CN119118968A - A compound for inhibiting IL-1β and its preparation method and application - Google Patents
A compound for inhibiting IL-1β and its preparation method and application Download PDFInfo
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- CN119118968A CN119118968A CN202411271290.3A CN202411271290A CN119118968A CN 119118968 A CN119118968 A CN 119118968A CN 202411271290 A CN202411271290 A CN 202411271290A CN 119118968 A CN119118968 A CN 119118968A
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
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- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
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Abstract
The invention belongs to the technical field of anti-inflammatory pharmacy, and relates to a compound for inhibiting IL-1 beta, a preparation method and application thereof, wherein the structural formula of the compound for inhibiting IL-1 beta is shown as formula I or formula II. The compound or the pharmaceutically acceptable salt thereof for inhibiting the IL-1 beta has the activity of inhibiting the IL-1 beta and does not generate cytotoxicity, can be used for preparing medicines for treating diseases caused by the high expression of the IL-1 beta, and develops a method for quickly constructing a series of compounds for inhibiting the IL-1 beta from simple and easily obtained raw materials, so that the anti-inflammatory potential of the Dispirocochlearoids A-C derivatives can be further explored.
Description
Technical Field
The invention belongs to the technical field of anti-inflammatory pharmacy, and particularly relates to a compound for inhibiting IL-1 beta, a preparation method and application thereof.
Background
The ganoderma lucidum fungus is widely used as a rare traditional Chinese medicine, can strengthen the resistance of a human body, prevent and resist cancers, protect liver and detoxify, reduce three highs and improve the cardiovascular system in traditional Chinese medicine, and has good conditioning effects on long-term insomnia, neurasthenia, gastroenteropathy, diabetes, chronic pneumonia, bronchitis, asthma, kidney deficiency and the like of middle-aged and elderly people. The active ingredients in the ganoderma lucidum have remarkable medicinal properties. To date, 680 more ganoderma lucidum diterpene natural products have been isolated from this mycological family. (±) -Dispirocochlearoids A-C is three non-polyketone hetero-terpene natural products isolated from ganoderma dorsi-handle, which belongs to the group of Cheng Yongxian subjects of the university of Shenzhen in 2020. In terms of biological activity (-) -Dispirocochlearoid B and its analogues have COX-2 inhibiting and anti-inflammatory effects both in vivo and in vitro. The in vitro results showed good anti-inflammatory activity for (-) -Dispirocochlearoid B, IC 50 =386 nM, 75-fold selectivity for COX-2 over COX-1 (IC 50 = 29.621. Mu.M), and no cytotoxicity as demonstrated by the in vitro cytotoxicity test. Preliminary in vitro mechanism of action studies have shown that the mRNA levels and protein expression of the pro-inflammatory factors IL-6 and IL-1β can be inhibited in a macrophage polarization model to be induced by Lipopolysaccharide (LPS). In vivo studies demonstrate that (-) -Dispirocochlearoid B can significantly inhibit inflammation in LPS-induced acute lung injury animal model (ALI) mice. (-) -Dispirocochlearoid B can inhibit COX-2 expression in lung tissue of ALI mice, and relieve lung injury. The natural products contain unique structures of 6/6/5/6/6/6 six-ring common frameworks of two continuous spiro chiral centers, and have very novel natural product frameworks. Furthermore, dispirocochlearoids is considered to have potential anti-inflammatory research value, and the anti-inflammatory activity of Dispirocochlearoids has a large improvement space.
Inflammation is the defensive response of the body against invasion of pathogenic microorganisms, physical injury, etc. Moderate inflammation facilitates the clearance of pathogenic microorganisms and repair of damaged tissue, while excessive, uncontrolled inflammation can further exacerbate bodily injury and even lead to eventual death. IL-1 beta is a typical pro-inflammatory cytokine which can induce the release of inflammatory cytokines such as IL-6 and TNF-alpha and stimulate T cell activation, and can stimulate local and systemic inflammatory responses.
Interleukin-1 beta (IL-1 beta), also known as leukocyte heat source, leukocyte endogenous mediators, monocyte factors, lymphocyte activators, and the like, human IL-1 beta is a cytokine protein encoded by the IL-1 beta gene. The expression (synthesis, processing and secretion) of L-1 beta is regulated by double signals, the initial signals induce cells to express non-bioactive pro-IL-1 beta, the activation signals activate inflammatory bodies, and then mature Caspase-1 cleaves pro-IL-1 beta into bioactive IL-1 beta, and finally the pro-IL-1 beta is secreted outside cells through different pathways to play a role.
IL-1β was originally cloned in the 1980 s and soon was considered a key factor in regulating inflammatory processes. IL-1β is a typical pro-inflammatory cytokine and is critical for the host's defensive response to infection and injury. It is expressed in various tissues and cells, especially in macrophages of lymphoid organs including thymus, spleen, lymph node, bone marrow, etc., and in tissue macrophages of non-lymphoid organs including lung, digestive tract, liver, etc., IL-1. Beta. Is also expressed.
IL-1β is considered a typical multifunctional cytokine affecting almost all cell types, whether acting alone or in combination with other cytokines. IL-1β is critical for cellular defense and tissue repair in nearly all tissues, and is associated with pain, inflammation, and autoimmunity. IL-1β is also involved in neuroprotection, tissue remodeling and repair. Because of the central role of IL-1β in the inflammatory process, human IL-1β is associated with a variety of inflammatory diseases, such as rheumatoid arthritis, acute liver injury, acute lung injury, gout, periodic fever, and neuroinflammation. Recently, hIL-1β has also been implicated in the pathogenesis of atherosclerosis and the progression of cancer.
While anti-hIL-1β antibody-based methods have demonstrated substantial benefit to patients, oral IL-1β inhibitors can target a wider range of diseases. In particular, there is growing evidence that inflammatory bodies contribute to neuroinflammation, which cannot be well studied with antibody tools due to the limited passage of anti-hIL-1. Beta. Antibodies across the blood brain barrier. Therefore, the development of IL-1 beta small molecule compounds has wide research prospect for treating related inflammatory diseases.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention starts from natural products Dispirocochlearoids, and a series of IL-1 beta natural product Dispirocochlearoids derivatives with good anti-inflammatory effect and no toxic or side effect are obtained by simplifying the structure of the novel natural products, carrying out innovative research on a synthesis method and modifying the structure diversity, and the specific technical scheme is as follows:
The first object of the present invention is to provide a compound for inhibiting IL-1β, which has the structural formula shown in formula I or formula II:
wherein the ring A is phenyl or other five-membered or six-membered heterocyclic ring;
R 1 and R 2 are each independently selected from H、3-CH3、4-CH3、5-CH3、6-CH3,5-OMOM、4-OMe、4-F、4-Cl、4-Br、4-I、4-OMOM,R2 is H, R 1 is independently selected from R 1 and R 2 is H
R 3 is independently selected from OMOM, OMe, OH, H, R 4 is independently selected from OMe and OEt;
R 5 and R 6 are
R 7 is 4-methylpentyl-3-enyl, methyl, ethyl, propyl, isopropyl, isobutyl, cyclopentyl, cyclohexyl, phenyl or trifluoromethyl.
Further, the compound for inhibiting IL-1 beta is one of the following structures:
The compound for inhibiting IL-1β has the structure shown in formula I, wherein ring A is phenyl or other five-membered or six-membered heterocyclic ring, R 1 and R 2 are independent, R 1 is independently selected from H、3-CH3、4-CH3、5-CH3、6-CH3,5-OMOM、4-OMe、4-F、4-Cl、4-Br、4-I、4-OMOM,R2 and H, R 3 and R 4 are independent, R 3 is independently selected from OMOM, OMe, OH, H, R 4 is independently selected from OMe and OEt, and R 5 and R 6 are independent R 7 is a preferred structure in 4-methylpentyl-3-enyl, methyl, ethyl, propyl, isopropyl, isobutyl, cyclopentyl, cyclohexyl, phenyl or trifluoromethyl.
Further, the compound for inhibiting IL-1 beta has the following structure:
The compound for inhibiting IL-1 beta has the structure shown in formula I, wherein ring A is phenyl or other five-membered or six-membered heterocyclic ring, R 1 and R 2 are R 3 and R 4 are each independently selected from OMOM, OMe, OH, H, R 4 is independently selected from OMe, OEt, R 5 and R 6 are R 7 is a preferred structure in 4-methylpentyl-3-enyl, methyl, ethyl, propyl, isopropyl, isobutyl, cyclopentyl, cyclohexyl, phenyl or trifluoromethyl. Wherein the ring A is phenyl, R 3 is OMOM, R 4 is OMe, R 5 and R 6 areR 7 is 4-methylpentyl-3-enyl. Further, the compound for inhibiting IL-1 beta is one of the following structures:
the compound for inhibiting IL-1 beta has a structure shown in formula II, wherein ring A is phenyl or other five-membered or six-membered heterocyclic ring, R 1 and R 2 are independent, R 1 is independently selected from H、3-CH3、4-CH3、5-CH3、6-CH3,5-OMOM、4-OMe、4-F、4-Cl、4-Br、4-I、4-OMOM,R2 as H, and R 5 and R 6 are R 7 is a preferred structure in 4-methylpentyl-3-enyl, methyl, ethyl, propyl, isopropyl, isobutyl, cyclopentyl, cyclohexyl, phenyl or trifluoromethyl.
The second object of the present invention is to provide a preparation method of a compound for inhibiting IL-1β, wherein the compound is shown in formula I, starting from a compound of formula S1, S1 reacts with methyl dimethyl phosphate under a strong alkali condition to obtain a corresponding phosphate S2, S2 undergoes a Horner-Wadsworth-Emmons reaction to obtain a corresponding (Z) -unsaturated gamma-keto ester S4, starting from S4 and S5, an intermediate state Z1 is obtained by Aldol condensation, and cyclizing to obtain a compound shown in formula I, wherein the reaction equation is as follows:
According to the invention, starting from a simple and easily available raw material S1, when R 3 of S1 is hydroxyl, bromomethyl methyl ether is used for protecting the hydroxyl, S1 reacts with methyl dimethyl phosphate under a strong alkali condition to obtain corresponding phosphate S2, and the corresponding (Z) -unsaturated gamma-keto ester S4 is obtained by Horner-Wadsworth-Emmons reaction of S2. Then starting from S4 and S5, a series of compounds for inhibiting IL-1 beta shown in the formula I, namely Dispirocochlearoids A-C derivatives, can be successfully constructed through Aldol condensation/cyclization reaction, and the anti-inflammatory potential of the Dispirocochlearoids A-C derivatives can be further explored.
Further, the preparation method of the compound for inhibiting IL-1 beta is that the compound is shown as a formula II, the compound is shown as a formula I, the intermediate state Z2 is obtained by deprotection, and then cyclization is carried out to obtain a compound shown as a formula II, which is a tetracyclic skeleton derivative product with two continuous spiro rings, wherein the reaction equation is shown as follows:
R 3 is independently selected from OMOM, OMe, OH.
The invention can further react from the compound shown in the formula I to quickly construct a series of compounds shown in the formula II for inhibiting IL-1 beta, namely Dispirocochlearoids A-C derivatives, develops a novel synthesis method for quickly constructing four-ring skeleton derivatives with two continuous spiro rings through two steps of Aldol condensation/cyclization/deprotection/cyclization cascade reaction, and can further explore the anti-inflammatory potential of the Dispirocochlearoids A-C derivatives.
Further, the preparation method of the compound shown in the formula I comprises the following steps:
Under the protection of nitrogen, S1 (1.0 equiv) and dimethyl methylphosphonate (DMMP) (1.0-2.0 equiv) are dissolved in anhydrous tetrahydrofuran, LDA (2 mol/L,1.1-4.0 equiv) is slowly added under the condition of-40-0 ℃, the mixture is stirred for 1.5-3 hours at the temperature, saturated NH 4 Cl is used for quenching reaction, ethyl acetate is used for extraction for 3 times, organic phases are combined, the combined organic layers are washed by saturated sodium chloride, anhydrous Na 2SO4 is dried, and solvent is evaporated under reduced pressure, and the crude product is purified by column chromatography to obtain an intermediate S2;
dissolving an intermediate S2 (1.0 equiv) and an alpha-ketoester S3 (1.0-2.0 equiv) in tetrahydrofuran at-30-10 ℃ and stirring, then adding sodium tert-butoxide (1.0-3.0 equiv) at the same temperature, quenching the saturated NH 4 Cl after the reaction is finished, extracting with ethyl acetate for 3 times, merging organic phases, washing the merged organic layers with saturated sodium chloride, drying anhydrous Na 2SO4, evaporating the solvent under reduced pressure, and purifying the crude product by column chromatography to obtain an intermediate S4;
Under the protection of nitrogen, S5 (1.0-3.0 equiv) is dissolved in tetrahydrofuran at-80 ℃ to-50 ℃, then the solution is added into tetrahydrofuran solution of Lithium Diisopropylamide (LDA) (2 mol/L,1.1-3.3 equiv) in a dropwise manner, then S4 (1.0 equiv) is added in a dropwise manner, the temperature is slowly raised to room temperature, after the reaction of S4 is finished, saturated ammonium chloride solution is added for quenching reaction, ethyl Acetate (EA) is extracted for 3 times, an EA layer is combined and washed by saturated sodium chloride, anhydrous Na 2SO4 is dried, an organic phase is concentrated, and a compound shown in a formula I is obtained through silica gel column chromatography.
Further, the preparation method of the compound shown in the formula II comprises the following steps:
Dissolving a compound (1.0 equiv) shown in a formula I in toluene, carrying out a catalytic reaction on p-toluenesulfonic acid (0.1-1.0 equiv) at 50-70 ℃, and directly carrying out silica gel column chromatography to obtain a compound shown in a formula II.
A third object of the present invention is to provide a pharmaceutical composition comprising the compound for inhibiting IL-1 β (compound of formula I or II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The pharmaceutically acceptable salt is a salt obtained by reacting the compound for inhibiting IL-1 beta (a compound shown as a formula I or a formula II) with an inorganic base or an organic base compound. The salt obtained by reacting the compound for inhibiting IL-1 beta (the compound of formula I or formula II) with an inorganic base compound includes, but is not limited to, aluminum salt, ammonium salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganous salt, potassium salt, sodium salt, zinc salt, etc., preferably ammonium salt, calcium salt, magnesium salt, potassium salt and sodium salt. The compounds for inhibiting IL-1 beta (compounds of formula I or formula II) are reacted with organic bases to obtain pharmaceutically acceptable salts of organic non-toxic bases, including but not limited to salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
By "pharmaceutically acceptable carrier" is meant one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with the active ingredient of the present invention (the compound for inhibiting IL-1β or a pharmaceutically acceptable salt thereof) without significantly reducing the efficacy of the active ingredient.
Further, the pharmaceutically acceptable carrier is cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifying agents, wetting agents (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
Further, the pharmaceutical composition is orally administered in the form of a capsule, a tablet, a granule, a solution, a powder or syrup, or is non-orally administered in the form of an injection.
The compounds and pharmaceutical compositions of the present invention may be present in a suitable solid or liquid carrier and in a suitable disinfection apparatus for injection or instillation, the above formulations being prepared by conventional pharmaceutical methods.
The fourth object of the invention is to provide the application of the compound or the pharmaceutically acceptable salt or the pharmaceutical composition thereof, wherein the application comprises the preparation of an IL-1 beta inhibitor, the application of the compound or the pharmaceutically acceptable salt or the pharmaceutical composition as the IL-1 beta inhibitor and the preparation of medicaments for treating related diseases caused by the high expression of IL-1 beta.
Further, the disease is rheumatoid arthritis, acute liver injury, acute lung injury, gout, periodic fever, neuroinflammation, and the like.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
The beneficial effects of the invention are as follows:
The compound for inhibiting IL-1 beta or pharmaceutically acceptable salt thereof has the activity of inhibiting IL-1 beta, can inhibit IL-1 beta better than celecoxib, shows good anti-inflammatory activity and does not generate cytotoxicity, and can be used as an IL-1 beta inhibitor or used for preparing medicines for treating diseases caused by high expression of IL-1 beta, wherein the diseases comprise rheumatoid arthritis, acute liver injury, acute lung injury, gout, periodic fever, neuroinflammation and the like.
The invention starts from simple and easily available raw materials, and develops a method for quickly constructing a series of compounds (compounds in the formula I and II) for inhibiting IL-1 beta, namely Dispirocochlearoids A-C derivatives, and further explores the anti-inflammatory potential of the Dispirocochlearoids A-C derivatives.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. Percentages and parts are weight percentages and parts unless otherwise indicated.
In the examples below, NMR was measured with an Avance NEO 600 instrument, NMR calibration was δH
7.26Ppm (CDCl 3), reagent mainly provided by Shandong chemical reagent company, TLC thin layer chromatography silica gel plate produced by Shandong Kaiyaku silica gel development Co., ltd., model HSGF254, and normal phase column chromatography silica gel used for purifying the compound is produced by Shandong Qingdao ocean chemical factory, model 200-300 mesh.
Example 1:
preparation of compound 442-1 for inhibiting IL-1β:
To a stirred solution of compound A1 (5.0 g,33 mmol) in anhydrous THF (50 mL) at 0deg.C was slowly added NaH (2.2 g,52.8 mmol). The mixture was stirred at 0 ℃ for 10 minutes. MOMBr (6.2 g,49.5 mmol) was slowly added. The mixture was stirred at 0 ℃ for 1 hour. The reaction was quenched with NH 4 Cl at 0deg.C and extracted 3 times with ethyl acetate. The organic phases were combined, the combined organic layers were washed with saturated sodium chloride, dried over anhydrous Na 2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give intermediate A2.
Intermediate A2 (2.0 g,10.2 mmol) and dimethyl methylphosphonate (DMMP) (2.3 g,18.4 mmol) were dissolved in anhydrous THF (50 mL) under nitrogen, and LDA (2 mol/L,18.4mL 36.7 mmol) was slowly added at-30 ℃. The mixture was stirred at-30 ℃ for 2 hours. The reaction was quenched with NH 4 Cl at-30℃and extracted 3 times with ethyl acetate. The organic phases were combined, the combined organic layers were washed with saturated sodium chloride, dried over anhydrous Na 2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate) to give intermediate A3.
Intermediate A3 (1.0 g,3.5 mmol) and alpha-keto ester A4 (0.9 g,5.2 mmol) were dissolved in THF (40 mL) and stirred at 0deg.C. Then t-BuNa (0.7 g,6.9 mmol) was added at the same temperature. After the reaction was completed, the reaction was quenched with NH 4 Cl at 0 ℃ and extracted 3 times with ethyl acetate. The organic phases were combined, the combined organic layers were washed with saturated sodium chloride, dried over anhydrous Na 2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=15/1) to give intermediate A5.
Methyl cyclohexylformate (0.9 g,6.0 mmol) was dissolved in tetrahydrofuran under nitrogen protection, LDA (2 mol/L,3.3mL, 6.6 mmol) was added dropwise, A5 (1.0 g,3.0 mmol) in tetrahydrofuran was then added dropwise, stirring was carried out at-78℃for 30min, the temperature was slowly raised to room temperature, after the reaction of A5 was completed, saturated ammonium chloride solution was added to quench the reaction, and ethyl acetate was used for extraction 3 times. The organic phases were combined, the combined organic layers were washed with saturated sodium chloride, dried over anhydrous Na 2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=15/1) to give 442-1.1HNMR(600MHz,CDCl3)δ7.98(t,J＝1.4Hz,1H),7.57(dd,J＝7.9,1.7Hz,1H),7.28-7.25(m,1H),7.07(dd,J＝8.4,1.2Hz,1H),7.00(ddd,J＝8.2,7.3,1.2Hz,1H),5.22(d,J＝6.6Hz,1H),5.08(d,J＝6.6Hz,1H),5.06(ddt,J＝6.9,5.4,1.5Hz,1H),3.64(s,3H),3.49(s,3H),2.33-2.19(m,4H),2.16-2.10(m,1H),2.05-1.99(m,1H),1.66-1.60(m,5H),1.52(s,4H),1.46(td,J＝13.2,4.0Hz,1H),1.28(d,J＝3.6Hz,1H),1.21-1.14(m,1H),1.13-1.02(m,2H)ppm.
The following compounds were synthesized using the same preparation method as in example 1, as shown in table 1:
TABLE 1 Compounds synthesized by the same preparation method as in example 1
Example 2
Preparation of compound 366 for inhibiting IL-1 beta:
442-1 (1000 mg,2.26 mmol) was dissolved in 40mL toluene, and water and p-toluene sulfonic acid (43 mg,0.23 mmol) were added for catalytic reaction at 60℃and after 442-1 reaction was completed, direct silica gel column chromatography (petroleum ether/ethyl acetate=15/1) was carried out 366.1H NMR(600MHz,CDCl3)δ7.37(ddd,J＝8.5,6.6,2.3Hz,1H),7.13(q,J＝7.3Hz,2H),7.08(d,J＝8.1Hz,1H),6.92(s,1H),5.02(t,J＝7.2Hz,1H),2.39(q,J＝7.6Hz,2H),2.27(q,J＝8.4,7.9Hz,2H),1.84(q,J＝16.9,14.5Hz,2H),1.77-1.61(m,8H),1.57(s,4H),1.26(td,J＝13.2,4.5Hz,1H),1.10(tdd,J＝13.0,9.0,3.6Hz,1H)ppm.
The following compounds were synthesized using the same preparation method as in example 2, as shown in table 2:
TABLE 2 Compounds synthesized by the same preparation method as in example 2
Test of IL-1 beta anti-inflammatory Activity of Compounds:
1. Material source
Male C57BL/6J mice were purchased from Jinan Pengyue laboratory animal breeding Co., ltd, fed to SPF-class animal houses, and were free to drink and ingest. All animal experiments were performed according to the national laboratory animal authorities and approved by the laboratory animal ethics committee.
2. Experimental procedure
Isolation and culture of bone marrow-derived macrophages
C57BL/6J mice with the age of about 6-8 weeks are killed by cervical vertebra removal and then are soaked in 75% alcohol for 5min for disinfection. The femur was isolated, the muscle tissue was removed and placed in sterile PBS and transferred to a biosafety cabinet. Cutting two ends of the femur, sucking PBS by using a 10mL syringe to blow out bone marrow, repeatedly flushing until the femur turns white, repeatedly flushing by a pipette gun until single cell suspension is formed, transferring into a 50mL centrifuge tube, and centrifuging for 5min at 500 g. The supernatant was aspirated, 1mL of erythrocyte lysate was added to resuspend the cells, and the mixture was allowed to stand for 5min. 5mL of complete medium (HG DMEM+10% FBS) was added, lysis was terminated, and after gentle mixing by a pipette, 500g was centrifuged for 5min. The supernatant was pipetted off, resuspended in complete medium, passed through a 40 μm cell strainer and transferred to a 50mL centrifuge tube. Cell counts, at 1X 10 6 cells/mL, at 10cm dish. The culture was supplemented with 10mL of complete medium on the next day, half-changed on the fifth day, and treatment was performed on day 7. Macrophage colony stimulating factor (M-CSF, final concentration of 20 ng/mL) was added throughout the culture for induction.
LPS-induced BMDM cell differentiation
After BMDM cells were matured, they were inoculated into 12-well plates (1 mL/well) at 5X 10 5 cells/mL, incubated overnight in an incubator (37 ℃ C., 5% CO 2), treated with drug at 5, 10, 20. Mu.M after cell attachment, treated with LPS (10 ng/mL) after 2 hours, and protein samples were collected after 4 hours to determine IL-1. Beta. Protein expression. After maturation of BMDM cells, 5X 10 5 cells/mL were inoculated into 96-well plates (100. Mu.L/well), incubated overnight in an incubator (37 ℃ C., 5% CO 2), treated with the synthetically prepared derivatives of natural product Dispirocochlearoids at a concentration of 3, 30. Mu.M, treated with LPS (10 ng/mL) after 2 hours, treated with ATPase (ATP) (5 mM) after 4 hours, the cell supernatants were harvested after 45 minutes, and the IL-1β content of the supernatants was determined. After the end of the cell experiment, the supernatant was collected, centrifuged at 4000rpm/4℃for 5min, the cell pellet was removed and the supernatant was collected for detection. The detection was performed according to the assay method described in the kit instructions. The specific operation steps of (MOUSE IL1 BETA KIT#62MIL1BPEG) are as follows:
① Thawing all reagents and samples on ice;
② Preparing a standard substance;
③ Uniformly mixing IL-1 beta E mu antibody and IL-1 beta d2 antibody with equal volumes to obtain an antibody working solution;
④ 2. Mu.L of antibody working solution and 8. Mu.L of standard substance/sample were added to each well in 384-well plates;
⑤ Incubating overnight at 4 ℃;
⑥ The fluorescence values at 620/655nm were read using Envision, a standard curve was created using a four parameter Logistic curve, and the sample concentrations were calculated.
The experimental results are shown in table 3:
compounds of table 3 inhibit the pro-inflammatory factor IL-1 beta
Note that 0< 40%,40% less than 80%,80% less than 100%
As can be seen from the condition that the compounds shown in the table 3 inhibit the proinflammatory factor IL-1 beta, the compounds used for inhibiting the IL-1 beta, namely the natural products Dispirocochlearoids derivatives, can effectively inhibit the proinflammatory factor IL-1 beta, and the activity of part of the compounds is better than celecoxib (celecoxib), so that the compounds prepared by the invention have good anti-inflammatory activity and no cytotoxicity, and show that the compounds can be used for treating related diseases caused by the high expression of the IL-1 beta, wherein the diseases comprise rheumatoid arthritis, acute liver injury, acute lung injury, gout, periodic fever, neuroinflammation and the like.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.
Claims (10)
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