CN101099566B - 山窝苣素及其制备方法和用途 - Google Patents
山窝苣素及其制备方法和用途 Download PDFInfo
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- CN101099566B CN101099566B CN2007101467266A CN200710146726A CN101099566B CN 101099566 B CN101099566 B CN 101099566B CN 2007101467266 A CN2007101467266 A CN 2007101467266A CN 200710146726 A CN200710146726 A CN 200710146726A CN 101099566 B CN101099566 B CN 101099566B
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- extract
- witloof
- lactucin
- ethyl acetate
- compound
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Abstract
本发明涉及一种化合物山窝苣素及其制备方法和用途,该化合物是从毛菊苣根中采用提取、减压浓缩、萃取、干燥、梯度洗脱、硅胶柱色谱分离、纯化得到的山莴苣素,其结构是由理化常数测定及波谱数据分析而确定的,经初步的活性筛选试验证明:该化合物具有蛋白酪氨酸磷酸酶(PTP1B)抑制剂作用,可用于治疗糖尿病的药物或保健品的应用,同时该化合物或其衍生物可作为药物组合物的应用。
Description
技术领域
本发明涉及一种山窝苣素及其制备方法和用途,具体的说是从新疆毛菊苣根中提取的山莴苣素,作为治疗糖尿病药物及功能食品的用途。
背景技术
菊苣是一种用途广泛的植物,意大利居民用菊苣叶做蔬菜沙拉,味美可口,除此之外,菊苣更多是具有很多药用价值。
1)降血脂、降血糖
在国内外研究的已相当之多。北京中医药大学中药学院研制了菊苣胶囊,张冰等发现菊苣胶囊对糖尿病复合高脂兔血糖血脂及血尿酸有一定影响,作者采用四氧嘧啶静脉注射合高脂食饵的复台兔模型,观察菊苣胶囊对高血糖、高血脂模型兔血搪、血脂及血尿酸的影响。结果发现,菊苣胶囊在连续口服培药时,可降低模型动物第2周、第4周、第8周时空腹血糖、甘油三酯、总胆固醇水平,同时降强第4周、第8周时血尿醚水平,作用时间持久,表明菊苣经化学提取后制成的胶囊剂可降低复合动物模型的血糖、血脂、血尿酸水平,具有改善代谢紊乱的多方面作用。
随后张冰又发现菊苣醇提取物对实验性高脂家兔的血液流变性有一定影响,作者采用复合高血糖高血脂兔模型,观察菊苣醇提取物对血液流变性的影响,结果发现,菊苣醇提物能降低全血、血浆粘稠度;降低模型动物红细胞沉降速率及血沉方程K值。
张冰还发现菊苣提取物对α-amyrin对高糖高脂环境中家兔主动脉平滑肌细胞膜微粘度及过氧化脂质有一定影响力,能明显降低高脂高糖模型细胞膜粘度、改善细胞流动性,降低培养液中LPO含量,两者之间作用强度无明显差异。
高云艳等采用四氧嘧啶高血糖模型大鼠、观察菊苣不同提取物对模型动物血糖、血TC及TG的影响。结果得出菊苣醇提物对模型降低血糖、血TC及TG方面疗效优于水煮醇沉提取物。
郑红梅等将菊苣降血糖和降血脂的有效部位进一步缩小,通过对大鼠药理实验,发现菊苣正己烷提取物能降低四氧嘧啶大鼠血糖,对其胰岛素水平无显著影响,能降低高血脂大鼠血清总胆固醇、总甘油三脂、低密度脂蛋白含量,并能显著降低其全血粘度、血浆粘度、血浆纤维蛋白原含量。
在菊苣胶囊的对血糖影响的机理方面,张冰初步探讨了菊苣胶囊防治糖尿病的作用机理,他采用体内方法,通过对不同高血糖模型小鼠给药,实验结果发现,菊苣胶囊可显著降低四氧嘧啶及肾上腺素模型小鼠血糖含量,同时升高肾上腺素模型小鼠肝糖原含量。初步表明,菊苣胶囊降糖作用与胰外途径有关,尤其是与增加肝糖原含量、减少肝糖原分解作用有关。
郑红梅等从组织形态学上阐述了菊苣双降胶囊药理作用机理,她认为菊苣双降胶囊能降糖作用与修复胰岛β细胞和胰外途径特别是促进肝糖原合成,抑制糖异性有关,另外还推测,菊苣双降胶囊可能直接影响糖代谢,且其降糖作用与抑制肠道对葡萄糖的吸收有关。
张冰等在已证明菊苣提取物在降糖降脂和改善血液流变性以及对兔动脉平滑肌细胞膜有良好的保护作用的基础上,又对模型动物血浆相关因子做了测试,他们得出结论认为菊苣提取物能改善血浆多种细胞因子水平,减少高糖高脂等不良因素对血管壁壁的刺激,对抗由高脂高糖导致的内皮素(ET)、血管性假血友病因子(Vwf)水平升高,调节前列环素(PGI2)和血栓素(TXA2)的比值,维持正常舒缩状态,减少兔动脉平滑肌细胞异常增殖的刺激,减少班块的形成,起到抗动脉粥样硬化的综合作用,进一步阐述了菊苣提取物药理作用机理。
刘小青等将快速塑造大鼠高脂血模型用于小鼠高脂血模型,实验结果证明不同剂量的菊苣提取物能明显降低高脂血症小鼠的血清总胆固醇、总甘油三脂、一氧化氮和过氧化脂质水平,增强超氧化物歧化酶活性,结论菊苣提取物能改善高脂饮食引起的高脂血症。萨翼等发现菊苣提取物N2还能降低该模型小鼠血清中的黄嘌呤氧化酶。刘小青等又用与人类代谢类似的鹌鹑高尿酸血症模型证明小剂量菊苣提取物能明显降低模型动物的血尿酸水平,菊苣提取物有明显的降尿酸作用,但药理作用机制并未提及。而孔悦等初步探讨了其作用机理,他们通过用大、中、小不同剂量菊苣提取物给药于高尿酸高甘油三酯血症的鹌鹑,相对于对照组,三个不同剂量组的菊苣提取物能明显降低鹌鹑血清中的尿酸和甘油三脂含量,而对肾功能没有影响,证明菊苣提取物对这种交互紊乱具有良好的调节作用,其药理作用具有多方面、多靶点的优势。
最近又报道治疗2型糖尿病复方草药专利,这其中就包括菊苣提取物,R.Petlevski用该复方草药的用两种不同的工艺路线得到粗提物,同样的药材用60%醇水冷浸28天,过滤,分成两份,一份冻干,得提取物1;另一份低压回收醇水,同样冻干,得提取物2,将提取物1和提取物2对四氧嘧啶诱导的非肥胖糖尿病小鼠进行实验,结果提取物2相对于提取物1更能降低小鼠血清葡萄糖和果糖胺水平。
在国外,Zahra Amirghofran对菊苣的免疫调节生理活性也做了评价:他的实验证明菊苣提取物在植物血球凝集素(PHA)存在下能明显抑制淋巴细胞增殖。
2)保肝
Gilani A.H.从菊苣里面分离到的七叶内酯能够保护由于扑热息痛和四氯化碳引起的肝损伤,这在一定程度上能够解释民间用菊苣作为治疗肝损伤的药。
Chhaya Gadgoli等将菊苣种子的水提取物,依次用丙酮、甲醇萃取,得到三个部位:丙酮部位、甲醇部位和水溶性部位,将三个部位给药于四氯化碳引起的肝损伤大鼠,结果证明:甲醇部位能够明显降低由于四氯化碳引起的大鼠肝脏谷草转氨酶(AST)、谷丙转氨酶(ALT)、碱性磷酸馓酶(ALKP)和总胆红素水平,具有最好抗肝毒活性,对由于四氯化碳引起的大鼠肝损伤具有很好的保护作用,其次是水溶性部位,丙酮部位没有活性。
Rasheeduz Zafar等发现菊苣的根和根皮的水提物都能够对由于四氯化碳引起的肝细胞损伤有很好的保护作用,作者进一步做了根和根皮水提物抗肝毒性活性的比较,结果根皮水提物优于根的水提物。随后,Go¨knur Aktay发现菊苣叶子80%水醇提取物对小鼠肝脏脂质过氧化起到一定的抑制作用,但不能改变谷草转氨酶(AST)、谷丙转氨酶(ALT)活性,总体上,菊苣叶子的水醇提取物对由于四氯化碳引起的大鼠肝中毒有很好的保护作用。
Joung-Hoon Kim用菊苣根的95%醇提取物对由于酒精中毒小鼠实验,菊苣根醇提取物对小鼠酒精中毒具有一定的保护作用,如果给药300mg/Kg/Day菊苣根95%醇提取物能明显增强小鼠免疫功能。
Bahar Ahmed对菊苣种子的醇提物分别用石油醚、乙酸乙酯、甲醇依次萃取,并且从甲醇部位分到一化合物AB-IV。得到的总的菊苣种子醇提物、石油醚部位、乙酸乙酯部位、甲醇部位及化合物AB-IV分别对由于四氯化碳引起肝损伤大鼠实验,结果甲醇部位和化合物AB-IV相对于其他部位和阳性对照水飞蓟素大幅度降低肝损伤大鼠谷草转氨酶(AST)、谷丙转氨酶(ALT)、碱性磷酸馓酶(ALKP)水平及增强总蛋白TP水平,其中作者说明了化合物AB-IV是一种苯酚类化合物,但未阐明其结构。
Gabriella Gazzani发现在菊苣中同时存在氧化强化剂和抗氧化剂化合物,且两者可以在化学系统或生物系统中同时具有活性。作者体外实验和大鼠实验的基础上,利用电泳技术从菊苣中分离到了三个部位:无色的氧化强化剂部位、抗氧化剂部位和“黄色”部位,其中“黄色”部位抗氧化活性最高,其分子量在300000以上,且不溶于酸性介质中。作者还指出在三个部位同时存在于植物中时,菊苣的总提取物表现的抗氧化活性,相对于分离到的抗氧化剂化合物都弱,其中的原因可能是由于氧化强化剂部位掩盖了一部分抗氧化剂部位。Adele Papetti利用反相高效液相色谱从菊苣中分离除了抗氧化剂化合物,并通过小鼠实验,对抗DPPH·稳定自由基,说明了菊苣中存在的氧化强化剂在与抗氧化剂存在时能完全抵消抗氧化剂的生理活性,但这种氧化强化剂又是不稳定的,在温度≥50℃水溶液20min,会自动分解失去活性。最近,Adele Papetti在化学与生物学两个系统中研究了菊苣族植物的抗氧化活性和氧化强化活性,同样得出了分子量在3500Da以上的化合物在所选用的化学和生物学两种系统中表现一定的抗氧化活性,而分子量在3500Da以下的小分子量化合物则具有氧化强化剂的活性,且这种结果在对其进行热学处理例如:加热煮沸,冷却,冷却干燥等,都会得出相同的结论。Chang W.Choi将菊苣叶子的提取物抗氧化能力和清楚自由基作用与儿茶酚、芸香苷、栎精、桑色素、4,5,7-三羟黄烷酮等黄酮的抗氧化和清除自由基作用做了对比。作者分别用二氯甲烷、甲醇或乙醇依次作为菊苣提取物,和黄酮对比能给出较好抗氧化活性和清除自由基作用。
3)抗肿瘤
Hyun-Ja Jeong提到了一种韩国民间复方CancerB(CCB,IMSF-5)在韩国民间广泛的用来治疗各种瘤。其中菊苣在CancerB的质量分数约为18%。Hyun-Ja Jeong通过对家兔实验,证明了该复方能够明显增加一氧化氮水平和肿瘤坏死因子-α(tumor necrosis-alpha)水平,并指出核转录因子-κ factor-kappaB)在调节该复方药效上起到了重要作用。
B.Hazra发现菊苣根醇提物具有肿瘤抑制作用,通过对Swiss小鼠实验,菊苣根粗提取物在300-700mg/kg/day能明显抑制欧利希氏腹水癌(Ehrlich ascites carcinoma)肿瘤的生长。作者将新鲜菊苣根阴凉处干燥后放入80%醇水中冷浸三周,虑出冷浸液,减压除去溶剂得菊苣根醇提物。
4)抗拒食
菊苣具有繁茂的绿叶且没有任何外部的防御,但无论是野生的菊苣还是人工培养的菊苣都能很好的防御外部食草动物的侵袭和另一些昆虫不能靠近食用,SARAH B.REES通过拒食素实验证明了的菊苣抗拒食作用,并指出菊苣中存在的具有拒食活性的化学物质是倍半萜内酯类化合物和酚类化合物,其中主要在发挥作用的是以下三个倍半萜内酯类化合物:山莴苣素(lactucin),山莴苣苦素(lactupicrin),8-脱氧莴苣苦素(8-deoxylactuc in)。这三种倍半萜内酯类化合物具有让人恶心的苦味,菊苣微苦也是由于这三种倍半萜内酯类化合物的苦味所引起的。M.J.Pascual-Villalobos对50种地中海植物做了抗拒食活性实验,这其中就包括菊苣,他选用了菊苣叶子:菊苣叶1g,在室温20℃下,先用10ml正己烷浸泡48h,再用10ml丙酮浸泡48h,最后用50%甲醇水浸泡48h,得到三个部位:正己烷部位、丙酮部位和50%甲醇部位。通过抗拒食活性实验,发现正己烷部位能使幼虫蛹产生毒性,丙酮部位能使幼虫拒食,丙酮部位和甲醇部位都能使幼虫产生毒性。在3μg/每只的剂量下,丙酮部位和50%甲醇部位都能产生100%幼虫死亡率。
Abdul L.Molan做了菊苣中的凝缩类鞣质和总倍半萜内酯类化合物对红鹿肺蠕虫和胃肠线虫运动性的影响。作者提取和精制了凝缩类鞣质和总的倍半萜化合物,得到了凝缩类鞣质(Condensed Tannins)和黄色倍半萜内酯类化合物粗提 SesquiterpeneLactones)。
Abdul L.Molan的实验阐明了凝缩类鞣质和黄色倍半萜内酯类化合物粗提物都能显著的抑制不同红鹿肺蠕虫和胃肠道线虫的运动性。
菊苣除作为草药之外,还没广泛的种植用来做饲料,因为菊苣具有拒食性杀虫性,所以用菊苣做饲料必然也会对牲畜的消化道的寄生虫产生影响。C.L.Marley用菊苣做草料喂养绵羊,并观察了绵羊粪便种的寄生蠕虫的变化。结果发现用作菊苣做饲料于黑麦草做对比,前者绵羊的粪便中的寄生虫密度明显减小。
5)抗菌
H.A.de Silva又发现菊苣提取物具有抗菌作用。作者将菊苣根和菊苣地上部分分开,分别用水、乙醇和乙酸乙酯做溶剂在100℃水浴中浸泡菊苣1h。得到菊苣根的水提物、醇提物和乙酸乙酯提取物,菊苣地上部分的水提物、醇提物和乙酸乙酯提取物。作者将这九个部位分别对三种革兰氏阳性菌和六种革兰氏阴性菌抗菌实验。结果显示所有的提取物至少对四种菌有抗菌活性,其中,乙酸乙酯部位对所有的九种菌类都表现出最好的抗菌活性,水提物能抑制四种菌株的生长,根部提取物抗菌活性要优于全草菊苣提取物。作者指出了在菊苣根中含有超过40%的安茴酰牛扁碱,其他还有单宁酸和胶质。菊苣叶中含有菊苣苷。菊苣的苦味是由于菊苣中存在的倍半萜内酯类化合物。但作者并未指出菊苣的抗菌作用与这些成分有关。
6)抗疟
菊苣中的苦味和抗拒食活性都是由于菊苣中存在的倍半萜内酯类化合物。Theodore A.Bi schoff等又发现菊苣中的倍半萜内酯类化合物山莴苣素和山莴苣苦素具有抗疟活性。阿富汗民间用菊苣根的水提液作为治疗疟疾的药方:选择晚上取一株菊苣,将地上部分弃去,留根代用,然后将根的周围用刀划开几个口,最后避光下将其浸在水中,隔夜,天明之前服用可治疗疟疾,如果不按照上述程序操作,菊苣提取液没有抗疟活性。菊苣作者利用VLC从菊苣中分离到山莴苣素和山莴苣苦素,并对其进行抗疟实验,这两种化合物山莴苣素在10μg/ml和山莴苣苦素50μg/ml均能抑制疟原虫的生长。
Hyung Min Kim等发现菊苣水提取物(CIAE)在体外和体内都能很好的抑制细胞介质上的过敏反应。CIAE以0.1-1000mg Kg-1的剂量能明显抑制由于化合物4880引起的小鼠身体组织过敏反应,且小鼠血浆组胺水平降低。菊苣水提取物以1-1000mg Kg-1的剂量能明显抑制由于化合物compound4880激发的大鼠腹间皮细胞(RPMC)对组胺的释放。且CIAE剂量在1000μg ml-1时大鼠腹间皮细胞中环化腺苷酸(cAMP)的含量升高。总之,菊苣水提物能在体外和体内明显的抑制过敏反应。
樱井信子等从菊苣中分离得到(S,S)-酒石酸与咖啡酸的二酯化合物(即菊苣酸),并通过对Wistar大鼠实验证明这种二酯化合物能使血管平滑肌松弛,其机理是该化合物对NE所致收缩的抑制作用,部分与其阻滞受体依赖性Ca2+通道有关。
在抗病毒方面,菊苣也表现一定的疗效,有专利报道新的抗病毒成分体系包括菊苣。该专利提到的新的抗肿瘤成分体系由1加2组成:1.埃及田菁。2.a)家黑种草。b)菊苣嫩枝等。该品主要用来治疗病毒感染,如乙肝丙肝,对人的副作用极小。
另外,菊苣还和其他药配伍起来治疗胃溃疡和胰腺炎,IlhanGurbuz和Ibolya Kocsisl分别用兔子实验从组织病理学上阐明了其药理活性。以上主要阐述了菊苣的药理活性进展,其主要的药理活性主要包括:降血脂、降血糖,保肝,抗氧化,抗菌,抗疟,抗肿瘤,抗病毒以及治疗胃溃疡和胰腺炎等众多的药理活性。本论文的研究对象是作为其菊苣同属植物的毛菊苣根,因为同属植物的亲缘性会在药理活性和化学成分有很大相似,以上这些关于菊苣的化学成分研究和药理活性研究都为我们研究毛菊苣根的化学成分和体外生物活性筛选提供了科学依据和指导思想。
总之,对于天然植物的化学成分研究,科学家们也在不断地探索动物机体间和物质间的相互关系的自然基础,使人类对物质的认识以更多的特征来加以判断。早在17世纪,国外学者开始提出,自然植物类群具有化学成分和药理活性上的相似性。直到20世纪初,格拉斯柯夫证明了产生氰化合物在大枫子科的亚科中存在,之后英国植物化学家斯密奇查明了数百科属植物成分和科属间的亲缘关系。
发明内容
本发明目的在于提供一种从毛菊苣根中采用提取、减压浓缩、萃取、干燥、梯度洗脱、硅胶柱色谱分离、纯化得到的化合物山莴苣素,该化合物的结构是由理化常数测定及波谱数据分析而确定的,经初步的活性筛选试验证明:该化合物具有蛋白酪氨酸磷酸酶(PTP1B)抑制剂作用,可用于治疗糖尿病的药物或保健品的应用,同时该化合物或其衍生物可作为药物组合物的应用。
本发明所述的一种从毛菊苣根中采用提取,减压浓缩、萃取、干燥、梯度洗脱、硅胶柱色谱分离、纯化得到化合物山莴苣素,按下列步骤进行:
a、取干燥新疆毛菊苣根,用70%乙醇液提取,减压浓缩至无醇味的浸膏,用水混悬,分别用石油醚、乙酸乙酯、正丁醇萃取,回收正丁醇萃取液,减压浓缩至浸膏状;
b、浸膏用乙醇溶解,用硅胶拌样,用旋转蒸发仪蒸去溶剂,干燥,以石油醚、石油醚-乙酸乙酯、乙酸乙酯、乙酸乙酯-甲醇、甲醇梯度洗脱,每500ml为一流分,TLC检测,将相同组分合并,各洗脱部分经多次硅胶柱色谱分离,葡聚糖凝胶LH-20凝胶柱层析,制备性薄层色谱分离、纯化,得到化合物山莴苣素,化学名为:Lactucin,化学结构式为:
该化合物或其衍生物作为药物的组合物。
山窝苣素的制备方法,按下列步骤进行:
a、取干燥新疆毛菊苣根,用70%乙醇液提取,减压浓缩至无醇味的浸膏,用水混悬,分别用石油醚、乙酸乙酯、正丁醇萃取,回收正丁醇萃取液,减压浓缩至浸膏状;
b、浸膏用乙醇溶解,用硅胶拌样,用旋转蒸发仪蒸去溶剂,干燥,以石油醚,石油醚-乙酸乙酯,乙酸乙酯,乙酸乙酯-甲醇,甲醇依次洗脱,每500ml为一流分,TLC检测,将相同组分合并,各洗脱部分经多次硅胶柱色谱分离,葡聚糖凝胶LH-20凝胶柱层析,制备性薄层色谱分离、纯化,得到化合物山莴苣素。
一种从毛菊苣根中提取化合物山窝苣素作为治疗糖尿病的药物或保健品的用途。
附图说明
图1为本发明Lineweaver-Burk作图法分析山莴苣素对蛋白酪氨酸磷酸酶(PTP1B)抑制作用的动力学图。
具体实施方式
实施例1
取干燥的毛菊苣根3KG,用30%乙醇提取,减压浓缩至无醇味的浸膏,用水混悬,分别用石油醚、乙酸乙酯、正丁醇萃取,回收正丁醇萃取液,减压浓缩至浸膏状;
浸膏用乙醇溶解,用硅胶拌样,用旋转蒸发仪蒸去溶剂,干燥,以石油醚,石油醚-乙酸乙酯,乙酸乙酯,乙酸乙酯-甲醇,甲醇依次洗脱,每500ml为一流分,TLC检测,将相同组分合并,再经葡聚糖凝胶LH-20凝胶柱层析分离、纯化,即可得到化合物山莴苣素。
实施例2
取干燥的毛菊苣根3KG,用70%乙醇依次提取,减压浓缩至无醇味的浸膏,用水混悬,分别用石油醚、乙酸乙酯、正丁醇萃取,回收正丁醇萃取液,减压浓缩至浸膏状;
浸膏用乙醇溶解,用硅胶拌样,用旋转蒸发仪蒸去溶剂,干燥,以石油醚,石油醚-乙酸乙酯,乙酸乙酯,乙酸乙酯-甲醇,甲醇依次洗脱,每500ml为一流分,TLC检测,将相同组分合并通过反复硅胶柱层析后,再经制备性薄层色谱分离、纯化,即可得到化合物山莴苣素。
实施例3
从毛菊苣根中提取化合物山窝苣素作为治疗糖尿病的药物或保健品的用途的生物活性筛选:
筛选方法:用对-硝基苯基磷酸二钠(pNPP)作为底物,以在阳性药物钒酸钠为对照,利用酶标仪进行(PTP1B)酶抑制剂的高通量筛选,根据蛋白酪氨酸磷酸酶(PTP1B)水解对-硝基苯基磷酸二钠(pNPP)的磷酸基团而产生颜色反应来测定蛋白酪氨酸磷酸酶(PTP1B)的活性。酶反应体系组成如下:缓冲液(50mM HEPES,pH7.3,100mM氯化钠,0.1%牛血清蛋白和1mM二硫代苏糖醇),GST-蛋白酪氨酸磷酸酶(PTP1B)融合蛋白,对-硝基苯基磷酸二钠(pNPP),蛋白酪氨酸磷酸酶(PTP1B)特异抑制剂钒酸钠(100μg/mL)。反应体系混匀后在37℃放置30rnin,加入1M氢氧化钠终止反应,置比色仪上测定405波长条件下的吸收值(A),测定结果减去本底值后计算酶活性。
筛选结果:
浓度(ug/ml)时间 | 0 | 200 | 300 | 500 |
加底物前 | 0.062 | 0.06 | 0.063 | 0.06 |
加底物后 | 0.079 | 0.088 | 0.078 | 0.081 |
10min | 0.217 | 0.149 | 0.108 | 0.109 |
15min | 0.28 | 0.266 | 0.152 | 0.156 |
20min | 0.321 | 0.352 | 0.195 | 0.181 |
25min | 0.4 | 0.377 | 0.209 | 0.191 |
30min | 0.456 | 0.415 | 0.255 | 0.198 |
结论:
从实验结果可知,从毛菊苣根中提取化合物山莴苣素具有蛋白酪氨酸磷酸酶(PTP1B)抑制剂的功效,其IC50约为1mM。
半抑制浓度的测定:
筛选方法:用对-硝基苯基磷酸二钠(pNPP)作为底物,以在阳性药物钒酸钠为对照,利用酶标仪进行PTP1B酶抑制剂的高通量筛选,根据蛋白酪氨酸磷酸酶(PTP1B)水解pNPP的磷酸基团而产生颜色反应来测定PTP1B的活性。酶反应体系组成如下:缓冲液(50mM HEPES,pH7.3,100mM氯化钠,0.1%牛血清蛋白和1mM二硫代苏糖醇),GST-蛋白酪氨酸磷酸酶(PTP1B)融合蛋白,对-硝基苯基磷酸二钠(pNPP),蛋白酪氨酸磷酸酶(PTP1B)特异抑制剂钒酸钠(100μg/mL)。混合均匀后,对溶液每隔4s测一次产物的浓度,共测150次,对实验结果进行线性回归。改变底物浓度按同样方法测试,以反应进程线的直线斜率为反应速率,已底物浓度倒数为横坐标作图,得1/[V]—1/[S]曲线,即酶反应动力学曲线,进而求得抑制剂对PTP1B半抑制浓度IC50值。本实验条件下以每分钟释放1.0μmol PNP为一个酶活力单位。其IC50约为1mM。
化合物鉴定:
无色针状结晶,mp:224—228℃.IR(KBr)cm-1:3354cm-1,1762cm-1,1664cm-1,1647cm-1,1618cm-1,1188cm-1,1137.7cm-1,1086cm-1,1038cm-1,898cm-1;ESI-MSm/z(%):277[M+H]+;1H-NMR(DMSO,400MHz)δppm:6.29(1H,s,H-3),6.14(1H,d,J=2Hz,H-13′),6.02(1H,s,J=2Hz,H-13),4.6(1H,d,J=20Hz,H-15),4.26(1H,d,J=20Hz,H-15′),3.8(1H,m,H-5),3.75(1H,m,H-6),3.7(1H,m,H-8),3.09(1H,m,H-7),2.76(1H,dd,J=12Hz,12Hz,H-9α),2.42(3H,s,H-14),2.34(1H,dd,J=12Hz,2Hz,H-9β);13C-NMR(DMSO,100MHz)δppm:194.4(C-2),174.9(C-4),168.8(C-12),146.6(C-10),138.0(C-11),132.3(C-1),131.9(C-3),121.5(C-13),80.7(C-6),66.4(C-8),61.2(C-15),55.3(C-7),48.3(C-9),47.9(C-5),21.1(C-14)。
Claims (1)
1.一种从毛菊苣根中提取山窝苣素的制备方法,其特征在于按下列步骤进行:
a、取干燥新疆毛菊苣根,用70%乙醇液提取,减压浓缩至无醇味的浸膏,用水混悬,分别用石油醚、乙酸乙酯、正丁醇萃取,回收正丁醇萃取液,减压浓缩至浸膏状;
b、浸膏用乙醇溶解,用硅胶拌样,用旋转蒸发仪蒸去溶剂,干燥,以石油醚,石油醚-乙酸乙酯,乙酸乙酯,乙酸乙酯-甲醇,甲醇依次洗脱,每500ml为一流分,TLC检测,将相同组分合并,各洗脱部分经多次硅胶柱色谱分离,葡聚糖凝胶LH-20凝胶柱层析,制备性薄层色谱分离、纯化,得到化合物山莴苣素。
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CN102351824B (zh) * | 2011-07-28 | 2013-08-14 | 中国科学院新疆理化技术研究所 | 一种山莴苣素和山莴苣苦素的制备方法 |
CN102657693B (zh) * | 2012-05-24 | 2014-08-13 | 王乐观 | 蛋白质酪氨酸磷酸酶shp-1抑制剂及其制备 |
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CN112939912A (zh) * | 2020-09-30 | 2021-06-11 | 石河子大学 | 一种毛菊苣提取物莴苣苦素的制备方法及其应用 |
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