CN115403571A - 一种牛蒡子苷元衍生物、制备方法及应用 - Google Patents
一种牛蒡子苷元衍生物、制备方法及应用 Download PDFInfo
- Publication number
- CN115403571A CN115403571A CN202211132063.3A CN202211132063A CN115403571A CN 115403571 A CN115403571 A CN 115403571A CN 202211132063 A CN202211132063 A CN 202211132063A CN 115403571 A CN115403571 A CN 115403571A
- Authority
- CN
- China
- Prior art keywords
- arctigenin
- drying
- derivative
- arctigenin derivative
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- NQWVSMVXKMHKTF-JKSUJKDBSA-N (-)-Arctigenin Chemical class C1=C(OC)C(OC)=CC=C1C[C@@H]1[C@@H](CC=2C=C(OC)C(O)=CC=2)C(=O)OC1 NQWVSMVXKMHKTF-JKSUJKDBSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 229940124599 anti-inflammatory drug Drugs 0.000 claims abstract description 6
- 239000002260 anti-inflammatory agent Substances 0.000 claims abstract 2
- YYGRXNOXOVZIKE-UHFFFAOYSA-N Arctigenin Natural products COC1CCC(CC2COC(=O)C2CC3CCC(O)C(C3)OC)CC1OC YYGRXNOXOVZIKE-UHFFFAOYSA-N 0.000 claims description 16
- OIFFJDGSLVHPCW-UHFFFAOYSA-N Guayarol Natural products COc1ccc(CC2C(Cc3ccc(O)c(O)c3)COC2=O)cc1OC OIFFJDGSLVHPCW-UHFFFAOYSA-N 0.000 claims description 16
- NQWVSMVXKMHKTF-UHFFFAOYSA-N L-Arctigenin Natural products C1=C(OC)C(OC)=CC=C1CC1C(CC=2C=C(OC)C(O)=CC=2)C(=O)OC1 NQWVSMVXKMHKTF-UHFFFAOYSA-N 0.000 claims description 16
- NWFYESYCEQICQP-UHFFFAOYSA-N methylmatairesinol Natural products C1=C(OC)C(OC)=CC=C1CC1C(=O)OCC1CC1=CC=C(O)C(OC)=C1 NWFYESYCEQICQP-UHFFFAOYSA-N 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 235000019439 ethyl acetate Nutrition 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 3
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 239000012267 brine Substances 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- WFJRIDQGVSJLLH-UHFFFAOYSA-N methyl n-aminocarbamate Chemical compound COC(=O)NN WFJRIDQGVSJLLH-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims 1
- 206010061218 Inflammation Diseases 0.000 abstract description 10
- 230000004054 inflammatory process Effects 0.000 abstract description 10
- 150000001875 compounds Chemical class 0.000 abstract description 9
- 238000002474 experimental method Methods 0.000 abstract description 4
- 102000009571 Macrophage Inflammatory Proteins Human genes 0.000 abstract description 3
- 108010009474 Macrophage Inflammatory Proteins Proteins 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 15
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 6
- NSGDYZCDUPSTQT-UHFFFAOYSA-N N-[5-bromo-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxopyridin-3-yl]cycloheptanecarboxamide Chemical compound Cc1c(Br)cn(Cc2ccc(F)cc2)c(=O)c1NC(=O)C1CCCCCC1 NSGDYZCDUPSTQT-UHFFFAOYSA-N 0.000 description 6
- 230000003110 anti-inflammatory effect Effects 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 210000002540 macrophage Anatomy 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 102000011767 Acute-Phase Proteins Human genes 0.000 description 1
- 108010062271 Acute-Phase Proteins Proteins 0.000 description 1
- 208000020576 Adrenal disease Diseases 0.000 description 1
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 1
- 240000005528 Arctium lappa Species 0.000 description 1
- 235000003130 Arctium lappa Nutrition 0.000 description 1
- 235000008078 Arctium minus Nutrition 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- FIMJSWFMQJGVAM-UHFFFAOYSA-N chloroform;hydrate Chemical compound O.ClC(Cl)Cl FIMJSWFMQJGVAM-UHFFFAOYSA-N 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 108010017796 epoxidase Proteins 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种牛蒡子苷元衍生物、制备方法及应用,其中,所述牛蒡子苷元衍生物的分子式为:C31H32FN3O7;分子量为:577.61;经试验证明,本发明有效抑制LPS诱导的巨噬细胞炎症反应,可用于抗炎药物制备领域。本发明化合物的制备方法具有反应过程操作简单,反应条件温和,所用试剂便宜易得的优点。
Description
技术领域
本发明化合物技术领域,具体涉一种牛蒡子苷元衍生物、制备方法及应用。
背景技术
炎症作为严重威胁到人类健康的一种常见病和多发病,多种外界刺激以及细菌感染均可导致机体发生炎症反应。它通过促进细胞因子,趋化因子和急性期蛋白的产生并协调转运等一系列步骤,使免疫系统细胞迁移至刺激靶点。一方面炎症快速应答可保护机体,清除伤害性刺激使创伤部位逐渐恢复原状。另一方面,过度的炎症反应和慢性炎症会导致组织损伤和纤维化,因此,它与多种疾病密切相关。
同时,在治疗炎症反应中,最初使用的最多的是可以良好的控制炎症并且能高效地消除炎症反应引起的机体功能性障碍的糖皮质激素类固醇类。抗炎药物中有一些皮质类固醇等甾体抗炎药物,价格昂贵之外可能还会引起机体的几种不利影响,如可引起机体肾上腺皮质功能障碍以及器官性骨质疏松等并发症。非甾体类抗炎药是最早从含水杨酸的植物中提取出来的一类具有镇痛、解热、抗炎作用的药物,非留体类抗炎药的抗炎作用机制是通过抑制机体环氧化酶活性,进一步来抑制机体局部前列腺素的产生,从而发挥抗炎药理作用。自古以来,很多人患有炎症的病人会用植物中的化学物质来处理,这一事实从阿司匹林的发现中可以看出,这时在抗炎研究中具有生物活性的天然产物以及他的修饰是值得关注的。
发明内容
针对现有技术的不足,本发明旨在提供一种牛蒡子苷元衍生物、制备方法及应用。
为了实现上述目的,本发明采用如下技术方案:
一种牛蒡子苷元衍生物,其特征在于,所述牛蒡子苷元衍生物的结构式如下:
其中,所述牛蒡子苷元衍生物的分子式为:C31H32FN3O7;分子量为:577.61。
需要说明的是,本发明的牛蒡子苷元衍生物名称为:
2-(2-(4-(((3R,4R)-4-(3,4-dimethoxybenzyl)-2-oxotetrahydrofuran-3-yl)methyl)-2-methoxyphenoxy)ethyl)-4-(4-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one。简称:C2。
本发明还提供一种牛蒡子苷元衍生物的制备方法,所述方法包括以下步骤:
S1将4-氟苯胺(1.11g,0.01mol),肼基甲酸甲酯(1.45g,0.015mol),原甲酸三乙酯(2.22g,0.015mol),乙醇(25mL)置于圆底烧瓶中,78℃搅拌48小时;接着加入甲醇钠(0.81g,0.015mol)在78℃回流24h;将反应物倒入冰水中搅拌,析出大量白色固体,抽滤烘干得到中间体A;
S2中间体A(100mg,0.56mmol)和1,2-二溴乙烷(209mg,1.11mmol),K2CO3(231mg,1.68mmol)在DMF(5mL)中60℃搅拌4h;用TLC测试反应完全后,用EtOAc萃取3次,有机相用饱和氯化钠溶液洗涤,洗涤2次,用适量的无水Na2SO4干燥,减压过滤旋干,得到粗产物B;
S3再称取牛蒡子苷元(50mg,0.11mmol),中间体B(135mg,0.13mmol)加入K2CO3(41.4mg,0.30mmol)和DMF(5mL),全部置于25mL的圆底烧瓶中,在60℃的剧烈搅拌下过夜反应。用TLC测试反应完全后,用EtOAc萃取3次,有机相用饱和碳酸氢钠溶液和盐水洗涤,洗涤2次,用适量的无水Na2SO4干燥,减压过滤旋干,得到粗产物。用硅胶色谱法进行纯化,得到化合物C31H32FN3O7。
需要说明的是,上述制备过程的反应式如下:
本发明还提供一种牛蒡子苷元衍生物的应用,所述牛蒡子苷元衍生物可用于抗炎药物的成分之一。
本发明有益效果在于:
提供了一种新的化合物—牛蒡子苷元衍生物,体外毒性实验表明,化合物在100μM没有毒性。体外抗炎症活性实验表明,该化合物在30μM显著的减少了LPS诱导的RAW264.7细胞释放NO,抑制率达38.01%,且抑制能力显著优于先导化合物牛蒡子苷元(抑制率为21.41%),可以有效抑制LPS诱导的巨噬细胞炎症反应,用于抗炎药物制备领域。本发明化合物的制备方法具有反应过程操作简单,反应条件温和,所用试剂便宜易得的优点。
附图说明
图1为牛蒡子苷元(ARG)和化合物C2在100μM浓度下对小白鼠巨噬细胞(RAW264.7)的细胞存活率影响;
图2为牛蒡子苷元(ARG)和化合物C2对LPS诱导的RAW264.7细胞NO释放的抑制作用。
具体实施方式
以下将对本发明作进一步的描述,需要说明的是,以下实施例以本技术方案为前提,给出了详细的实施方式和具体的操作过程,但本发明的保护范围并不限于本实施例。
实施例
本发明的牛蒡子苷元衍生物的制备方法如下:
S1将4-氟苯胺(1.11g,0.01mol),肼基甲酸甲酯(1.45g,0.015mol),原甲酸三乙酯(2.22g,0.015mol),乙醇(25mL)置于圆底烧瓶中,78℃搅拌48小时;接着加入甲醇钠(0.81g,0.015mol)在78℃回流24h;将反应物倒入冰水中搅拌,析出大量白色固体,抽滤烘干得到中间体A;
S2中间体A(100mg,0.56mmol)和1,2-二溴乙烷(209mg,1.11mmol),K2CO3(231mg,1.68mmol)在DMF(5mL)中60℃搅拌4h;用TLC测试反应完全后,用EtOAc萃取3次,有机相用饱和氯化钠溶液洗涤,洗涤2次,用适量的无水Na2SO4干燥,减压过滤旋干,得到粗产物B;
S3再称取牛蒡子苷元(50mg,0.11mmol),中间体B(135mg,0.13mmol)加入K2CO3(41.4mg,0.30mmol)和DMF(5mL),全部置于25mL的圆底烧瓶中,在60℃的剧烈搅拌下过夜反应。用TLC测试反应完全后,用EtOAc萃取3次,有机相用饱和碳酸氢钠溶液和盐水洗涤,洗涤2次,用适量的无水Na2SO4干燥,减压过滤旋干,得到粗产物。用硅胶色谱法进行纯化,得到化合物C31H32FN3O7。
所述牛蒡子苷元衍生物的结构式如下:
C2核磁共振数据如下:yield 83%.1H-NMR(300MHz,CDCl3)δ:7.67(s,1H,triazolone-H),7.53(s,2H,Ar-H),7.19(t,J=9Hz,2H,Ar-H),6.89(t,J=9Hz,1H,Ar-H),6.78-6.64(m,3H,Ar-H),6.58-6.48(m,2H,Ar-H),4.38-4.10(m,5H),3.84(t,J=9Hz,10H),2.95(s,2H),2.71-2.51(m,4H).13C-NMR(75MHz,CDCl3)δ:178.63,151.70,150.04,149.03,147.87,146.69,133.39,132.92,132.78(2C),131.68,130.39,123.26(2C),121.46,121.12,120.55,114.88,113.31,111.85,111.37,71.21,66.47,56.08,56.00,55.92,46.54,45.07,41.11,38.16,34.51.
通过以下实施例进一步验证本发明的具备抗炎能力。
实施例2
药物组合物
每片含100mg活性成分的1000片片剂配方:
化合物C2 100g
羟丙基纤维素 2g
小麦淀粉 10g
乳糖 100g
硬质酸镁 3g
滑石 3g
所用剂量应适应与疾病的性质和严重程度,给药途径以及患者的年龄和体重。日剂量在0.1mg-1.0g之间变化,而且可以一次或数次给药。
实施例3
采用MTT法通过观察的细胞活力分析评估牛蒡子苷元(ARG)及牛蒡子苷元衍生物C2在100μM浓度下对RAW264.7细胞的毒性。
实验材料:培养箱(美国Thermo公司)、小白鼠巨噬细胞(RAW264.7)细胞株(美国ATCC公司)、DMEM培养基、胎牛血清(FBS)、青霉素、链霉素、MTT(美国Sigma公司)。
实验方法:将RAW264.7巨噬细胞以1×104细胞/孔的密度接种在96孔板中的完全培养基中,待细胞贴壁后,分别用牛蒡子苷元和衍生物C2(100μM)预处理细胞24小时后,弃去培养液,加入MTT溶液,终浓度为2mg/mL,避光,继续孵育4h,取出MTT溶液,再加入150μLDMSO溶解,摇床震荡10min,在波长为492nm的酶标仪(ELx 800,BioTek,Highland Park,Winooski,VT,USA)上读取光密度(OD),然后分析数据。
实验结果:在100μM浓度下,牛蒡子苷元及其衍生物C2无明显细胞毒性。
实施例4
通过构建LPS诱导的RAW264.7细胞模型,采用Griess法检测合物对NO释放量的影响来评价化合物的抗炎活性。
实验材料:培养箱(美国Thermo公司)、小白鼠巨噬细胞(RAW264.7)细胞株(美国ATCC公司)、DMEM培养基、胎牛血清(FBS)、青霉素、链霉素(美国Sigma公司),Griess试剂盒(碧云天生物技术有限公司)。
实验方法:将RAW264.7小鼠巨噬细胞接种在24孔板上,密度为3×105至5×105细胞/孔,将接种过细胞的24孔板置于细胞培养箱中孵育12小时。吸除原培养基,实验组加入溶解牛蒡子苷元或衍生物C2(30μM)的DMEM培养基,剩余组加入等体积的空白DMEM培养基,预处理1小时后,模型组和实验组加入含有LPS(0.5μg/mL)的DMEM培养基,空白组给予相同体积的空白DMEM培养基,孵育24小时,收集培养上清液,使用Griess法,参照试剂盒附带说明书逐步操作,最终测定并计算NO含量。
实验结果:化合物C2可显著减少LPS诱导的RAW264.7细胞释放NO。与同浓度(30μM)的先导化合物牛蒡子苷元(ARG)相比,化合物C2的抑制能力明显增强。说明化合物C2可以有效抑制LPS诱导的巨噬细胞炎症反应。
对于本领域的技术人员来说,可以根据以上的技术方案和构思,给出各种相应的改变和变形,而所有的这些改变和变形,都应该包括在本发明权利要求的保护范围之内。
Claims (3)
2.一种制备如权利要求1所述的牛蒡子苷元衍生物的方法,其特征在于,所述方法包括以下步骤:
S1将4-氟苯胺(1.11g,0.01mol),肼基甲酸甲酯(1.45g,0.015mol),原甲酸三乙酯(2.22g,0.015mol),乙醇(25mL)置于圆底烧瓶中,78℃搅拌48小时;接着加入甲醇钠(0.81g,0.015mol)在78℃回流24h;将反应物倒入冰水中搅拌,析出大量白色固体,抽滤烘干得到中间体A;
S2中间体A(100mg,0.56mmol)和1,2-二溴乙烷(209mg,1.11mmol),K2CO3(231mg,1.68mmol)在DMF(5mL)中60℃搅拌4h;用TLC测试反应完全后,用EtOAc萃取3次,有机相用饱和氯化钠溶液洗涤,洗涤2次,用适量的无水Na2SO4干燥,减压过滤旋干,得到粗产物B;
S3再称取牛蒡子苷元(50mg,0.11mmol),中间体B(135mg,0.13mmol)加入K2CO3(41.4mg,0.30mmol)和DMF(5mL),全部置于25mL的圆底烧瓶中,在60℃的剧烈搅拌下过夜反应。用TLC测试反应完全后,用EtOAc萃取3次,有机相用饱和碳酸氢钠溶液和盐水洗涤,洗涤2次,用适量的无水Na2SO4干燥,减压过滤旋干,得到粗产物。用硅胶色谱法进行纯化,得到化合物C31H32FN3O7。
3.一种如权利要求2制备方法获得的的牛蒡子苷元衍生物的应用,其特征在于,所述牛蒡子苷元衍生物可用于抗炎药物的成分之一。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211132063.3A CN115403571B (zh) | 2022-09-16 | 2022-09-16 | 一种牛蒡子苷元衍生物、制备方法及应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211132063.3A CN115403571B (zh) | 2022-09-16 | 2022-09-16 | 一种牛蒡子苷元衍生物、制备方法及应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115403571A true CN115403571A (zh) | 2022-11-29 |
CN115403571B CN115403571B (zh) | 2024-03-01 |
Family
ID=84165972
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211132063.3A Active CN115403571B (zh) | 2022-09-16 | 2022-09-16 | 一种牛蒡子苷元衍生物、制备方法及应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115403571B (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101036643A (zh) * | 2006-03-13 | 2007-09-19 | 海南盛科天然药物研究院有限公司 | 含牛蒡子苷元的药物组合物及其制备方法 |
CN101284823A (zh) * | 2007-04-13 | 2008-10-15 | 烟台靶点药物研究有限公司 | 牛蒡苷元前体药物及其制备方法与用途 |
CN103467417A (zh) * | 2012-06-07 | 2013-12-25 | 中国科学院上海药物研究所 | 牛蒡子苷元碳酰胺衍生物及其制备方法、包含该衍生物的组合物、及其用途 |
CN105616400A (zh) * | 2014-11-05 | 2016-06-01 | 中国科学院上海药物研究所 | 一类牛蒡子苷元氨基甲酸酯衍生物在制备用于治疗阿尔茨海默病的药物中的用途 |
CN109053701A (zh) * | 2018-08-03 | 2018-12-21 | 内蒙古民族大学附属医院 | 牛蒡子苷元类化合物、制备方法和用途 |
-
2022
- 2022-09-16 CN CN202211132063.3A patent/CN115403571B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101036643A (zh) * | 2006-03-13 | 2007-09-19 | 海南盛科天然药物研究院有限公司 | 含牛蒡子苷元的药物组合物及其制备方法 |
CN101284823A (zh) * | 2007-04-13 | 2008-10-15 | 烟台靶点药物研究有限公司 | 牛蒡苷元前体药物及其制备方法与用途 |
CN103467417A (zh) * | 2012-06-07 | 2013-12-25 | 中国科学院上海药物研究所 | 牛蒡子苷元碳酰胺衍生物及其制备方法、包含该衍生物的组合物、及其用途 |
CN105616400A (zh) * | 2014-11-05 | 2016-06-01 | 中国科学院上海药物研究所 | 一类牛蒡子苷元氨基甲酸酯衍生物在制备用于治疗阿尔茨海默病的药物中的用途 |
CN109053701A (zh) * | 2018-08-03 | 2018-12-21 | 内蒙古民族大学附属医院 | 牛蒡子苷元类化合物、制备方法和用途 |
Non-Patent Citations (3)
Title |
---|
CHEN, WEI-CHAO 等: "The 4\'-(8-imidazole-octyloxy)-arctigenin efficiently inhibits spring viraemia of carp virus infection in vitro and in vivo", AQUACULTURE, vol. 547, pages 737521 * |
HU, YANG 等: "Synthesis and antiviral activity of a new arctigenin derivative against IHNV in vitro and in vivo", FISH & SHELLFISH IMMUNOLOGY, vol. 92, pages 736 - 745, XP085776844, DOI: 10.1016/j.fsi.2019.07.006 * |
LIMA, LEONARDO MANDALHO 等: "Anti-inflammatory and analgesic activities of the ethanolic extracts from Zanthoxylum riedelianum (Rutaceae) leaves and stem bark", JOURNAL OF PHARMACY AND PHARMACOLOGY, vol. 59, no. 08, pages 1151 - 1158, XP055009222, DOI: 10.1211/jpp.59.8.0014 * |
Also Published As
Publication number | Publication date |
---|---|
CN115403571B (zh) | 2024-03-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7174102B2 (ja) | ミトコンドリア機能向上と、神経変性疾患および認知障害治療とのための組成物および方法 | |
EP0415850B1 (fr) | Sels de métaux bivalents de l'acide N, N-di(carboxyméthyl)amino-2 cyano-3 carboxyméthyl-4 carboxy-5 thiophène,leur procédé de préparation et les compositions pharmaceutiques les renfermant | |
JPH02233610A (ja) | 血管新生阻害剤 | |
EP2595620A2 (fr) | Traitement d'une pathologie liee a un effet excessif du tnf par un compose de benzene sulfonamide | |
KR101745304B1 (ko) | 아제티디닐옥시페닐피롤리딘 화합물 | |
JP2017501163A (ja) | ピラノクロメニルフェノール誘導体、及び代謝症候群または炎症疾患治療用医薬組成物 | |
KR101274543B1 (ko) | 인간 아드레날린 β3 수용체 리간드, 이를 포함하는 식품 및 의약품 | |
CN115403571B (zh) | 一种牛蒡子苷元衍生物、制备方法及应用 | |
JP2005298379A (ja) | IκBキナーゼ阻害剤 | |
CN114349700B (zh) | 一种氧化异阿朴菲生物碱衍生物及其制备方法和抗抑郁用途 | |
CN112245424B (zh) | 一种没药烷倍半萜结构类似物在制备抗冠状病毒药物中的用途 | |
WO2001074753A1 (de) | Synthetische derivate von lunularsäure, arzneimittel enthaltend diese verbindungen, verfahren zur herstellung der lunularsäurederivate sowie deren verwendung | |
CN108440508B (zh) | 吡嗪药物及其制备方法、组合物及在胃肠病人护理的应用 | |
JPH09124489A (ja) | インターロイキン−6生産抑制剤 | |
JP2016190801A (ja) | 難消化性グルカンを含有する血中中性脂肪上昇抑制剤および血中レムナント様リポ蛋白コレステロール上昇抑制剤 | |
KR20200000048A (ko) | 체불라닌을 포함하는 인지장애 관련 질환의 예방 또는 치료용 조성물 | |
CN114539130B (zh) | 苯基哌嗪或苯基哌啶类化合物及其应用 | |
CN114736252B (zh) | 一种连翘苷衍生物及其制备方法和医用用途 | |
BG61057B2 (bg) | Трициклично пиридоново производно | |
CN108003001B (zh) | 化合物Cur20及其制备方法与应用 | |
CN112022858B (zh) | 中药单体化合物组合在改善认知功能中的应用 | |
CN110117301B (zh) | 用于防治神经退行性疾病的新化合物及其应用 | |
AU2009236303B2 (en) | Inhibitors of Protein Phosphatase-1 and uses thereof | |
CN117085005A (zh) | 5-羟甲基-2-呋喃甲酸在制备促血管生成相关产品中的应用 | |
TW201018462A (en) | Novel mixture and compounds from mycelia of antrodia camphorata having hepatoprotection, anti-inflammatory and anti-tumor activities |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |