, the extraction temperature is set to be 50 ℃, and the extraction time is 60min, so that a pre-extraction liquid is obtained.
(3) And (3) separating the primary extract: the primary extract enters a separating tank, the temperature is increased to 60 ℃, the pressure is reduced to below 6.5MPa, liquid carbon dioxide is pumped out of the separating tank, and the carbon dioxide flow is 150m 3 And/h, obtaining a crude product.
(4) And (3) post-extraction: the crude product was again placed in an extraction tank, supercritical extraction was performed by increasing the pressure to 30MPa, decreasing the temperature to 40 ℃, introducing 200mL of liquid carbon dioxide for 60min, and after the extraction was completed, slag was removed, and after the slag removal, a post-extraction compound was obtained, the structure of which was the same as in example 1.
2. Hydroformylation of the extracted compounds
The compound obtained by the extraction is subjected to hydroformylation, and the specific steps are as follows:
(1) 1 part by mass of the compound obtained by the above extraction was sufficiently dissolved in DMF at a concentration of 100mg/mL, followed by addition of 1.6 parts by mass of p-aldehyde benzoic acid, 0.8 parts by mass of 4-Dimethylaminopyridine (DMAP), 8.0 parts by mass of N, N' -Diisopropylcarbodiimide (DIPC), and stirring at room temperature under closed conditions (air-insulated) for 16 hours.
(2) And (3) precipitating the product obtained in the step (1) by using deionized water, centrifuging and washing for three times to remove unreacted substances and a small amount of byproducts, and then freeze-drying the precipitate to obtain light yellow powder, namely the hydroformylation compound of the invention, wherein the structure of the hydroformylation compound is the same as that of the example 1.
EXAMPLE 4 preparation of the antibacterial peptide-Compound nanoparticles of the invention
The preparation method of the antibacterial peptide-compound nanoparticle comprises the following specific steps:
(1) The aldehyde-based sanshool prepared in example 1 was sufficiently dissolved in DMSO solution at a concentration of 20mg/mL.
(2) Antibacterial peptide KS26 was dissolved in deionized water and placed in a round bottom flask at a concentration of 1.0mg/mL. 1mL of the aldehyde-group sanshool DMSO solution is taken and added dropwise into 12mL, 20mL, 30mL or 40mL of antibacterial peptide aqueous solution, and the uniform stirring speed is maintained.
(3) After 2h reaction at room temperature, the reaction solution was centrifuged (15000 r/min,10 min), washed three times with deionized water, and the resulting precipitate was lyophilized to obtain four antibacterial peptide-compound nanoparticles.
Four reactions were performed in parallel, 1 part by mass of the antibacterial peptide and 1.67,1.00,0.67,0.50 parts by mass of the aldehyde sanshool, and the obtained products were named as PSA-1, PSA-2, PSA-3, and PSA-4, respectively.
EXAMPLE 5 preparation of the antibacterial peptide-Compound nanoparticles of the invention
The preparation method of the antibacterial peptide-compound nanoparticle comprises the following specific steps:
(1) The aldehyde-based sanshool prepared in example 1 was sufficiently dissolved in DMSO solution at a concentration of 10mg/mL.
(2) Antibacterial peptide KS26 was dissolved in deionized water and placed in a round bottom flask at a concentration of 0.5mg/mL. 1mL of the aldehyde-group sanshool DMSO solution is taken and added dropwise into 6mL, 10mL, 15mL or 20mL of antibacterial peptide aqueous solution, and the uniform stirring speed is maintained.
(3) After 1h reaction at room temperature, the reaction solution was centrifuged (15000 r/min,10 min), washed three times with deionized water, and the resulting precipitate was lyophilized to obtain four antibacterial peptide-compound nanoparticles.
EXAMPLE 6 preparation of the antibacterial peptide-Compound nanoparticles of the invention
The preparation method of the antibacterial peptide-compound nanoparticle comprises the following specific steps:
(1) The aldehyde-based sanshool prepared in example 1 was sufficiently dissolved in DMSO solution at a concentration of 25mg/mL.
(2) Antibacterial peptide KS26 was dissolved in deionized water and placed in a round bottom flask at a concentration of 1.5mg/mL. 1mL of the aldehyde group pricklyash peel extract DMSO solution is taken and added dropwise into 15mL, 25mL, 42.5mL or 50mL of antibacterial peptide aqueous solution, and the uniform stirring speed is maintained.
(3) After 4h reaction at room temperature, the reaction solution was centrifuged (15000 r/min,10 min), washed three times with deionized water, and the resulting precipitate was lyophilized to obtain four antibacterial peptide-compound nanoparticles.
The beneficial effects of the present invention are demonstrated by specific test examples below.
Test example 1 characterization of particle size of antibacterial peptide-Compound nanoparticles of the invention
Particle size characteristics of PSA-1, PSA-2, PSA-3 and PSA-4 prepared in example 4 were examined using a bench-top scanning electron microscope. PSA-1, PSA-2, PSA-3 and PSA-4 are respectively prepared into sample solutions with the concentration of 1mg/mL by deionized water, spin-coated on the surface of a smooth mica sheet, and observed after drying and metal spraying treatment in sequence. Particle size statistics were performed using Image J software and the results are shown in fig. 4. As can be seen from FIG. 4, the particle size of PSA-1 was 125.+ -.6 nm, the particle size of PSA-2 was 171.+ -.6 nm, the particle size of PSA-3 was 239.+ -.9 nm, and the particle size of PSA-4 was 302.+ -.12 nm. It was found that with increasing mass ratio of aldehyde group sanshool, particle size showed a tendency to gradually rise, since the increase of active aldehyde group content gave a better growth state for the reaction, and particle size increased.
Test example 2 in vitro DPPH radical scavenging ability of antibacterial peptide-Compound nanoparticles of the invention
The in vitro DPPH radical scavenging ability of the four nanoparticles of PSA-1, PSA-2, PSA-3 and PSA-4 prepared in example 4 was assessed by the 2, 2-diphenyl-1-picrylhydrazine (DPPH) method. Antibacterial peptide KS26 and aldehyde sanshool prepared in example 1 were used as controls.
DPPH ethanol solution with the concentration of 0.1mmol/L and PSA-1, PSA-2, PSA-3, PSA-4, antimicrobial peptide KS26 and aldehyde group sanshool sample aqueous solutions with the concentration of 1mg/mL are respectively prepared. 300. Mu.L of DPPH ethanol solution was diluted with an appropriate amount of ethanol, and then 120. Mu.L of the aqueous sample solution was added thereto so that the final volume of the solution was kept at 3mL, to obtain a sample solution having a concentration of 40. Mu.g/mL. The absorbance at 517nm was used to evaluate the free radical scavenging effect and the absorbance was measured at different time points over 30 minutes to obtain the free radical scavenging profile. As shown in FIG. 5, it can be seen that the antibacterial peptide KS26 has little DPPH radical scavenging ability in vitro, but the aldehyde group Zanthoxylum piperitum has DPPH radical scavenging ability but is weak; the antibacterial peptide-compound nano particles prepared by the invention have good DPPH free radical scavenging capability, and are obviously superior to the single use of aldehyde group sanshool. The antibacterial peptide-compound nano particles prepared by the invention exert synergistic oxidation resistance. Among them, PSA-1 has the strongest DPPH radical scavenging ability because it has the smallest particle size, i.e., the largest specific surface area, and the oxidation resistance of particles gradually decreases as the particle size increases.
Test example 3 aqueous free radical scavenging Capacity of antibacterial peptide-Compound nanoparticles of the invention
The aqueous phase radical scavenging ability of the four nanoparticles of PSA-1, PSA-2, PSA-3 and PSA-4 prepared in example 4 was assessed using the 2,2' -diazabis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) method. Antibacterial peptide KS26 and aldehyde sanshool prepared in example 1 were used as controls. The specific operation is as follows:
(1) Respectively preparing 7mM ABTS aqueous solution and 2.45mM potassium persulfate aqueous solution; ABTS aqueous solution and potassium persulfate aqueous solution at 1:2, and left standing at room temperature overnight, and left in a dark state to give the final ABTS detection reagent.
(2) An aqueous solution of samples of PSA-1, PSA-2, PSA-3, PSA-4, antimicrobial peptide KS26 and aldehydo sanshool was prepared at a concentration of 1 mg/mL.
(3) 100. Mu.L of the ABTS assay reagent solution was diluted with an appropriate amount of deionized water, and then 120. Mu.L of the aqueous sample solution was added to maintain the final volume of the solution at 3mL, resulting in a sample solution having a concentration of 40. Mu.g/mL.
(4) The absorbance at 734nm was used to evaluate the free radical scavenging effect and absorbance was measured at different time points over 30 minutes to obtain the free radical scavenging profile.
The results are shown in FIG. 6, from which it can be seen that the ABTS radical scavenging ability is consistent with the DPPH radical scavenging ability results. Antibacterial peptide KS26 has little ABTS radical scavenging ability, aldehyde group sanshool has ABTS radical scavenging ability, but is weaker; the antibacterial peptide-compound nano particles prepared by the method have good ABTS free radical scavenging capability, and are obviously superior to the single use of aldehyde group sanshool. The antibacterial peptide-compound nano particles prepared by the invention exert synergistic oxidation resistance. Among them, PSA-1 has the strongest ABTS radical scavenging ability because it has the smallest particle size, i.e., the largest specific surface area, and the antioxidant ability of the particles gradually decreases as the particle size increases.
Test example 4 release behavior of the antibacterial peptide-Compound nanoparticles of the present invention
Four nanoparticles of PSA-1, PSA-2, PSA-3 and PSA-4 prepared in example 4 were individually packed in dialysis bags (mwco=3200 Da) and dialyzed for 24 hours to measure the release rate of the antimicrobial peptides from the nanoparticles. The release behaviour of the resulting samples was assessed by a maturation derivatization method using ninhydrin. To prepare the derivatizing reagent, 85mg of ninhydrin and 15mg of ninhydrin were dissolved in 10mL of ethylene glycol methyl ether and the derivatizing reagent was freshly prepared prior to measurement. The released solution sample (500 μl) was thoroughly mixed with 500 μl of derivatizing reagent and 500 μl of acetic acid-sodium acetate buffer (ph=5.4). The mixture was then heated to 100 ℃ for 15 minutes and then cooled to room temperature. In this process, the color of the reaction system changes from brown yellow to bluish violet. The absorbance of the sample at 570nm was recorded for colorimetric analysis. The resulting release rates are shown in FIG. 7, from which it can be seen that under slightly acidic conditions, particles can be effectively released, with the smallest particle size PSA-1 having the highest release efficiency, which is associated with its higher specific surface area, as demonstrated by the release rate with decreasing particle size, and hence PSA-1 is selected as the target material in the following test analysis.
Test example 5 biocompatibility of the antibacterial peptide-compound nanoparticle of the present invention
Taking NIH mouse embryo fibroblast 3T3 cells as cell lines, and adopting an MTT colorimetric method to verify cytotoxicity of the sample. The cells were cultured by adding 10% Fetal Bovine Serum (FBS) to DMEM medium and co-incubating in an atmosphere containing 5% CO 2 Is maintained at 37 ℃. The cultured NIH 3T3 cells were incubated in 96-well plates at a density of 2000 cells per well for 24 hours, treated with 50, 100, 200, 300 and 500. Mu.g/mL samples (PSA-1 prepared in example 4, prepared with medium) for additional 24 hours, and then tested for the viability of the corresponding cells according to the MTT colorimetric test protocol, as shown in FIG. 8. As can be seen from the figure, the PSA-1 particles have good biocompatibility, and the survival rate of cells is more than 95% below 100 mug/mL, so that the PSA-1 particles have good biological application prospect.
Test example 6 antioxidant Capacity of antibacterial peptide-Compound nanoparticles of the invention
NIH 3T3 cells cultured in experimental example 5 were seeded at 10 ten thousand per well in 12-well plates and incubated in the well plates for 24 hours. After the incubation was completed, the medium was removed, 500. Mu.L of the PSA-1 nanoparticle sample solution prepared in example 4 at different concentrations (100. Mu.g/mL, 200. Mu.g/mL) prepared from DMEM medium was added, 500. Mu.L of the whole composition culture solution was further added to dilute the concentration of PSA-1 nanoparticles to 50. Mu.g/mL, 100. Mu.g/mL (PSA-1-50, PSA-1-100), 100. Mu.L of diluted hydrogen peroxide (100. Mu. Mol/L) was further added to culture for 24 hours, and then the culture solution was removed, 200. Mu.L of pancreatin digested cells was added and 200. Mu.L of medium was added to terminate the pancreatin digestion; centrifuging to remove supernatant, adding 1ml PBS solution for re-suspension, and adding 250 μl of prepared probe; and finally, suspending the cell sample in PBS again after centrifugal treatment, and quantitatively analyzing by adopting a flow cytometer for 24 hours to obtain the result shown in the figure 9, wherein NC is pure cells in the figure 9, and PC is only hydrogen peroxide and no PSA-1 is added. Compared with a positive control (only hydrogen peroxide is added and no PSA-1 is added), the fluorescent intensity is reduced by applying sample solutions with different concentrations, and the higher the concentration is, the more the reduction is, so that the good oxidation resistance of the cell surface of the PSA-1 nano particle is shown.
Test example 7 antibacterial Properties of antibacterial peptide-Compound nanoparticles of the invention
The antibacterial property test was performed on the PSA-1 nanoparticles prepared in example 4. Antibacterial peptide KS26 and the aldehyde sanshool prepared in example 1 were used as controls, and no drug was added as a blank.
Before the test, the reagents and the test tubes required for the test are sterilized. The antibacterial activity of the bacteria was evaluated by the diffusion plate method. Coli and staphylococcus aureus were used as models, respectively. Taking 10. Mu.L of bacterial suspension (bacterial suspension density 3X 10) 9 cfu/mL) is an exponential growth stage, and is added into a test tube containing 2mL of sterile LB liquid medium, and different amounts of PSA-1 nano particles, antibacterial peptide KS26 or aldehyde group sanshool are respectively added into different test tubes, so that the concentration of the PSA-1 nano particles in bacterial liquid is 50 mug/mL or 100 mug/mL, the concentration of the antibacterial peptide KS26 in the bacterial liquid is 100 mug/mL, and the concentration of the aldehyde group sanshool in the bacterial liquid is 100 mug/mL. After 24h of culture, the absorbance of the sample at 600nm wavelength is measured by an enzyme-labeled instrument, the OD value is recorded, bacterial activity statistics are further calculated according to the OD value, the statistics are shown in figure 10, and the no antibacterial activity and the resistance of the aldehyde group sanshool can be seenThe mycopeptide KS26 has a certain antibacterial activity, but the activity is weaker, and the nano particles prepared by the method have excellent antibacterial effect, have obvious inhibition effect on escherichia coli and staphylococcus aureus, have better effect than the independently used mycopeptide KS26, and play the synergistic antibacterial effect. And the more obvious the sterilization effect is along with the increase of the concentration of the nano particles, so that the nano particles of the invention have good antibacterial application prospect.
Test example 8 effect of the antibacterial peptide-Compound nanoparticle of the present invention on promoting wound healing
This test example demonstrates the therapeutic effect of PSA-1 nanoparticles (prepared in example 4) on a contaminated wound repair model. 20 SD rats (females) were anesthetized by intraperitoneal injection of 10% chloral hydrate (350 mg/kg). Next, two 1.5X1.5 cm pieces of tissue were created under loose subcutaneous tissue on the back side of the skin 2 Is then treated with a suspension of Staphylococcus aureus (100. Mu.L, 10) 9 CFU mL -1 ) Infection for 24h established a wound infection model. After 24h, 20 rats were randomly divided into 4 groups (5 per group): untreated (bacterial but untreated), 100. Mu.g/mL of PSA-1 nanoparticle aqueous solution treatment, 100. Mu.g/mL of pure aldehyde sanshool aqueous solution, and 100. Mu.g/mL of pure antimicrobial peptide KS26 aqueous solution. After the staphylococcus aureus infection wound surface model is established, all infected rats are treated in groups, the dosage is 10mg/kg, and the dosage concentration is 100 mug/mL. On days 1, 5, 10 and 15, the appearance of the wound was photographed and statistically analyzed. The results are shown in fig. 11, and it can be seen that the application of the antimicrobial peptide-compound nanoparticles of the present invention effectively accelerates the wound healing rate, whereas the application of either the antimicrobial peptide KS26 or the aldehyde-based sanshool alone, which is slower, shows that the combination of the compound of the present invention and the antimicrobial peptide exerts a synergistic wound healing promoting effect.
The compound of the invention is combined with the antibacterial peptide to realize the effect by reacting aldehyde group with amino group of the antibacterial peptide, and has universality for the antibacterial peptide. The invention is exemplified by the antibacterial peptide KS26, but is not limited to the antibacterial peptide KS26, and any other antibacterial peptide can realize the effect.
In conclusion, the invention carries out hydroformylation on the compound extracted from the pricklyash peel to obtain a novel compound which has antioxidant capacity. The antibacterial peptide-compound nano particles prepared by mixing the compound with the antibacterial peptide have good biocompatibility and synergistic antioxidation and antibacterial capability. The nano particles can controllably release the antibacterial peptide according to the microenvironment of the wound, can effectively remove bacteria brought by infection and regulate the oxidative stress state of the wound, can promote the rapid healing of the wound, simultaneously play a role in promoting the healing of the wound in a synergistic way, and have important application prospect for clinically promoting the healing of the wound.

Claims (16)

1. A compound or salt thereof, characterized in that: the compound is as follows:
2. a process for the preparation of a compound as claimed in claim 1, characterized in that: it comprises the following steps:
in a solvent, the compound A and p-aldehyde benzoic acid react with an esterification catalyst under a closed condition to obtain the catalyst; the compound a is shown below:
3. the preparation method according to claim 2, characterized in that:
the solvent is N, N-dimethylformamide;
and/or the esterification catalyst is 4-dimethylaminopyridine and N, N' -diisopropylcarbodiimide;
and/or, the reaction temperature is room temperature;
and/or the reaction time is 12-24 hours;
and/or, the reaction is followed by precipitation with deionized water, centrifugation, washing, and drying.
4. A method of preparation according to claim 3, characterized in that: the mass ratio of the compound A to the p-aldehyde benzoic acid to the 4-dimethylaminopyridine to the N, N' -diisopropylcarbodiimide is 1: (1-2): (0.1-1): (1-10).
5. The preparation method according to claim 2, characterized in that: the preparation method of the compound A comprises the following steps: and performing supercritical extraction on the pepper fruits by using liquid carbon dioxide to obtain the Chinese prickly ash fruit extract.
6. The method of manufacturing according to claim 5, wherein: the method comprises the steps of performing supercritical extraction on the pepper fruits for 2 times by using liquid carbon dioxide;
in the first supercritical extraction, the mass-volume ratio of the pricklyash peel to the liquid carbon dioxide is 1kg: (100-200) mL; the pressure of the supercritical extraction is 15-20 MPa; the temperature of the supercritical extraction is 40-50 ℃; and/or the supercritical extraction time is 30-60 min;
separating the extract after the first supercritical extraction to obtain a crude product, and performing the second supercritical extraction on the crude product; during the separation, the temperature is 40-60 ℃; the pressure is less than 6.5MPa; liquid carbon dioxide with the length of 100-150 m 3 Extracting at a speed of/h;
in the second supercritical extraction, the mass-volume ratio of the pepper fruit to the liquid carbon dioxide is 1kg: (100-200) mL; the pressure of the supercritical extraction is 20-30 MPa; the temperature of the supercritical extraction is 40-50 ℃; and/or the supercritical extraction time is 30-60 min.
7. The method of manufacturing according to claim 6, wherein: the pepper fruits are crushed to 50-100 meshes.
8. Use of a compound of claim 1 or a salt thereof for the preparation of an antioxidant drug and/or material;
the medicament and/or material is a medicament and/or material for promoting wound healing.
9. A medicament, characterized in that: a pharmaceutical preparation prepared by adding pharmaceutically acceptable auxiliary materials or auxiliary components into the compound or salt thereof as an active ingredient in claim 1.
10. An antibacterial and antioxidant nanoparticle, characterized in that: the composite material is prepared from the following raw materials in parts by weight:
0.1 to 10 parts of the compound or the salt thereof according to claim 1, 1 part of the antibacterial peptide;
the antibacterial peptide is antibacterial peptide KS26.
11. The antimicrobial antioxidant nanoparticle of claim 10, wherein: the composite material is prepared from the following raw materials in parts by weight:
the compound according to claim 1 or a salt thereof in an amount of 0.5 to 2 parts and 1 part of an antibacterial peptide.
12. The antimicrobial antioxidant nanoparticle of claim 11, wherein: the composite material is prepared from the following raw materials in parts by weight:
the compound according to claim 1 or a salt thereof in an amount of 0.5 to 1.67 parts and 1 part of an antibacterial peptide.
13. The method for preparing the antibacterial and antioxidant nanoparticle according to any one of claims 10 to 12, characterized in that: it comprises the following steps:
(1) Dissolving the compound of claim 1 or a salt thereof in a solvent;
(2) Dissolving an antimicrobial peptide in a solvent;
(3) Adding the solution obtained in the step (1) into the solution obtained in the step (2), stirring for reaction, centrifuging the reaction solution, washing and drying to obtain the catalyst.
14. The method of manufacturing according to claim 13, wherein:
in the step (1), the solvent is DMSO;
and/or, in step (1), the concentration of the compound of claim 1 or salt thereof is 10-25mg/mL;
and/or, in the step (2), the solvent is water;
and/or, in the step (2), the concentration of the antibacterial peptide is 0.5-1.5mg/mL;
and/or, in the step (3), the reaction time is 1-4h;
and/or, in the step (3), the centrifugation condition is 15000r/min for 10min.
15. The method of manufacturing according to claim 14, wherein:
in step (1), the compound of claim 1 or a salt thereof is at a concentration of 20mg/mL;
and/or, in step (2), the concentration of the antibacterial peptide is 1.0mg/mL;
and/or, in the step (3), the reaction time is 2h.
16. Use of the antibacterial and antioxidant nanoparticle according to any one of claims 10 to 12 for the preparation of antibacterial and/or antioxidant drugs and/or materials;
the medicament and/or material is a medicament and/or material for promoting wound healing.
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