CN117550978A - KS-3 derivative, preparation method and application thereof - Google Patents
KS-3 derivative, preparation method and application thereof Download PDFInfo
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- CN117550978A CN117550978A CN202311535860.0A CN202311535860A CN117550978A CN 117550978 A CN117550978 A CN 117550978A CN 202311535860 A CN202311535860 A CN 202311535860A CN 117550978 A CN117550978 A CN 117550978A
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/734—Ethers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Transplantation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the technical field of chemical medicines, and particularly relates to a KS-3 derivative, a preparation method and application thereof. The structural general formula of the KS-3 derivative isThe KS-3 derivative not only can reduce the generation of skin scales, folds and erythema caused by psoriasis and the condition of vascular proliferation, but also can reverse the weight loss caused by the psoriasis, which indicates that the KS-3 derivative can effectively treat the psoriasis.
Description
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to a KS-3 derivative, a preparation method and application thereof.
Background
Due to changes in natural environment and special work needs, parts of the human body are exposed to ultraviolet radiation, industrial dust or harmful microorganism environments, so that the human body is subjected to exogenous stimulus; long-term exogenous stimulation can overproduce reactive oxygen species (reactive oxygen species, ROS) or damage the antioxidant system and thus develop oxidative stress, ultimately leading to the development of various diseases such as cancer, diabetes, neurological diseases, and various inflammatory diseases.
Human skin is the first line of defense against exogenous stimuli, and under continuous exogenous stimuli, the exposed areas of the skin oxidize to cause a dramatic increase in inflammatory mediators, and with drug abuse, age aging and the appearance of immune aging, immune-mediated inflammatory skin diseases are frequently caused, and psoriasis is more common. In addition, the novel coronaviruses which are widely transmitted in recent years can continuously attack the autoimmune system, so that unbalance of the human immune system is caused, and 'cytokine storm' is generated, thereby exacerbating the progress of psoriasis.
Research shows that the global prevalence of psoriasis is 0.2% -3%, but the prevalence in China is as high as about 0.47%, and the prevalence still tends to be continuously increased. The main treatment mode of psoriasis is biological targeting therapy at present, which comprises the treatment of preparations such as TNF-alpha inhibitor, calcineurin inhibitor, retinoic acid medicament, immunosuppressant and the like. However, biological agents require a number of complex proceduresSuch as gene cloning, expression, purification, medicine morphology preparation, etc., each process requires high technical and equipment investment [1] And meanwhile, the method also bears stricter supervision requirements and has relatively high cost. These formulations are not only complicated to prepare but also expensive to prepare and may be accompanied by the generation of anti-drug antibodies.
Therefore, the development of a new medicament which can be used for treating psoriasis is of great importance.
Disclosure of Invention
In order to solve the problems, an object of the present invention is to provide a compound which can effectively treat psoriasis, wherein a KS-3 derivative is obtained after acid modification, the KS-3 derivative has excellent therapeutic effect on psoriasis, raw materials are easy to obtain, and a preparation method is simple.
In order to achieve the above purpose, the present invention may adopt the following technical scheme:
in one aspect, the invention provides a KS-3 derivative or a salt thereof, the structural general formula of the KS-3 derivative is shown as the following,
wherein R is selected from CH 3 (CH 2 ) n COO-、HCOO-、CH 3 COO(CH=CH) y COO-orR' is selected from H-or CH3O-; wherein n is an integer and not less than 0, y is an integer and not less than 1, and x is an integer and not less than 1.
The invention also provides a preparation method of the KS-3 derivative, which comprises the following steps: uniformly mixing a compound A, a compound B and TsCl, then adding a compound C, and reacting at 55-65 ℃ to obtain a crude product containing KS-3 derivatives;
wherein the compound A is selected from The compound B is selected from CH 3 (CH 2 ) n COOH、HCOOH、CH 3 COO(CH=CH) y COOH or->Wherein n is an integer and is not less than 0, y is an integer and is not less than 1, and x is an integer and is not less than 1; compound C is selected from->
In yet another aspect, the present invention provides a pharmaceutical composition for treating psoriasis, comprising the KS-3 derivative and/or salt thereof described above.
In a further aspect, the present invention provides a pharmaceutical formulation for the treatment of psoriasis comprising the KS-3 derivative and/or salt thereof as defined above or the pharmaceutical composition for the treatment of psoriasis as defined above and a pharmaceutically acceptable carrier.
In a further aspect, the invention provides the use of a KS-3 derivative or a salt thereof as described above or a pharmaceutical composition for treating psoriasis as described above in the preparation of a medicament for treating autoimmune diseases.
In still another aspect, the invention provides an application of a compound A in preparing a medicament for treating psoriasis, wherein the structural formula of the compound A is shown as a formula A,
the beneficial effects of the invention at least comprise:
(1) The KS-3 derivative provided by the invention not only can reduce the generation of skin scales, folds and erythema caused by psoriasis and the condition of vascular proliferation, but also can reverse the weight loss caused by the psoriasis, which shows that the KS-3 derivative can effectively treat the psoriasis.
(2) The KS-3 derivative provided by the invention has the advantages of easily available preparation raw materials and simple preparation method.
Drawings
FIG. 1 shows skin and vascular conditions of mice from different groups (control, model, KS-3 butyrate and KS-3 valerate);
FIG. 2 shows the PASI score for skin lesions of different groups (control, model, KS-3 butyrate and KS-3 valerate) of mice;
FIG. 3 shows the body weight of mice from different groups (control, model, KS-3 butyrate and KS-3 valerate);
FIG. 4 shows skin conditions of mice from different groups (control, model, KS-3 butyrate and KS-3 valerate);
FIG. 5 shows the PASI score for skin lesions of mice from different groups (control, model, KS-3 butyrate and KS-3 valerate);
FIG. 6 shows the body weight of mice from different groups (control, model, KS-3 butyrate and KS-3 valerate);
FIG. 7 shows skin conditions of mice from different groups (control, model, KS-3 butyrate, KS-3 valerate, KS-3+ butyrate and KS-3+ valerate);
FIG. 8 is a graph showing the PASI score for skin lesions in mice from different groups (control, model, KS-3 butyrate, KS-3 valerate, KS-3+ butyrate and KS-3+ valerate);
FIG. 9 is a graph showing the body weight of mice from different groups (control, model, KS-3 butyrate, KS-3 valerate, KS-3+ butyrate and KS-3+ valerate);
FIG. 10 shows skin conditions of mice from different groups (control, model, KS-3 monomethyl fumarate and KS-3 monomethyl itaconate);
FIG. 11 is a graph showing the PASI score for skin lesions in mice from different groups (control, model, KS-3 monomethyl fumarate, and KS-3 monomethyl itaconate);
FIG. 12 shows the body weight of mice from different groups (control, model, KS-3 monomethyl fumarate and KS-3 monomethyl itaconate).
FIG. 13 is a graph showing skin condition of mice from different groups (control, model, butyrylated ferulic acid methyl ester);
FIG. 14 is a graph showing the PASI score of skin lesions in mice from different groups (control, model, butyrylated methyl ferulate);
figure 15 shows the body weight of mice from different groups (control, model, butyrylated ferulic acid methyl ester).
Detailed Description
The examples are presented for better illustration of the invention, but the invention is not limited to the examples. Those skilled in the art will appreciate that various modifications and adaptations of the embodiments described above are possible in light of the above teachings and are intended to be within the scope of the invention.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. Unless the context clearly differs, singular forms of expression include plural forms of expression. As used herein, it is understood that terms such as "comprising," "having," "including," and the like are intended to indicate the presence of features, numbers, operations, materials, or combinations. The terms of the present invention are disclosed in the specification and are not intended to exclude the possibility that one or more other features, numbers, operations, materials or combinations thereof may be present or may be added. As used herein, "/" may be interpreted as "and" or "as appropriate.
The embodiment of the invention provides a KS-3 derivative or a salt thereof, the structural general formula of the KS-3 derivative is shown as the following,
wherein R is selected from CH 3 (CH 2 ) n COO-、HCOO-、CH 3 COO(CH=CH) y COO-orR' is selected from H-or CH3O-; wherein n is an integer and not less than 0, y is an integer and not less than 1, and x is an integer and not less than 1.
In some embodiments, the structural formula of the KS-3 derivative may be any one of the following:
it will be appreciated that the salts of the KS-3 derivatives are pharmaceutically acceptable salts known in the art, the type of salt being selected according to the particular clinical need, and the hydrochloride salt generally being selected.
It should be noted that the above KS-3 derivatives (such as KS-3 butyrate, KS-3 valerate, KS-3 monomethyl itaconate, KS-3 monomethyl fumarate and butyrylated methyl ferulate) all have higher bioavailability and activity. Especially KS-3 butyrate and KS-3 valerate, the butyric acid and the valerate have the immunoregulation function, and can better play the activity after being combined with the methyl p-hydroxy cinnamate in a covalent bond way, and simultaneously, the metabolism rate of the methyl p-hydroxy cinnamate can be slowed down, so that the half-life period of the methyl p-hydroxy cinnamate is prolonged, and the bioavailability and the activity of the methyl p-hydroxy cinnamate are improved.
The invention also provides a preparation method of the KS-3 derivative, which comprises the following steps: uniformly mixing a compound A, a compound B and TsCl, then adding a compound C, and reacting at 55-65 ℃ to obtain a crude product containing KS-3 derivatives;
wherein the compound A is selected from
The compound B is selected from CH 3 (CH 2 ) n COOH、HCOOH、CH 3 COO(CH=CH) y COOH or
Wherein n is an integer not less than 0, y is an integer not less than 1, x is an integer not less than 1,
the compound C is selected from
In one placeIn some embodiments, the preparation method further includes: cooling the mixture containing the KS-3 derivative to room temperature, mixing with water and extracting with dichloromethane; after extraction is completed, saturated NaHCO is used 3 Washing the organic layer with a solution; after washing, the mixture was washed with anhydrous MgSO 4 Drying; and (3) purifying by using a PE/EA column after the drying is finished to obtain the KS-3 derivative.
It should be understood that the terms such as "mixing", "washing", "drying" and "purifying" in the above preparation method are all terms of operation conventional in the art, and have no specific meaning.
In some embodiments, compound a is selected fromCompound B selects CH 3 (CH 2 ) n COOH (n=3, formula +.>) When the corresponding KS-3 derivative is KS-3 valerate +.>
In some embodiments, compound a is selected fromCompound B selects CH 3 (CH 2 ) n COOH (n=2, formula +.>) When the corresponding KS-3 derivative is KS-3 butyrate
In some embodiments, compound a is selected fromCompound B selects CH 3 COO(CH=CH) y COOH (y=1, formula +.>) When the corresponding KS-3 derivative is KS-3 monomethyl fumarate +.>
In some embodiments, compound a is selected fromCompound B selection->(x=1, structural formula +.>) When the corresponding KS-3 derivative is KS-3 monomethyl itaconate +.>
In some embodiments, compound a is selected fromCompound B selects CH 3 (CH 2 ) n COOH (n=2, formula +.>) In the case of the corresponding KS-3 derivative butyrylated ferulic acid methyl ester +.>
In the above preparation method, mixing may be performed while stirring during mixing or reaction, and the reaction temperature may be 58 ℃, 60 ℃ or 62 ℃, with 60 ℃ being preferred. In some embodiments, the reaction is carried out at 60℃for 50 minutes with stirring to give a crude product comprising the KS-3 derivative.
In one placeIn some embodiments, the PE/EA volume ratio of the KS-3 derivative obtained by purification with a PE/EA column after the drying is completed may be (4-6): 1, and the optimal selection ratio of different KS-3 may be different, for example, KS-3 valerate and KS-3 butyrate may be preferably 6:1, KS-3 monomethyl fumarate and KS-3 monomethyl itaconate may be preferably 4:1, and butyrylated ferulic acid methyl ester may be preferably 5:1. In addition, in order to achieve better purification effect, dichloromethane can be used for extraction for multiple times, saturated NaHCO is used 3 The solution was washed multiple times.
It is understood that the main raw materials for preparing the KS-3 derivative comprise methyl ferulate, methyl p-hydroxy cinnamate, butyric acid, valeric acid, monomethyl fumarate or monomethyl itaconate, which are relatively easily available, and the preparation method has mild reaction conditions and simple reaction steps; therefore, the KS-3 derivative has certain advantages in the cost of raw materials and the preparation cost compared with the existing biological preparations such as TNF-alpha inhibitor, calcineurin inhibitor, retinoic acid medicine, immunosuppressant and the like.
In yet another embodiment, the present invention provides a pharmaceutical composition for treating psoriasis, comprising the KS-3 derivative and/or a salt thereof described above. KS-3 (methyl p-hydroxycinnamate) has excellent anti-inflammatory and antioxidant properties and has therapeutic effects on psoriasis. The KS-3 derivatives (such as KS-3 butyrate, KS-3 valerate, KS-3 monomethyl itaconate, KS-3 monomethyl fumarate and butyrylated methyl ferulate) are obtained by acylating the phenolic hydroxyl group of KS-3 with butyric acid, valeric acid, fumaric acid or itaconic acid, etc., and are also effective in the treatment of psoriasis; and wherein KS-3 butyrate and KS-3 valerate are superior to KS-3 in the treatment of psoriasis. In addition, the carboxylic acid group of KS-3 dissociates into negative ion groups in the human body, which makes it difficult to penetrate the cell membrane and is repelled outside the cell, limiting the exertion of its activity; furthermore, due to the presence of phenolic hydroxyl groups, they are readily metabolized in vivo by hydrolysis and conjugation of catechol-O-methyltransferase (COMT), glucuronyltransferase (UGT) and Sulfotransferase (SULT); in the invention, the phenolic hydroxyl groups of KS-3 are subjected to acylation modification by using butyric acid and valeric acid, so that the problems are alleviated, and the bioavailability and activity of KS-3 are improved. In addition, the activity of butyric acid, valeric acid, monomethyl fumarate and monomethyl itaconate also has an immunomodulatory effect; and the alpha, beta-unsaturated carbonyl of KS-3, this fragment is capable of activating the Nrf2 pathway to exert anti-inflammatory and antioxidant activity.
Based on the above, the above KS-3 derivatives (such as KS-3 butyrate, KS-3 valerate, KS-3 monomethyl itaconate, KS-3 monomethyl fumarate and butyrylated ferulic acid methyl ester) can be combined with other psoriasis treatment substances to form a medicament for treating psoriasis, and other psoriasis treatment substances are known in the art as chemical drugs and organisms, and can be specifically selected according to clinical situations. It should be noted that, since the KS-3 derivative is a novel agent for treating psoriasis, the problem of weakening the therapeutic effect due to antibody production by the body can be avoided.
A further embodiment of the present invention provides a pharmaceutical formulation for the treatment of psoriasis comprising a KS-3 derivative as described above and/or a salt thereof or a pharmaceutical composition for the treatment of psoriasis as described above and a pharmaceutically acceptable carrier.
It should be noted that the KS-3 derivatives or the pharmaceutical compositions may be combined with different pharmaceutical carriers to prepare different dosage forms according to clinical needs, for example, the pharmaceutically acceptable carriers are suitable for solid dosage forms, liquid dosage forms or paste dosage forms.
In addition, it should be understood that solid dosage forms include tablets, powders, pills, capsules, and the like. Different dosage forms are selected, and pharmaceutically acceptable carriers thereof are different, for example, diluents (such as starch, dextrin, sucrose or glycation, etc.), absorbents (such as calcium sulfate, calcium hydrophosphate or light magnesium oxide, etc.), binders (such as povidone, syrup or hypromellose, etc.), wetting agents (such as water, etc.) or disintegrants (such as dry starch, sodium carboxymethyl starch or crospovidone, etc.) are mainly used for preparing tablets; for example, the preparation of liquid agents mainly uses compatibilizer, suspending agent, emulsifying agent or coloring agent.
In a further embodiment, the invention provides the application of the KS-3 derivative or the salt thereof or the pharmaceutical composition for treating psoriasis in preparing a medicament for treating autoimmune diseases.
The KS-3 derivative or the salt thereof and the pharmaceutical composition can treat autoimmune diseases, and can be applied to the preparation of medicines for treating autoimmune diseases.
In some embodiments, the autoimmune disease may be psoriasis, atopic dermatitis, multiple sclerosis, systemic lupus erythematosus, crohn's disease, or ulcerative colitis, among others.
In a further embodiment of the invention, the application of the compound A in preparing a medicament for treating psoriasis is provided, the structural formula of the compound A is shown as the formula A,
the compound A (methyl p-hydroxy cinnamate) has very good anti-inflammatory and antioxidant properties, has a therapeutic effect on psoriasis, and can be applied to the preparation of medicaments for treating psoriasis.
For a better understanding of the present invention, the content of the present invention is further elucidated below in connection with the specific examples, but the content of the present invention is not limited to the examples below.
1.KS-3 derivatives preparation and characterization
(1) KS-3 butyrate preparation and characterization
The structural formula of the KS-3 derivative (KS-3 butyrate) is shown as follows:
the synthetic route is as follows:
the preparation method comprises the following specific steps:
(a) Compound a (2.0 g), compound B (1.026 mL) and compound D (2.146 g) were added to a test tube, stirred well after the addition was completed, then compound C (2.798 mL) was added to obtain a reaction mixture, and the reaction mixture was heated to 60 ℃ and kept stirring for 50 minutes;
(b) After the completion of the reaction, which was shown by TLC plates, the reaction mixture was cooled to room temperature, poured into 20mL of water, extracted 2 times with 20mL of dichloromethane, and then extracted with 20mL of saturated NaHCO 3 Washing the organic layer with the solution, and after washing, washing with anhydrous MgSO 4 Drying for 2 hours. After drying, the product was purified by passing through a PE/EA (volume ratio 6:1) column to give 2.5g of a white solid, KS-3 butyrate, in 89.6% yield.
Subjecting the KS-3 butyrate prepared by the method to hydrogen spectrum nuclear magnetic resonance 1 HNMR) detection, the results are shown below:
KS-3 butyrate (CDCl 3, 600 MHz) delta (ppm) 7.67 (d, j=16.0 hz, 1H), 7.56-7.50 (m, 2H), 7.15-7.08 (m, 2H), 6.39 (d, j=16.0 hz, 1H), 3.80 (s, 3H), 2.55 (t, j=7.4 hz, 2H), 1.79 (H, j=7.4 hz, 2H), 1.05 (t, j=7.4 hz, 3H).
(2) KS-3 valerate preparation and characterization
The structural formula of the KS-3 derivative (KS-3 valerate) is shown as follows:
the synthetic route is as follows:
the preparation method comprises the following specific steps:
(a) Compound a (2.0 g), compound B (1.221 mL) and compound D (2.146 g) were added to a test tube, stirred well after the addition was completed, then compound C (2.798 mL) was added to obtain a reaction mixture, and the reaction mixture was heated to 60 ℃ and kept stirring for 50 minutes;
(b) After completion of the reaction, the reaction mixture was cooled to a TLC plateAt room temperature, poured into 20mL of water, extracted 2 times with 20mL of dichloromethane, and then extracted 2 times with 20mL of saturated NaHCO 3 Washing the organic layer with the solution, and after washing, washing with anhydrous MgSO 4 Drying for 2 hours. After drying, the product was purified by passing through a PE/EA (volume ratio 6:1) column to give 1.7g of a white solid, namely KS-3 valerate, in 57.6% yield.
Subjecting the KS-3 valerate obtained by the preparation to hydrogen spectrum nuclear magnetic resonance 1 HNMR) detection, the results are shown below:
KS-3 valerate (CDCl 3, 600 MHz) δ (ppm) 7.67 (d, j=16.0 hz, 1H), 7.56-7.49 (m, 2H), 7.14-7.06 (m, 2H), 6.39 (d, j=16.0 hz, 1H), 3.80 (s, 3H), 2.56 (t, j=7.5 hz, 2H), 1.80-1.68 (m, 2H), 1.51-1.39 (m, 2H), 0.97 (t, j=7.3 hz, 3H).
(3) Preparation and characterization of KS-3 monomethyl fumarate
The structural formula of the KS-3 derivative (KS-3 monomethyl fumarate) is shown as follows:
the synthetic route is as follows:
the preparation method comprises the following specific steps:
(a) A (2.0 g), C (1.892 mL), D (0.274 g) were added to compound B at room temperature(1.607 g) in dichloromethane (0.3M) followed by E (2.157 g). The reaction system is kept stirring overnight to make it react fully;
(b) After completion of the reaction, which was indicated by TLC plate, 20mL of ammonium chloride and 20mL of water were added to the reaction mixture, stirred for about 5 minutes, then poured into a separating funnel, allowed to stand for delamination, the lower organic layer was discharged, the operation was repeated 1 time, and after completion of washing, anhydrous MgSO was used 4 Drying for 2 hours. After drying was completed, PE/EA (body)Product was purified by column chromatography at a product ratio of 4:1) to give 0.2g of a white solid, namely KS-3 monomethyl fumarate.
Carrying out hydrogen spectrum nuclear magnetic resonance on the KS-3 monomethyl fumarate prepared by the method 1 HNMR) detection, the results are shown below:
KS-3 monomethyl fumarate (CDCl 3, 600 MHz) δ (ppm) 7.68 (d, j=16.0 hz, 1H), 7.59-7.55 (m, 2H), 7.19 (d, j=8.6 hz, 2H), 7.05 (s, 2H), 6.41 (d, j=16.0 hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H).
(4) Preparation and characterization of KS-3 monomethyl itaconate
The structural formula of the KS-3 derivative (KS-3 monomethyl itaconate) is shown as follows:
the synthetic route is as follows:
the preparation method comprises the following specific steps:
(a) A (2.0 g), C (1.892 mL), D (0.274 g) were added to compound B at room temperature(1.780 g) in dichloromethane (0.3M) followed by E (2.157 g) was added. The reaction system is kept stirring overnight to make it react fully;
(b) After completion of the reaction, which was indicated by TLC plate, 20mL of ammonium chloride and 20mL of water were added to the reaction mixture, stirred for about 5 minutes, then poured into a separating funnel, allowed to stand for delamination, the lower organic layer was discharged, the operation was repeated 1 time, and after completion of washing, anhydrous MgSO was used 4 Drying for 2 hours. After drying, the product was purified by passing through a PE/EA (volume ratio 4:1) column to give 2.6g of a white solid, namely KS-3 monomethyl itaconate.
Carrying out hydrogen spectrum nuclear magnetic resonance on the KS-3 itaconic acid monomethyl ester prepared by the method 1 HNMR) detection, the results are shown below:
KS-3 monomethyl itaconate (CDCl 3, 600 MHz) δ (ppm) 7.68 (d, j=16.0 hz, 1H), 7.56-7.52 (m, 2H), 7.18-7.14 (m, 2H), 6.57 (d, j=0.7 hz, 1H), 6.40 (d, j=16.0 hz, 1H), 5.91 (q, j=1.0 hz, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 3.46 (d, j=1.0 hz, 2H).
(5) Preparation and characterization of butyrylated ferulic acid methyl ester
The structural formula of butyrylated ferulic acid methyl ester is shown as follows:
the synthetic route is as follows:
the preparation method comprises the following specific steps:
(a) Compound a (0.9 g), compound B (0.432 mL) and compound D (0.825 g) were added to a test tube, stirred well after the addition was completed, then compound C (1.077 mL) was added to obtain a reaction mixture, and the reaction mixture was heated to 60 ℃ and kept stirring for 50 minutes;
(b) After the completion of the reaction, which was shown by TLC plates, the reaction mixture was cooled to room temperature, poured into 20mL of water, extracted 2 times with 20mL of dichloromethane, and then extracted with 20mL of saturated NaHCO 3 Washing the organic layer with the solution, and after washing, washing with anhydrous MgSO 4 Drying for 2 hours. Purifying the product by using PE/EA (volume ratio of 5:1) column after drying to obtain 0.5g white solid, namely butyrylated ferulic acid methyl ester.
Subjecting the butyrylated ferulic acid methyl ester to hydrogen spectrum nuclear magnetic resonance 1 HNMR) detection, the results are shown below:
butyrylated ferulic acid methyl ester (CDCl 3, 600 MHz) δ (ppm) 7.65 (d, j=16.0 hz, 1H), 7.12 (dd, j=8.1, 1.9hz, 1H), 7.09 (d, j=1.9 hz, 1H), 7.04 (d, j=8.1 hz, 1H), 6.38 (d, j=16.0 hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 2.57 (t, j=7.3 hz, 2H), 1.80 (H, j=7.4 hz, 2H), 1.05 (t, j=7.4 hz, 3H). 2. KS-3 butyrate and KS-3 valerate alleviating psoriasis verification
The 32 balb/c mice were divided into 4 groups (8 each) of control group, model group, test group 1 and test group 2, and the construction methods thereof were as follows:
control group: shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; mice were perfused (i.g) with 0.2mL of corn oil on days 0, 3, 6, the mice weights were recorded daily for 8 days, and the back skin changes were recorded using cameras on days 0, 3, 6, and 8;
model group: the hair in the central back area of the mice is removed by using mild depilatory cream 1 day before the experiment, and the hair removal area is about 2cm multiplied by 2cm; the back of the mice was then topically smeared with IMQ (IMQ) cream daily and the weight of the mice was recorded for 8 days, 0.2mL of gastric corn oil was infused on days 0, 3, 6, and skin changes on the back of the mice were recorded using cameras on days 0, 3, 6, and 8;
test group 1: dissolving the prepared compound KS-3 butyrate in corn oil to obtain KS-3 butyrate corn oil solution; shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the backs of the mice were then topically applied daily with IMQ (IMQ) cream; and lavage of 0.2ml ks-3 butyrate corn oil solution at days 0, 3, 6; and mice body weight was recorded for 8 days, and mice back skin changes were recorded using cameras on days 0, 3, 6 and 8;
test group 2: dissolving the prepared compound KS-3 valerate in corn oil to obtain KS-3 valerate corn oil solution; shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the backs of the mice were then topically applied daily with IMQ (IMQ) cream; and lavage 0.2mL KS-3 valerate corn oil solution at days 0, 3, 6; and mice body weight was recorded for 8 days, and mice back skin changes were recorded using cameras on days 0, 3, 6 and 8;
the construction list of the above-mentioned mice in different groups is shown in table 1.
Table 1 validated regimen for the administration of KS-3 butyrate and KS-3 valerate to alleviate psoriasis
Grouping | Compounds of formula (I) | Route of administration | Concentration of | Quantity (n) |
Control group | Corn oil | i.g,0.2mL | - | n=8 |
Model group | Imiquimod | Smearing, 0.2mL | - | n=8 |
Test group 1 | KS-3 butyrate | i.g,0.2mL | 30mM | n=8 |
Test group 2 | KS-3 valerate | i.g,0.2mL | 30mM | n=8 |
Totals to | 32 |
After day 6, the skin and blood vessel conditions of each group of mice were observed, and as shown in fig. 1, on day six of imiquimod infection, a number of scales, folds and erythema were observed in the model group mice, accompanied by vascular proliferation; the mice of test group 1 and test group 2 showed significantly less scales, wrinkles and erythema and vascular proliferation than the model group, demonstrating that KS-3 butyrate and KS-3 valerate were able to reduce the production of scales, wrinkles and erythema and inhibit vascular proliferation; in addition, the control mice did not develop scaling, wrinkling and erythema and vascular proliferation, indicating that corn oil did not affect treatment.
In addition, the skin lesions of each group of mice were scored by PASI, and the results are shown in FIG. 2 (p < 0.05, p < 0.01), and the results are consistent with the phenotype of the mice, and KS-3 butyrate and KS-3 valerate were able to significantly reduce the production of scales, wrinkles and erythema.
In addition, the weight changes of the mice in the different groups are shown in FIG. 3, and the results show that KS-3 butyrate and KS-3 valerate can reverse the weight loss of psoriatic mice.
In conclusion, KS-3 butyrate and KS-3 valerate can effectively treat psoriasis, not only can reduce the generation of skin scales, wrinkles and erythema and the condition of vascular proliferation, but also can reverse the weight loss caused by psoriasis.
3. KS-3 and structural modified derivatives for the treatment of psoriasis
The 20 balb/c mice were divided into 5 groups (4 each) of control group, model group, test group 1, test group 2 and test group 3, and the construction methods thereof were as follows:
control group: shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; mice were perfused with 0.2mL of corn oil on days 0, 3, 6, the body weight of the mice was recorded daily for 8 days, and the back skin changes of the mice were recorded using cameras on days 0, 3, 6, and 8;
model group: shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the back of the mice was then topically smeared with IMQ (IMQ) cream daily and the weight of the mice was recorded for 8 days, 0.2mL of gastric corn oil was infused on days 0, 3, 6, and skin changes on the back of the mice were recorded using cameras on days 0, 3, 6, and 8;
test group 1: dissolving the prepared compound KS-3 butyrate in corn oil to obtain KS-3 butyrate corn oil solution; shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the backs of the mice were then topically applied daily with IMQ (IMQ) cream; and lavage of 0.2ml ks-3 butyrate corn oil solution at days 0, 3, 6; and mice body weight was recorded for 8 days, and mice back skin changes were recorded using cameras on days 0, 3, 6 and 8;
test group 2: dissolving the prepared compound KS-3 valerate in corn oil to obtain KS-3 valerate corn oil solution; shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the backs of the mice were then topically applied daily with IMQ (IMQ) cream; and lavage of 0.2ml ks-3 valerate corn oil solution on days 0, 3, 6; and mice body weight was recorded for 8 days, and mice back skin changes were recorded using cameras on days 0, 3, 6 and 8;
test group 3: dissolving KS-3 (methyl p-hydroxy cinnamate) in corn oil to obtain KS-3 corn oil solution; shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the backs of the mice were then topically applied daily with IMQ (IMQ) cream; and lavage 0.2mL KS-3 corn oil solution at days 0, 3, 6; and mice body weight was recorded for 8 days, and mice back skin changes were recorded using cameras on days 0, 3, 6 and 8;
the list of mouse constructions for the different groupings described above is shown in table 2.
Table 2 KS-3 and modified derivatives validated dosing regimen for treatment of psoriasis
Grouping | Compounds of formula (I) | Route of administration | Concentration of | Quantity (n) |
Control group | Corn oil | i.g,0.2mL | - | n=4 |
Model group | Imiquimod | Smearing, 0.2mL | - | n=4 |
Test group 1 | KS-3 butyrate | i.g,0.2mL | 30mM | n=4 |
Test group 2 | KS-3 valerate | i.g,0.2mL | 30mM | n=4 |
Test group 3 | KS-3 | i.g,0.2mL | 30mM | n=4 |
Totals to | 20 |
After day 6, the skin condition of each group of mice was observed, and as shown in fig. 4, a large number of scales, wrinkles and red spots were observed in the mice of the model group at the sixth day of imiquimod infection; the mice of test group 1 and test group 2 showed significantly less scaling, wrinkling and erythema than the model group, indicating that KS-3 butyrate and KS-3 valerate were able to reduce scaling, wrinkling and erythema; mice in test group 3 had reduced symptoms compared to mice in model group, but the degree of reduction was significantly lower than in test group 1 and test group 2, indicating that the modified derivatives KS-3 butyrate and KS-3 valerate had better therapeutic effects on psoriasis than KS-3; in addition, the control mice did not develop scales, wrinkles and erythema, indicating that corn oil did not affect treatment.
In addition, the skin lesions of each group of mice were scored by PASI, as shown in FIG. 5 (p < 0.05, p < 0.01), and the results were consistent with the phenotype of the mice, with KS-3, KS-3 butyrate and KS-3 valerate being able to significantly reduce the production of scales, wrinkles and erythema; KS-3 was reduced less than KS-3 butyrate and KS-3 valerate.
In addition, the weight changes of the mice in the different groups are shown in FIG. 6, and the results show that KS-3 butyrate and KS-3 valerate can reverse the weight loss of the psoriatic mice; KS-3 aggravates weight loss in psoriatic mice.
In conclusion, KS-3 butyrate and KS-3 valerate can be used for effectively treating psoriasis, not only can reduce the generation of skin scales, wrinkles and erythema, but also can reverse the weight loss caused by the psoriasis; among them, KS-3 butyrate and KS-3 valerate have far better therapeutic effects than KS-3.
4. Simple mixing of KS-3 with butyric or valeric acid and comparison of KS-3 derivatives for the treatment of psoriasis
The 42 balb/c mice were divided into 4 groups, namely a control group (4), a model group (6), a test group 1 (8), a test group 2 (8), a test group 3 (4) and a test group 4 (4), and the construction methods are respectively as follows:
control group: shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; mice were perfused with 0.2mL of corn oil on days 0, 3, 6, the body weight of the mice was recorded daily for 8 days, and the back skin changes of the mice were recorded using cameras on days 0, 3, 6, and 8;
model group: shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the back of the mice was then topically smeared with IMQ (IMQ) cream daily and the weight of the mice was recorded for 8 days, 0.2mL of gastric corn oil was infused on days 0, 3, 6, and skin changes on the back of the mice were recorded using cameras on days 0, 3, 6, and 8;
test group 1: dissolving the prepared compound KS-3 butyrate in corn oil to obtain KS-3 butyrate corn oil solution; shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the backs of the mice were then topically applied daily with IMQ (IMQ) cream; and lavage of 0.2ml ks-3 butyrate corn oil solution at days 0, 3, 6; and mice body weight was recorded for 8 days, and mice back skin changes were recorded using cameras on days 0, 3, 6 and 8;
test group 2: dissolving the prepared compound KS-3 valerate in corn oil to obtain KS-3 valerate corn oil solution; shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the backs of the mice were then topically applied daily with IMQ (IMQ) cream; and lavage of 0.2ml ks-3 valerate corn oil solution on days 0, 3, 6; and mice body weight was recorded for 8 days, and mice back skin changes were recorded using cameras on days 0, 3, 6 and 8;
test group 3: KS-3 and butyric acid are dissolved in corn oil according to a molar ratio of 1:1 to obtain KS-3 butyric acid mixed corn oil solution; shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the backs of the mice were then topically applied daily with IMQ (IMQ) cream; and the corn oil solution was mixed with 0.2ml ks-3 butyric acid by gavage on days 0, 3, 6; and mice body weight was recorded for 8 days, and mice back skin changes were recorded using cameras on days 0, 3, 6 and 8;
test group 4: KS-3 and valeric acid are dissolved in corn oil according to a molar ratio of 1:1 to obtain KS-3 valeric acid mixed corn oil solution; shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the backs of the mice were then topically applied daily with IMQ (IMQ) cream; and the corn oil solution is mixed by irrigating the stomach 0.2mLKS-3 valeric acid on days 0, 3 and 6; and mice body weight was recorded for 8 days, and mice back skin changes were recorded using cameras on days 0, 3, 6 and 8;
the construction list of the mice in the above-mentioned different groups is shown in Table 3.
Table 3 KS-3 simple mixing with butyric or valeric acid and KS-3 derivatives comparative dosing regimen for psoriasis treatment
Grouping | Compounds of formula (I) | Route of administration | Concentration of | Quantity (n) |
Control group | Corn oil | i.g,0.2mL | - | n=4 |
Model group | Imiquimod | Smearing, 0.2mL | - | n=6 |
Test group 1 | KS-3 butyrate | i.g,0.2mL | 15mM | n=8 |
Test group2 | KS-3 valerate | i.g,0.2mL | 15mM | n=8 |
Test group 3 | KS-3+ butyric acid | i.g,0.2mL | 15mM+15mM | n=4 |
Test group 4 | KS-3+ valeric acid | i.g,0.2mL | 15mM+15mM | n=4 |
Totals to | 42 |
After day 6, the skin condition of each group of mice was observed, and as shown in fig. 7, a large number of scales, wrinkles and red spots were observed in the mice of the model group at the sixth day of imiquimod infection; the mice in the test group 1, the test group 2, the test group 3 and the test group 4 can reduce the conditions of scales, wrinkles and erythema to different degrees, wherein the reduction condition of the mice in the test group 1 is obviously better than that of the mice in the test group 3, the reduction condition of the mice in the test group 2 is obviously better than that of the mice in the test group 4, and the treatment effect of KS-3 butyrate or KS-3 valerate prepared by the reaction of KS-3 and butyric acid or valeric acid on psoriasis is obviously better than that of the simple mixing of KS-3 and butyric acid or valeric acid on psoriasis; in addition, the control mice did not develop scaling, wrinkling and erythema, indicating that corn oil did not affect treatment.
In addition, the skin damage condition of each group of mice was scored by PASI, and the results are shown in FIG. 8 (p < 0.05, p < 0.01), and the results are consistent with the phenotype of the mice, and KS-3 butyrate or KS-3 valerate prepared by the reaction of KS-3 and butyric acid or valeric acid and the solution of KS-3 and butyric acid or valeric acid simply mixed can obviously reduce the generation of scales, wrinkles and erythema; however, the KS-3 butyrate or KS-3 valerate prepared by the reaction of KS-3 and butyric acid or valeric acid is obviously better than the curative effect of simple mixing of KS-3 and butyric acid or valeric acid;
in addition, the weight change of the mice in different groups is shown in FIG. 9, and the result shows that the KS-3 butyrate or KS-3 valerate prepared by the reaction of KS-3 and butyric acid or valeric acid can reverse the weight loss of the mice with psoriasis by the solution of KS-3 and butyric acid or valeric acid which are simply mixed; wherein the KS-3 butyrate or KS-3 valerate prepared by the reaction of KS-3 and butyric acid or valeric acid has better effect than the solution of simply mixing butyric acid or valeric acid.
In addition, it can be seen from comparison of FIGS. 4, 5 and 6 that the effect is still obtained by reducing the medicinal concentrations of KS-3 butyrate and KS-3 valerate to half of the original concentrations, indicating that the effect of KS-3 butyrate and KS-3 valerate is strong.
In conclusion, KS-3 butyrate or KS-3 valerate prepared by the reaction of KS-3 and butyric acid or valeric acid and a solution prepared by simply mixing KS-3 and butyric acid or valeric acid can be used for effectively treating psoriasis, so that the generation of skin scales, wrinkles and erythema can be reduced, and the weight loss caused by psoriasis can be reversed; wherein, the treatment effect of KS-3 butyrate or KS-3 valerate prepared by the reaction of KS-3 and butyric acid or valeric acid is obviously better than that of KS-3 and butyric acid or valeric acid which are simply mixed.
5. KS-3 monomethyl fumarate and KS-3 monomethyl itaconate psoriasis treatment effect
The 20 balb/c mice were divided into 5 groups (4 each) of control group, model group, test group 1, test group 2 and test group 3, respectively, and the construction method thereof was as follows:
control group: shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; mice were perfused with 0.2mL of corn oil on days 0, 3, 6, the body weight of the mice was recorded daily for 8 days, and the back skin changes of the mice were recorded using cameras on days 0, 3, 6, and 8;
model group: shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the back of the mice was then topically smeared with IMQ (IMQ) cream daily and the weight of the mice was recorded for 8 days, 0.2mL of gastric corn oil was infused on days 0, 3, 6, and skin changes on the back of the mice were recorded using cameras on days 0, 3, 6, and 8;
test group 1: dissolving the prepared compound KS-3 monomethyl itaconate in corn oil to obtain KS-3 monomethyl itaconate corn oil solution; shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the backs of the mice were then topically applied daily with IMQ (IMQ) cream; and lavage of 0.2ml ks-3 monomethyl itaconate corn oil solution at days 0, 3, 6; and mice body weight was recorded for 8 days, and mice back skin changes were recorded using cameras on days 0, 3, 6 and 8;
test group 2: dissolving the prepared compound KS-3 monomethyl fumarate in corn oil to obtain KS-3 monomethyl fumarate corn oil solution; shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the backs of the mice were then topically applied daily with IMQ (IMQ) cream; and lavage of 0.2ml ks-3 monomethyl fumarate corn oil solution on days 0, 3, 6; and mice body weight was recorded for 8 days, and mice back skin changes were recorded using cameras on days 0, 3, 6 and 8;
test group 3: dissolving KS-3 in corn oil to obtain KS-3 corn oil solution; shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the backs of the mice were then topically applied daily with IMQ (IMQ) cream; and lavage 0.2mL KS-3 corn oil solution at days 0, 3, 6; and mice body weight was recorded for 8 days, and mice back skin changes were recorded using cameras on days 0, 3, 6 and 8;
the construction list of the mice in the above-mentioned different groups is shown in Table 4.
Table 4 KS-3 and modified derivatives validated dosing regimen for treatment of psoriasis
Grouping | Compounds of formula (I) | Route of administration | Concentration of | Quantity (n) |
Control group | Corn oil | i.g,0.2mL | - | n=4 |
Model group | Imiquimod | Smearing, 0.2mL | - | n=4 |
Test group 1 | KS-3 monomethyl itaconate | i.g,0.2mL | 30mM | n=4 |
Test group 2 | KS-3 monomethyl fumarate | i.g,0.2mL | 30mM | n=4 |
Test group 3 | KS-3 | i.g,0.2mL | 30mM | n=4 |
Totals to | 20 |
After day 6, the skin condition of each group of mice was observed, and as shown in fig. 10, a large number of scales, wrinkles and red spots were observed in the mice of the model group at the sixth day of imiquimod infection; the mice of test group 1 and test group 2 showed significantly less scaling, wrinkling and erythema than the model group, indicating that KS-3 monomethyl itaconate and KS-3 monomethyl fumarate reduced scaling, wrinkling and erythema; in addition, the control mice did not develop scales, wrinkles and erythema, indicating that corn oil did not affect treatment.
In addition, the skin lesions of each group of mice were scored by PASI, and as shown in FIG. 11 (p < 0.05, p < 0.01), the results were consistent with the phenotype of the mice, with KS-3, KS-3 monomethyl itaconate and KS-3 monomethyl fumarate being able to reduce the production of scales, wrinkles and erythema.
In addition, the weight changes of the mice in the different groups are shown in FIG. 12, and the result shows that KS-3 monomethyl itaconate can reverse the weight loss of the psoriasis mice.
6. Butyrylated ferulic acid methyl ester psoriasis treatment effect
The 18 balb/c mice were divided into 3 groups, namely a control group (4), a model group (6) and a test group (8), and the construction methods are respectively as follows:
control group: shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; mice were perfused with 0.2mL of corn oil on days 0, 3, 6, the body weight of the mice was recorded daily for 8 days, and the back skin changes of the mice were recorded using cameras on days 0, 3, 6, and 8;
model group: shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the back of the mice was then topically smeared with IMQ (IMQ) cream daily and the weight of the mice was recorded for 8 days, 0.2mL of gastric corn oil was infused on days 0, 3, 6, and skin changes on the back of the mice were recorded using cameras on days 0, 3, 6, and 8;
test group: dissolving butyrylated ferulic acid methyl ester in corn oil to obtain butyrylated ferulic acid methyl ester corn oil solution; shaving the hair in the central back area of the mice with mild depilatory cream 1 day before the experiment, wherein the hair removal area is about 2cm multiplied by 2cm; the backs of the mice were then topically applied daily with IMQ (IMQ) cream; and lavage 0.2mL butyrylated methyl ferulate corn oil solution at day 0, day 3, day 6; and mice body weight was recorded for 8 days, and mice back skin changes were recorded using cameras on days 0, 3, 6 and 8;
the construction list of the mice in the above-mentioned different groups is shown in Table 4.
Table 5 KS-3 and modified derivatives validated dosing regimen for treatment of psoriasis
Grouping | Compounds of formula (I) | Route of administration | Concentration of | Quantity (n) |
Control group | Corn oil | i.g,0.2mL | - | n=4 |
Model group | Imiquimod | Smearing, 0.2mL | - | n=6 |
Test group | Butyrylated ferulic acid methyl ester | i.g,0.2mL | 15mM | n=8 |
Totals to | 18 |
After day 6, the skin condition of each group of mice was observed, and as shown in fig. 13, a large number of scales, wrinkles and red spots were observed in the mice of the model group at the sixth day of imiquimod infection; the test group has obviously fewer scales, folds and erythema than the model group, which indicates that butyrylated ferulic acid methyl ester can reduce the generation of scales, folds and erythema; in addition, the control mice did not develop scales, wrinkles and erythema, indicating that corn oil did not affect treatment.
In addition, the skin lesions of each group of mice were scored by PASI, and as shown in fig. 14 (p < 0.05, p < 0.01), butyrylated ferulic acid methyl ester was able to reduce the production of scales, wrinkles and erythema consistent with the phenotype of the mice.
In addition, the weight change of the mice in the different groups is shown in fig. 15, and the results show that butyrylated ferulic acid methyl ester can reverse the weight loss of the psoriasis mice.
In conclusion, KS-3 butyrate, KS-3 valerate, KS-3 monomethyl itaconate, KS-3 monomethyl fumarate and butyrylated methyl ferulate can be used for effectively treating psoriasis, can reduce the generation of skin scales, folds and erythema, and can reverse the loss of body weight caused by psoriasis.
In addition, the KS-3 derivatives have good anti-inflammatory and antioxidant activities and immunoregulatory effects, and can be used for treating psoriasis, atopic dermatitis, multiple sclerosis, systemic lupus erythematosus, crohn's disease, ulcerative colitis and other autoimmune diseases.
Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.
Claims (10)
- KS-3 derivative or salt thereof, characterized in that the structural general formula of the KS-3 derivative is shown as follows,wherein R is selected from CH 3 (CH 2 ) n COO-、HCOO-、CH 3 COO(CH=CH) y COO-orR' is selected from H-or CH3O-; wherein n is an integer and not less than 0, y is an integer and not less than 1, and x is an integer and not less than 1.
- 2. The KS-3 derivative or salt thereof according to claim 1, wherein the KS-3 derivative has a structural formula as shown in any one of the following:
- 3. a process for producing KS-3 derivatives according to claim 1 or 2, comprising: uniformly mixing a compound A, a compound B and TsCl, then adding a compound C, and reacting at 55-65 ℃ to obtain a crude product containing KS-3 derivatives;wherein the compound A is selected from The compound B is selected from CH 3 (CH 2 ) n COOH、HCOOH、CH 3 COO(CH=CH) y COOH or->Wherein n is an integer and is not less than 0, y is an integer and is not less than 1, and x is an integer and is not less than 1; the compound C is selected from
- 4. A method for producing a derivative according to claim 3, further comprising: cooling the mixture containing the KS-3 derivative to room temperature, mixing with water and extracting with dichloromethane; after extraction is completed, saturated NaHCO is used 3 Washing the organic layer with a solution; after washing, the mixture was washed with anhydrous MgSO 4 Drying; and (3) purifying the dried KS-3 derivative by using a PE/EA chromatographic column.
- 5. A pharmaceutical composition for the treatment of psoriasis, characterized by comprising a KS-3 derivative and/or a salt thereof according to claim 1 or 2.
- 6. A pharmaceutical formulation for the treatment of psoriasis, characterized by comprising a KS-3 derivative and/or a salt thereof according to claim 1 or 2 or a pharmaceutical composition for the treatment of psoriasis according to claim 5 and a pharmaceutically acceptable carrier.
- 7. The pharmaceutical formulation for treating psoriasis according to claim 6, wherein the pharmaceutically acceptable carrier is suitable for use in a solid, liquid or paste dosage form.
- 8. Use of KS-3 derivative or a salt thereof according to claim 1 or 2 or a pharmaceutical composition for the treatment of psoriasis according to claim 5 for the manufacture of a medicament for the treatment of autoimmune diseases.
- 9. The use according to claim 8, wherein the autoimmune disease is psoriasis, atopic dermatitis, multiple sclerosis, systemic lupus erythematosus, crohn's disease or ulcerative colitis.
- 10. Use of compound a in the manufacture of a medicament for the treatment of psoriasis, compound a having the formula:
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