WO2021135550A1 - 一种基于龙脑的聚合物及其制备方法与应用 - Google Patents

一种基于龙脑的聚合物及其制备方法与应用 Download PDF

Info

Publication number
WO2021135550A1
WO2021135550A1 PCT/CN2020/123223 CN2020123223W WO2021135550A1 WO 2021135550 A1 WO2021135550 A1 WO 2021135550A1 CN 2020123223 W CN2020123223 W CN 2020123223W WO 2021135550 A1 WO2021135550 A1 WO 2021135550A1
Authority
WO
WIPO (PCT)
Prior art keywords
borneol
based polymer
polymer
acid
preparation
Prior art date
Application number
PCT/CN2020/123223
Other languages
English (en)
French (fr)
Inventor
苏健裕
杨柳
方立明
孟晓风
Original Assignee
华南理工大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 华南理工大学 filed Critical 华南理工大学
Priority to JP2022564687A priority Critical patent/JP7464949B2/ja
Publication of WO2021135550A1 publication Critical patent/WO2021135550A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/002—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from unsaturated compounds
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/66—Polyesters containing oxygen in the form of ether groups
    • C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G67/00—Macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing oxygen or oxygen and carbon, not provided for in groups C08G2/00 - C08G65/00
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2230/00—Compositions for preparing biodegradable polymers

Definitions

  • the invention belongs to the technical field of polymer chemistry, and specifically relates to a borneol-based polymer and a preparation method and application thereof.
  • the research on the effective components of traditional Chinese medicine is a key issue in the development and application of traditional Chinese medicine, and is an important source of new medicine creation.
  • the development of new drugs based on the effective monomer components of traditional Chinese medicine includes two aspects. One is to discover new effective monomer compounds from traditional Chinese medicine and develop them into new drugs. The other is to modify or reform the structure based on the natural effective components to screen for high-efficiency Safe new drugs.
  • Borneol also known as plum and borneol, is a bicyclic monoterpene alcohol. Borneol is divided into natural borneol and synthetic borneol. Borneol has anti-inflammatory, analgesic, anti-oxidant and other pharmacological activities.
  • borneol when borneol is used as a single medicine, there are disadvantages such as low efficacy, strong volatility, and poor solubility. By modifying the hydroxyl group on borneol, the solubility and stability of borneol can be improved.
  • Acetal bond is an internationally recognized acid-sensitive group. In recent years, stimulus-responsive compounds as drug-carrying materials have received more and more attention.
  • the pH of the extracellular environment of tumors and inflammatory tissues is about 6.5, while the pH of the lysosome and nucleus will be lower, between 5.0 and 5.5.
  • the acetal bond group is very stable under alkaline and neutral conditions, but it will break in acidic tumor tissues, achieving the effect of rapid release of anti-cancer drugs. This not only prolongs the plasma half-life of the drug but also enables the rapid release of the drug from the tumor tissue.
  • the primary purpose of the present invention is to overcome the shortcomings and deficiencies of the prior art and provide a borneol-based polymer.
  • Another object of the present invention is to provide a method for preparing the above-mentioned borneol-based polymer.
  • Another object of the present invention is to provide the application of the above-mentioned borneol-based polymer.
  • Another object of the present invention is to provide a borneol-based polymer with acid degradation properties, and a preparation method and application thereof.
  • a borneol-based polymer named PBD its chemical structure is:
  • m is the degree of polymerization, and its value is 1 to 110, preferably 1 to 35.
  • the average molecular weight of the borneol-based polymer is 280-17427, preferably 280-4777.
  • the preparation method of the above-mentioned borneol-based polymer includes the following steps: taking dextro-borneol (natural borneol) and diethylene glycol monovinyl ether as raw materials, and p-toluenesulfonic acid as a catalyst, and undergoing substitution and ether formation reaction , To obtain borneol polydiethylene glycol monovinyl ether, named PBD; preferably, the following steps are included:
  • the stirring conditions described in step (1) are preferably: the rotation speed is 800-1000 r/min, and the time is 1 to 2 h; more preferably, the rotation speed is 1000 r/min and the time is 2 h.
  • Solution B described in step (2) is preferably added dropwise to solution A through a constant pressure funnel.
  • reaction conditions described in step (2) are preferably: temperature 0-10°C, rotation speed 800-1000 r/min, time 2-4 h; more preferably temperature 0°C, rotation speed 1000 r/min, and time 4 h.
  • the acid-base regulator described in step (3) is preferably a saturated sodium bicarbonate aqueous solution.
  • the said saturated sodium bicarbonate aqueous solution is added in batches.
  • the number of extractions described in step (3) is preferably 3 times.
  • the method for removing water in step (3) is preferably using a moisture absorbent to remove water; the moisture absorbent is preferably anhydrous sodium sulfate.
  • the time is 4-8 hours. After the water removal is completed, filter to remove the anhydrous sodium sulfate.
  • the number of precipitation in step (3) is preferably 2 to 4; more preferably, 3 times.
  • PBD-PCL A borneol-based polymer with acid degradation properties, named PBD-PCL, and its chemical structure is:
  • m and n are the degree of polymerization, and their numerical values are both from 1 to 110, preferably from 1 to 35.
  • the average molecular weight of the polymer is 2000-21000, preferably 2000-6124.
  • the method for preparing the above-mentioned borneol-based polymer with acid degradation properties includes the following steps: ⁇ -caprolactone and the above-mentioned borneol-based polymer are used as raw materials, and polymerized by stannous octoate catalyzed to obtain the target product PBD- PCL; preferably includes the following steps:
  • step A is preferably vacuum distillation.
  • the temperature of the vacuum distillation is preferably 85-95°C; more preferably 90°C.
  • the conditions of the reaction described in step B. are preferably: under nitrogen conditions, the temperature is 120-140°C, and the time is 24-48h; more preferably, the temperature is 130°C, and the time is 48h.
  • step B. The concentration described in step B. is preferably concentrated under reduced pressure.
  • the number of precipitation in step B. is preferably 2 to 4; more preferably, 3 times.
  • the tumors include lung cancer, breast cancer, cervical cancer, malignant melanoma, liver cancer and colon cancer.
  • the present invention has the following advantages and effects:
  • the raw materials used in the preparation of the compound of the present invention are simple and easy to obtain, the reaction conditions are mild, and the operation is simple and convenient.
  • the reaction product has a wide application prospect in the fields of food, chemistry and medical drug carriers.
  • the compounds of the present invention have acid-sensitive properties.
  • the sensitivity means that under weak acid or moderately strong acid conditions, the acetal bond is broken to generate corresponding aldehydes and alcohols.
  • Borneol itself has medicinal value, so the present invention also has a certain controlled release medicinal function.
  • the degradation reaction formula is as follows:
  • Figure 1 is the reaction flow equation of Example 1 of the present invention.
  • Fig. 2 is an infrared spectrogram of the intermediate product of Borneol polymer in Example 1 of the present invention.
  • Fig. 3 is a hydrogen nuclear magnetic resonance spectrum of the intermediate product of Borneol polymer in Example 1 of the present invention.
  • Figure 4 is an infrared spectrogram of the target product of Example 1 of the present invention.
  • Figure 5 is a proton nuclear magnetic resonance spectrum of the target product of Example 1 of the present invention.
  • Figure 6 is a permeation gel chromatogram of the target product of Example 1 of the present invention.
  • Fig. 7 is a chromatogram of polymer permeation gel before and after degradation in Example 1 of Use of the present invention.
  • step (4) Weigh 1.4435 g of bornyl polymer obtained in step (4), add 30 mL of toluene solvent, and distill off toluene and water under reduced pressure at 110°C. Then add 30mL of dry toluene, 0.1034g of stannous octoate and 1.1788g of ⁇ -caprolactone to the bornyl polymer.
  • the reaction system conditions are as follows: at 130°C, under nitrogen protection, react for 48h;
  • Example 2 The intermediate product Borneol polymer obtained in Example 1 was detected by infrared spectroscopy, and the infrared spectrogram is shown in FIG. 2.
  • FIGS 2 and 3 both prove that Example 1 successfully synthesized the intermediate product bornyl polymer (borneol polydiethylene glycol monovinyl ether, referred to as PBD), the molecular structure of which is: The m value is 15, and the molecular weight is 2,134.
  • PBD borneol polydiethylene glycol monovinyl ether
  • Example 1 The final product of Example 1 was detected by an infrared spectrometer, and the infrared spectrum is shown in FIG. 4.
  • Example 1 The product of Example 1 was detected by proton nuclear magnetic resonance spectroscopy, and the proton nuclear magnetic resonance spectrum is shown in FIG. 5.
  • the molecular weight of the final product of Example 1 was measured by gel permeation chromatography (GPC), and the gel permeation chromatogram is shown in FIG. 6.
  • Figure 4 Figure 5 and Figure 6 together prove the successful synthesis of the final product (abbreviated as PBD-PCL), the molecular structure of which is:
  • Example 3 Prepare according to the steps (1) to (4) of Example 1.
  • MIC minimum inhibitory concentration
  • the raw material a is dextroborneol
  • the raw material b is diethylene glycol monovinyl ether
  • the PBD superscript is the corresponding molecular weight.
  • the strains used include experimental Staphylococcus aureus ATCC25923, Escherichia coli ATCC25922, Salmonella enterica ATCC 14028, Pseudomonas aeruginosa ATCC 27853, Listeria monocytogenes Listeria ATCC 27853.
  • Diethylene glycol monovinyl ether is a kind of The bacteriostatic ability of the water-soluble organic intermediate is better than that of dextroborneol, but because diethylene glycol monovinyl ether is unstable in the air, it is easy to self-polymerize in acidic conditions, which affects its bacteriostatic effect .
  • the bacteriostatic ability of the dextroborneol polymer PBD produced by the acetal reaction is significantly better than that of dextroborneol and diethylene glycol monovinyl ether.
  • the minimum inhibitory concentration for several strains is 2.5 ⁇ 5mg/mL, while the block copolymer PBD 15 -PCL 35 has no antibacterial effect on several strains, and the minimum inhibitory concentration is above 40mg/mL.
  • Copolymerization with caprolactone affects the antibacterial performance of the dextroborneol polymer PBD, which may be due to the increase in the hydrophobic segment of the molecule resulting in a decrease in the water solubility of the polymer, thereby reducing its antibacterial activity.
  • the OD value can reflect the growth status of the bacteria. The higher the OD value, the higher the optical density absorbed by the tested strain and the higher its concentration.
  • the change of OD 630nm is close to the level and cannot grow normally, which indicates that at lower mass concentrations (2.5mg/mL for E. coli, 5mg/mL for Staphylococcus aureus), the dextroborneol polymer PBD solution can still Effectively inhibit the normal growth of Staphylococcus aureus and Escherichia coli.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Polyesters Or Polycarbonates (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

一种基于龙脑的聚合物及其制备方法与应用，属于高分子化学技术领域。该聚合物以右旋龙脑、二乙二醇单乙烯基醚为原料，以对甲苯磺酸为催化剂，经过取代、成醚反应，得到具有优异抗菌效果的基于龙脑的聚合物。再将其与ε-己内酯和为原料，通过辛酸亚锡催化进行聚合，得到基于龙脑且具有酸降解性质的聚合物，其可用于制备抗肿瘤药物。所用到的原料简单易得，反应条件温和，操作简便，具有广泛的应用前景。

Description

一种基于龙脑的聚合物及其制备方法与应用 技术领域
本发明属于高分子化学技术领域，具体涉及一种基于龙脑的聚合物及其制备方法与应用。
背景技术
中药有效成分研究是中药开发与应用的关键问题，是新药创制的重要来源。基于中药有效单体成分的新药开发包括两个方面，一是从中药中发现新的有效单体化合物并研制成新药，二是在天然有效成分的基础上，进行结构修饰或者改造，筛选出高效安全的新型药物。
龙脑，又称梅片、冰片，是一种双环单萜醇。龙脑分为天然龙脑和合成龙脑，龙脑具有抗炎杀菌、镇痛、抗氧化等药理活性。但是龙脑作单味药使用时，存在药效低、挥发性强、溶解性差等缺点。通过对龙脑上羟基进行修饰，能够改善龙脑的溶解度以及稳定性。
缩醛键是国际公认的酸敏感基团。近年来，作为载药材料的刺激-响应型化合物受到越来越多的关注。肿瘤及炎症组织细胞外环境的pH在6.5左右，而溶酶体和细胞核内的pH会更低，在5.0～5.5之间。而缩醛键基团，在碱性以及中性条件下很稳定，但是在酸性的肿瘤组织就会发生断裂，达到快速释放抗癌药物的效果。这样不仅可以延长药物血浆半衰期还能使肿瘤组织的药物快速释放。
发明内容
本发明的首要目的在于克服现有技术的缺点与不足，提供一种基于龙脑的聚合物。
本发明的另一目的在于提供上述基于龙脑的聚合物的制备方法。
本发明的再一目的在于提供上述基于龙脑的聚合物的应用。
本发明的又一目的在于提供一种基于龙脑且具有酸降解性质的聚合物及其制备方法与应用。
本发明的目的通过下述技术方案实现：
一种基于龙脑的聚合物，命名为PBD，其化学结构式为：
Figure PCTCN2020123223-appb-000001
式中，m为聚合度，其数值为1～110，优选为1～35。
所述的基于龙脑的聚合物的平均分子量为280～17427，优选为280～4777。
上述基于龙脑的聚合物的制备方法，包括如下步骤：以右旋龙脑(天然冰片)、二乙二醇单乙烯基醚为原料，以对甲苯磺酸为催化剂，经过取代、成醚反应，得到龙脑聚二乙二醇单乙烯基醚，命名为PBD；优选包括如下步骤：
(1)将右旋龙脑溶解在二氯甲烷中，加入对甲苯磺酸，搅拌，得到溶液A；
(2)将二乙二醇单乙烯基醚溶解二氯甲烷溶剂中，得到溶液B；将溶液B滴加入溶液A中，反应；
(3)向反应体系中加入酸碱调节剂至pH＝7～8，除去对甲苯磺酸；旋蒸除去溶剂，用二氯甲烷萃取，收集有机层，除水；旋蒸除去溶剂，在环己烷溶液中沉淀，得到龙脑聚二乙二醇单乙烯基醚；产物呈无色胶状固体。
所述的右旋龙脑、二乙二醇单乙烯基醚、甲苯磺酸的用量，优选按右旋龙脑：二乙二醇单乙烯基醚：甲苯磺酸＝质量比1：30～50：0.04～0.08计；更优选为1：25～30：0.06～0.07。
步骤(1)中所述的二氯甲烷的用量，优选按右旋龙脑：二氯甲烷＝1g:70～150mL计；更优选为1g:90～100mL。
步骤(2)中所述的二氯甲烷的用量，优选按二乙二醇单乙烯基醚：二氯甲烷＝1g:1～5mL计；更优选为1g:2～3mL。
步骤(1)中所述的搅拌的条件优选为：转速800～1000r/min、时间1～2h；更优选为转速1000r/min、时间2h。
步骤(2)中所述的溶液B优选通过恒压漏斗滴加入溶液A中。
步骤(2)中所述的反应的条件优选为：温度0～10℃、转速800～1000r/min、时间2～4h；更优选为温度0℃、转速1000r/min、时间4h。
步骤(3)中所述的酸碱调节剂优选为饱和碳酸氢钠水溶液。
所述的饱和碳酸氢钠水溶液的加入方式为分批加入。
步骤(3)中所述的萃取的次数优选为3次。
步骤(3)中所述的除水的方法优选为用吸湿剂除水；所述的吸湿剂优选为无水硫酸钠。用无水硫酸钠除水时，时间为4～8小时，除水完成后过滤除去无水硫酸钠。
步骤(3)中所述的沉淀的次数优选为2～4次；更优选为3次。
上述基于龙脑的聚合物在制备抗菌剂中的应用。
上述基于龙脑的聚合物在制备基于龙脑且具有酸降解性质的聚合物中的应用。
一种基于龙脑且具有酸降解性质的聚合物，命名为PBD-PCL，其化学结构式为：
Figure PCTCN2020123223-appb-000002
式中，m、n为聚合度，其数值均为1～110，优选为1～35。
所述的聚合物的平均分子量为2000～21000，优选为2000～6124。
上述基于龙脑且具有酸降解性质的聚合物的制备方法，包括如下步骤：以ε-己内酯和上述基于龙脑的聚合物为原料，通过辛酸亚锡催化进行聚合，得到目标产物PBD-PCL；优选包括如下步骤：
A.将上述基于龙脑的聚合物加入甲苯中，蒸馏除去甲苯和水；
B.加入干燥的甲苯、辛酸亚锡和ε-己内酯，反应；将反应产物浓缩，在冰环己烷中沉淀，得到基于龙脑且具有酸降解性质的聚合物。产物呈淡黄色胶状固体。
所述的基于龙脑的聚合物、辛酸亚锡、ε-己内酯的用量，优选按基于龙脑的聚合物：辛酸亚锡：ε-己内酯＝质量比1：0.01～0.08：0.2～2.5计；更优选为1：0.07～0.08：1～2。
步骤A.和步骤B.中所述的甲苯的用量，均优选为按基于龙脑的聚合物：甲苯＝1g：10～30mL计；更优选为1g：20～25mL。
步骤A.中所述的蒸馏优选为减压蒸馏。
所述的减压蒸馏的温度优选为85～95℃；更优选为90℃。
步骤B.中所述的反应的条件优选为：氮气条件下，温度120～140℃、时间24～48h；更优选为温度130℃、时间48h。
步骤B.中所述的浓缩优选为减压浓缩。
步骤B.中所述的沉淀的次数优选为2～4次；更优选为3次。
其制备路线如以下反应式所示：
Figure PCTCN2020123223-appb-000003
上述基于龙脑且具有酸降解性质的聚合物在制备抗肿瘤药物中的应用。
所述的肿瘤包括肺癌、乳腺癌、宫颈癌、恶性黑色素瘤、肝癌和结肠癌。
本发明相对于现有技术具有如下的优点及效果：
本发明化合物的制备所用到的原料均简单易得，反应条件温和，操作简便，反应产物在食品、化学和医学药物载体领域具有广泛的应用前景。
本发明化合物具有酸敏感的特性。其敏感性是指在弱酸或者是中强酸性条件下，缩醛键发生断裂，生成相应的醛和醇，而龙脑本身具有药用价值，因此本发明同时具有一定控制释放的药用功能。其降解反应式如下：
Figure PCTCN2020123223-appb-000004
附图说明
图1为本发明实施例1的反应流程方程式。
图2为本发明实施例1的中间产物龙脑聚合物的红外光谱图。
图3为本发明实施例1的中间产物龙脑聚合物的核磁共振氢谱图。
图4为本发明实施例1的目标产物的红外光谱图。
图5为本发明实施例1的目标产物的核磁共振氢谱图。
图6为本发明实施例1的目标产物的渗透凝胶色谱图。
图7为本发明用途实施例1降解前、降解后聚合物渗透凝胶色谱图。
图8为本发明效果实施例1右旋龙脑聚合物PBD 2K(m＝15)对两种菌作用的生长曲线图；其中，a为对大肠杆菌的生长曲线，b为对金黄色葡萄球菌的生长曲线。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实施例1
一种基于龙脑且具有酸降解性质的聚合物的制备，反应流程如图1所示，具体如下：
(1)在室温下，称取0.3031g龙脑，溶解于30mL二氯甲烷中，加入20.21mg催化剂对甲苯磺酸，在转速为1000r/min的条件下搅拌2小时，得到溶液A；
(2)在室温下，将7.794g二乙二醇单乙烯基醚溶解在20mL的二氯甲烷溶剂中，得到溶液B；在反应体系为0℃、1000r/min的条件下，通过50mL筒形恒压漏斗，缓慢将溶液B滴入溶液A中，反应时间为4小时；
(3)向反应体系中分批加入饱和碳酸氢钠水溶液至pH＝8，以除去对甲苯磺酸，旋蒸，用3×10mL二氯甲烷萃取3次，收集有机层，加入3g无水硫酸钠除水8小时；
(4)过滤除去无水硫酸钠，旋蒸除去溶剂，在3×50mL的环己烷溶液中沉淀3次，得到无色胶状固体龙脑聚合物(即龙脑聚二乙二醇单乙烯基醚)；
(5)称取步骤(4)中得到的龙脑聚合物1.4435g，加入30mL甲苯溶剂中，在110℃下，减压蒸馏除去甲苯和水。再向龙脑聚合物中加入30mL干燥的甲苯、0.1034g辛酸亚锡和的1.1788gε-己内酯，反应体系条件为，在130℃下，氮气保护，反应48h；
(6)减压浓缩，在3*50mL的冰环己烷中沉淀3次，得到最终产物，产物呈淡黄色胶状固体。
通过红外光谱检测实施例1得到的中间产物龙脑聚合物，红外光谱图如图2所示。
通过核磁共振氢谱检测实施例1中间产物龙脑聚合物，核磁共振氢谱图如图3所示。 1H NMR(600MHz,CDCl3)δ7.28(s,1H),5.30(s,1H),4.81(ddd,J＝12.9,6.9,3.2Hz,9H),3.98–3.82(m,7H),3.82–3.43(m,78H),2.21(t,J＝2.6Hz,2H),3.22–1.69(m,4H),2.33–1.69(m,3H),1.69–1.39(m,1H),1.43–1.29(m,27H),1.29–1.02(m,1H),1.00–0.80(m,2H),0.02–-0.02(m,1H).
图2和图3同时证明了实施例1成功合成了中间产物龙脑聚合物(龙脑聚二乙二醇单乙烯基醚，简称为PBD)，其分子结构式为：
Figure PCTCN2020123223-appb-000005
m值是15，分子量是2134。
红外光谱仪检测实施例1的最终产物，红外光谱图如图4所示。
通过核磁共振氢谱检测实施例1产物，核磁共振氢谱图参照图5所示。 1H NMR(600MHz,CDCl3)δ7.28(s,33H),4.88–4.72(m,35H),4.75–4.72(m,7H),4.75–4.62(m,10H),4.40–4.21(m,49H),4.21–4.01(m,78H),4.01–3.85(m,8H),3.82–3.48(m,542H),3.46–3.34(m,13H),2.97–2.09(m,197H),2.12–1.95(m,9H),1.70–0.78(m,487H),1.00–0.81(m,6H),1.00–0.78(m,6H),0.03–-0.03(m,33H).
通过凝胶渗透色谱仪(GPC)测定实施例1最终产物的分子量，凝胶渗透色谱图如图6所示。
图4、图5和图6共同证明了最终产物(简称为PBD-PCL)的成功合成，其分子结构式为：
Figure PCTCN2020123223-appb-000006
重均分子量为Mw＝6124，m、n值分别 是15，35。
用途实施例1
取100mg实施例1中获得的聚合物(PBD 15-PCL 35)，溶于2mL四氢呋喃，加入1mL 0.2mol/L、pH＝5.2的PBS溶液，搅拌30min后，凝胶渗透色谱仪(GPC)测定聚合物的分子量，结果如图7所示。由图中结果可以看出，经酸降解的一组，30min后重均分子量由原来的6124降至1040。
效果实施例1
根据发明内容合成了几种不同m/n的聚合物，其中包括当n＝0时不同分子量的龙脑聚合物PBD(PBD 2K(m＝15)、PBD 3K(m＝22)、PBD 4K(m＝30)、PBD 5K(m＝37))。n＝0时不同分子量的龙脑聚合物PBD的制备方法如下：
(1)按实施例1步骤(1)～(4)制备，与实施例1的区别仅在于：所用的二乙二醇单乙烯基醚量为7.794g，得到PBD 2K(m＝15)；
(2)按实施例1步骤(1)～(4)制备，与实施例1的区别仅在于：所用的二乙二醇单乙烯基醚量为11.691g，，得到PBD 3K(m＝22)；
(3)按实施例1步骤(1)～(4)制备，与实施例1的区别仅在于：所用的二乙二醇单乙烯基醚量为15.588g，，得到PBD 4K(m＝30)；
(4)按实施例1步骤(1)～(4)制备，与实施例1的区别仅在于：所用的二乙二醇单乙烯基醚量为19.485g，，得到PBD 5K(m＝37)。
将上述制备得到的聚合物与实施例1得到的嵌段聚合物PBD 15-PCL 35进行了抗菌性比对。我们采用了常规的光密度法评估了各物质的最小抑菌浓度(MIC)和细菌生长抑制曲线，结果如表1和图8所示。MIC是一种表示药物抗菌能力的指标，能够准确反映药物的抗菌活性。
表1不同物质的最小抑菌浓度(MIC)
Figure PCTCN2020123223-appb-000007
注：原料a为右旋龙脑，原料b为二乙二醇单乙烯基醚，PBD上标为对应的分子量大小。所用菌种包括实验用金黄色葡萄球菌Staphylococcus aureus ATCC25923、大肠杆菌Escherichia coli ATCC25922、沙门氏菌Salmonella enterica ATCC 14 028、铜绿假单胞菌Pseudomonas aeruginosa ATCC 27853、单增李斯特菌Listeria monocytogenes ATCC 13932.
右旋龙脑由于水溶性较差，挥发性强，导致右旋龙脑的水溶液抑菌效果并不明显，最小抑菌浓度均在40mg/mL以上，二乙二醇单乙烯基醚是一种溶于水的有机中间体，其水溶液抑菌能力优于右旋龙脑，但由于二乙二醇单乙烯基醚在空气中不稳定，在酸性条件中易自聚，从而影响其抑菌效果。由以上结果可以看出，通过缩醛反应生成的右旋龙脑聚合物PBD抑菌能力明显优于右旋龙脑和二乙二醇单乙烯基醚，对几种菌株的最小抑菌浓度为2.5～5mg/mL，而嵌段共聚物PBD 15-PCL 35对几种菌株没有表现出抑菌效果，最小抑菌浓度都在40mg/mL以上。
与己内酯共聚影响了右旋龙脑聚合物PBD的抑菌性能，可能是由于分子的疏水链段增加导致聚合物水溶性下降，从而降低其抑菌活性。
当n＝0时，随着m增大，即右旋龙脑聚合物PBD随着分子量的增大，最小抑菌浓度稍有增大的趋势，对于金黄色葡萄球菌、沙门氏菌以及单增李斯特菌5mg/mL增大至10mg/mL，可见分子量增大可能会降低右旋龙脑聚合物PBD的抑菌效果。
OD值能够反映菌体的生长状态，OD值越高，表明被检测菌株吸收的光密度就越高，其浓度也越高。如图8所示，曲线a、b分别为右旋龙脑聚合物PBD(PBD 2K(m＝15))对金黄色葡萄球菌和大肠杆菌生长曲线图。从图中可以看出，正常情况时，两种菌正常生长，OD 630nm先增加后趋于水平，而在右旋龙脑聚合物PBD溶液1×MIC、2×MIC的作用下，两种菌的OD 630nm变化趋近水平，不能正常生长，这表明在较低的质量浓度(2.5mg/mL对大肠杆菌，5mg/mL对金黄色葡萄球菌)下，右旋龙脑聚合物PBD溶液仍能有效地抑制金黄色葡萄球菌和大肠杆菌的正常生长。
以上仅为本发明的一个实施例和一个用途例，但是在本领域的技术人员应当理解，在不脱离本发明精神的情况下，可以对本文的实施例进行改变。当然不能以此来限定本发明之权利范围，因此依本发明权利要求所作的等同变化，仍属本发明所涵盖的范围。

Claims (10)

  1. 一种基于龙脑的聚合物，其特征在于：所述的基于龙脑的聚合物的化学结构式为：
    Figure PCTCN2020123223-appb-100001
    式中，m为聚合度，其数值为1～110，进一步为1～35。
  2. 权利要求1所述的基于龙脑的聚合物的制备方法，其特征在于：包括如下步骤：
    (1)将右旋龙脑溶解在二氯甲烷中，加入对甲苯磺酸，搅拌，得到溶液A；
    (2)将二乙二醇单乙烯基醚溶解二氯甲烷溶剂中，得到溶液B；将溶液B滴加入溶液A中，反应；
    (3)向反应体系中加入酸碱调节剂至pH＝7～8，除去对甲苯磺酸；旋蒸除去溶剂，用二氯甲烷萃取，收集有机层，除水；旋蒸除去溶剂，在环己烷溶液中沉淀，得到龙脑聚二乙二醇单乙烯基醚。
  3. 根据权利要求2所述的基于龙脑的聚合物的制备方法，其特征在于：
    所述的右旋龙脑、二乙二醇单乙烯基醚、甲苯磺酸的用量按右旋龙脑：二乙二醇单乙烯基醚：甲苯磺酸＝质量比1：30～50：0.04～0.08计；进一步按1：25～30：0.06～0.07计。
  4. 根据权利要求2所述的基于龙脑的聚合物的制备方法，其特征在于：
    步骤(1)中所述的二氯甲烷的用量按右旋龙脑：二氯甲烷＝1g:70～150mL计；
    步骤(2)中所述的二氯甲烷的用量按二乙二醇单乙烯基醚：二氯甲烷＝1g:1～5mL计；
    步骤(1)中所述的搅拌的条件为：转速800～1000r/min、时间1～2h；
    步骤(2)中所述的反应的条件为：温度0～10℃、转速800～1000r/min、时间2～4h；
    步骤(3)中所述的酸碱调节剂为饱和碳酸氢钠水溶液；
    步骤(3)中所述的除水的方法为用吸湿剂除水。
  5. 权利要求1所述的基于龙脑的聚合物在制备抗菌剂中的应用。
  6. 权利要求1所述的基于龙脑的聚合物在制备基于龙脑且具有酸降解性质的聚合物中的应用。
  7. 一种基于龙脑且具有酸降解性质的聚合物，其特征在于：所述的基于龙脑且具有酸降解性质的聚合物的化学结构式为：
    Figure PCTCN2020123223-appb-100002
    式中，m、n为聚合度，其数值均为1～110，进一步为1～35。
  8. 权利要求7所述的基于龙脑且具有酸降解性质的聚合物的制备方法，其特征在于：包括如下步骤：
    A.将权利要求1所述的基于龙脑的聚合物加入甲苯中，蒸馏除去甲苯和水；
    B.加入干燥的甲苯、辛酸亚锡和ε-己内酯，反应；将反应产物浓缩，在冰环己烷中沉淀，得到基于龙脑且具有酸降解性质的聚合物。
  9. 根据权利要求8所述的基于龙脑且具有酸降解性质的聚合物的制备方法，其特征在于：
    所述的基于龙脑的聚合物、辛酸亚锡、ε-己内酯的用量按基于龙脑的聚合物：辛酸亚锡：ε-己内酯＝质量比1：0.01～0.08：0.2～2.5计；进一步按1：0.07～0.08：1～2计；
    步骤A.和步骤B.中所述的甲苯的用量，均为按基于龙脑的聚合物：甲苯＝1g：10～30mL计；进一步按1g：20～25mL计；
    步骤B.中所述的反应的条件为：氮气条件下，温度120～140℃、时间24～48h。
  10. 权利要求7所述的基于龙脑且具有酸降解性质的聚合物在制备抗肿瘤药物中的应用。
PCT/CN2020/123223 2019-12-31 2020-10-23 一种基于龙脑的聚合物及其制备方法与应用 WO2021135550A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2022564687A JP7464949B2 (ja) 2019-12-31 2020-10-23 ボルネオールベースのポリマーならびにその調製方法および応用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201911412816.4 2019-12-31
CN201911412816.4A CN113121810B (zh) 2019-12-31 2019-12-31 一种基于龙脑的聚合物及其制备方法与应用

Publications (1)

Publication Number Publication Date
WO2021135550A1 true WO2021135550A1 (zh) 2021-07-08

Family

ID=76686400

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/123223 WO2021135550A1 (zh) 2019-12-31 2020-10-23 一种基于龙脑的聚合物及其制备方法与应用

Country Status (3)

Country Link
JP (1) JP7464949B2 (zh)
CN (1) CN113121810B (zh)
WO (1) WO2021135550A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113121810B (zh) 2019-12-31 2022-05-24 华南理工大学 一种基于龙脑的聚合物及其制备方法与应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103881010A (zh) * 2014-03-07 2014-06-25 北京化工大学 一种基于龙脑的高分子抗菌材料
CN105147647A (zh) * 2015-08-19 2015-12-16 华南理工大学 右旋龙脑作为抗肿瘤药物增敏剂的应用
CN108863734A (zh) * 2018-07-11 2018-11-23 华南理工大学 一种苯甲醛二冰片基缩醛衍生物及其制备方法与用途

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3280045A (en) * 1964-02-26 1966-10-18 Hercules Inc Process for polymerizing epoxides with an alkyl aluminum compound
JP4162845B2 (ja) * 2000-11-02 2008-10-08 花王株式会社 化粧料
JP2003270246A (ja) * 2002-03-20 2003-09-25 Takashi Kusui ２−メチルイソボルネオールの測定方法
CN102180832B (zh) * 2011-03-18 2012-09-12 苏州沪云肿瘤研究中心有限公司 脑缺血保护用化合物及制备方法
LT2689774T (lt) * 2011-03-21 2019-03-25 Broda Technologies Co., Ltd Atvirkščiai termiškai grįžtama hidrogelio kompozicija
CN107970230B (zh) * 2017-11-10 2020-04-28 华南理工大学 一种能瓦解和抑制细菌生物被膜的生成的皮克林乳液及其制备和应用
CN109503323B (zh) * 2018-10-29 2021-11-19 广东工业大学 一种从梅片树叶片中提取天然右旋龙脑的预处理方法
CN113121810B (zh) * 2019-12-31 2022-05-24 华南理工大学 一种基于龙脑的聚合物及其制备方法与应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103881010A (zh) * 2014-03-07 2014-06-25 北京化工大学 一种基于龙脑的高分子抗菌材料
CN105147647A (zh) * 2015-08-19 2015-12-16 华南理工大学 右旋龙脑作为抗肿瘤药物增敏剂的应用
CN108863734A (zh) * 2018-07-11 2018-11-23 华南理工大学 一种苯甲醛二冰片基缩醛衍生物及其制备方法与用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LUO LINGQIONG, LI GUOFENG, LUAN DI, YUAN QIPENG, WEI YEN, WANG XING: "Antibacterial Adhesion of Borneol-Based Polymer via Surface Chiral Stereochemistry", APPLIED MATERIALS & INTERFACES, AMERICAN CHEMICAL SOCIETY, US, vol. 6, no. 21, 12 November 2014 (2014-11-12), US, pages 19371 - 19377, XP055826075, ISSN: 1944-8244, DOI: 10.1021/am505481q *
ROTH STEFFEN, FUNK IRINA, HOFER MICHAEL, SIEBER VOLKER: "Chemoenzymatic Synthesis of a Novel Borneol-Based Polyester", CHEMSUSCHEM, WILEY-VCH, DE, vol. 10, no. 18, 22 September 2017 (2017-09-22), DE, pages 3574 - 3580, XP055826074, ISSN: 1864-5631, DOI: 10.1002/cssc.201701146 *

Also Published As

Publication number Publication date
CN113121810B (zh) 2022-05-24
JP2023512114A (ja) 2023-03-23
JP7464949B2 (ja) 2024-04-10
CN113121810A (zh) 2021-07-16

Similar Documents

Publication Publication Date Title
Qu et al. A nanoplatform with precise control over release of cargo for enhanced cancer therapy
WO2021135550A1 (zh) 一种基于龙脑的聚合物及其制备方法与应用
CN102596178B (zh) 具有磺丁基醚环糊精盐内水相的脂质体
EP2514441B1 (en) Passive solid tumor targeting anticancer prodrug and preparation method thereof
CN102898641A (zh) 一种含单一活性官能团的y型聚乙二醇及其制备方法
CN113081965B (zh) 一种基于ros敏感及h2s响应的多功能脂质体及其制备方法和应用
Shen et al. Preparation of bergenin-Poly (lactic acid) polymers and in vitro controlled release studies
CN102293736B (zh) 紫杉醇-聚合物载药胶束制备工艺
Kupchan et al. Intramolecular Catalysis. VIII. 1 General Base-General Acid Catalysis of Ester Solvolysis2, 3
CN107028913B (zh) 一种聚己内酯-环糊精给药纳米粒的制备方法
CN115745757B (zh) 一种液态多甘醇柱芳烃衍生物的合成及对经皮药效分子缓释的应用
CN104151284B (zh) 一种甲基丙烯酰胺原酸酯类单体及其酸敏感两亲性嵌段共聚物的合成方法和应用
Luo et al. Amphiphilic block copolymers bearing six-membered ortho ester ring in side chains as potential drug carriers: synthesis, characterization, and in vivo toxicity evaluation
Tang et al. Preparation of hyaluronic acid-loaded Harmine polymeric micelles and in vitro effect anti-breast cancer
CN103467746A (zh) 一种两亲性聚合物及其制备方法
CN111471185B (zh) 三重刺激响应性嵌段聚合物胶束及其制备方法和应用
CN106361697A (zh) 一种含有布洛芬的载紫杉醇胶束聚合物、制剂及制备方法
CN108689943A (zh) 含钌超分子化合物及其制备方法和应用
CN102977378B (zh) 一种两亲性肝素基嵌段聚合物及其制备方法与应用
Guo et al. GE11 peptide-decorated acidity-responsive micelles for improved drug delivery and enhanced combination therapy of metastatic breast cancer
CN110615891A (zh) 一类茄呢基硫代水杨酸化合物、其制备方法及应用
CN106806899A (zh) 聚乳酸键载布洛芬缓释前药及其直接熔融共聚制备方法与应用
CN102228442B (zh) 一种星形高分子纳米微球及其制法和用途
CN106133024A (zh) 用于疏水性药物递送的新颖的基于聚合物的助水溶物
CN103044677A (zh) 一种异端基遥爪聚乙二醇及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20908826

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022564687

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 09/11/2022).

122 Ep: pct application non-entry in european phase

Ref document number: 20908826

Country of ref document: EP

Kind code of ref document: A1