CN112175036A - Glycyrrhetinic acid derivative and preparation method and application thereof - Google Patents
Glycyrrhetinic acid derivative and preparation method and application thereof Download PDFInfo
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- CN112175036A CN112175036A CN202011219923.8A CN202011219923A CN112175036A CN 112175036 A CN112175036 A CN 112175036A CN 202011219923 A CN202011219923 A CN 202011219923A CN 112175036 A CN112175036 A CN 112175036A
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- glycyrrhetinic acid
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- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical class C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 title claims abstract description 145
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 239000000017 hydrogel Substances 0.000 claims abstract description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000003960 organic solvent Substances 0.000 claims abstract description 17
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 14
- 239000011737 fluorine Substances 0.000 claims abstract description 14
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 claims description 56
- 229960003720 enoxolone Drugs 0.000 claims description 49
- 238000006243 chemical reaction Methods 0.000 claims description 40
- 238000010791 quenching Methods 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
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- 230000000171 quenching effect Effects 0.000 claims description 14
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- MRPAGRCGPAXOGS-UHFFFAOYSA-N 6-(trifluoromethyl)pyridine-3-carbaldehyde Chemical compound FC(F)(F)C1=CC=C(C=O)C=N1 MRPAGRCGPAXOGS-UHFFFAOYSA-N 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
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- -1 6-trifluoromethylpyridyl Chemical group 0.000 claims description 3
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- 125000002168 glycyrrhetinic acid group Chemical group 0.000 abstract 1
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- 239000000243 solution Substances 0.000 description 61
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 230000005526 G1 to G0 transition Effects 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
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- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 3
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- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 2
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- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
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Abstract
The invention discloses a glycyrrhetinic acid derivative, and a preparation method and application thereof, and belongs to the field of organic synthesis and medicine. The hydroxyl on the C3 site in the glycyrrhetinic acid structure is oxidized into carbonyl, and a fluorine-containing group is introduced to the C2 site, so that the glycyrrhetinic acid derivative with more excellent antibacterial activity, hydrophilicity and biological activity is obtained; the glycyrrhetinic acid derivative can be self-assembled to form hydrogel with a three-dimensional rod-shaped structure through the non-covalent bond effect between molecules without providing energy from the outside after being mixed with water and an organic solvent, and the formed hydrogel has antibacterial and anti-inflammatory effects, can be completely absorbed by a human body after being applied, has no harmful residue, is safe to the human body, has biodegradability, cannot cause pollution to the environment, is simple in preparation method, is suitable for mass production, and has very high commercial value.
Description
Technical Field
The invention belongs to the field of organic synthesis and the field of medicines, and particularly relates to a glycyrrhetinic acid derivative, and a preparation method and application thereof.
Background
Hydrogels are a class of soft material materials consisting of a 3D polymer network and a large amount of water, with many structural similarities to the soft tissues of living organisms. The hydrogel is a novel ideal medical dressing, can lock moisture when being externally applied, maintains the moist environment of a wound surface, is beneficial to healing of the wound, is not easy to scab the wound, reduces scars and keeps the beauty of the skin; when used as the filler for the internal invasive surgery, the adhesive is well attached to the wound surface. Therefore, the hydrogel can be widely used in the biomedical engineering field, such as internal wound operation fillers, wound dressings, drug delivery and the like.
The main modes of hydrogel formation at present are chemical crosslinking and physical crosslinking, and the hydrogels formed by the two modes need to introduce bridging agents such as proteins, metal ions, small molecule surfactants and the like into a system so as to induce the formation of the hydrogel through the bridging action. However, most of the hydrogel formed by the two modes has low purity, cannot be completely absorbed by a human body, and influences the normal metabolism of the human body. And the traditional dressing is easy to cause secondary damage when being replaced, thereby bringing pain to patients. At present, the antibacterial effect of the hydrogel dressing is generally from the added antibacterial drugs or the introduction of metal ions for antibiosis, hydrogel often only has the effect of providing a humid environment, the function and the effect are single, the use requirement of clinical medicine can not be met for a long time, the raw material source of the biological dressing is limited, the preparation process is complex, and the biological dressing is not suitable for large-scale popularization. In addition, most of the current hydrogel dressings are inevitably prepared by using some toxic and harmful chemicals, toxic and harmful substances are generated in the production and preparation processes, and the hydrogel dressings pollute the environment and spread viruses if not recovered in time after being used.
The glycyrrhetinic acid is a typical medicine-food homologous traditional Chinese medicine, the main component of the glycyrrhetinic acid has extremely high pharmacological application value, and has the effects of diuresis resistance, inflammation resistance, cough relief, virus resistance and the like on healthy people and various animals, but the glycyrrhetinic acid has limited application range due to weak antibacterial activity, poor hydrophilicity, low biological activity and the like, and the product developed by the glycyrrhetinic acid has single functionality.
Disclosure of Invention
In order to solve the defects and shortcomings in the prior art, the invention aims to provide a glycyrrhetinic acid derivative, a preparation method and an application thereof, so as to solve the problems of weak antibacterial activity, poor hydrophilicity, low bioactivity, narrow application range, single efficacy of the prepared product and the like of glycyrrhetinic acid, and the problems of single functionality, incapability of being completely absorbed by a human body, potential harm to the human body, complex and non-environment-friendly preparation process, easy environmental pollution after use, virus scattering and the like of the traditional hydrogel dressing.
In order to achieve the above object, in a first aspect, the present invention provides a glycyrrhetinic acid derivative, the structural formula of which is shown as follows:
wherein R is a fluorine-containing group.
Compared with glycyrrhetinic acid, hydroxyl at the C3 position in the structure of the glycyrrhetinic acid derivative is oxidized into carbonyl, and a fluorine-containing group is introduced at the C2 position, so that the glycyrrhetinic acid derivative has more excellent antibacterial activity, hydrophilicity and biological activity; after the glycyrrhetinic acid derivative is mixed with water and an organic solvent, the glycyrrhetinic acid derivative can be self-assembled to form hydrogel with a three-dimensional rod-shaped structure through the non-covalent bond effect between small drug molecules (namely the glycyrrhetinic acid derivative molecules), no external energy is needed to be provided, and the hydrogel integrates the characteristics of antibiosis, anti-inflammation and gel, so that the integration of the antibiosis and anti-inflammation gel is realized, the hydrogel can be completely absorbed by a human body after being applied, has no harmful residue, is safe to the human body, has biodegradability, and cannot cause pollution to the environment.
As a preferred embodiment of the glycyrrhetinic acid derivative of the present invention, said R is 6-trifluoromethylpyridyl. The inventor carries out structure optimization aiming at the structure-activity relationship and finds that when R is 6-trifluoromethyl pyridyl, the obtained glycyrrhetinic acid derivative has better bacteriostatic effect.
In a second aspect, the invention provides a preparation method of the glycyrrhetinic acid derivative, which comprises the following steps:
(1) selective oxidation: oxidizing Glycyrrhetinic Acid (GA) in an organic solvent with an oxidant, and then quenching to obtain glycyrrhetinic acid oxide, wherein the structural formula of the glycyrrhetinic acid oxide is shown as follows:
(2) modification treatment: under the protection of protective gas, reacting the glycyrrhetinic acid oxide, the hydroxide and the compound containing the fluorine group in an organic solvent, and then quenching the reaction to obtain the glycyrrhetinic acid derivative.
The preparation method comprises the steps of firstly, selectively oxidizing glycyrrhetinic acid to oxidize hydroxyl on C3 site in the structure into carbonyl to obtain glycyrrhetinic acid oxide, then, reacting the glycyrrhetinic acid oxide to introduce fluorine-containing group on C2 site in the structure to obtain the glycyrrhetinic acid derivative, wherein the yield of the glycyrrhetinic acid oxide can reach 85% -91%, and the yield of the glycyrrhetinic acid derivative can reach 75% -85%; the preparation method is simple to operate, nontoxic or low-toxicity raw materials can be selected, and the preparation process is more environment-friendly.
In the above preparation method, the organic solvent used in step (1) is any organic solvent capable of dissolving glycyrrhetinic acid, and preferably acetone.
As a preferable embodiment of the method for producing a glycyrrhetinic acid derivative according to the present invention, in step (1), the oxidizing agent is jones reagent, and the quenching reagent is methanol.
As a preferred embodiment of the method for preparing a glycyrrhetinic acid derivative according to the present invention, in the step (1), the oxidation reaction is performed at 0 ℃; the oxidant is dripped into the glycyrrhetinic acid to carry out oxidation reaction, and the dosage of the oxidant is excessive; in the process of the oxidation reaction, a TLC plate is adopted to confirm whether the reaction is complete, and if the reaction is complete, quenching reaction is carried out; the glycyrrhetinic acid oxide is further subjected to purification treatment before being used in the step (2). Wherein the excessive amount of the oxidant means that the amount of the oxidant exceeds the theoretical amount, namely the amount calculated according to the chemical reaction equation.
As a preferable embodiment of the method for producing a glycyrrhetinic acid derivative according to the present invention, the oxidizing agent is added dropwise to the reaction system in a pale yellow color and remains unchanged, i.e., the addition is stopped.
In the above preparation method, the organic solvent used in step (2) is any organic solvent capable of dissolving the glycyrrhetinic acid oxide, the hydroxide, and the fluorine-containing group-containing compound, and preferably ethanol.
As a preferable embodiment of the method for preparing a glycyrrhetinic acid derivative according to the present invention, in step (2), the hydroxide is at least one of potassium hydroxide and sodium hydroxide, the fluorine-containing compound is 6-trifluoromethylpyridine-3-carbaldehyde, and the reagent used for quenching is an acid solution. Preferably, the acid solution is hydrochloric acid.
As a preferable embodiment of the preparation method of glycyrrhetinic acid derivatives of the present invention, in the step (2), the reaction is performed at room temperature, and the reaction time is 1 to 12 hours; the molar ratio of the glycyrrhetinic acid oxide to the hydroxide to the fluorine-containing group-containing compound is glycyrrhetinic acid oxide: hydroxide: a fluorine-containing group-containing compound 1:1:1 to 1:2.5: 2.5; in the reaction process, a TLC plate is adopted to confirm whether the reaction is complete, and if the reaction is complete, quenching reaction is carried out; after the quenching reaction, purification treatment is also carried out.
In a third aspect, the invention provides a hydrogel, wherein the hydrogel is prepared from the glycyrrhetinic acid derivative.
In a fourth aspect, the present invention provides a method for preparing the above hydrogel, comprising the following steps: and (3) completely dissolving the glycyrrhetinic acid derivative in an organic solvent, and then adding water to obtain the hydrogel. The hydrogel is formed by self-assembly of non-covalent bond between glycyrrhetinic acid derivative molecules, and T isgelThe thermal transition temperature is higher than that of common hydrogel, can reach 65 ℃, has good antibacterial effect, can be completely absorbed by human body, has biodegradability, does not cause pollution to the environment, has simple preparation method, is suitable for mass production, and has very high commercial value.
As a preferred embodiment of the method for producing the hydrogel of the present invention, the volume ratio of the water to the organic solvent is 1 to 3: 1.
In a preferred embodiment of the method for producing a hydrogel of the present invention, the organic solvent is at least one of acetone, ethanol, ethyl acetate, and dimethyl sulfoxide.
In a preferred embodiment of the method for producing a hydrogel according to the present invention, the glycyrrhetinic acid derivative is completely dissolved in the organic solvent, and then the solution is shaken or stirred while adding water.
As a preferable embodiment of the method for producing the hydrous gel of the present invention, the water is added dropwise to the glycyrrhetinic acid derivative.
As a preferred embodiment of the method for preparing the hydrogel of the present invention, the glycyrrhetinic acid is completely dissolved in the organic solvent by ultrasonic assistance.
As a preferred embodiment of the preparation method of the hydrogel, the temperature of the ultrasonic assistance is 35-50 ℃, and the processing time is 60-110 s.
In a fifth aspect, the invention also provides a medical hydrogel dressing which comprises the hydrogel.
Compared with the prior art, the invention has the following advantages:
(1) the glycyrrhetinic acid is modified, the hydroxyl at the C3 position in the structure of the glycyrrhetinic acid is oxidized into carbonyl, and the fluorine-containing group is introduced at the C2 position, so that the antibacterial activity, the hydrophilicity and the biological biochemistry of the glycyrrhetinic acid are improved;
(2) after the fluorine-containing glycyrrhetinic acid derivative is mixed with water and an organic solvent, the hydrogel with a three-dimensional rod-shaped structure can be formed by self-assembly through the non-covalent bond effect among small molecules of the medicine, external energy is not required to be provided, the obtained hydrogel integrates the characteristics of antibiosis, anti-inflammation and gel, the integration of antibiosis and anti-inflammation gel is realized, the hydrogel is safe to a human body, can be completely absorbed by the human body, has biodegradability, cannot pollute the environment, is simple in preparation method, is suitable for mass production, and has very high commercial value.
Drawings
FIG. 1 is a flow chart of the preparation of hydrogel from GA-O-09 in each example;
FIG. 2 is a scheme showing the synthesis of GA-O-09 in each example;
FIG. 3 is a schematic diagram of the antibacterial and anti-inflammatory hydrogel obtained by the present invention;
FIG. 4 is the xerogel appearance under the GA-O-09 gel small molecule SEM.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example 1
The embodiment provides a preparation method of medical hydrogel based on glycyrrhetinic acid derivatives, which comprises the following steps:
1. synthesis of glycyrrhetinic acid derivatives
(1) Weighing 18 beta-glycyrrhetinic acid (1g, 2.12mmol) in a dry round-bottom flask, adding 5-10mL of acetone, and stirring under the condition of ice bath (0 ℃) until the glycyrrhetinic acid is completely dissolved in the acetone;
(2) 26.72g of chromium trioxide is dissolved in a beaker by a small amount of water, then 2-3mL of concentrated sulfuric acid (mass concentration is 98%) is slowly dropped, and then the solution is diluted to 100mL by water to obtain a Jones reagent (Jones Regent);
(3) dropwise adding the prepared Jones reagent into the reaction solution of the round-bottom flask, stopping dropwise adding the Jones reagent when the solution is light yellow and is kept for more than 30s, namely the Jones reagent is excessive, and adding methanol to quench the reaction after confirming the reaction is complete through a TLC plate to obtain a solution containing GA-O (namely 18 beta-glycyrrhetinic acid oxide);
(4) carrying out rotary evaporation on the solution containing GA-O until the solution is dried, then extracting with ethyl acetate and water, collecting the organic phase solution, drying with anhydrous magnesium sulfate, and then carrying out rotary evaporation until the solution is dried to obtain a crude product of GA-O;
(5) performing column chromatography separation on the GA-O crude product (the stationary phase is silica gel, the mobile phase is a mixed solution of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is 4:1) to obtain a product GA-O (white solid, 909mg, and the yield is 91%);
(6) GA-O (200mg, 0.43mmol, 1eq), 6-trifluoromethylpyridine-3-carbaldehyde (149.4mg, 0.99mmol, 2.5eq) and potassium hydroxide (47.9mg, 0.85mmol, 2eq) were placed in a reactor and dissolved in 10-20mL of ethanol;
(7) reacting for 1h at room temperature under the protection of nitrogen, and determining whether the reaction is completely carried out through a TLC plate;
(8) after confirming the completion of the reaction by TLC plate, 2-3mL of hydrochloric acid solution was added to the reactor to quench the reaction, resulting in a solution containing GA-O-09 (i.e., the objective glycyrrhetinic acid derivative);
(9) carrying out rotary evaporation on the solution containing GA-O-09 until the solution is dried, extracting the solution by using ethyl acetate and water, collecting the organic phase solution, drying the organic phase solution by using anhydrous magnesium sulfate, and then carrying out rotary evaporation until the organic phase solution is dried to obtain a crude GA-O-09;
(10) performing column chromatography on the crude GA-O-09 (the stationary phase is silica gel, the mobile phase is a mixed solution of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is 4:1) to obtain a product GA-O-09 (a white solid, 185mg, and the yield is 76.8%);
2. preparation of hydrogels
(11) Weighing GA-O-0915 mg obtained in the step (10) in a sample bottle with the diameter of 1cm and the volume of 4mL, adding 1mL of absolute ethyl alcohol into the sample bottle by using a 1000-microliter pipette gun, and then performing ultrasonic treatment at 40 ℃ for 100s to fully dissolve the absolute ethyl alcohol;
(12) adding 1mL of deionized water into the solution by using a 1000-microliter pipette, slowly dripping the deionized water while slowly shaking the sample bottle, and waiting for 30-60s to obtain the hydrogel capable of stably existing (as shown in figure 3);
3. preparation of medical dressing for wound
(13) The hydrogel prepared by the method is combined with the medical adhesive tape, and according to the wound injury degree, the hydrogel can be smeared on the adhesive surface of the medical adhesive tape, or the hydrogel can be made into blocks to be applied to the wound and fixed by the medical adhesive tape.
Example 2
The embodiment provides a preparation method of medical hydrogel based on glycyrrhetinic acid derivatives, which comprises the following steps:
1. synthesis of glycyrrhetinic acid derivatives
(1) Weighing 18 beta-glycyrrhetinic acid (1g, 2.12mmol) in a dry round-bottom flask, adding 5-10mL of acetone, and stirring under the condition of ice bath (0 ℃) until the glycyrrhetinic acid is completely dissolved in the acetone;
(2) 26.72g of chromium trioxide is dissolved in a beaker by a small amount of water, then 2-3mL of concentrated sulfuric acid (mass concentration is 98%) is slowly dropped, and then the solution is diluted to 100mL by water to obtain a Jones reagent (Jones Regent);
(3) dropwise adding the prepared Jones reagent into the reaction solution of the round-bottom flask, stopping dropwise adding the Jones reagent when the solution is light yellow and remains unchanged, namely the Jones reagent is excessive, confirming that the reaction is complete through a TLC plate, and adding methanol to quench the reaction to obtain a solution containing GA-O (namely 18 beta-glycyrrhetinic acid oxide);
(4) carrying out rotary evaporation on the solution containing GA-O until the solution is dried, then extracting with ethyl acetate and water, collecting the organic phase solution, drying with anhydrous magnesium sulfate, and then carrying out rotary evaporation until the solution is dried to obtain a crude product of GA-O;
(5) performing column chromatography on the crude GA-O product (the stationary phase is silica gel, the mobile phase is a mixed solution of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is 13:3) to obtain a product GA-O (white solid, 948mg, 93.1% of yield);
(6) GA-O (200mg, 0.43mmol, 1eq), 6-trifluoromethylpyridine-3-carbaldehyde (132.4mg, 0.88mmol, 2eq) and potassium hydroxide (47.9mg, 0.85mmol, 2eq) were placed in a reactor and dissolved in 12-20mL of an ethanol solution;
(7) reacting for 5 hours at room temperature under the protection of nitrogen, and determining whether the reaction is completely carried out through a TLC plate;
(8) after confirming the completion of the reaction by TLC plate, mL of hydrochloric acid solution was added to the reactor to quench the reaction, resulting in a solution containing GA-O-09 (i.e., the target glycyrrhetinic acid derivative);
(9) carrying out rotary evaporation on the solution containing GA-O-09 until the solution is dried, extracting the solution by using ethyl acetate and water, collecting the organic phase solution, drying the organic phase solution by using anhydrous magnesium sulfate, and then carrying out rotary evaporation until the organic phase solution is dried to obtain a crude GA-O-09;
(10) performing column chromatography on the GA-O-09 crude product (the stationary phase is silica gel, the mobile phase is a mixed solution of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is 4:1) to obtain a product GA-O-09 (white solid, 202mg, yield 83.8%);
2. preparation of hydrogels
(11) Weighing GA-O-0915 mg obtained in the step (10) in a sample bottle with the diameter of 1cm and the volume of 4mL, adding 1mL of acetone into the sample bottle by using a 1000-mu L pipette, and then performing ultrasonic treatment at 30 ℃ for 90s to fully dissolve the acetone;
(12) adding 1.5mL of deionized water into the solution by using a 1000-microliter pipette, slowly dripping the deionized water while slowly shaking the sample bottle, and waiting for 30-60s to obtain the hydrogel capable of stably existing (as shown in figure 3);
3. preparation of medical dressing for wound
(13) The hydrogel prepared by the method is combined with the medical adhesive tape, and according to the wound injury degree, the hydrogel can be smeared on the adhesive surface of the medical adhesive tape, or the hydrogel can be made into blocks to be applied to the wound and fixed by the medical adhesive tape.
Example 3
The embodiment provides a preparation method of medical hydrogel based on glycyrrhetinic acid derivatives, which comprises the following steps:
1. synthesis of glycyrrhetinic acid derivatives
(1) Weighing 18 beta-glycyrrhetinic acid (1g, 2.12mmol) in a dry round-bottom flask, adding 7-11mL of acetone, and stirring under the condition of ice bath (0 ℃) until the glycyrrhetinic acid is completely dissolved in the acetone;
(2) 26.72g of chromium trioxide is dissolved in a beaker by a small amount of water, then 2-3mL of concentrated sulfuric acid (mass concentration is 98%) is slowly dropped, and then the solution is diluted to 100mL by water to obtain a Jones reagent (Jones Regent);
(3) dropwise adding the prepared Jones reagent into the reaction solution of the round-bottom flask, stopping dropwise adding the Jones reagent when the solution is light yellow and remains unchanged, namely the Jones reagent is excessive, confirming that the reaction is complete through a TLC plate, and adding methanol to quench the reaction to obtain a solution containing GA-O (namely 18 beta-glycyrrhetinic acid oxide);
(4) carrying out rotary evaporation on the solution containing GA-O until the solution is dried, then extracting with ethyl acetate and water, collecting the organic phase solution, drying with anhydrous magnesium sulfate, and then carrying out rotary evaporation until the solution is dried to obtain a crude product of GA-O;
(5) performing column chromatography on the crude GA-O product (the stationary phase is silica gel, the mobile phase is a mixed solution of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is 7:2) to obtain a product GA-O (a white solid, 885mg, and the yield is 87.8%);
(6) GA-O (200mg, 0.43mmol, 1eq), 6-trifluoromethylpyridine-3-carbaldehyde (149.4mg, 0.99mmol, 2.5eq) and potassium hydroxide (40.2mg, 0.78mmol, 1.8eq) were placed in a reactor and dissolved in 10-16mL of an ethanol solution;
(7) reacting for 12 hours at room temperature under the protection of nitrogen, and determining whether the reaction is completely carried out through a TLC plate;
(8) after confirming the completion of the reaction by TLC plate, mL of hydrochloric acid solution was added to the reactor to quench the reaction, resulting in a solution containing GA-O-09 (i.e., the target glycyrrhetinic acid derivative);
(9) carrying out rotary evaporation on the solution containing GA-O-09 until the solution is dried, extracting the solution by using ethyl acetate and water, collecting the organic phase solution, drying the organic phase solution by using anhydrous magnesium sulfate, and then carrying out rotary evaporation until the organic phase solution is dried to obtain a crude GA-O-09;
(10) performing column chromatography on the crude GA-O-09 (the stationary phase is silica gel, the mobile phase is a mixed solution of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is 4:1) to obtain a product GA-O-09 (white solid, 193mg, yield 81.7%);
2. preparation of hydrogels
(11) Weighing GA-O-0915 mg obtained in the step (10) in a sample bottle with the diameter of 1cm and the volume of 4mL, adding 1mL of ethyl acetate into the sample bottle by using a 1000-mu L pipette, and then carrying out ultrasonic treatment at 50 ℃ for 110s to fully dissolve the ethyl acetate;
(12) adding 3mL of deionized water into the solution by using a 1000-microliter pipette, slowly dripping the deionized water while slowly shaking the sample bottle, and waiting for 30-60s to obtain the hydrogel capable of stably existing (shown in figure 3);
3. preparation of medical dressing for wound
(13) The hydrogel prepared by the method is combined with the medical adhesive tape, and according to the wound injury degree, the hydrogel can be smeared on the adhesive surface of the medical adhesive tape, or the hydrogel can be made into blocks to be applied to the wound and fixed by the medical adhesive tape.
T of the hydrogels obtained in examples 1 to 3gelThe temperature is 65 ℃, the obtained medical dressing for the wound is applied to the wound, and the hydrogel in the medical dressing can be completely absorbed by the human body.
Comparative example 1
The comparative example provides a preparation method of medical hydrogel based on glycyrrhetinic acid, which comprises the following steps:
(1) weighing 18mg of 18 beta-glycyrrhetinic acid in a sample bottle with the diameter of 1cm and the volume of 4mL, adding 0.25mL of absolute ethyl alcohol into the bottle by using a 250 mu L pipette, performing ultrasonic treatment at 40 ℃ for 100s to fully dissolve the absolute ethyl alcohol, and then placing the bottle in a room temperature environment;
(2) to this, 0.25mL of deionized water was added using a 250. mu.L pipette, and the sample bottle was slowly shaken with slowly dropping deionized water and then allowed to stand for 2 hours, whereby hydrogel could not be formed.
Comparative example 2
The comparative example provides a preparation method of medical hydrogel based on glycyrrhetinic acid oxide, which comprises the following steps:
(1) weighing 18mg of glycyrrhetinic acid oxide (GA-O) obtained in example 1 into a sample bottle with the diameter of 1cm and the volume of 4mL, adding 0.25mL of absolute ethanol into the bottle by using a 250-mu-L pipette, performing ultrasonic treatment at 40 ℃ for 100s to fully dissolve the glycyrrhetinic acid oxide (GA-O), and then placing the mixture in a room-temperature environment;
(2) to this, 0.25mL of deionized water was added using a 250. mu.L pipette, and the sample bottle was slowly shaken with slowly dropping deionized water and then allowed to stand for 2 hours, whereby hydrogel could not be formed.
Effect example 1: MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) tests
The experimental method comprises the following steps:
(1) measuring 5 mu L of the natural medicine medical hydrogel to be tested with the series gradient obtained by the two-fold dilution method by using a 10 mu L pipette, adding the measured 5 mu L of the natural medicine medical hydrogel into a sterile 96-well plate, wherein the positive control is gatifloxacin, the negative control is DMSO, and repeating the steps for four times in each well;
(2) will be prepared in advance for MIC determination at a concentration of 1.5X105Adding 195 mu L of bacterial suspension into a sterile 96-well plate through a liquid transfer device, adding 195 mu L of sterile Miller-Haiton liquid culture medium into a blank group, shaking for about 10s, and covering a cover on the microporous plate;
(3) putting the microporous plate into a thermostat, culturing at 37 ℃ for 24h, and taking out the microporous plate;
(4) determining the OD value of each hole under the wavelength of 610nm by using a multifunctional microplate reader or observing whether the micropores are turbid or not by using naked eyes, and defining the sample concentration corresponding to the critical holes which are not turbid in the microplate as the minimum inhibitory concentration of the sample to be detected to the bacterial strain to be detected;
(5) the minimum inhibitory concentration of the natural drug medical hydrogel precursor of the invention on staphylococcus aureus (ATCC6538) is 6.25 mu mol/L, the minimum inhibitory concentration on staphylococcus epidermidis (ATCC12228) is 3.125 mu mol/L, and the minimum inhibitory concentration on staphylococcus albus (ATCC 29213) is 3.125 mu mol/L, and the result is shown in Table 1;
(6) the minimum inhibitory concentration of the dried medical hydrogel (namely xerogel) of the natural medicine of the invention on staphylococcus aureus (ATCC6538) is 6.25 mu mol/L, the minimum inhibitory concentration on staphylococcus epidermidis (ATCC12228) is 3.125 mu mol/L, and the minimum inhibitory concentration on staphylococcus albus (ATCC 29213) is 3.125 mu mol/L, and the results are shown in Table 1;
(7) taking 50 μ L of the test solution from the wells of a 96-well plate for MIC, uniformly coating the solution on a solid culture medium (taking several concentrations which are not long-lived and are larger than the cells) and placing the culture dish upside down in a 37 ℃ constant temperature incubator for 24 h;
(8) the petri dish was removed and the number of colonies therein was observed. The concentration corresponding to the number of colonies growing <8 was the corresponding concentration of MBC, calculated according to the MBC definition (the minimum drug concentration required to kill 99.9% of the test microorganisms).
Table 1: test results of minimum inhibitory concentration and minimum bactericidal concentration
As can be seen from Table 1, the glycyrrhetinic acid micromolecules prepared by the method and the hydrogel prepared by self-assembly by taking the glycyrrhetinic acid micromolecules as precursors have antibacterial effects, can inhibit staphylococcus aureus, staphylococcus epidermidis and staphylococcus albus at the same time, and have greatly improved antibacterial effects compared with GA micromolecules, so that the hydrogel prepared by the method has very excellent antibacterial effects.
Effect example 2: zone of inhibition test
The experimental method comprises the following steps:
(1) the determination of the inhibition zone is completed by adopting a classical filter paper sheet-agar diffusion method. Pouring about 45mL of nutrient agar culture medium into a 120mm culture dish when the prepared Miller-Hayton agar culture medium is at about 50 ℃, cooling and solidifying for later use;
(2) 400 μ L of the prepared solution was measured with a 1000mL pipette at a concentration of 1.5X106CFU/mL test bacterial suspension is added into each culture dish, and the bacterial suspension is uniformly coated on the surface of the agar culture medium by using a sterile coater (triangular glass rod);
(3) clamping a sterile filter paper sheet with the diameter of 6mm by using a sterile forceps, pressing the sterile filter paper sheet on an agar plate, measuring 5 mu L of each diluted sample to be detected by using a 10 mu L pipette, and slightly dropping the diluted sample to be detected on the filter paper sheet to ensure that the sample to be detected is completely adsorbed by the filter paper sheet;
(4) the gatifloxacin is used as a positive control group, the DMSO is used as a negative control group, and each group is repeated for three times;
(5) standing for a moment, reversely placing the culture dish in a thermostat for culturing for 24 hours, taking out the culture medium, measuring the diameter of the bacteriostatic zone by using a vernier caliper and counting;
(5) the natural medicinal hydrogel micromolecules have the inhibition zones of 8.22 +/-0.08 mm on staphylococcus aureus (ATCC6538), 8.31 +/-0.21 mm on staphylococcus albus (ATCC 29213) and 8.80 +/-0.03 mm on staphylococcus epidermidis (ATCC12228) according to the detection result, and the results are shown in Table 2;
(6) the result of the measurement shows that the inhibition zone of the dried medical hydrogel of the invention for the natural medicine is 7.82 +/-0.12 mm on staphylococcus aureus (ATCC6538), the minimum inhibition concentration for the staphylococcus albus (ATCC 29213) is 8.73 +/-0.10 mm, and the inhibition zone for the staphylococcus epidermidis (ATCC12228) is 8.89 +/-0.13 mm, and the result is shown in Table 2.
TABLE 2 zone of inhibition test results
Effect example 3: SEM test
The natural medicine medical hydrogel prepared by the invention is a nano rod-shaped structure through SEM test. (see attached FIG. 4)
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. A glycyrrhetinic acid derivative is characterized in that the structural formula of the glycyrrhetinic acid derivative is as follows:
wherein R is a fluorine-containing group.
2. The glycyrrhetinic acid derivative according to claim 1, wherein R is 6-trifluoromethylpyridyl.
3. The method for preparing glycyrrhetinic acid derivatives according to claim 1 or 2, characterized in that it comprises the steps of:
(1) oxidizing glycyrrhetinic acid with an oxidant in an organic solvent, and then quenching to obtain glycyrrhetinic acid oxide, wherein the structural formula of the glycyrrhetinic acid oxide is as follows:
(2) under the protection of protective gas, reacting the glycyrrhetinic acid oxide, the hydroxide and the compound containing the fluorine group in an organic solvent, and then quenching the reaction to obtain the glycyrrhetinic acid derivative.
4. The method according to claim 3, wherein in the step (1), the oxidizing agent is Jones' reagent, and the quenching reagent is methanol.
5. The production method according to claim 4, wherein in the step (1), the oxidation reaction is carried out at 0 ℃; the oxidant is dripped into the glycyrrhetinic acid to carry out oxidation reaction, and the dosage of the oxidant is excessive; in the process of the oxidation reaction, a TLC plate is adopted to confirm whether the reaction is complete, and if the reaction is complete, quenching reaction is carried out; the glycyrrhetinic acid oxide is further subjected to purification treatment before being used in the step (2).
6. The preparation method according to claim 3, wherein in the step (2), the hydroxide is at least one of potassium hydroxide and sodium hydroxide, the fluorine-containing compound is 6-trifluoromethylpyridine-3-carbaldehyde, and the reagent for quenching is an acid solution.
7. The method according to claim 6, wherein in the step (2), the reaction is carried out at room temperature for 1-12 h; the molar ratio of the glycyrrhetinic acid oxide to the hydroxide to the fluorine-containing group-containing compound is glycyrrhetinic acid oxide: hydroxide: a fluorine-containing group-containing compound 1:1:1 to 1:2.5: 2.5; in the reaction process, a TLC plate is adopted to confirm whether the reaction is complete, and if the reaction is complete, quenching reaction is carried out; after the quenching reaction, purification treatment is also carried out.
8. A hydrogel prepared from the glycyrrhetinic acid derivative of claim 1 or 2.
9. A method of making the hydrogel of claim 8, comprising the steps of: the hydrous gel is obtained by completely dissolving the glycyrrhetinic acid derivative of claim 1 or 2 in an organic solvent and then adding water.
10. A medical dressing comprising the hydrogel of claim 8.
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| CN113336821A (en) * | 2021-06-18 | 2021-09-03 | 五邑大学 | Glycyrrhetinic acid derivative Z-type isomer and preparation method thereof |
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