WO2023232125A1 - 一类倍半萜聚酮化合物、药物组合物及其用途 - Google Patents

一类倍半萜聚酮化合物、药物组合物及其用途 Download PDF

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WO2023232125A1
WO2023232125A1 PCT/CN2023/097906 CN2023097906W WO2023232125A1 WO 2023232125 A1 WO2023232125 A1 WO 2023232125A1 CN 2023097906 W CN2023097906 W CN 2023097906W WO 2023232125 A1 WO2023232125 A1 WO 2023232125A1
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salt
formula
sesquiterpene
compound
pharmaceutically acceptable
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French (fr)
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高昊
尹芝南
王传喜
唐欣
姚新生
杨恒文
胡丹
李振华
邝润桥
任菲菲
韩雪
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暨南大学
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Definitions

  • the invention belongs to the field of natural medicines, and more specifically relates to a class of sesquiterpene polyketide compounds, pharmaceutical compositions and their uses as immunomodulators and in the prevention and treatment of immune diseases.
  • autoimmune diseases include inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA). ), including more than 100 kinds of diseases, have severe morbidity, high incidence rate, long onset period, no cure, and seriously endanger human health.
  • Immunomodulators can be used to treat immune diseases caused by immune dysfunction by regulating the body's immune response (enhancement, suppression or bidirectional regulation).
  • modulators that enhance the body's immunity can be used to intervene.
  • immunosuppressants are currently mainly used to improve disease symptoms and prognosis.
  • CD4 + T cells differentiate into Th17 cells with the participation of TGF ⁇ and IL6.
  • IL17 is a strong pro-inflammatory cytokine mainly secreted by Th17 cells, which mediates a variety of inflammatory and autoimmune diseases [2] .
  • IL17 plays a role in inflammatory bowel disease, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, asthma, Sjogren's syndrome and ankylosing spondylitis.
  • IL17 inhibitors have been used clinically for therapeutic intervention in various immune diseases such as psoriasis, arthritis, and multiple sclerosis, and have shown certain efficacy [3] .
  • IL10 is a class of cytokines with immunosuppressive properties and broad anti-inflammatory properties. IL10 can regulate the activity of a variety of myeloid or lymphoid cells, inhibit their production of pro-inflammatory factors, and thus play a role in inhibiting immune rejection, allergies, inflammation and autoimmune diseases in organ transplantation [4] .
  • Type I regulatory T cells (Tr1) secrete a large amount of IL10 and are a type of cell with immunosuppressive effects.
  • Tr1 secrete a large amount of IL10 and are a type of cell with immunosuppressive effects.
  • Tr1 secrete a large amount of IL10 and are a type of cell with immunosuppressive effects.
  • Currently, clinical trials of transferring Tr1 cells to prevent and treat autoimmune diseases or protect immune rejection of organ transplants have shown efficacy [5] .
  • compounds that inhibit IL17 and/or promote IL10 can be used as immunomodulators to prevent and treat organ transplant immune rejection, allergies, inflammation and autoimmune diseases (inflammatory bowel disease, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, silver Sclerosis, systemic lupus erythematosus, asthma, Sjogren's syndrome and ankylosing spondylitis, uveitis, autoimmune nephritis, autoimmune thyroiditis, Behcet's disease, lichen planus, various respiratory diseases, various liver diseases and various cardiovascular diseases, etc.).
  • organ transplant immune rejection inflammatory bowel disease, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, silver Sclerosis, systemic lupus erythematosus, asthma, Sjogren's syndrome and ankylosing spondylitis, uveitis, autoimmune nephritis, autoimmune thyroiditis, Behcet's disease, lichen planus, various respiratory diseases, various
  • compounds that inhibit IL17 and/or promote IL10 can also be used as immunomodulators for the treatment of inflammation-related diseases such as sepsis, acne, disc herniation, and celiac disease.
  • IL17 is also closely related to the occurrence of tumors, especially inflammation-related tumors.
  • IL10 has a bidirectional regulatory effect on the occurrence and development of tumors.
  • IL10 can exert anti-tumor effects by inhibiting the production of inflammatory factors that promote tumor development and activating tumor-specific CD8 + T [4] . Therefore, compounds that inhibit IL17 and/or promote IL10 can also be used as immunomodulators for tumor treatment.
  • Th2 cells mainly secrete the cytokine IL4.
  • IL4 has a variety of biological functions and plays an important role in humoral immunity and acquired immunity [6] .
  • IL4 can induce the activation of B cells and T cells and the differentiation of B cells into plasma cells.
  • IL4 can also inhibit lymphocyte apoptosis, promote the antigen presentation ability of macrophages, and improve the function of killing tumor cells. Therefore, compounds that promote IL4 can be used as immunomodulators for diseases related to anti-tumor and anti-infection (especially anti-parasitic infection).
  • the object of the present invention is to provide a class of sesquiterpene polyketide compounds, pharmaceutical compositions and their uses. Specifically, the inventor discovered, isolated and identified a type of sesquiterpene polyketide compound from a strain of Rhizoma fungus. Experiments have shown that it has immunomodulatory activity and can be used for the prevention and/or treatment of immune-related diseases.
  • a first aspect of the present invention provides a class of sesquiterpene polyketide compounds or pharmaceutically acceptable salts thereof.
  • the sesquiterpene polyketide compounds are represented by formula (I):
  • R 1 is selected from: hydroxyl, carbonyl, acetoxy
  • R 2 is selected from: methyl, hydroxymethyl, acetylhydroxymethyl, acetoxy, aldehyde, dimethoxymethyl;
  • R 3 is selected from: methyl, hydroxymethyl, acetylhydroxymethyl, acetoxy, aldehyde, dimethoxymethyl;
  • R 2 , R 3 and benzene ring form a 5-membered lactam ring or lactone ring;
  • R 4 , R 5 , R 6 , and R 7 are carbon atoms, and any adjacent group is selected from double bonds, and the remaining groups are selected from single bonds;
  • R 4 , R 5 , R 6 , and R 7 are carbon atoms, R 5 and R 6 are selected from double bonds, and the remaining groups are selected from single bonds, R 2 is selected from hydroxymethyl, and R 3 is selected from aldehyde groups.
  • R 1 cannot be selected from hydroxyl or acetoxy.
  • the pharmaceutically acceptable salt is a salt formed by a compound of formula (I) and an organic base or an inorganic base.
  • the salt formed is sodium salt, potassium salt, calcium salt, iron salt, magnesium salt, zinc salt, aluminum salt, barium salt or ammonium salt.
  • the sesquiterpene polyketide compound is selected from compounds of formula II to formula X, and the specific structural formula is as follows:
  • a second aspect of the present invention provides a method for preparing the above-mentioned compound, which includes: fermenting a microorganism that produces a sesquiterpene polyketide compound represented by formula (I) and then separating it by chromatography.
  • microorganism is a fungus of the genus Lactobacillus.
  • the fungus of the genus Lactobacillus is ZLW0801-19, and its preservation number is CGMCC No. 19039.
  • the third aspect of the present invention also provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt thereof for preparing an immunomodulator.
  • the immunomodulatory agent is used for the prevention and/or treatment of immune-related diseases.
  • the immunomodulator is used to prevent and treat diseases or conditions for which inhibiting IL17 and/or promoting IL10 is beneficial.
  • the disease or indication is selected from the group consisting of psoriasis, inflammatory bowel disease, type I diabetes, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, asthma, Sjogren's syndrome, ankylosing spondylitis , immune rejection of organ transplantation, allergy, sepsis, uveitis, autoimmune nephritis, autoimmune thyroiditis, Behcet's disease, autoimmune liver disease, lichen planus, sepsis, acne, disc herniation, celiac disease .
  • the immunomodulator is used to prevent and treat diseases or conditions for which promoting IL4 is beneficial.
  • the disease or indication is related to parasitic infection.
  • the fourth aspect of the present invention provides a pharmaceutical composition for immunomodulation, including the above-mentioned sesquiterpene polyketide compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the salt is any one of sodium salt, potassium salt, calcium salt, iron salt, magnesium salt, zinc salt, aluminum salt, barium salt and ammonium salt.
  • the amount of the active ingredient (i.e., the compound of the present invention) contained in the pharmaceutical composition can be specifically applied according to the patient's condition and the situation diagnosed by the doctor.
  • the amount or concentration of the active compound is within a relatively small range. Adjusted within a wide range, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 1-90% by weight of the composition.
  • pharmaceutically acceptable carriers include diluents, lubricants, binders, disintegrants, stabilizers, solvents, etc.
  • diluents of the present invention include but are not limited to starch, microcrystalline cellulose, sucrose, dextrin, lactose, powdered sugar, glucose, etc.
  • lubricants include but are not limited to magnesium stearate, stearic acid, and sodium chloride.
  • the binders include but are not limited to water, ethanol, starch slurry, syrup, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, seaweed sodium bicarbonate, polyvinylpyrrolidone, etc.
  • the disintegrants include but are not limited to starch effervescent mixture, namely sodium bicarbonate and citric acid, tartaric acid, low-substituted hydroxypropyl cellulose, etc.
  • the stabilizers include but are not limited to polysaccharides Such as acacia gum, agar, alginic acid, cellulose ether, carboxymethyl chitosan, etc.
  • the solvent includes but is not limited to water, balanced salt solution, etc.
  • the pharmaceutical composition is an oral preparation or injection; preferably, the oral preparation includes but is not limited to ordinary tablets, dispersible tablets, enteric-coated tablets, granules, capsules, dropping pills, powders, oral liquids or Any one of emulsions; preferably, the injection is selected from any one of small water injections, infusions or freeze-dried powder injections.
  • sesquiterpene polyketide compound of the present invention is derived from microbial fermentation and is convenient for large-scale fermentation and industrial preparation; Activity experiments found for the first time that this type of compound has significant immunomodulatory activity.
  • the mass spectrometer is an LCQ-Advantage mass spectrometer produced by Finnigan Company in the United States.
  • the superconducting NMR instrument was Bruker AV-400.
  • Silica gel GF254 for thin layer chromatography and silica gel for column chromatography (200-300 mesh) are both products of Qingdao Ocean Chemical Factory.
  • the reversed-phase ODS filler 50 ⁇ m is a product of Japan YMC Company.
  • the medium and low pressure liquid chromatograph is a product of Shanghai Lisui Electronic Technology Co., Ltd.
  • the chromatographic column used for liquid phase separation is Phenomenex Gemini C18 column (10.0 ⁇ 250mm, 5 ⁇ m). Methanol and acetonitrile used for liquid chromatography were of chromatographic grade, water was double distilled water, and other reagents were of analytical grade.
  • the experimental data at the in vitro cell level shown in the examples are expressed as mean ⁇ SD.
  • Statistical differences are marked as follows: * represents P ⁇ 0.05, ** represents P ⁇ 0.01, *** represents P ⁇ 0.001, **** represents P ⁇ 0.0001, ns represents not significant difference.
  • the acquired data were analyzed using Graphpad Prism 7.00 and FlowJo V10 (for flow cytometry).
  • Example 1 Large-scale fermentation of the fungus ZLW0801-19 and its sample pretreatment method
  • the fungal strain ZLW0801-19 of the genus ZLW0801-19 was cultured on potato dextrose agar (PDA) slant at 25°C for 5 days. After activation by PDA slope, inoculate into four Erlenmeyer flasks (250mL) containing potato dextrose (PDB) medium to prepare seed liquid. Each Erlenmeyer flask contains 100mL PDB medium. The rotation speed is 200rpm and cultured at 25°C for 5 days to prepare seeds. liquid. Fermentation was carried out in 24 Erlenmeyer flasks (500mL), each containing 70g of rice.
  • PDA potato dextrose agar
  • Distilled water (105mL) was first added to each Erlenmeyer flask, the rice was soaked overnight and then autoclaved at 120°C. 30 minutes. After cooling to room temperature, 5.0 mL of seed solution was inoculated into each Erlenmeyer flask and cultured at room temperature in the dark for 51 days.
  • Example 1 the crude extract of ethyl acetate (81.7g) was subjected to silica gel column chromatography, using cyclohexane-ethyl acetate (100:0, 98:2, 95:5, 90:10, 80:20, 70:30, 50:50, 0:100, v/v) and methanol were eluted, each gradient elution volume was 6L, and 7 fraction samples (F1-F7) were obtained.
  • Fraction F5 was subjected to medium and low pressure liquid phase ODS column chromatography, using methanol-water (70:30, 80:20, 90:10, and 100:0, v/v), each gradient elution volume was 2.5L, and 9 fraction samples (F5.1-F5.9) were obtained.
  • Fraction F5.2 was subjected to medium and low pressure liquid phase ODS column chromatography, and was eluted sequentially with methanol-water (60:40, 70:30, 80:20, 90:10, v/v), with each gradient elution volume of 0.7 L, 5 fraction samples (F5.2.1-F5.2.5) were obtained.
  • Fraction F5.2.4 (387mg) was prepared by reversed-phase preparative HPLC (Cosmosil Packed C18 column), using acetonitrile-water (50:50, v/v) with a flow rate of 3mL/min for elution, to obtain the compound of formula (VIII) (t R :53.6min, 26.2mg).
  • Fraction F5.2.5 (365 mg) was prepared by reverse-phase preparative HPLC (Phenomenex, Packed C18 column), and acetonitrile-water (55:45, v/v) with a flow rate of 8 mL/min was used for elution to obtain formula (X ) compound (t R :86.4min, 7.0mg).
  • Fraction F5.3 was subjected to gel column LH-20 column chromatography and eluted with methanol to obtain 7 fractions (F5.3.1–F5.3.7).
  • Fraction F5.3.7 (144mg) was prepared by reversed-phase preparative HPLC (Cosmosil Packed C18 column), using methanol-water (75:25, v/v) with a flow rate of 3mL/min for elution, to obtain the compound of formula (II) (t R : 63.7 min, 17.0 mg) and the compound of formula (III) (t R : 69.9 min, 17.5 mg).
  • Fraction F5.7 was subjected to silica gel column chromatography, using cyclohexane-ethyl acetate (90:10, 85:15, 80:20, 75:25, 70:30, 60:40, 50:50, 0: 100, v/v), each gradient elution volume was 1.0L, and 8 fraction samples (F5.7.1-F5.7.8) were obtained.
  • Fraction F5.7.4 (62.1mg) was prepared by reversed-phase preparative HPLC (Cosmosil Packed C18 column), using methanol-water (82:18, v/v) with a flow rate of 3mL/min for elution, to obtain formula (IV) Compound (t R :21.3min, 12.1mg).
  • Fraction F6 was subjected to medium and low pressure liquid phase ODS column chromatography, and was eluted with methanol-water (60:40, 70:30, 80:20, 90:10, 100:0, v/v) in sequence, with each gradient elution volume 2.5 L, 7 fraction samples (F6.1-F6.7) were obtained.
  • Fraction F6.3 was subjected to silica gel column chromatography, and eluted with cyclohexane-ethyl acetate (75:25, 70:30, 60:40, 50:50, 0:100v/v) in sequence, each gradient elution The volume is 0.3L, and 6 fraction samples (F6.3.1-F6.3.6) are obtained.
  • Fraction F6.3.6 (349.7mg) was prepared by reversed-phase preparative HPLC (Cosmosil Packed C18 column), using acetonitrile-water (40:60, v/v) with a flow rate of 3mL/min for elution, to obtain formula (VII) Compound (t R :17.5min, 7.7mg).
  • Fraction F6.4 was subjected to medium and low pressure liquid phase ODS column chromatography, using methanol-water (70:30, v/v) to elute, with an elution volume of 0.7L, and 5 fraction samples (F6.4.1-F6.4.5) were obtained. .
  • Fraction F6.4.3 (212.9 mg) was prepared by reverse-phase preparative HPLC (Cosmosil Packed C18 column), using acetonitrile-water (55:45, v/v) with a flow rate of 3 mL/min for elution, to obtain formula (V) Compound (t R : 63.3 min, 10.3 mg) and compound of formula (VI) (t R : 25.0 min, 10.1 mg).
  • T cells produce specific cytokines after differentiation, such as Th17 producing the cytokine IL17, Th2 producing the cytokine IL4, and Tr1 producing the cytokine IL10.
  • IL17-GFP mice, IL4-eGFP mice and IL10-eGFP mice are transgenic mice with a green fluorescent reporter gene (GFP), which produces specific cytokines after T cell differentiation.
  • the gene downstream is connected to the GFP fluorescent protein coding sequence. Therefore, a fluorescence detection system can be used to detect the expression of GFP to measure the expression level of cytokines.
  • Anti-mouse CD3 Ab (antibody, antibody) coating plate Add anti-mouse CD3 Ab diluted in IMDM medium to a final concentration of 10 ⁇ g/mL in a 96-well plate, and incubate at 37°C for 2 hours.
  • IL17-GFP mice raised in a specific pathogen-free (SPF) environment were sacrificed by cervical dislocation.
  • the spleens were removed and placed in IMDM culture medium.
  • the spleens were ground in a clean bench using sterilized pathology slides.
  • the ground cell suspension was filtered into a centrifuge tube using a 40 ⁇ m cell strainer filter; centrifuge (4°C, 1400 rpm, 7 minutes), discard the supernatant, add red blood cell lysate, mix well, let stand at room temperature for 5 minutes, and then add IMDM terminates the lysis of red blood cells; filter through a 40 ⁇ m cell strainer filter and then centrifuge (4°C, 1400 rpm, 7 minutes), discard the supernatant, and resuspend the cells in IMDM containing 10% FBS; dilute the cells 100 times, and count the cells under a microscope. Count the results and prepare a cell suspension of 1 ⁇ 10 6 cells/mL (final concentration).
  • Th17 cell differentiation inducing factors anti-mouse CD28 Ab (1 ⁇ g/mL), rhTGFb1.2 (0.25ng/mL), rmIL6 (40ng/mL), anti-mouse IL4 (5 ⁇ g/mL), anti-mouse IFN ⁇ ( 5 ⁇ g/mL) (cytokines here are final concentrations).
  • Dilution of the sample to be tested Dilute the compound to 10 ⁇ M (final concentration) with IMDM containing 10% FBS; dilute the positive compound SR2211 that inhibits IL17 to 1 ⁇ M (final concentration).
  • Plating Aspirate the antibodies on the plate, wash them with IMDM, add 100 ⁇ L cell suspension and 100 ⁇ L final concentration sample solution to each well for co-culture (such as 100 ⁇ L cell suspension with a concentration of 4 ⁇ 10 6 cells/mL and 100 ⁇ L 20 ⁇ M compound co-culture , the final concentration of cells in the culture system was 2 ⁇ 10 6 cells/mL, and the compound concentration was 10 ⁇ M).
  • Cell culture The sample solution and cells were cultured in a humidified incubator at 37°C, 5% CO2 for a total of 72 hours.
  • Cell surface staining and flow cytometry detection Collect the cultured cells into a flow tube, add 3 mL of pre-cooled PBS, centrifuge (4°C, 1400 rpm, 7 minutes), discard the supernatant, and add 0.25 ⁇ L APC to 50 ⁇ L cell suspension. The surface was stained with anti-mouse CD4 antibody and placed in the dark at 4°C for 20 minutes. Then resuspend the cells in 1 mL of pre-cooled PBS, add 2 mL of PBS, and centrifuge again (4°C, 1400 rpm, 7 minutes). Discard the supernatant, add 200 ⁇ L of PBS to each tube, and analyze the proportion of GFP + cells to CD4 + cells by flow cytometry. The ratio.
  • IMDM medium and fetal bovine serum (FBS) were purchased from Gibco; anti-mouse CD28 Ab, anti-mouse CD3Ab, anti-mouse IL4, anti-mouse IFN ⁇ , APC anti-mouse CD4 were purchased from Surgie; rmIL6 was purchased from Peprotech Company; rhTGFb1.2 was purchased from R&D Company; red blood cell lysate was purchased from Tiangen Company; PBS was purchased from Solarbio Company.
  • the relative inhibitory activity (Relative Inhibition) of the compound on IL17 expression was calculated using the formula: (ratio of GFP + in DMSO group to CD4 + - ratio of GFP + in compound group to CD4 + )/ratio of GFP + in DMSO group to CD4 + ⁇ 100% Activity).
  • Th2 differentiation conditions Primary spleen lymphocytes from fluorescent reporter mice IL4-eGFP mice were extracted, co-cultured with compounds under Th2 differentiation conditions, and IL4-GFP levels were detected by flow cytometry to evaluate the effects of compounds on IL4 expression.
  • the culture medium used for Th2 is RPMI-1640; the cell density is 2 ⁇ 10 6 cells/mL; the differentiation conditions used are: anti-mouse CD28 Ab (1 ⁇ g/mL), rmIL2 (2ng/mL), rmIL4 (40ng/mL ), Anti-mouse IFN ⁇ (10 ⁇ g/mL).
  • Other experimental steps for Th2 differentiation are the same as those for Th17 differentiation in Example 3.
  • rmIL4 and rmIL2 were purchased from Peprotech Company; RPMI-1640 culture medium was purchased from Sigma Company.
  • Tr1 differentiation conditions Primary spleen lymphocytes from fluorescent reporter IL10-eGFP mice were extracted and sorted, co-cultured with compounds under Tr1 differentiation conditions, and the effects of compounds on IL10 expression were evaluated by detecting IL10-eGFP levels by flow cytometry.
  • the culture medium used for Tr1 is RPMI-1640; the cell density is 1 ⁇ 10 6 cells/mL; the differentiation conditions used are: anti-mouse CD28 Ab (1 ⁇ g/mL), rmIL27 (50ng/mL), rhTGFb1.2 (0.5 ng/mL).
  • Other experimental steps for Tr1 differentiation are the same as those for Th17 differentiation in Example 3.
  • rmIL27 was purchased from Biolegend; RPMI-1640 culture medium was purchased from Sigma.
  • sesquiterpene polyketides have the activity of inhibiting IL17, promoting IL4 and promoting the expression of IL10, and can be used for the prevention and treatment of immune diseases.

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Abstract

本发明涉及一类可用作免疫调节剂的倍半萜聚酮化合物或药物组合物。活性实验显示本发明涉及的倍半萜聚酮类化合物，可作为免疫调节剂用于免疫相关疾病的预防和/或治疗。

Description

一类倍半萜聚酮化合物、药物组合物及其用途
相关申请的交叉引用
本申请要求2022年06月02日提交的中国申请号2022106262290的权益。所述申请号2022106262290据此全文以引用方式并入本文。
技术领域
本发明属于天然药物领域，更具体的涉及一类倍半萜聚酮化合物、药物组合物及其作为免疫调节剂和防治免疫性疾病的用途。
背景技术
免疫系统平衡对身体健康至关重要，当其被打破时容易患免疫性疾病。肿瘤和感染与机体免疫低下相关。器官移植免疫排斥、过敏和自身免疫病与机体免疫反应过强相关[1]，其中，自身免疫病包括炎症性肠病(IBD)、多发性硬化症(MS)和类风湿性关节炎(RA)在内的100余种疾病，发病重，发病率高，发病周期长，无治愈方法，严重危害人类健康。免疫调节剂可通过调节机体的免疫反应(增强、抑制或双向调节作用)，用于治疗免疫功能紊乱所引起的免疫性疾病。对于肿瘤和感染等与免疫力低下相关的疾病，可采用增强机体免疫力的调节剂进行干预。而对于器官移植免疫排斥、过敏和自身免疫病等与机体免疫反应过强相关的疾病，目前主要使用免疫抑制剂来改善疾病症状和预后。
皮质激素、甲氨蝶呤、环孢素A等化学药物属于非特异性免疫抑制剂，长期使用毒副作用大；生物制剂价格昂贵，治疗效果个体差异大，且具有增加病人感染与患肿瘤的风险。因此，开发新型免疫抑制剂来防治与免疫反应过强相关的疾病仍受到全世界的重视。近年来，我们对免疫性疾病的致病机制的研究取得了重要进展。抑制致炎因子IL17表达和促进抑炎因子IL10表达已成为抑制与免疫反应过强相关的免疫性疾病的有效策略，这为研发新型免疫抑制剂提供了新思路。
CD4+T细胞在TGFβ、IL6的参与下分化成Th17细胞。IL17是由Th17细胞主要分泌的强致炎性细胞因子，介导了多种炎症和自身免疫病[2]。越来越多的证据表明，IL17在炎症性肠病、Ⅰ型糖尿病、多发性硬化症、类风湿性关节炎、银屑病、系统性红斑狼疮、哮喘、干燥综合症和强直性脊柱炎等发病中起着关键性的作用，并且与葡萄膜炎、自身免疫性肾炎、自身免疫甲状腺炎、白塞氏病、扁平苔藓、呼吸道疾病(包括非嗜酸粒细胞性哮喘、类固醇抵抗型哮喘和囊性纤维化)、肝脏疾病(包括药物性肝损伤、酒精性肝病、非酒精性脂肪肝、病毒性肝炎、肝细胞癌、自身免疫性肝炎，原发性胆汁性肝硬化和原发性硬化性胆管炎)以 及心血管疾病(包括动脉粥样硬化、心肌梗死、动脉瘤和缺血性脑卒中)相关联。临床使用IL17的抑制剂对银屑病、关节炎和多发性硬化症等多种免疫性疾病进行治疗干预，均显示出一定的疗效[3]。
IL10是一类具有免疫抑制特性和广泛抗炎特性的细胞因子。IL10能调节多种髓系或淋系来源细胞的活性，抑制其产生促炎因子，从而发挥抑制器官移植免疫排斥、过敏、炎症以及自身免疫病的作用[4]。I型调节性T细胞(Tr1)分泌大量的IL10，是一类具有免疫抑制作用的细胞，目前，转输Tr1细胞防治自身免疫性疾病或保护器官移植免疫排斥的临床实验已现疗效[5]。
因此抑制IL17和/或促进IL10的化合物可作为免疫调节剂防治器官移植免疫排斥、过敏、炎症和自身免疫病(炎症性肠病、Ⅰ型糖尿病、多发性硬化症、类风湿性关节炎、银屑病、系统性红斑狼疮、哮喘、干燥综合症和强直性脊柱炎、葡萄膜炎、自身免疫性肾炎、自身免疫甲状腺炎、白塞氏病、扁平苔藓、多种呼吸道疾病、多种肝脏疾病以及多种心血管疾病等)。此外，抑制IL17和/或促进IL10的化合物还可作为免疫调节剂用于脓毒症、痤疮、椎间盘突出、腹腔疾病等与炎症相关的疾病的治疗。IL17还与肿瘤的发生密切相关，尤其是炎症相关的肿瘤。IL10对肿瘤的发生发展具有双向调节的作用。IL10可通过抑制促进肿瘤发生发展的炎性因子的产生以及通过活化肿瘤特异性CD8+T来发挥抗肿瘤作用[4]。因此抑制IL17和/或促进IL10的化合物还可作为免疫调节剂用于肿瘤治疗。
Th2细胞主要分泌细胞因子IL4。IL4具有多种生物学功能，在体液免疫和获得性免疫中发挥重要作用[6]。IL4能诱导B细胞、T细胞活化以及B细胞向浆细胞分化。此外，IL4还能抑制淋巴细胞凋亡、促进巨噬细胞的抗原提呈能力和提高杀伤肿瘤细胞的功能。因此，促进IL4的化合物可作为免疫调节剂用于抗肿瘤、抗感染(尤其是抗寄生虫感染)相关的疾病。
发明内容
本发明的目的在于提供一类倍半萜聚酮化合物、药物组合物及其用途。具体地，发明人从一株漆斑属真菌中发现并分离鉴定了一类倍半萜聚酮化合物，实验证明其具有免疫调节活性，可用于用于免疫相关疾病的预防和/或治疗。
本发明的第一方面提供了一类倍半萜聚酮化合物或其药学上可接受的盐，所述倍半萜聚酮类化合物如式(I)所示：
其中，R1选自：羟基，羰基，乙酰氧基；
R2选自：甲基，羟甲基，乙酰羟甲基，乙酰氧基，醛基，二甲氧基甲基；
R3选自：甲基，羟甲基，乙酰羟甲基，乙酰氧基，醛基，二甲氧基甲基；
或者R2，R3与苯环组成5元内酰胺环或内酯环；
R4，R5，R6，R7为碳原子，并且任一相邻基团间选自双键，其余基团间选自单键；
当R4，R5，R6，R7为碳原子，R5与R6间选自双键，其余基团间选自单键，R2选自羟甲基，R3选自醛基时，R1不可选自羟基或乙酰氧基。
进一步的，所述药学上可接受的盐为式(I)化合物与有机碱或无机碱形成的盐。
更进一步的，所述形成的盐为钠盐、钾盐、钙盐、铁盐、镁盐、锌盐、铝盐、钡盐或铵盐。
优选的，所述倍半萜聚酮类化合物选自式Ⅱ-式X的化合物，具体结构式如下：
本发明的第二方面提供了一种上述化合物的制备方法，包括：由产生如式(I)所示的倍半萜聚酮类化合物的微生物发酵后，再用色谱法分离后得到。
进一步的，所述微生物为漆斑属真菌。
进一步可选的，所述漆斑属真菌为ZLW0801-19，其保藏号为CGMCC No.19039。
本发明的第三方面还提供了制备免疫调节剂的上述式(I)化合物或其药学上可接受的盐。
进一步的，所述免疫调节剂用于免疫相关疾病的预防和/或治疗。
更进一步的，所述免疫调节剂用于防治抑制IL17和/或促进IL10是有益的疾病或适应症。
优选的，所述疾病或适应症选自银屑病、炎症性肠病、I型糖尿病、多发性硬化症、类风湿性关节炎、系统性红斑狼疮、哮喘、干燥综合症、强直性脊柱炎、器官移植免疫排斥、过敏、脓毒症、葡萄膜炎、自身免疫性肾炎、自身免疫甲状腺炎、白塞氏病、自身免疫性肝病、扁平苔藓、脓毒症、痤疮、椎间盘突出、腹腔疾病。
更进一步的，所述免疫调节剂用于防治促进IL4是有益的疾病或适应症。
优选的，所述疾病或适应症为寄生虫感染相关。
本发明的第四方面提供了一种用于免疫调节的药物组合物，包括上述倍半萜聚酮类化合物或其药学上可接受的盐以及药学上可接受的载体。
进一步可选的，所述盐为钠盐、钾盐、钙盐、铁盐、镁盐、锌盐、铝盐、钡盐、铵盐中的任意一种。
进一步可选的，在一个实施方式中药物组合物中含有的活性成份(即本发明化合物)的量可以根据患者的病情、医生诊断的情况特定的加以应用，活性化合物的量或浓度在一个较宽的范围内调节，所述式(I)化合物或其药学上可接受的盐的含量为组合物重量的1-90％。
进一步可选的，药学上可接受的载体包括稀释剂、润滑剂、粘合剂、崩解剂、稳定剂、溶剂等。本发明所述稀释剂包括但不限于淀粉、微晶纤维素、蔗糖、糊精、乳糖、糖粉、葡萄糖等；所述润滑剂包括但不限于硬脂酸镁、硬脂酸、氯化钠、油酸钠、月桂醇硫酸钠、泊洛沙母等；所述粘合剂包括但不限于水、乙醇、淀粉浆、糖浆、羟丙基甲基纤维素、羧甲基纤维素钠、海藻酸钠、聚乙烯吡咯烷酮等；所述崩解剂包括但不限于淀粉泡腾混合物即碳酸氢钠和枸橼酸、酒石酸、低取代羟丙基纤维素等；所述稳定剂包括但不限于多糖如金合欢胶、琼脂、藻酸、纤维素醚和羧甲基甲壳酯等；所述溶剂包括但不限于水、平衡的盐溶液等。
进一步可选的，所述药物组合物为口服制剂或注射剂；优选的，所述口服制剂包括但不限于普通片剂、分散片、肠溶片、颗粒、胶囊、滴丸、散剂、口服液或乳剂中的任意一种；优选的，所述注射剂选自小水针剂、输液剂或冻干粉针剂中的任意一种。
有益效果
本发明所述的倍半萜聚酮类化合物是从微生物发酵来源，便于大量发酵和工业化制备； 活性实验首次发现该类化合物具有显著的免疫调节活性。
具体实施方式
下面将进一步的来举例说明本发明。需要指出的是，所述实施例说明了一些制备或使用方法，然而，要理解的是，这些实施例不限制本发明。本发明的保护范围以所附权利要求书记载的内容为准。
下列实施例中，质谱仪为美国Finnigan公司生产的LCQ-Advantage质谱仪。超导核磁共振仪为Bruker AV-400。薄层色谱用硅胶GF254和柱色谱硅胶(200-300目)均为青岛海洋化工厂产品。反相ODS填料50μm为日本YMC公司产品。中低压液相色谱仪为上海利穗电子科技有限公司产品。液相分离所使用色谱柱为Phenomenex Gemini C18 column(10.0×250mm,5μm)。液相色谱用甲醇和乙腈为色谱纯，水为双重蒸馏水，其他试剂均为分析纯。
实施例中显示的体外细胞水平的实验数据以平均值±标准差(Mean±SD)表示。对于比较两组数据间的差异，采用Two-tailed Student’s t test进行分析；比较多于2组的数据间的差异，采用One-way Anova进行分析。统计学差异采用以下标示：*代表P<0.05，**代表P<0.01，***代表P<0.001，****代表P<0.0001，ns代表差异不显著。采用Graphpad Prism 7.00和FlowJo V10(用于流式)分析获取的数据。
实施例1漆斑属真菌ZLW0801-19大量发酵及其样品前处理方法
(1)漆斑属真菌ZLW0801-19真菌菌株在25℃的马铃薯葡萄糖琼脂(PDA)斜面上培养5天。经PDA斜面活化后接种至4个含马铃薯葡萄糖(PDB)培养基的锥形瓶(250mL)中制备种子液，每个锥形瓶含有100mL PDB培养基，转速200rpm在25℃培养5天制备种子液。在24个锥形瓶(500mL)中进行发酵，每个锥形瓶中含有70g大米，首先向每个锥形瓶中加入蒸馏水(105mL)，将大米浸泡过夜，然后在120℃下高压灭菌30分钟。冷却至室温后，向每个锥形瓶接种5.0mL种子液，并在室温避光培养51天。
(2)将发酵物加入乙酸乙酯进行浸泡提取3次，将提取液减压浓缩至干，得到粗提物(81.7g)。
实施例2式(II)—式(X)化合物的制备
实施例1中乙酸乙酯粗提物(81.7g)利用硅胶柱层析，依次采用环己烷-乙酸乙酯(100:0,98:2,95:5,90:10,80:20,70:30,50:50,0:100,v/v)和甲醇进行洗脱，每个梯度洗脱体积6L，得到7个馏分样品(F1-F7)。馏分F5经中低压液相ODS柱层析，依次采用甲醇-水(70:30,80:20, 90:10,and 100:0,v/v)洗脱，每个梯度洗脱体积2.5L，得到9个馏分样品(F5.1-F5.9)。馏分F5.2经中低压液相ODS柱层析，依次采用甲醇-水(60:40,70:30,80:20,90:10,v/v)洗脱，每个梯度洗脱体积0.7L，得到5个馏分样品(F5.2.1-F5.2.5)。馏分F5.2.4(387mg)经反相制备级HPLC制备(Cosmosil Packed C18 column)，使用流速为3mL/min的乙腈-水(50:50,v/v)进行洗脱，得到式(VIII)化合物(tR:53.6min,26.2mg)。将馏分F5.2.5(365mg)经反相制备级HPLC制备(Phenomenex,Packed C18 column)，使用流速为8mL/min的乙腈-水(55:45,v/v)进行洗脱，得到式(X)化合物(tR:86.4min,7.0mg)。馏分F5.3经凝胶柱LH-20柱层析，采用甲醇洗脱得到7个馏分(F5.3.1–F5.3.7)。馏分F5.3.7(144mg)经反相制备级HPLC制备(Cosmosil Packed C18 column)，使用流速为3mL/min的甲醇-水(75:25,v/v)进行洗脱，得到式(II)化合物(tR:63.7min,17.0mg)和式(III)化合物(tR:69.9min,17.5mg)。馏分F5.7经硅胶柱层析，依次采用环己烷-乙酸乙酯(90:10,85:15,80:20,75:25,70:30,60:40,50:50,0:100,v/v)洗脱，每个梯度洗脱体积1.0L，得到8个馏分样品(F5.7.1-F5.7.8)。馏分F5.7.4(62.1mg)经反相制备级HPLC制备(Cosmosil Packed C18 column)，使用流速为3mL/min的甲醇-水(82:18,v/v)进行洗脱，得到式(IV)化合物(tR:21.3min,12.1mg)。馏分F6经中低压液相ODS柱层析，依次采用甲醇-水(60:40,70:30,80:20,90:10,100:0,v/v)洗脱，每个梯度洗脱体积2.5L，得到7个馏分样品(F6.1-F6.7)。馏分F6.3经硅胶柱层析，依次采用环己烷-乙酸乙酯(75:25,70:30,60:40,50:50,0:100v/v)洗脱，每个梯度洗脱体积0.3L，得到6个馏分样品(F6.3.1-F6.3.6)。馏分F6.3.6(349.7mg)经反相制备级HPLC制备(Cosmosil Packed C18 column)，使用流速为3mL/min的乙腈-水(40:60,v/v)进行洗脱，得到式(VII)化合物(tR:17.5min,7.7mg)。馏分F6.4经中低压液相ODS柱层析，采用甲醇-水(70:30,v/v)洗脱，洗脱体积0.7L，得到5个馏分样品(F6.4.1-F6.4.5)。将馏分F6.4.2(1630mg)经反相制备级HPLC制备(Phenomenex,Packed C18 column)，使用流速为8mL/min的甲醇-水(70:30,v/v)进行洗脱，得到式(IX)化合物(tR:25.4min,4.0mg)。馏分F6.4.3(212.9mg)经反相制备级HPLC制备(Cosmosil Packed C18 column)，使用流速为3mL/min的乙腈-水(55:45,v/v)进行洗脱，得到式(V)化合物(tR:63.3min,10.3mg)和式(VI)化合物(tR:25.0min,10.1mg)。
理化常数如下：
式(II)化合物：无色片状晶体；(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)205(4.31),225(4.28),221(4.10),300(4.27)nm；ECD(c 3.4×10–4M CH3OH)λmax(Δε)221(+1.86),245(+1.71),334(–0.55),306(–0.74)；IR(KBr)νmax 3399,3137,2974,2929,2864,1616,1430,1293,1262,1117,1045cm–1；ESI-MS(positive)m/z 373[M+H]+,395[M+Na]+；ESI-MS (negative)m/z 371[M–H]–,743[2M–H]–；HR-ESI-MS(positive)m/z 373.2379[M+H]+(calcd.for C23H33O4,373.2379)，确定化合物分子式为C23H32O4；1H和13C NMR见表1。
式(III)化合物：淡黄色固体；(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)205(4.47),226(4.43),242(4.31),300(4.44)nm；IR(KBr)νmax 3430,2961,2931,2868,1719,1622,1435,1265,1039cm–1；ESI-MS(positive)m/z 453[M+Na]+,883[2M+Na]+；ESI-MS(negative)m/z429[M–H]–,859[2M–H]–；HR-ESI-MS(positive)m/z 431.2433[M+H]+(calcd.for C25H35O6,431.2434)，确定化合物分子式为C25H34O6；1H和13C NMR见表1。
式(IV)化合物：淡黄色油状；(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)205(4.52),226(4.47),242(4.31),298(4.45)nm；IR(KBr)νmax 3279,2934,2867,1708,1618,1434,1267,1032cm–1；ESI-MS(positive)m/z 495[M+Na]+,967[2M+Na]+；ESI-MS(negative)m/z 471[M–H]–,943[2M–H]–；HR-ESI-MS(positive)m/z 495.2368[M+Na]+(calcd.for C27H36O7Na,495.2359)，确定化合物分子式为C27H36O7；1H和13C NMR见表1。
式(V)化合物：淡黄色油状；(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)205(4.37),225(4.35),239(4.18),300(4.35)nm；ECD(c 3.2×10–4M CH3OH)λmax(Δε)201(+1.34),235(+2.04),274(–0.80),324(+0.46)；IR(KBr)νmax 3411,2929,2858,1618,1434,1386,1267,1240,1125,1050cm–1；ESI-MS(positive)m/z 387[M+H]+,409[M+Na]+；ESI-MS(negative)m/z 385[M–H]–,771[2M–H]–；HR-ESI-MS(positive)m/z 409.2009[M+Na]+(calcd.for C23H30O5Na,409.2015)，确定化合物分子式为C23H30O5；1H和13C NMR见表2。
式(VI)化合物：淡黄色固体；(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)206(4.36),226(4.30),240(4.16),299(4.33)nm；ECD(c 5.8×10–4M CH3OH)λmax(Δε)224(+0.99),249(+3.46),302(–0.76),361(–1.02)；IR(KBr)νmax 3399,2934,2850,1617,1386,1267,1245,1125,1050,988cm–1；ESI-MS(positive)m/z 455[M+Na]+,895[2M+Na]+；ESI-MS(negative)m/z 431[M–H]–,863[2M–H]–；HR-ESI-MS(positive)m/z 455.2415[M+Na]+(calcd.for C25H36O6Na,455.2410)，确定化合物分子式为C25H36O6；1H和13C NMR见表2。
式(VII)化合物：淡绿色固体；(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)215(4.57),262(4.06),305(3.27)nm；IR(KBr)νmax 3385,2929,2863,1675,1452,1386,1262cm–1；ESI-MS(positive)m/z 386[M+H]+,793[2M+Na]+；ESI-MS(negative)m/z 769[2M–H]–；HR-ESI-MS(positive)m/z 386.2340[M+H]+(calcd.for C23H32NO4,386.2331)，确定化合物分子式为C23H31NO4；1H和13C NMR见表2。
式(VIII)化合物：淡绿色固本；(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)206(4.44),223(4.46),240(4.42),298(4.33)nm；ECD(c 6.0×10–4M CH3OH)λmax(Δε)204(+7.00), 247(+18.5),330(+1.81)；IR(KBr)νmax 3283,2970,2925,2867,1621,1618,1430,1267,1005cm–1；ESI-MS(positive)m/z 409[M+Na]+,795[2M+Na]+；ESI-MS(negative)m/z 385[M–H]–,771[2M–H]–；HR-ESI-MS(positive)m/z 387.2176[M+H]+(calcd.for C23H31O5,387.2176)，确定化合物分子式为C23H30O5；1H和13C NMR见表3。
式(IX)化合物：白色固体；(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)206(4.39),226(4.06),289(3.69)nm；ECD(c 6.4×10–4M CH3OH)λmax(Δε)220(+3.81),236(+3.09),246(+3.74),323(–0.54)；IR(KBr)νmax3301,2961,2872,1628,1462,1284,1125,1076cm–1；ESI-MS(positive)m/z 389[M+H]+,411[M+Na]+；ESI-MS(negative)m/z 387[M–H]–,775[2M–H]–；HR-ESI-MS(positive)m/z 389.2329[M+H]+(calcd.for C23H33O5,389.2328)，确定化合物分子式为C23H32O5；1H和13C NMR见表3。
式(X)化合物：白色固体；(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)206(4.41),227(4.09),290(3.76)nm；ECD(c 2.9×10–4M CH3OH)λmax(Δε)220(+5.47),235(+4.19),246(+5.58),320(–1.30)；IR(KBr)νmax 3479,29743,2881,1740,1623,1489,1270,1045cm–1；ESI-MS(positive)m/z 453[M+Na]+；ESI-MS(negative)m/z 429[M–H]–,HR-ESI-MS(positive)m/z 453.2246[M+Na]+(calcd.for C25H34O6Na,453.2353)，确定化合物分子式为C25H34O6；1H和13C NMR见表3。
表1式(II)—式(IV)化合物的13C NMR及1H NMR数据和归属


a The data recorded in DMSO-d6(1H NMR for300MHz,13C NMR for75MHz)
b The data recorded in DMSO-d6(1H NMR for400MHz,13C NMR for100MHz)
表2式(V)—式(VII)化合物的13C NMR及1H NMR数据和归属


a The data recorded in DMSO-d6(1H NMR for300MHz,13C NMR for75MHz)
b The data recorded in DMSO-d6(1H NMR for400MHz,13C NMR for100MHz)
表3式(VIII)—式(X)化合物的13C NMR及1H NMR数据和归属

a The data recorded in DMSO-d6(1H NMR for 300MHz,13C NMR for 75MHz)
实施例3倍半萜聚酮类化合物式(II)—式(X)对IL17表达的影响
T细胞分化后产生特定细胞因子，如Th17产生细胞因子IL17，Th2产生细胞因子IL4，Tr1产生细胞因子IL10。IL17-GFP小鼠、IL4-eGFP小鼠和IL10-eGFP小鼠(均引自JAX公司)是带有绿色荧光报告基因(GFP)的转基因小鼠，其在T细胞分化后产生的特定细胞因子的基因下游连接上GFP荧光蛋白编码序列。因此可用荧光探测系统检测GFP的表达量来衡量细胞因子的表达水平。
提取荧光报告小鼠IL17-GFP小鼠的原代脾脏淋巴细胞，在Th17分化条件下与化合物共培养，通过流式细胞术检测IL17-GFP水平来评价化合物对IL17表达的影响(此方法使用原代淋巴细胞更好模拟复杂的生理过程；使用GFP小鼠和流式细胞术使实验简便，重复性好且结果可靠)。具体实验步骤如下：
Anti-mouse CD3 Ab(antibody，抗体)包板：在96孔板中加入IMDM培养基稀释的终浓度为10μg/mL的anti-mouse CD3 Ab，37℃孵育2小时。
制备单细胞悬液：无特定病原体(SPF)环境下饲养的IL17-GFP小鼠，颈椎脱臼处死，取脾脏置于IMDM培养基中，用灭菌的病理玻片在超净台中磨碎脾脏，磨碎后的细胞悬液用40μm cell strainer滤网过滤至离心管；后离心(4℃，1400rpm，7分钟)，弃上清，加红细胞裂解液，混匀，室温静置5分钟，后加IMDM终止裂解红细胞；40μm cell strainer滤网过滤后再离心(4℃，1400rpm，7分钟)，弃上清，用含10％FBS的IMDM重悬细胞；细胞稀释100倍，显微镜下细胞计数，根据计数结果，配成1×106个/mL(终浓度)的细胞悬液。
加入Th17细胞分化诱导因子：anti-mouse CD28 Ab(1μg/mL)，rhTGFb1.2(0.25ng/mL)，rmIL6(40ng/mL)，anti-mouse IL4(5μg/mL)，anti-mouse IFNγ(5μg/mL)(此处细胞因子均为终浓度)。
待检测样本稀释：用含10％FBS的IMDM将化合物稀释成10μM(终浓度)；将抑制IL17的阳性化合物SR2211稀释成1μM(终浓度)。
铺板：将包板的抗体吸去，用IMDM洗一遍，每孔加入100μL细胞悬液和100μL终浓度样本溶液共培养(如100μL4×106个/mL浓度的细胞悬液和100μL 20μM化合物共培养，培养体系中细胞终浓度为2×106个/mL，化合物浓度为10μM)。
细胞培养：样本溶液和细胞置于37℃，5％的CO2的湿润培养箱中共培养72小时。
细胞表面染色和流式检测：收取培养的细胞于流式管，加入3mL预冷的PBS，离心(4℃，1400rpm，7分钟)，弃上清，后在50μL细胞悬液中加入0.25μL APC anti-mouse CD4抗体表面染色，4℃避光放置20分钟。后用1mL预冷的PBS重悬细胞，补2mL PBS，再离心(4℃，1400rpm，7分钟)，弃上清，每管加200μL PBS，流式检测分析GFP+的细胞占CD4+细胞 的比率。
其中IMDM培养基和胎牛血清(FBS)购自Gibco公司；anti-mouse CD28 Ab，anti-mouse CD3Ab，anti-mouse IL4，anti-mouse IFNγ，APC anti-mouse CD4购自Sungene公司；rmIL6购自Peprotech公司；rhTGFb1.2购自R&D公司；红细胞裂解液购自Tiangen公司；PBS购自Solarbio公司。
采用公式：(DMSO组GFP+占CD4+的比率-化合物组GFP+占CD4+的比率)/DMSO组GFP+占CD4+的比率×100％来计算化合物对IL17表达的相对抑制活性(Relative Inhibition Activity)。
结果如表4所示：脾脏淋巴细胞向Th17细胞分化条件下，本发明化合物式(II)、式(III)、式(IX)和式(X)对IL17表达的相对抑制活性显著增强。这表明，本发明化合物式(II)、式(III)、式(IX)和式(X)具有抑制IL17表达的效果，可用于防治免疫相关疾病尤其是IL17介导的免疫性疾病。
表4式(II)—式(X)化合物对IL17表达影响(10μM)
实施例4倍半萜聚酮类化合物式(II)—式(X)对IL4表达的影响
提取荧光报告小鼠IL4-eGFP小鼠的原代脾脏淋巴细胞，在Th2分化条件下与化合物共培养，通过流式细胞术检测IL4-GFP水平来评价化合物对IL4表达的影响。Th2使用的培养基为RPMI-1640；细胞密度为2×106个/mL；使用的分化条件为：anti-mouse CD28 Ab(1μg/mL)，rmIL2(2ng/mL)，rmIL4(40ng/mL)，Anti-mouse IFNγ(10μg/mL)。其他Th2分化的实验步骤同实施例3中的Th17分化一致。
其中rmIL4，rmIL2购自Peprotech公司；RPMI-1640培养基购自Sigma公司。
在评价化合物对IL4的影响时，采用公式：化合物组GFP+占CD4+的比率/DMSO组GFP+占CD4+的比率×100％来计算化合物对IL4的相对活性(Relative Activity)。
具体结果如表5所示：脾脏淋巴细胞向Th2细胞分化条件下，本发明化合物式(II)、式(VIII)、式(IX)和式(X)对IL4的相对活性显著增强。这表明本发明化合物式(II)、式(VIII)、式(IX)和式(X)具有促进IL4表达的效果，可用于抗寄生虫感染。
表5式(II)—式(XII)化合物对IL4表达影响(10μM)
实施例5倍半萜聚酮类化合物式(II)—式(X)对IL10表达的影响
提取分选荧光报告小鼠IL10-eGFP小鼠的原代脾脏淋巴细胞，在Tr1分化条件下与化合物共培养，通过流式细胞术检测IL10-eGFP水平来评价化合物对IL10表达的影响。Tr1使用的培养基为RPMI-1640；细胞密度为1×106个/mL；使用的分化条件为：anti-mouse CD28 Ab(1μg/mL)，rmIL27(50ng/mL)，rhTGFb1.2(0.5ng/mL)。其他Tr1分化的实验步骤同实施例3中的Th17分化一致。
其中rmIL27购自Biolegend公司；RPMI-1640培养基购自Sigma公司。
在评价化合物对IL10的影响时，采用公式：化合物组GFP+占CD4+的比率/DMSO组GFP+占CD4+的比率×100％来计算化合物对IL10的相对活性(Relative Activity)。
具体结果如表6所示：脾脏淋巴细胞向Tr1细胞分化条件下，本发明化合物式(II)、式(IV)、式(V)、式(VI)、式(VII)、式(VIII)、式(IX)和式(X)对IL10表达的相对活性显著增强。这表明上述化合物具有促进IL10表达的效果，可发挥广谱的抗炎作用，用于抗炎和自身免疫性疾病。
表6式(II)—式(X)化合物对IL10表达影响(20μM)
综合上述实施例3、4和5的结果可知：倍半萜聚酮类化合物具有抑制IL17、促进IL4和促进IL10表达的活性，可用于免疫性疾病的防治。
本发明内容仅仅举例说明了要求保护的一些具体实施方案，其中一个或更多个技术方案中所记载的技术特征可以与任意的一个或多个技术方案相组合，这些经组合而得到的技术方案也在本申请保护范围内，就像这些经组合而得到的技术方案已经在本发明公开内容中具体记载一样。
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Claims (17)

  1. 一类倍半萜聚酮化合物或其药学上可接受的盐，其特征在于，所述倍半萜聚酮化合物如式(I)所示：
    其中，R1选自：羟基，乙酰氧基，或＝O；
    R2选自：甲基，羟甲基，乙酰羟甲基，醛基，或二甲氧基甲基；
    R3选自：甲基，羟甲基，乙酰羟甲基，或醛基；
    或者R2，R3与苯环组成5元内酰胺环或内酯环；
    R4，R5，R6，R7为碳原子，并且任一相邻基团间选自双键，其余基团间选自单键；
    当R4，R5，R6，R7为碳原子，R5与R6间选自双键，其余基团间选自单键，R2选自羟甲基，R3选自醛基时，R1不可选自羟基或乙酰氧基。
  2. 根据权利要求1所述一类倍半萜聚酮化合物或其药学上可接受的盐，其特征在于，所述药学上可接受的盐为式(I)化合物与有机碱或无机碱形成的盐。
  3. 根据权利要求2所述的倍半萜聚酮类化合物或其药学上可接受的盐，其特征在于，所述形成的盐为钠盐、钾盐、钙盐、铁盐、镁盐、锌盐、铝盐、钡盐或铵盐。
  4. 根据权利要求1-3中任一项所述的倍半萜聚酮类化合物或其药学上可接受的盐，其特征在于，所述倍半萜聚酮类化合物选自式Ⅱ-式X的化合物，具体结构式如下：
  5. 根据权利要求1-4中任一项所述倍半萜聚酮化合物或其药学上可接受的盐的制备方法，其特征在于，包括：由产生如式(I)所示的倍半萜聚酮类化合物的微生物，经发酵后再用色谱法分离后得到。
  6. 根据权利要求5所述的制备方法，其特征在于，所述微生物为漆斑属真菌。
  7. 根据权利要求6所述的制备方法，其特征在于，所述漆斑属真菌为ZLW0801-19，其保藏号为CGMCC No.19039。
  8. 权利要求1-4中任意一项所述倍半萜聚酮类化合物或其药学上可接受的盐在制备免疫调节剂中的用途。
  9. 根据权利要求8所述的用途，其特征在于，所述免疫调节剂用于免疫相关疾病的预防和/或治疗。
  10. 根据权利要求9所述的用途，其特征在于，所述的免疫相关疾病的预防和/或治疗是防治抑制IL17和/或促进IL10是有益的疾病或适应症。
  11. 根据权利要求10所述的用途，其特征在于，所述疾病或适应症选自银屑病、炎症性肠病、I型糖尿病、多发性硬化症、类风湿性关节炎、系统性红斑狼疮、哮喘、干燥综合症、强直性脊柱炎、器官移植免疫排斥、过敏、脓毒症、葡萄膜炎、自身免疫性肾炎、自身免疫甲状腺炎、白塞氏病、自身免疫性肝病、药物性肝损伤、扁平苔藓、痤疮、椎间盘突出、腹腔疾病。
  12. 根据权利要求9所述的用途，其特征在于，所述的免疫相关疾病的预防和/或治疗是防治促进IL4是有益的疾病或适应症。
  13. 根据权利要求12所述的用途，其特征在于，所述疾病或适应症为寄生虫感染相关。
  14. 一种用于免疫调节的药物组合物，其特征在于，包括权利要求1-4中任意一项所述倍 半萜聚酮化合物或其药学上可接受的盐以及药学上可接受的载体。
  15. 根据权利要求14所述的药物组合物，其特征在于，所述倍半萜聚酮化合物或其药学上可接受的盐的含量为组合物重量的1-90％。
  16. 根据权利要求14-15所述的药物组合物，其特征在于，所述药物组合物为口服制剂或注射剂。
  17. 根据权利要求16所述的药物组合物，其特征在于，所述口服制剂选自普通片剂、分散片、肠溶片、颗粒、胶囊、滴丸、散剂、口服液或乳剂，所述注射剂为小水针剂、输液剂或冻干粉针。
PCT/CN2023/097906 2022-06-02 2023-06-01 一类倍半萜聚酮化合物、药物组合物及其用途 WO2023232125A1 (zh)

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