CN114539092A - Oat bran phenolic amide alkaloid, preparation method thereof and application thereof in preparation of itching-relieving products - Google Patents
Oat bran phenolic amide alkaloid, preparation method thereof and application thereof in preparation of itching-relieving products Download PDFInfo
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Abstract
The invention relates to the technical field of medicinal chemistry, and particularly discloses oat bran phenolic amide alkaloid, a preparation method thereof and application thereof in preparation of an itching relieving product. The oat bran phenolic amide alkaloid has a structure shown in a formula I or a formula II. The preparation method of the oat bran phenolic amide alkaloid specifically comprises the following steps: taking a reaction substrate caffeic acid analogue, adding an organic solvent, adding 4- (2-aminoethyl) phenol and triethylamine under stirring, and adding HATU after 3-6 minutes; after the feeding is finished, continuously reacting for 3-6 hours at room temperature, and monitoring the disappearance of reaction raw materials by TLC; stopping stirring, evaporating the reaction system under reduced pressure to remove the solvent, and purifying the residue by silica gel column chromatography to obtain the oat bran phenolic amide alkaloid. Research shows that the oat bran phenolic amide alkaloid or the composition thereof has excellent antipruritic effect; therefore, the oat bran phenolic amide alkaloid or the composition thereof can be used for developing an anti-itching product.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to oat bran phenolic amide alkaloid, a preparation method thereof and application thereof in preparing an itching relieving product.
Background
Skin pruritus is the most common skin disease of the elderly, and antihistamines are common medicines for clinically treating skin pruritus. The balance of Th1/Th2 cells is closely related to the abnormal expression of inflammatory factors of patients with skin pruritus, and the fact that the abnormal expression of the inflammatory factors is remarkably increased by the Th1 cytokines in an atopic dermatitis rat model plays an important role in the pathogenesis of the skin pruritus, so that the anti-inflammatory treatment has a good effect on the clinical curative effect of the skin pruritus.
The traditional Chinese medicine has long history and rich experience in treating skin diseases, can control repeated skin diseases or prolong the recurrence time of the skin diseases, reduces or avoids the side effect of chemical drugs, delays the pathological change process and prolongs the survival time, so the trend of pursuing the traditional Chinese medicine with stable curative effect, safety and reliability is more and more obvious.
Oats are one of the major cereals worldwide and are recognized by the U.S. FDA as functional foods, an important source of protein, vitamins and various mineral elements. Research shows that the oat is rich in various active ingredients, wherein the avenanthramide is the main functional ingredient in the oat, has the functions of reducing blood fat, blood sugar and blood pressure and the like, and is related to the antioxidation of the oat. In addition, avenanthramides may mediate inflammatory cell responses through interactions with cytokines and signaling pathways, have anti-inflammatory and bacteriostatic effects, and colloidal extracts containing avenanthramides have been shown to have anti-histamine and anti-inflammatory activities. Avenanthramides have a variety of biological activities and are very beneficial to human and animal health. The application of the oat alkaloid is greatly limited by factors such as single structure of oat alkaloid, low content of oat and the like. Therefore, the method has important application value in improving and optimizing the structure based on the avenanthramide, synthesizing the analogue with the avenanthramide structure or the avenanthramide compound with better activity and developing the avenanthramide analogue with the function of resisting skin itch.
Disclosure of Invention
In view of the above, the invention firstly provides oat bracteoamide alkaloid with a brand-new structure, and researches show that the oat bracteoamide alkaloid has an antipruritic effect.
The detailed technical scheme of the invention is as follows:
an oat bran phenolic amide alkaloid having a structure represented by formula I or formula II:
wherein, formula I or R in formula II1、R2And R3Each independently selected from H, OH or OCH3。
Preferably, the oat bracteoamide alkaloid is any one of oat bracteoamide alkaloid-1-6; the structural formula of the oat bran phenolic amide alkaloid-1-6 is as follows:
the inventor finds that R in the compound shown in formula I or formula II1、R2And R3The oat bran phenolic amide alkaloid obtained after being substituted by different groups has great difference in itching relieving effect; the inventors are studyingSurprisingly, the oat bran phenolic amide alkaloid-3 has a far greater itching relieving effect than other compounds, and has a very remarkable itching relieving effect; the antipruritic effect of the compound is also obviously higher than that of the known avenanthramide and the positive control medicament diphenhydramine; significant technological advances have been made.
The present invention also provides a composition comprising oat spartinamide alkaloid-3 and oat spartinamide alkaloid-4; wherein the weight ratio of oat bracteoamide alkaloid-3 to oat bracteoamide alkaloid-4 is 1-5: 1;
further preferably, the weight ratio of the oat bracteoamide alkaloid-3 to the oat bracteoamide alkaloid-4 is 2-4: 1;
most preferably, the oat brazzolamide alkaloid-3 and oat brazzolamide alkaloid-4 are present in a weight ratio of 3: 1.
The inventors have surprisingly found in further studies that: synergistic antipruritic effects are not achieved by any combination of compounds; however, after the oat bracteoamide alkaloid-3 and the oat bracteoamide alkaloid-4 are combined, the two can generate a synergistic itching relieving effect, and the itching relieving effect is obviously higher than that of the oat bracteoamide alkaloid-3 or the oat bracteoamide alkaloid-4 alone.
The invention also provides a preparation method of the oat bran phenolic amide alkaloid, which is prepared by taking caffeic acid analogues and 4- (2-aminoethyl) phenol as raw materials;
the structure of the caffeic acid analog is as follows:
wherein R is1、R2、R3Independently selected from H, OH or OCH3。
Preferably, the molar ratio of the caffeic acid analog to 4- (2-aminoethyl) phenol is 1: 1-3.
Preferably, taking a reaction substrate caffeic acid analogue, adding an organic solvent, adding 4- (2-aminoethyl) phenol and triethylamine under stirring, and adding HATU after 3-6 minutes; after the feeding is finished, continuously reacting for 3-6 hours at room temperature, and monitoring by TLC that reaction raw materials disappear; stopping stirring, evaporating the reaction system under reduced pressure to remove the solvent, and purifying the residue by silica gel column chromatography to obtain the oat bran phenolic amide alkaloid.
Preferably, the dosage ratio of the organic solvent, the triethylamine and the HATU to the reaction substrate caffeic acid analogues is 30-60 mL: 5-6 mL: 4.5-5.0 g:1 g.
Most preferably, the ratio of the organic solvent, triethylamine and HATU to the reaction substrate caffeic acid analog is 40mL:5.5mL:4.85g:1 g.
The invention also provides the application of the compound or the composition in preparing an antipruritic product; the product comprises medicine, skin care product or cosmetic.
Preferably, the itch is itch caused by dermatitis, burns, eczema, urticaria, xeroderma, superficial fungal infection, or psoriasis.
Preferably, the itch is itch caused by diabetes, cholestasis, chronic kidney disease, tumors, or aids.
Has the advantages that: (1) the oat bran phenolic amide alkaloid compound can obviously inhibit the excessive secretion of inflammatory cytokines of mice with skin pruritus; (2) the oat bran phenolic amide alkaloid compound can obviously reduce scratching times of mice with skin itch; (3) in particular to the composition formed by combining oat bracteoamide alkaloid-3, oat bracteoamide alkaloid-3 and oat bracteoamide alkaloid-4, which has stronger anti-inflammatory and antipruritic activities than diphenhydramine and the known compound oat alkaloid; the oat bran phenolic amide alkaloid or the composition thereof can be used for developing an anti-itching product; (4) the method has the characteristics of rapid reaction, simple steps, high yield, high product purity, economy and applicability.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only drawings of some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a schematic representation of oat bran phenolic amide alkaloid compound-11H-NMR spectrum.
FIG. 2 is a schematic representation of oat bran phenolic amide alkaloid compound-113C-NMR spectrum.
FIG. 3 is a preparation of oat bran phenolic amide alkaloid compound-21H-NMR spectrum.
FIG. 4 shows the preparation of oat bran phenolic amide alkaloid compound-213C-NMR spectrum.
FIG. 5 is a preparation of oat bran phenolic amide alkaloid compound-31H-NMR spectrum.
FIG. 6 shows the preparation of oat bran phenolic amide alkaloid compound-313C-NMR spectrum.
FIG. 7 shows the preparation of oat bran phenolic amide alkaloid compound-41H-NMR spectrum.
FIG. 8 shows the preparation of oat bran phenolic amide alkaloid compound-513C-NMR spectrum.
FIG. 9 shows the preparation of oat bran phenolic amide alkaloid compound-51H-NMR spectrum.
FIG. 10 shows the preparation of oat bran phenolic amide alkaloid compound-513C-NMR spectrum.
FIG. 11 shows the preparation of oat bran phenolic amide alkaloid compound-61H-NMR spectrum.
FIG. 12 is a preparation of oat bran phenolic amide alkaloid compound-613C-NMR spectrum.
Detailed Description
The technical solution of the present invention will be clearly and completely described with reference to the following examples. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
preparation of oat Glutamine amide alkaloid compound-1 (abbreviated as PAA-1) compound
(E) -3- (4-hydroxy-3-methoxyphenyl) acrylic acid (1.0g) was weighed into a 100mL clean round bottom flask, magneton was placed, 40mL of anhydrous dichloromethane was added, 4- (2-aminoethyl) phenol (1.84g), triethylamine (5.5mL) was added with stirring, and HATU (4.85g) was added after 5 minutes. After the end of the addition, the reaction was continued at room temperature for 5 hours and the disappearance of the reaction material was monitored by TLC. Stopping stirring, evaporating the reaction system under reduced pressure to remove the solvent, and purifying the residue by silica gel column chromatography (200-300 mesh) to obtain oat bracteoamide alkaloid compound-1. The structure is as follows:
example 2:
preparation of oat Glutamine amide alkaloid compound-2 (abbreviated as PAA-2) compound
(E) -3- (4-hydroxyphenyl) acrylic acid (1.0g) was weighed into a 100mL clean round bottom flask, magneton was placed, 40mL of anhydrous dichloromethane was added, 4- (2-aminoethyl) phenol (1.84g), triethylamine (5.5mL) was added with stirring, and HATU (4.85g) was added after 5 minutes. After the end of the addition, the reaction was continued at room temperature for 5 hours and the disappearance of the reaction material was monitored by TLC. Stopping stirring, evaporating the reaction system under reduced pressure to remove the solvent, and purifying the residue by silica gel column chromatography (200-300 mesh) to obtain oat bracteoamide alkaloid compound-2. The structure is as follows:
example 3:
preparation of oat Glutamine amide alkaloid compound-3 (abbreviated as PAA-3) compound
(E) -3- (3,4-dihydroxyphenyl) acrylic acid (1.0g) was weighed into a 100mL clean round bottom flask, magneton was placed, 40mL of anhydrous dichloromethane was added, 4- (2-aminoethyl) phenol (1.84g), triethylamine (5.5mL) was added with stirring, and HATU (4.85g) was added after 5 minutes. After the end of the addition, the reaction was continued at room temperature for 5 hours and the disappearance of the reaction material was monitored by TLC. Stopping stirring, evaporating the reaction system under reduced pressure to remove the solvent, and purifying the residue by silica gel column chromatography (200-300 mesh) to obtain oat bracteoamide alkaloid compound-3. The structure is as follows:
example 4:
preparation of oat Glutamine amide alkaloid compound-4 (abbreviated as PAA-4) compound
(E) -3- (3,4-dihydroxyphenyl) acrylic acid (1.0g) was weighed into a 100mL clean round bottom flask, magneton was placed, 40mL of anhydrous dichloromethane was added, 4- (2-aminoethyl) phenol (1.84g), triethylamine (5.5mL) was added with stirring, and HATU (4.85g) was added after 5 minutes. After the end of the addition, the reaction was continued at room temperature for 5 hours and the disappearance of the reaction material was monitored by TLC. Stopping stirring, evaporating the reaction system under reduced pressure to remove the solvent, and purifying the residue by silica gel column chromatography (200-300 mesh) to obtain oat bracteoamide alkaloid compound-4. The structure is as follows:
example 5:
preparation of oat Glutamine amide alkaloid Compound-5 (abbreviated as PAA-5)
(E) -3- (4-hydroxy-3-methoxyphenyl) acrylic acid (1.0g) was weighed into a 100mL clean round bottom flask, magneton was placed, 40mL of anhydrous dichloromethane was added, 4- (2-aminoethylnol) -2-methoxyphenol (1.84g), triethylamine (5.5mL) was added with stirring, and HATU (4.85g) was added after 5 minutes. After the end of the addition, the reaction was continued at room temperature for 5 hours and the disappearance of the reaction material was monitored by TLC. Stopping stirring, evaporating the reaction system under reduced pressure to remove the solvent, and purifying the residue by silica gel column chromatography (200-300 mesh) to obtain oat bracteoamide alkaloid compound-5. The structure is as follows:
example 6:
preparation of oat Glutamine amide alkaloid Compound-6 (abbreviated as PAA-6)
(E) -3- (4-hydroxy-3,5-dimethoxyphenyl) acrylic acid (1.0g) was weighed into a 100mL clean round bottom flask, magneton was placed, 40mL of anhydrous dichloromethane was added, 4- (2-aminoethyl) phenol (1.84g), triethylamine (5.5mL) was added with stirring, and HATU (4.85g) was added after 5 minutes. After the end of the addition, the reaction was continued at room temperature for 5 hours and the disappearance of the reaction material was monitored by TLC. Stopping stirring, evaporating the reaction system under reduced pressure to remove the solvent, and purifying the residue by silica gel column chromatography (200-300 mesh) to obtain oat bracteoamide alkaloid compound-6. The structure is as follows:
experimental example:
the invention utilizes a mouse skin itch model inhibition experiment to confirm the itch relieving activity of the oat bran phenolic amide alkaloid compound and the composition. The enzyme-linked immunosorbent assay is used for detecting the content of IL-1 beta, IL-4, PAR-2 and P substances in serum.
Antipruritic activity of the oat bran phenolic amide alkaloid compounds and compositions of the present invention
Kunming mice, SPF level, male, weight (35 +/-2) g, feeding in a constant temperature environment at 20 +/-2 ℃ and humidity of 40% -70%, wherein the feeding environment is a light rhythm of 12h:12h (7:00-19:00), feeding freely with water, and feeding adaptively for 1 week. Randomly dividing mice into a normal group, a skin itch model group, a diphenhydramine group, an oat alkaloid group, oat branoxamine alkaloid compounds-1-6 groups and an oat branoxamine alkaloid compound composition group (the mass ratio of oat branoxamine alkaloid compound-3 to oat branoxamine alkaloid compound-4 is 1:1), and 10 mice in each group. After the start of the experiment, the neck and back of each group of mice were injected with 125 mg/kg of D-galactose injection subcutaneously for 6 weeks (the normal group was given the same amount)Dose saline). Starting at week 7, mice in each group were dosed at 0.5mg/cm2The application is carried out 1 time in the evening for 7 days (the normal group and the skin aging and pruritus model group are respectively provided with distilled water with the same dose every day). In the experiment process, the hair of the neck and the back of the mouse is shaved by scissors, so that no hair exists on the neck and the back of the mouse.
TABLE 1 Effect of oat Glutamine alkaloid Compounds on mouse itch latency and itch frequency
Note comparison with skin itch model group*p＜0.05,**p＜0.01.
As can be seen from the experimental data in Table 1, the incubation time of oat branoxamide alkaloid compound-3 (PAA-3) to mouse itch is significantly longer than that of other oat branoxamide alkaloid compounds and the known oat alkaloids and the positive control drug diphenhydramine; it has significantly less itch times in mice than other oat bracteamide alkaloid compounds and known oat alkaloids and the positive control diphenhydramine. This indicates that: in the compounds of formula I or formula II1、R2And R3The oat bran phenolic amide alkaloid obtained after being substituted by different groups has great difference in itching relieving effect; the oat bran phenolic amide alkaloid-3 has a far greater antipruritic effect than other compounds, and has a very obvious antipruritic effect; the antipruritic effect of the compound is also obviously higher than that of the known avenanthramide and the positive control medicament diphenhydramine; significant technological advances have been made.
It can also be seen from the experimental data in table 1 that the antipruritic effect of oat brazzolamide alkaloid-3 and oat brazzolamide alkaloid-4 in combination is significantly higher than that of either oat brazzolamide alkaloid-3 or oat brazzolamide alkaloid-4 alone; the content of the compound is also obviously higher than that of the known avenanthramide and the positive control drug diphenhydramine; this shows that when oat bracteoamide alkaloid-3 and oat bracteoamide alkaloid-4 are combined, they can produce synergistic antipruritic effect.
In addition, we tested the effect of oat bran phenolic amide alkaloid compound-3 (PAA-3) of the present invention on IL-1 β, IL-4, PAR-2, substance P: the occurrence of cutaneous pruritus is important in relation to immune cells (eosinophils, mast cells, etc.) and inflammatory factors (interleukins, histamine, etc.). Mast cells are widely present around blood vessels of skin and tissues, and contain inflammatory factors such as histamine, heparin, 5-hydroxytryptamine, etc., and the mast cells and the inflammatory factors play important roles in the induction of allergic reactions. In addition, IL-1 β and IL-4 are common inflammatory factors in disease, and PAR is a member of the G-protein coupled receptor family. PAR-2 can promote the adhesion and migration of vascular endothelial leukocytes, promote the expression and release of IL-1 and the like, and has important proinflammatory effects and the effect of mediating tissue injury. At the same time, PAR-2 stimulates IL-4 secretion from mast cells. Therefore, after 1h of application on day 7, 0.025% low molecular dextran-40 injection was injected intravenously, and 30min later, the video camera recorded the scratching performance of the mice. The method comprises the steps of taking blood from eyeballs, centrifuging at 3000r/min for 10min, taking serum, and detecting the contents of IL-1 beta, IL-4, PAR-2 and P substances in the serum by an enzyme-linked immunosorbent assay.
TABLE 2 Effect of oat Glutamine alkaloid Compound-3 on mouse IL-1 β, IL-4
Note: comparison with Normal group#p＜0.05,##p is less than 0.01; comparison with skin itch model group*p＜0.05,**p＜0.01.
TABLE 3 Effect of oat Glutamine alkaloid Compound-3 on mouse serum PAR-2
Note: comparison with Normal group#p＜0.05,##p is less than 0.01; comparison with skin itch model group*p＜0.05,**p＜0.01.
TABLE 4 Effect of oat Glutamine alkaloid Compound-3 on mouse serum substance P
Note: comparison with Normal group#p＜0.05,##p is less than 0.01; comparison with skin itch model group*p＜0.05,**p＜0.01.
As can be seen from the data in Table 2, IL-1. beta. was significantly increased and IL-4 was significantly decreased in the skin pruritus model group, as compared with the normal group. Compared with the skin itch model group, the IL-1 beta of the oat bracteamide alkaloid compound-3 group is remarkably reduced and the IL-4 is remarkably increased after the medicine is taken, which shows that the oat bracteamide alkaloid compound-3 has the function of relieving the skin itch. As can be seen from the data in Table 3, the skin itch model group had significantly increased PAR-2 content compared to the normal group. After administration, the PAR-2 content of oat bran phenolic amide alkaloid compound-3 group was significantly reduced compared to the skin itch model group. As can be seen from the data of table 4, substance P was significantly increased in the skin itch model group compared with the normal group. After administration, oat bran phenolic amide alkaloid compound-3 group P substance was significantly reduced compared to the skin itch model group.
The above deep level of mechanism research description; oat bran phenolic amide alkaloid compounds or compositions may be used to achieve antipruritic effects by modulating reduced expression of PAR-2 and substance P, and reduced secretion of inflammatory cytokines.
While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention.
Claims (10)
1. An oat bran phenolic amide alkaloid having a structure represented by formula I or formula II:
wherein, formula I or R in formula II1、R2And R3Each independently selected from H, OH or OCH3。
2. The oat bracteoamide alkaloid of claim 1, which is selected from any one of oat bracteoamide alkaloid-1-6; the structural formula of the oat bran phenolic amide alkaloid-1-6 is as follows:
3. a composition comprising phenamide alkaloid-3 and phenamide alkaloid-4; wherein the weight ratio of oat bracteoamide alkaloid-3 to oat bracteoamide alkaloid-4 is 1-5: 1;
further preferably, the weight ratio of the oat bracteoamide alkaloid-3 to the oat bracteoamide alkaloid-4 is 2-4: 1;
most preferably, the oat brazzolamide alkaloid-3 and oat brazzolamide alkaloid-4 are present in a weight ratio of 3: 1.
4. A method for preparing oat bran phenolic amide alkaloid having a structure as shown in claim 1 or 2, characterized in that the oat bran phenolic amide alkaloid is prepared by using caffeic acid analogues and 4- (2-aminoethyl) phenol as raw materials;
the structure of the caffeic acid analog is as follows:
wherein R is1、R2、R3Independently selected from H, OH or OCH3。
5. The method according to claim 4, wherein the molar ratio of the caffeic acid analog to 4- (2-aminoethyl) phenol is 1:1 to 3.
6. The method according to claim 4, comprising the steps of: taking a reaction substrate caffeic acid analogue, adding an organic solvent, adding 4- (2-aminoethyl) phenol and triethylamine under stirring, and adding HATU after 3-6 minutes; after the feeding is finished, continuously reacting for 3-6 hours at room temperature, and monitoring the disappearance of reaction raw materials by TLC; stopping stirring, evaporating the reaction system under reduced pressure to remove the solvent, and purifying the residue by silica gel column chromatography to obtain the oat bran phenolic amide alkaloid.
7. The preparation method according to claim 4, wherein the amount ratio of the organic solvent, triethylamine and HATU to the reaction substrate caffeic acid analog is 30-60 mL: 5-6 mL: 4.5-5.0 g:1 g;
most preferably, the ratio of the organic solvent, triethylamine and HATU to the caffeic acid analog of the reaction substrate is 40mL:5.5mL:4.85g:1 g.
8. Use of a compound or composition as claimed in any one of claims 1 to 3 in the preparation of an anti-itch product; the product comprises medicine, skin care product or cosmetic.
9. The use according to claim 8, wherein the itch is itch caused by dermatitis, burns, eczema, urticaria, xeroderma, superficial fungal infections, or psoriasis.
10. The use of claim 8, wherein said itch is itch caused by diabetes, cholestasis, chronic kidney disease, tumors, or AIDS.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20070183996A1 (en) * | 2005-11-08 | 2007-08-09 | Sabrina Okombi | Para-coumaric acid or para-hydroxycinnamic acid derivatives and their use in cosmetic or dermatological compositions |
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