CN101612147A - α-mangostin在制备抗炎镇痛药物中的应用 - Google Patents
α-mangostin在制备抗炎镇痛药物中的应用 Download PDFInfo
- Publication number
- CN101612147A CN101612147A CN200910041377A CN200910041377A CN101612147A CN 101612147 A CN101612147 A CN 101612147A CN 200910041377 A CN200910041377 A CN 200910041377A CN 200910041377 A CN200910041377 A CN 200910041377A CN 101612147 A CN101612147 A CN 101612147A
- Authority
- CN
- China
- Prior art keywords
- mangostin
- effect
- pain
- group
- extract
- 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
- QTDMGAWIBXJNRR-UHFFFAOYSA-N Mangostin Natural products CC(=CCc1c(O)cc2Oc3cc(C)c(O)c(CC=C(C)C)c3C(=O)c2c1O)C QTDMGAWIBXJNRR-UHFFFAOYSA-N 0.000 title claims abstract description 61
- GNRIZKKCNOBBMO-UHFFFAOYSA-N alpha-mangostin Chemical compound OC1=C(CC=C(C)C)C(O)=C2C(=O)C3=C(CC=C(C)C)C(OC)=C(O)C=C3OC2=C1 GNRIZKKCNOBBMO-UHFFFAOYSA-N 0.000 title claims abstract description 61
- ZVFQDLCERPGZMO-UHFFFAOYSA-N alpha-mangostin Natural products OC1=C(CC=C(C)C)C(O)=C2C(=O)C3=C(CC=C(C)C)C(OC)=C(O)C=C3CC2=C1 ZVFQDLCERPGZMO-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 206010061218 Inflammation Diseases 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 206010058019 Cancer Pain Diseases 0.000 claims description 2
- 206010065390 Inflammatory pain Diseases 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 208000004296 neuralgia Diseases 0.000 claims description 2
- 208000021722 neuropathic pain Diseases 0.000 claims description 2
- 229940124583 pain medication Drugs 0.000 claims 3
- 230000000694 effects Effects 0.000 abstract description 21
- 208000002193 Pain Diseases 0.000 abstract description 18
- 230000036407 pain Effects 0.000 abstract description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 17
- 239000000284 extract Substances 0.000 abstract description 17
- 230000000202 analgesic effect Effects 0.000 abstract description 14
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 9
- 230000004054 inflammatory process Effects 0.000 abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 8
- 229910052760 oxygen Inorganic materials 0.000 abstract description 6
- 239000001301 oxygen Substances 0.000 abstract description 6
- 150000003180 prostaglandins Chemical class 0.000 abstract description 6
- 238000000926 separation method Methods 0.000 abstract description 6
- 230000003467 diminishing effect Effects 0.000 abstract description 3
- 102000003834 Histamine H1 Receptors Human genes 0.000 abstract description 2
- 108090000110 Histamine H1 Receptors Proteins 0.000 abstract description 2
- 230000003064 anti-oxidating effect Effects 0.000 abstract description 2
- 230000000903 blocking effect Effects 0.000 abstract description 2
- 230000000324 neuroprotective effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 239000000126 substance Substances 0.000 description 19
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical group CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 12
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 10
- 229960004380 tramadol Drugs 0.000 description 10
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 230000002000 scavenging effect Effects 0.000 description 9
- 102000004317 Lyases Human genes 0.000 description 8
- 108090000856 Lyases Proteins 0.000 description 8
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- -1 after filtration Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000031700 light absorption Effects 0.000 description 6
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 6
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 6
- 239000013641 positive control Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 208000000114 Pain Threshold Diseases 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000037040 pain threshold Effects 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 240000006053 Garcinia mangostana Species 0.000 description 3
- 235000017048 Garcinia mangostana Nutrition 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 238000006701 autoxidation reaction Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229960000905 indomethacin Drugs 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000546193 Clusiaceae Species 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229960004025 sodium salicylate Drugs 0.000 description 2
- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 241000593508 Garcinia Species 0.000 description 1
- 229940124056 Histamine H1 receptor antagonist Drugs 0.000 description 1
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 229940121954 Opioid receptor agonist Drugs 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 102000011971 Sphingomyelin Phosphodiesterase Human genes 0.000 description 1
- 108010061312 Sphingomyelin Phosphodiesterase Proteins 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000000146 antalgic effect Effects 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000002518 distortionless enhancement with polarization transfer Methods 0.000 description 1
- 238000002072 distortionless enhancement with polarization transfer spectrum Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000007760 free radical scavenging Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000938 histamine H1 antagonist Substances 0.000 description 1
- 108010084652 homeobox protein PITX1 Proteins 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 238000001225 nuclear magnetic resonance method Methods 0.000 description 1
- 239000003402 opiate agonist Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 238000007427 paired t-test Methods 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
- 230000001575 pathological effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000003075 phytoestrogen Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 229940079877 pyrogallol Drugs 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229960003107 tramadol hydrochloride Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Landscapes
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开α-mangostin在制备抗炎镇痛药物中的应用。本发明采用95体积%乙醇浸提从山竹子果壳中得到山竹子果壳提取物,然后通过过柱分离进一步从提取物中得到α-mangostin,所得α-mangostin纯度高,且具有比总提取物更好的镇痛消炎作用,同时本发明研究发现α-mangostin具有较好的羟自由基和氧自由基清除作用,具有抗氧化和神经保护的作用;可抑制前列腺素合成,阻断组胺H1受体从而在中枢以及外周起到消炎镇痛的作用。
Description
技术领域
本发明涉及天然产物化学和药物化学领域,具体涉及山竹子果壳中有效成分的应用,尤其涉及α-mangostin在制备抗炎镇痛药物中的应用。
背景技术
疼痛与炎症反应是一种警戒信号,表示机体已经发生组织损伤或预示即将遭受损伤,是机体自我保护的一种防御反应。如果疼痛与炎症长期持续不止,会对机体构成一种难以忍受的精神折磨,严重影响学习、工作、饮食和睡眠,最终因生活质量降低而产生不可忽视的经济和社会问题。
疼痛与炎症是一个连锁反应,二者互为因果,互相影响,由此产生了消炎镇痛药物,目前市场上主流的消炎镇痛药为非甾体类药物(NSAID),其通过抑制环氧合酶,减少前列腺素的合成而发挥抗炎镇痛作用。
前列腺素对许多组织本有保护作用,用非甾体抗炎药抑制其生物合成,在抑制了炎症组织合成前列腺素的同时使得患者体内其他各种组织失去前列腺素的保护而受到损害。非甾体抗炎药会引起很多不良作用,如胃肠道受损、肾功能异常、干细胞损害坏死等。鉴于非甾体类抗炎药物严重的副反应,开发新的消炎镇痛药刻不容缓。
山竹子(Garcinia mangostana L.)为藤黄科(Guttiferae)山竹子属植物,又称倒捻子、凤果或莽吉柿,属热带常绿中型乔木,其果壳被广泛用于治疗腹泻、疟疾、抗炎、抗溃疡以及抗白血病和败血病等。
α-倒捻子素(α-mangostin)是从山竹子果壳中分离出的主要生物活性的化合物,其结构式如式(II)所示,为组胺H1受体拮抗剂,具有抑制环氧化酶和神经鞘磷脂酶,拮抗组胺受体和5-羟色胺受体,抗氧化,抗菌,植物雌激素样,促进细胞凋亡,治疗乳腺癌的作用以及抗艾滋病作用等药理作用。
高纯度α-mangostin可作为医药原料、保健品等,α-mangostin具有十分广泛的药理作用,近年来引起人们的极大重视。目前尚未有将α-mangostin用于抗炎镇痛药物的相关报道。
发明内容
本发明的目的在于针对现有技术的不足,提供α-mangostin在制备抗炎镇痛药物中的应用。
上述发明目的是通过如下方案予以实现的:
α-mangostin在市面上已经有纯品销售,可采用市售的α-mangostin进行镇痛、抗炎活性检测,也可以采用下述方法对山竹子果壳有效成分进行分离提纯,得到较高纯度的α-mangostin。
采用95体积%乙醇对山竹子果壳进行浸提处理,收集浸提液,经过滤、浓缩和干燥后得到提取物,用水-乙酸乙酯溶液(水和乙酸乙酯等体积比混合所得溶液)对该提取物进行萃取,收集乙酸乙酯萃取层;将前述乙酸乙酯萃取层经硅胶柱层析,乙酸乙酯-石油醚溶液为洗脱剂,当作为洗脱剂的乙酸乙酯-石油醚溶液中乙酸乙酯和石油醚的体积比为25∶75时,收集洗脱组分,重结晶得到物质A,对物质A进行结构鉴定以及纯度测定,经过核磁共振、有机质谱以及熔点鉴定检测,物质A为α-mangostin,同时将物质A进行急性毒性和药理实验(包括镇痛活性、抗炎活性、对羟基自由基清除作用以及氧自由基清除作用的试验),结果发现物质A具有很好的镇痛、抗炎活性,而且对羟基自由基和氧自由基都具有一定的清除作用,由此说明α-mangostin可制备抗炎镇痛药物。
上述提取方法中,山竹子果壳在粉碎前可先进行预处理:将山竹子果壳清洗干净后,60℃干燥至恒重,将干燥的山竹子果壳掰碎或粉碎后用于后期的提取。
将山竹子果壳用95体积%乙醇分别以1∶5,1∶1.25,1∶1.25的比例浸提3次,浸提时间为一周左右,收集浸提液,将该浸提液过滤,取滤液浓缩,将得到的浓缩液真空干燥24小时,得到真空干燥的提取物;所述过滤、浓缩和干燥均为本领域的常规操作。
上述用水-乙酸乙酯溶液(水和乙酸乙酯1∶1混合所得溶液)对提取物进行萃取,可连续萃取三次,然后合并乙酸乙酯萃取层。对粗提物进行硅胶柱层析,流动相为25∶75的乙酸乙酯和石油醚混合溶液。对过柱分离后得到的组分进行重结晶可得到物质A,可选择甲醇作为溶剂进行重结晶。
以α-mangostin为主药的药物组合物作为镇痛药的开发,可用于治疗神经病理性疼痛,炎性疼痛,癌症性疼痛,糖尿病、风湿病等病理性疼痛。其单次服用剂量范围为2~10mg/kg。
与现有技术相比,本发明具有如下有益效果:
1.本发明采用95体积%乙醇浸提从山竹子果壳中得到山竹子果壳提取物,该提取物毒性小,且具有较好的镇痛消炎作用,然后通过过柱分离进一步从提取物中得到α-mangostin,所得α-mangostin纯度高,且具有比提取物更好的镇痛消炎作用;
2.本发明研究发现α-mangostin具有较好的羟自由基和氧自由基清除作用,可抑制前列腺素合成,阻断组胺H1受体从而在中枢以及外周起到消炎镇痛的作用。
附图说明
图1为热板致痛法检测α-mangostin镇痛活性的柱状图;
其中,1,2,3,4,5分别代表溶酶对照组,阳性对照吲哚美辛组,α1组,α2组,阳性对照曲马多组,*表示与对照组相比P<0.05,**表示与对照组相比P<0.01。
图2为福尔马林测定α-mangostin镇痛活性柱状图;
其中,1,2,3,4,5分别代表溶酶对照组,阳性对照吲哚美辛组,α1组,α2组,阳性对照曲马多组,*表示与对照组相比P<0.05,**表示与对照组相比P<0.01。
图3为α-mangotin对·OH的清除作用折线图;
图4为α-mangotin对·O2 -的清除作用折线图。
具体实施方式
下面结合具体实施例对本发明做进一步地解释,但具体实施例并不对本发明做任何限定。
实验动物:清洁级昆明小鼠,雌雄各半,体重18-24g,动物均购自中山大学医学院实验动物中心
本实施例涉及的各实验试剂均为市售:乙醇,甲醇,乙酸乙酯(EtOAC),石油醚,二甲苯,氯仿,乙酸,二甲亚砜(DMSO),甘油,FeSO4·7H2O,30%H2O2,水杨酸钠,连苯三酚,消炎痛肠溶包衣片,盐酸曲马多注射液。
各实验组的剂量设置:
(1)α-mangostin分为2个浓度组,α1组和α2组,其浓度分别为50和25mg/kg;
(2)溶酶组给药剂量为10ml/kg,其中溶酶液由甘油、DMSO和蒸馏水按1∶1∶9的体积比配成;
(3)吲哚美辛组浓度为10mg/kg;
(4)曲马多组浓度为50mg/kg;
上述各组除了曲马多是腹腔注射给药(i.p.)外,其余均为灌胃给药(i.g.)。
实施例1α-mangostin的分离制备
1、山竹子果壳总提取物的制备
把山竹子果壳洗干净,置于恒温干燥箱中,60℃干燥至恒重,称重得到4.37kg;把干燥的山竹子果壳掰碎,加入6.4L 95体积%乙醇浸提。一周后,过滤浸提液,取滤液,浓缩;浓缩液真空干燥24小时,制备得到真空干燥的山竹子果壳总提取物。
2、α-mangostin的分离制备
装柱、上样和洗脱均采用本领域技术人员的常规操作。
将上述制备得到的山竹子果壳总提取物,取31g进行如下过柱纯化分离:
(1)用水-乙酸乙酯溶液(V水∶V乙酸乙酯=1∶1)对山竹子果壳总提取物进行萃取,收集乙酸乙酯萃取层;
(2)将上述乙酸乙酯萃取层经硅胶柱层析,乙酸乙酯-石油醚溶液为洗脱剂;当洗脱剂为V乙酸乙酯∶V石油醚=25∶75时,收集洗脱组分,甲醇重结晶得到物质A。
将上述经过柱分离得到的物质A用核磁共振法,测定13C、1H、DEPT NMR以及D2O交换NMR,以确证化合物结构。用有机质谱测定化合物分子量,把结果与文献值作对照,从分子量大小验证分离得到的物质A是否为α-mangostin。
DEPT谱结果显示物质A有5个-CH3,2个-CH2,4个-CH,测定结果与文献报导的α-mangostin的分子式均相符。
有机质谱结果显示,物质A的分子量是410,与文献报导的α-mangostin理论分子量相符。
具体结果如下:
物质A:亮黄色晶体(8.3411g),mp 176~179℃
1H-NMR(CDCl3,ppm):13.765(1H,s,C1-OH),6.108(1H,s,-OH),1.577(1H,s,-OH),3.808(3H,s,C7-OCH3),6.284(1H,s,H-4),6.824(1H,s,H-5),3.808(3H,s,C7-OCH3),4.093(2H,d,J=6.5,H-11),3.456(2H,d,J=7H-16),5.288(1H,t,J=6,H-12),5.265(1H,t,J=5.5,H-17),1.831(1H,s,H-14),1.844(1H,s,H-15),1.693(1H,s,H-19),1.774(1H,s,H-20).
13C-NMR:17.896(C-19),18.201(C-14),21.453(C-16),25.788(C-20),25.817(C-15),26.573(C-11),62.060(-OCH3),93.307(C-4),101.555(C-5),103.657(C-9a),108.443(C-2),112.247(C-8a),121.434(C-17),123.157(C-12),132.118(C-8),135.791(C-18),137.064(C-13),142.585(C-7),154.258(C-6),155.095(C-10a),155.808(C-4a),160.638(C-1),161.619(C-3),182.043(C-9).
Fab-MS m/z:411[M]+1(51),355(33),339(15),91(17),77(28),69(28),55(19).
物质A的1H-NMR测定结果与文献报导的α-mangostin H-NMR相符,初步确定物质A是α-mangostin。
同时用熔点测定仪测定物质A的熔点,并与文献值作对照,以进一步确证待定物质A是否为α-mangostin。熔点测定具体方法是取少量化合物置于玻片上加热,当加热温度距离化合物熔点参考值还有10℃时,控制温度增高率,使之每分钟升高约1℃,在显微镜下观察化合物的熔点。
熔点实验结果是物质A的熔点是176~179℃,与文献报导的α-mangostin(181.6~182.6℃)熔点大致相符。
结合上述核磁共振、质谱以及熔点试验的结果,可以断定本实施例分离得到的物质A为α-mangostin。
实施例2热板致痛法测定α-mangostin的镇痛活性
热板致痛法采用本领域技术人员的常规操作,对本实施例1制备所得α-mangostin(物质A)进行镇痛活性测定。
小鼠选取条件:给药前先测定每只小鼠的痛阈,以平均值不超过30s者合格,出现跳跃现象的弃之不用。
选取70只符合上述条件的雌性小鼠,分为溶酶组、吲哚美辛组、α1组、α2组和曲马多组共五组,10只/组,其中溶酶组作为对照组,曲马多组和吲哚美辛组均为阳性对照组。
实验前禁食12小时,给药后1小时开始测定,以后每隔1小时测定一次,4小时后结束。金属盘放在事先调至55±0.5℃水浴锅中,加热后作热刺激,秒表记录小鼠自投入热板至出现舔足时间(s)作为该鼠的痛阈值,如痛阈值超过60s,即停止测试,按60s计算。
痛阈提高百分率=(用药后平均痛阈值-对照组平均痛阈值)/组照组平均痛阈值×100%。
实验表明α-mangostin对热板引致的疼痛反应有抑制作用,均能使小鼠舔后足现象出现的潜伏期延长,说明都具有中枢镇痛活性。
如图1所示,在α-mangostin的镇痛活性测定中,α1和α2在第一小时内的痛阈提高值分别为67%和37%与对照组相比有显著差异;阿片受体激动剂曲马多在第一个小时内效果显著,其痛阈提高率达到了338%,但在第二个小时后失效;非甾体类镇痛药吲哚美辛在给药后前三个小时内效果均不如α1和α2组。
实施例3小鼠福尔马林实验测定α-mangostin的镇痛抗炎活性
本实施例采用本领域技术人员的常规操作进行扭体法对实施例1制备所得α-mangostin进行镇痛活性测定。
70只雌性小鼠,分为溶酶组、吲哚美辛组、α1组、α2组和曲马多组共5组,10只/组,溶酶组作为对照组,曲马多组和吲哚美辛组均为阳性对照组。
实验前禁食12小时,给药1小时后,给小鼠一只脚掌皮下注射20μl 5%福尔马林溶液,计算小鼠在之后两个时相内舔脚的时间,第一时相为注射后的5min内的持续舔脚时间,第二时相为在之后的第25min到60min的持续舔脚时间,其中每次记录时间依然为5min,每轮记录间隔为10min。
抑制百分率=(对照组平均舔脚时间-给药组平均舔脚时间)/对照组平均舔脚时间×100%。
实验结果:如图2所示,α1和α2组对福尔马林早期反应(第一相)的疼痛抑制率分别为36%和52%,而对晚期反应(第二相)的疼痛抑制率分别为47%和60%。阳性药曲马多对福尔马林一二相反应的抑制率分别为55%和75%,而吲哚美辛仅在第一相有抑制作用,且未达到显著性水平,结果如图2所示。
实施例5α-mangostin对羟自由基(·OH)的清除作用
用DMSO(二甲基亚砜)溶解实施例1制备所得α-mangostin,然后用蒸馏水稀释成不同质量浓度(2.5,5,6.67,13.3,20,40μg/ml)的α-mangostin溶液。
根据FeSO4+H2O2产生·OH,以·OH氧化水杨酸所得产物的吸光值示·OH多少,吸光值越大,·OH越多。3mL反应液中含0.15mol/LFeSO4,6mmol/LH2O2,2mmol/L水杨酸钠和不同质量浓度的α-mangostin溶液,最后加H2O2启动反应,37℃反应1h,测510nmOD值,吸光值越小,清除效果越好。用{[A0-(Ai-A0i)]/A0}×100%计算·OH的清除率,其中A0为对照,不加α-mangostin溶液;Ai为某质量浓度的α-mangostin溶液的吸光值,为无水杨酸时α-mangostin溶液的吸光值。
实验结果:如图3所示,α-mangotin具有很强的清除·OH作用。α-mangotin随着浓度的增大,·OH清除作用逐渐增强,当浓度增大到10μg/ml时,清除作用最强,清除率达到最大值75.7%,当浓度超过10μg/ml,清除作用减弱,清除率低于75.7%。
实施例6α-mangostin对氧自由基(·O2-)的清除作用
用DMSO(二甲基亚砜)溶解实施例1制备所得α-mangostin,然后用50mmol/L pH8.2的Tris-HCl缓冲液配制成不同质量浓度(20,40,50,60,80μg/ml)的α-mangostin溶液,并分别加入10μl 45mmol/L连苯三酚。
连苯三酚在碱性条件下会发生自动氧化而产生·O2 -和有色中间体,其反应速度依赖于自氧化产生的·O2 -的浓度。·O2 -越多,吸光度就越大,因此通过测定不同质量浓度的α-mangostin对邻苯三酚自氧化速率的抑制作用而评价α-mangostin清除·O2 -作用的强弱。
在25℃下测定325nm处吸光值,每隔20s测一次(在4min内测完)。·O2 -的清除率(%)=(ΔA1/Δt-ΔA2/Δt)/(ΔA1/Δt)×100%,其中ΔA1/Δt不加α-mangostin的体系整个吸光度变化率;ΔA2/Δt是加了α-mangostin后体系整个的吸光度变化率。实验数据用Excel2003分析,并进行配对t检验,结果用Origin 7.5软件作图。
实验结果:如图4所示,α-mangostin从20μg/ml开始才表现出一定的抑制作用,当浓度在60μg/ml以上时,α-mangostin具有极明显的清除·O2 -的作用,α-mangostin浓度为80μg/ml时,清除作用最强,抑制率达到最高值78.9%。
由实施例3和4可以看出,α-mangostin具有很好的镇痛作用,由实施例5和6可以看出,α-mangostin具有很好的清除羟基自由基和氧自由基的作用,由此说明,α-mangostin可用于制备抗炎镇痛药物,能够起到较好的效果。
Claims (3)
1、α-mangostin在制备抗炎镇痛药物中的应用。
2、根据权利要求1所述应用,其特征在于所述抗炎镇痛药物为治疗神经病理性疼痛药物、治疗炎性疼痛药物、治疗癌症性疼痛药物、治疗糖尿病疼痛药物、治疗风湿病疼痛药物。
3、根据权利要求1所述应用,其特征在于所述α-mangostin的单次服用剂量为2~10mg/kg。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2009100413770A CN101612147B (zh) | 2009-07-24 | 2009-07-24 | α-mangostin在制备抗炎镇痛药物中的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2009100413770A CN101612147B (zh) | 2009-07-24 | 2009-07-24 | α-mangostin在制备抗炎镇痛药物中的应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101612147A true CN101612147A (zh) | 2009-12-30 |
CN101612147B CN101612147B (zh) | 2012-08-22 |
Family
ID=41492156
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2009100413770A Expired - Fee Related CN101612147B (zh) | 2009-07-24 | 2009-07-24 | α-mangostin在制备抗炎镇痛药物中的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN101612147B (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106176713A (zh) * | 2016-08-24 | 2016-12-07 | 雷闽湘 | α-山竹黄酮的新用途 |
CN107362159A (zh) * | 2016-05-13 | 2017-11-21 | 上海交通大学医学院 | 呫酮类化合物及其衍生物在制备降血脂药物中的应用 |
CN109463386A (zh) * | 2018-10-25 | 2019-03-15 | 华南农业大学 | 倒捻子素在防治青枯病中的应用 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101428046A (zh) * | 2007-11-06 | 2009-05-13 | 王莉 | 一种新型广谱抗炎镇痛的外用药物 |
CN101428044A (zh) * | 2007-11-06 | 2009-05-13 | 王莉 | 一种治疗多种口腔疾病的新型广普抗炎镇痛药物 |
CN101606957A (zh) * | 2008-06-17 | 2009-12-23 | 陈霞 | 一种治疗和预防关节炎和滑膜炎等骨科病及并发病的配方 |
-
2009
- 2009-07-24 CN CN2009100413770A patent/CN101612147B/zh not_active Expired - Fee Related
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107362159A (zh) * | 2016-05-13 | 2017-11-21 | 上海交通大学医学院 | 呫酮类化合物及其衍生物在制备降血脂药物中的应用 |
CN106176713A (zh) * | 2016-08-24 | 2016-12-07 | 雷闽湘 | α-山竹黄酮的新用途 |
CN109463386A (zh) * | 2018-10-25 | 2019-03-15 | 华南农业大学 | 倒捻子素在防治青枯病中的应用 |
Also Published As
Publication number | Publication date |
---|---|
CN101612147B (zh) | 2012-08-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Mahendran et al. | Synthesis and evaluation of analgesic and anti-inflammatory activities of most active free radical scavenging derivatives of Embelin—A Structure–Activity relationship | |
CN101353299B (zh) | 一种异甘草素的合成方法 | |
He et al. | Quinolizidine alkaloids from Sophora tonkinensis and their anti-inflammatory activities | |
Hu et al. | Anti-inflammatory octahydroindolizine alkaloid enantiomers from Dendrobium crepidatum | |
Yuan et al. | Diverse isoquinolines with anti-inflammatory and analgesic bioactivities from Hypecoum erectum | |
CN101891728A (zh) | 灯盏乙素苷元衍生物及其制备方法和其应用 | |
Jiang et al. | Analgesic corynanthe-type alkaloids from Strychnos angustiflora | |
CN101612147B (zh) | α-mangostin在制备抗炎镇痛药物中的应用 | |
Li et al. | Monoterpenoid indole alkaloids from the fruits of Gelsemium elegans and their anti-inflammatory activities | |
CN101658517B (zh) | γ-倒捻子素在制备抗炎镇痛药物中的应用 | |
CA3080001C (en) | Piper laetispicum extract and preparation method therefor and use thereof | |
CN104688749A (zh) | 治疗肥胖症的女贞属苯乙醇苷类组合物及其用途 | |
CA2847971C (en) | Stilbenoid compounds as inhibitors for squamous carcinoma and hepatoma and uses thereof | |
CN113491679A (zh) | 植醇在制备抗偏头痛药物中的应用 | |
Wei et al. | Synthesis and biological evaluation of pyranoisoflavone derivatives as anti-inflammatory agents | |
CN105669621A (zh) | 一种盐酸金霉素的药物组合物及其医药用途 | |
Liu et al. | Synthesis and anti-inflammatory effects of a series of novel 9-O-substituted berberine derivatives | |
CN105250391B (zh) | 一种秃疮花生物碱有效部位的制备方法 | |
CN105801590A (zh) | 一种阿普唑仑的药物组合物及其抗炎镇痛作用 | |
CN109206392B (zh) | 一种香豆素类化合物及其制备方法与应用 | |
CN101851271A (zh) | 蓝萼丁素衍生物、制备方法及其用途 | |
CN101665480B (zh) | 猪仔笠黄酮类提取物的提取方法 | |
CN101612174B (zh) | 山竹子果壳总提取物在制备抗炎镇痛药物中的应用 | |
CN102850203B (zh) | 一种胡桃醌衍生物及其应用 | |
CN105884773A (zh) | 一种苯佐卡因的药物组合物及其医药用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120822 Termination date: 20140724 |
|
EXPY | Termination of patent right or utility model |