CN111943919B - 一种间苯三酚类化合物Hyperacmosin C及其制备方法和用途 - Google Patents
一种间苯三酚类化合物Hyperacmosin C及其制备方法和用途 Download PDFInfo
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- CN111943919B CN111943919B CN201910401951.2A CN201910401951A CN111943919B CN 111943919 B CN111943919 B CN 111943919B CN 201910401951 A CN201910401951 A CN 201910401951A CN 111943919 B CN111943919 B CN 111943919B
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Abstract
本发明涉及一种从尖萼金丝桃(Hypericum acmosepaium N.Robson)中首次提取分离得到的一种间苯三酚类化合物Hyperacmosin C,其制备方法及其用途。生物活性测试显示:化合物Hyperacmosin C在10μM浓度下对APAP引起的肝细胞损伤有显著保护作用,从而可用于制备肝保护药物。
Description
技术领域
本发明涉及医药技术领域。涉及从尖萼金丝桃(Hypericum acmosepaiumN.Robson)地上部分提取分离得到的间苯三酚类化合物Hyperacmosin C及其制备方法与其在肝保护活性治疗中的应用。
背景技术
尖萼金丝桃为藤黄科金丝桃属植物,别名:香针树。分布于我国广西、四川、贵州、云南等地。民间用于消炎消肿,治疗肝炎等。现代对其化学成分的研究较少,且并不作为中药常用处方中用药。但已有大量文献报道间苯三酚类化合物具有抗病毒、抗炎等一系列良好的药理活性,而尖萼金丝桃富含丰富的间苯三酚类成分,因此,对其化学成分及药理作用进一步研究,发挥其功用是十分有意义的。
发明内容
本发明解决的技术问题是提供了从尖萼金丝桃中首次提取分离得到的间苯三酚类化合物Hyperacmosin C及其药学上可接受的盐,其制备方法及其用途。
为解决本发明的技术问题,本发明提供了如下技术方案:
本发明技术方案的第一方面是提供了间苯三酚类化合物Hyperacmosin C及其药学上可接受的盐,其化合物结构如下:
本发明技术方案的第二方面是提供了间苯三酚类化合物Hyperacmosin C的制备方法,它是从尖萼金丝桃地上部分中分离得到的,具体步骤如下:
提取:将粉碎的尖萼金丝桃地上部分用乙醇提取,所得提取液浓缩后得粗浸膏;将该粗浸膏溶于水,混悬均匀后用石油醚萃取,所得萃取液浓缩后得到石油醚浸膏。
分离:石油醚浸膏进行硅胶柱层析,第一次以石油醚/乙酸乙酯梯度洗脱,其中,石油醚/乙酸乙酯体积比1:0的洗脱部分进一步使用中压色谱凝胶填料进行减压柱层析,以75%乙醇、85%乙醇、95%乙醇及丙酮洗脱,每种溶剂用两个柱体积洗脱,每个柱体积为一个组分,共得到编号为A、B、C、D、E、F、G、H八个组分,其中85%乙醇洗脱的组分C进一步硅胶柱层析,第二次以石油醚/乙酸乙酯梯度洗脱,每种溶剂用两个柱体积洗脱,石油醚/乙酸乙酯的梯度洗脱的浓度依次为体积比1:0,9:1,4:1,2:1,0:1,得到C1-C20共20个组分,其中,石油醚/乙酸乙酯体积比9:1洗脱部分编号为C7经制备型高效液相色谱柱,以甲醇/水体积比96:4洗脱,得到化合物Hyperacmosin C。
在上述制备方法中,在提取步骤中,采用的乙醇为95%乙醇。
在上述制备方法中,在提取步骤中,所述提取采用的方法为加热回流提取。
在上述制备方法中,在分离步骤中,第一次石油醚/乙酸乙酯的梯度洗脱的浓度依次为体积比1:0,9:1,2:1,0:1。
在上述制备方法中,在分离步骤中,第二次石油醚/乙酸乙酯的梯度洗脱的浓度依次为体积比1:0,9:1,4:1,2:1,0:1。
在上述制备方法中,在分离步骤中,所述制备型HPLC的色谱柱填料为反相十八烷基键合硅胶。
本发明技术方案的第三方面是提供了一种药物组合物,其特征在于,所述的药物组合物含有权利要求1所述的间苯三酚类化合物及药学上可接受的盐或附加剂,以及权利要求1所述的间苯三酚类化合物及其药学上可接受的盐在肝保护药物中的用途。
该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量%。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助溶剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助溶剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明化合物与稀释剂、助溶剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助溶剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。一般来讲,本发明化合物的每天的合适剂量范围为0.001-5mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
本发明技术方案的第四方面是提供了化合物Hyperacmosin C及其药学上可接受的盐在制备肝保护药物中的用途。
有益技术效果
本发明采用单体化合物对葡萄糖消耗实验及对体外APAP引起肝细胞损伤保护作用评价的方法。实验证实Hyperacmosin C在10μM浓度下对APAP引起的肝细胞损伤有显著保护作用,从而它可用于制备肝保护药物。
具体实施方式
实施例中所指的Hyperacmosin C的化学结构式(结构式中的阿拉伯数字是化学结构中碳原子的标位)如下所示:
实施例1 Hyperacmosin C的制备
提取:将干燥的尖萼金丝桃(Hypericum acmosepaium N.Robson)地上部分17.0kg,粉碎后用95%乙醇加热回流提取3次,所得提取液减压浓缩后得粗浸膏;将该粗浸膏溶于水,混悬均匀后用石油醚萃取三次,所得萃取液减压浓缩后得到石油醚浸膏。
分离:石油醚浸膏进行硅胶柱层析将所述石油醚浸膏进行硅胶柱层析,以石油醚/乙酸乙酯梯度洗脱,
石油醚/乙酸乙酯的梯度洗脱的浓度依次为体积比1:0,9:1,2:1,0:1。
根据TLC茴香醛显色合并相似流份得到11个组分Fr.1~11;
其中组分Fr.1即石油醚/乙酸乙酯体积比1:0洗脱部分进一步进行MCI减压柱层析,以75%、85%、95%乙醇及丙酮洗脱,
根据TLC显色合并相似流份得到8个组分A、B、C、D、E、F、G、H。
组分C进一步硅胶柱层析,以石油醚/乙酸乙酯梯度洗脱,
石油醚/乙酸乙酯体积比1:0,9:1,4:1,2:1,0:1。
根据TLC茴香醛显色合并相似流份得到20个组分,石油醚/乙酸乙酯体积比9:1洗脱部分即组分C7。
经制备型HPLC【C18柱(5μm,250×10mm)甲醇/水96:4体积比洗脱,流速3mL/min,254nm波长下检测】,得到本发明化合物Hyperacmosin C(7mg)。
结构鉴定:按常规经NMR、HRESIMS、UV、IR及旋光等多种现代光谱技术,确定了化合物Hyperacmosin C的化学结构,其理化性质如下:
Hyperacmosin C:
无色油状,分子式为C38H60O6;
紫外光谱UV(MeOH)λmax(logε)204(4.46)nm;
红外光谱IR(KBr)νmax;3386,2961,2919,1712,1454,1377cm-1;
旋光度
圆二色谱ECD(MeOH)λmax(Δε)248.5(+0.53)nm;
高分辨质谱HRESIMS m/z 635.42896[M+Na]+(calculated for C38H60O6,635.42931);
Hyperacmosin C的核磁共振氢谱1H NMR(400MHz)及核磁共振碳谱13C NMR(150MHz)数据见表一。
表一Hyperacmosin C的1H和13C NMR(ppm in CDCl3)
实验例1 Hyperacmosin C对体外APAP引起肝细胞损伤保护作用评价
实验样品
被测样品溶液的配置:测试样品为实施例1中制备的纯品化合物(HyperacmosinC)。准确称取适量样品,使用DMSO配制成10mM的储存溶液,供药理活性测试。
细胞株:细胞株:人肝癌HepG2细胞,该细胞较好的保留了人正常肝细胞的特性。在含10%胎牛血清的DMEM培养液(含青霉素100U/ml,链霉素100μg/ml)中生长,培养条件为37℃、5%CO2,饱和湿度。用含0.25%胰蛋白酶和0.02%EDTA液消化传代。
实验方法
1.化合物对HepG2细胞增殖的影响
采用MTT方法。HepG2细胞接种于96孔细胞培养板中,培养24h后,加入不同浓度的待测化合物,同时设溶剂对照组,每个药物浓度设3个平行孔。药物作用细胞48h后,弃去培养液,每孔加入MTT(0.5mg/ml)液100μl,继续培养4h,弃去MTT液,每孔加入DMSO150μl,混和振荡器振荡,于酶标仪570nm波长处测定吸光度值。细胞存活率(%)=(给药细胞OD平均值/溶剂对照细胞OD平均值)×100%。
2.化合物对扑热息痛引起体外肝细胞损伤的保护作用
采用MTT方法。HepG2细胞接种于96孔细胞培养板中,培养24h后,加入无毒浓度的待测化合物及扑热息痛(APAP,终浓度8mM),同时设阳性药物对照组(双环醇,bicyclol)、溶剂空白对照组及模型组。继续作用细胞48h。弃去培养液,每孔加入MTT(0.5mg/ml)液100μl,继续培养4h,弃去MTT液,每孔加入DMSO 150μl,混和振荡器振荡,于酶标仪570nm波长处测定吸光度值。细胞存活率(%)=(给药组OD平均值/溶剂对照组OD平均值)×100%。
实验结果
1.细胞毒性:Hyperacmosin C在10μM浓度作用HepG2细胞48h,对HepG2细胞增殖均无明显影响,细胞存活率大于90%,以10μM浓度用于后续实验。
2.对APAP引起肝细胞损伤的保护作用:APAP 8mM作用HepG2细胞48h,对HepG2细胞产生显著损伤,细胞存活率仅为48.98%。在目前实验方案下,Hyperacmosin C与APAP合用,对后者引起的HepG2细胞损伤均有保护作用,在10μM浓度下对APAP引起的体外肝细胞损伤均有显著保护作用,与模型组比较均有统计学差异。
表1化合物对APAP引起HepG2细胞损伤的保护作用
***P<0.001,与空白对照组比较;#P<0.05,##P<0.01,与APAP模型组比较。
实验结论
化合物Hyperacmosin C在10μM浓度下对APAP引起的肝细胞损伤有显著保护作用,可用于制备肝保护药物。
Claims (6)
1.一种化学结构式如下所示的间苯三酚类化合物及其药学上可接受的盐:
2.权利要求1所述的间苯三酚类化合物的制备方法,其特征在于,该方法包括以下步骤:
提取:将粉碎的尖萼金丝桃(Hypericum acmosepaium N.Robson)地上部分用乙醇提取,所得提取液浓缩后得粗浸膏;将该粗浸膏溶于水,混悬均匀后用石油醚萃取,所得萃取液浓缩后得到石油醚浸膏;
分离:石油醚浸膏进行硅胶柱层析,第一次以石油醚/乙酸乙酯梯度洗脱,其中,石油醚/乙酸乙酯体积比1:0的洗脱部分进一步使用中压色谱凝胶填料进行减压柱层析,以75%乙醇、85%乙醇、95%乙醇及丙酮洗脱,每种溶剂用两个柱体积洗脱,每个柱体积为一个组分,共得到编号为A、B、C、D、E、F、G、H八个组分,其中85%乙醇洗脱的组分C进一步硅胶柱层析,第二次以石油醚/乙酸乙酯梯度洗脱,每种溶剂用两个柱体积洗脱,石油醚/乙酸乙酯的梯度洗脱的浓度依次为体积比1:0,9:1,4:1,2:1,0:1,得到C1-C20共20个组分,其中,石油醚/乙酸乙酯体积比9:1洗脱部分编号为C7经制备型高效液相色谱柱,以甲醇/水体积比96:4洗脱,得到化合物Hyperacmosin C;
提取步骤中,采用的乙醇为95%乙醇;分离步骤中,第一次石油醚/乙酸乙酯的梯度洗脱的浓度依次为体积比1:0,9:1,2:1,0:1。
3.根据权利要求2所述的制备方法,其特征在于,提取步骤中,所述提取采用的方法为加热回流提取。
4.根据权利要求2所述的制备方法,其特征是,在分离步骤中,所述制备型高效液相色谱柱填料为反相十八烷基键合硅胶。
5.一种药物组合物,其特征在于,所述的药物组合物含有权利要求1所述的间苯三酚类化合物及药学上可接受的盐和赋形剂。
6.权利要求1所述的间苯三酚类化合物及其药学上可接受的盐在制备肝保护药物中的用途。
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