CN113896629B - 一种吉玛烷型倍半萜类化合物的制备方法和应用 - Google Patents
一种吉玛烷型倍半萜类化合物的制备方法和应用 Download PDFInfo
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Abstract
本方案公开了医药技术领域的一种吉玛烷型倍半萜类化合物的制备方法及其在抗炎药物中的应用,制备过程如下:一:对宽叶缬草根浸提,回收得到浸膏;二:浸膏用水混溶成浑浊物,经萃取、浓缩得乙酸乙酯层浸膏;三:乙酸乙酯层浸膏经硅胶柱层析,梯度洗脱,检测并合并后,得到4个馏分:Fr.1~Fr.4;四:将Fr.3和Fr.4分别进行硅胶柱层析,梯度洗脱,检测并合并后,分别被分为Fr.3a~Fr.3f和Fr.4a~Fr.4e;将Fr.3c和Fr.4b分别进行硅胶柱层析,梯度洗脱,得化合物1和化合物3;Fr.3e和Fr.4c分别经Sephadex LH‑20凝胶柱层析和半制备高效液相色谱,得化合物2和化合物4。
Description
技术领域
本发明属于医药技术领域,特别涉及一种吉玛烷型倍半萜类化合物的制备方法和应用。
背景技术
炎症是具有血管系统的活体组织对各种损伤因子的刺激所发生的以防御反应为主的病理生理过程,参与多种疾病(如心血管疾病、骨质疏松、糖尿病、自身免疫性疾病、动脉粥样硬化、神经退行性疾病等)的发生发展。目前,抗炎药物在临床治疗中是仅次于抗感染药物的第二大类药物,临床使用的抗炎药物主要包括非甾体类抗炎药和甾体类抗炎药,但都会出现不同程度的不良反应,如非甾体类抗炎药对胃肠道的刺激和肾脏损害、糖皮质激素类药可能诱发或加重感染等。而天然药用植物是开发抗炎药物的重要资源,因此从天然药用植物中开发成分明确、质量可控、安全有效的抗炎药物对临床治疗疾病具有重要意义。
宽叶缬草也叫阔叶缬草(Valeriana officinalis L.),是欧洲缬草的变种,在我国主要分布在贵州、四川、云南部分地区。缬草油对治疗革兰氏阳性细菌效力较好;缬草制剂有加速体内凝血过程、抗利尿、抗氧化、抗疲劳作用它的抗水肿作用。缬草挥发油具有很强的抗实验性肺水肿作用,其疗效优于消心痛与654-2,与酚妥拉明相近,其作用是其强烈扩张小动脉、静脉,改善微循环,显著降低心脏前、后负荷,增加心输出量;迅速扩张冠状动脉,增加冠状流量,有效地改善心肌微循环灌注,从而大大改善了心肌缺血状态与舒缩功能障碍;抗心律失常;镇静降低机体氧耗;减慢心律降低心肌氧耗等综合影响的结果。
发明内容
本发明意在提供一种吉玛烷型倍半萜类化合物的制备方法,以增加吉玛烷型倍半萜类化合物的获取途径。
本方案中的一种吉玛烷型倍半萜类化合物的制备方法,所述吉玛烷型倍半萜类化合物的的化学结构式如式Ⅰ、式Ⅱ、式Ⅲ或式Ⅳ所示,如下:
制备过程包括以下步骤:
步骤1:取宽叶缬草根并粉碎,采用95%工业乙醇或甲醇在室温下对粉碎后的宽叶缬草根浸提3~5次,每次3天,回收醇浓缩得到浸膏;
步骤2:将步骤1所得浸膏用水混溶成浑浊物,经过乙酸乙酯等体积萃取、经旋转蒸发仪浓缩得乙酸乙酯层浸膏;
步骤3:将步骤2所得乙酸乙酯层浸膏经过硅胶柱层析,采用石油醚与乙酸乙酯体积比为60:1、20:1、10:1、8:2、7:3、1:1比例的洗脱剂梯度洗脱,每个梯度400份,运用硅胶薄层色谱技术对不同洗脱馏分进行检测,具有相同的薄层色谱结果的馏分进行合并,得到4个馏分:Fr.1、Fr.2、Fr.3和Fr.4;
步骤4:(1)将步骤3中Fr.3进行硅胶柱层析,采用石油醚与丙酮体积比为100:1~1:1比例的洗脱剂梯度洗脱,运用硅胶薄层色谱技术对不同洗脱馏分进行检测,具有相同的薄层色谱结果的馏分进行合并,被分为6个亚馏分:Fr.3a、Fr.3b、Fr.3c、Fr.3d、Fr.3e和Fr.3f;Fr.3c进行硅胶柱层析,氯仿与乙酸乙酯体积比为100:1~100:10比例的洗脱剂梯度洗脱,得到化合物1;Fr.3e经甲醇的Sephadex LH-20凝胶柱层析和经半制备高效液相色谱,甲醇与水比例为80:20,得到化合物2;
(2)将步骤3中Fr.4进行硅胶柱层析,采用石油醚与丙酮体积比为100:1~1:1比例的洗脱剂梯度洗脱,运用硅胶薄层色谱技术对不同洗脱馏分进行检测,具有相同的薄层色谱结果的馏分进行合并,被分为5个亚馏分:Fr.4a、Fr.4b、Fr.4c、Fr.4d和Fr.4e;Fr.4b进行硅胶柱层析,氯仿与乙酸乙酯体积比为100:1~100:10比例的洗脱剂梯度洗脱,得到化合物3,Fr.4c经甲醇的Sephadex LH-20凝胶柱层析和经半制备高效液相色谱,甲醇与水比例为80:20,得到化合物4。
基于吉玛烷型倍半萜类化合物,本申请还提供了该化合物的应用。经过试验证明,前述式Ⅰ、式Ⅱ、式Ⅲ和式Ⅳ中的吉玛烷型倍半萜类化合物均具有良好的抗炎活性,可应用于抗炎药物中。
进一步,所述药物为吉玛烷型倍半萜类化合物,或其溶剂化物、光学异构体、外消旋体、前药分子或其代谢物、或其药学上可接受的盐;其中,吉玛烷型倍半萜类化合物的化学结如构式Ⅰ、式Ⅱ、式Ⅲ或式Ⅳ所示,如下:
进一步,药学上可接受的盐包括盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
进一步,所述抗炎药物的剂型为液体制剂、固体制剂、半固体制剂或气体制剂。
进一步,所述液体制剂为注射剂、溶液剂、混悬剂、糖浆剂或洗剂。
进一步,所述固体制剂为片剂、颗粒剂、散剂或胶囊剂。
进一步,所述半固体制剂为软膏剂或栓剂。
进一步,所述气体制剂为气雾剂或喷雾剂。
具体地,前述药物根据药学上可接受的辅料进行恰当选择,可以按照药剂学领域的常规生产方法制备所需药物的各种剂型。如将该化合物或者其药学上可接受的盐、溶剂化物、异构体、前药分子或代谢物与一种或多种载体混合,然后制成相应的剂型。
本申请中,所述化合物1、化合物2、化合物3、化合物4分别对应指化学结构式为式Ⅰ、式Ⅱ、式Ⅲ和式Ⅳ的四种化合物。
附图说明
图1为本发明中吉玛烷型倍半萜类化合物在浓度为50μM时对小鼠原代腹腔巨噬细胞活力影响的对比图。图1中,**p<0.01vs Control,#p>0.05vs Control。
具体实施方式
下面通过具体实施方式进一步详细说明:
实施例1:一种吉玛烷型倍半萜类化合物的制备方法,操作步骤如下:
步骤1:取宽叶缬草干燥花80份,粉碎,采用95%工业乙醇或甲醇320份,在室温下浸提3~5次,每次3天,回收醇浓缩得浸膏5份;
步骤2:将步骤1所得浸膏用180份水混溶成浑浊物,经过乙酸乙酯等体积萃取3次、经旋转蒸发仪浓缩得乙酸乙酯层浸膏3份;
步骤3:将步骤2所得乙酸乙酯层浸膏经过硅胶柱层析,采用石油醚与乙酸乙酯体积比为60:1、20:1、10:1、8:2、7:3、1:1比例的洗脱剂梯度洗脱,每个梯度400份,运用硅胶薄层色谱技术对不同洗脱馏分进行检测,具有相同的薄层色谱结果的馏分进行合并,得到4个馏分:Fr.1、Fr.2、Fr.3和Fr.4;合并时,按照梯度洗脱的顺序进行检测并合并,即按照梯度洗脱的顺序检测出第一种馏分时,得到Fr.1、检测到第二种不同的馏分时,得到Fr.2,以此类推得到Fr.3和Fr.4。
步骤4:(1)将步骤3中Fr.3进行硅胶柱层析,采用石油醚与丙酮体积比为100:1~1:1比例的洗脱剂梯度洗脱,被分为6个亚馏分:Fr.3a、Fr.3b、Fr.3c、Fr.3d、Fr.3e和Fr.3f,6个亚馏分在进行分类命名时,也是按照梯度洗脱的顺序进行分类和命名;Fr.3c进行硅胶柱层析,氯仿与乙酸乙酯体积比为100:1~100:10比例的洗脱剂梯度洗脱,得到化合物1,Fr.3e(4g)经甲醇的Sephadex LH-20凝胶柱层析和经半制备高效液相色谱,甲醇与水比例为80:20,得到化合物2。
(2)将步骤3中Fr.4进行硅胶柱层析,采用石油醚与丙酮体积比为100:1~1:1比例的洗脱剂梯度洗脱,被分为5个亚馏分:Fr.4a、Fr.4b、Fr.4c、Fr.4d和Fr.4e,5个亚馏分在进行分类命名时,也是按照梯度洗脱的顺序进行分类和命名;Fr.4b进行硅胶柱层析,氯仿与乙酸乙酯体积比为100:1~100:10比例的洗脱剂梯度洗脱,得到化合物3,Fr.3c(4g)经甲醇的Sephadex LH-20凝胶柱层析和经半制备高效液相色谱,甲醇与水比例为80:20,得到化合物4。
实施例2:本发明吉玛烷型倍半萜类化合物的抗炎活性评价
1.实验材料
1、实验对象:小鼠原代腹腔巨噬细胞(peritoneal macrophage,PMs)
1.1主要试剂:LPS(Lipoplysaccharides from Escherichia coli O55B5)L2880-500MG,Lot#127M4030V,美国Sigma公司;Mouse TNF alpha Uncoated ELISA试剂盒,美国Thermo Fisher Scientific公司;细胞增殖及毒性检测试剂盒(CCK-8),大连美仑生物技术有限公司。
1.2主要仪器:FORMA371二氧化碳培养箱,赛默飞世尔科技(中国)有限公司;HCB-1300V垂直层流工作台,青岛海尔特种电器有限公司;SC-3610低速离心机,安徽中科中佳科学仪器有限公司;IC1000自动细胞计数仪,上海睿钰生物科技有限公司;Thermo MultiskanGO酶标仪,美国Thermo Fisher Scientific公司。
2.实验方法
2.1PMs细胞的制备及培养
昆明小鼠腹腔注射3%巯基乙酸盐培养基3mL/只,三天后异氟烷将小鼠吸入麻醉致死,放入75%酒精浸泡1-2分钟,超净工作台操作,腹腔注射10mL生理盐水灌洗腹腔,轻柔两分钟,富集腹腔游离细胞,1000rpm/3min离心细胞液,弃上清,适量DMEM完全培养基重悬细胞,细胞计数仪计数,调整活细胞密度为1.0×106个/mL,以100μL/孔接种于96孔板,置于37℃、5%CO2培养箱培养,待2~3h细胞贴壁后进行实验。
2.2ELISA法检测化合物对LPS刺激小鼠原代腹腔巨噬细胞释放炎症细胞因子的影响将培养贴壁后的PMs进行如下处理:Control组,加入等体积的完全培养基;LPS50组(模型组),加入终浓度为50ng/mL的LPS;LPS50+化合物组(化合物1、2、3、4),加入终浓度为50ng/mL的LPS和终浓度为50μmol/L的化合物,继续培养4h。将所收集细胞上清按酶联免疫吸附实验(enzyme linked immunosorbent assay,ELISA)试剂盒操作手册检测细胞因子TNF-α水平,检测方法具体步骤简述如下:
(1)包被捕获抗体。取出酶标板,每孔加入100μL稀释后的捕获抗体4℃孵育过夜;
(2)活化酶标板。将孵育过夜的酶标板用PBS洗液洗板4次,每孔加入200μL样本稀释液37℃孵育1h;
(3)上样。酶标板用PBS洗液洗板4次,每孔加入标准品100μL,以及加入稀释五倍的待测样本,37℃孵育2h,或4℃孵育过夜;
(4)检测抗体。酶标板用PBS洗液洗板4次,每孔加入100μL稀释后的检测抗体,37℃孵育1h;
(5)Avidin-HRP酶。酶标板用PBS洗液洗板4次,每孔加入100μL稀释后的Avidin-HRP酶结合工作液,37℃孵育30min;
(6)显色。酶标板用PBS洗液洗板5次,每孔加入100μL的TMB显色液,避光显色15min;
(7)终止显示。每孔加入100μL终止液,立即测定OD450吸光值。根据标准品所浓度梯度及OD450绘制标准曲线,并按照标准曲线公式计算出各样品中TNF-α浓度。
抑制率=[(模型组细胞因子平均含量-化合物处理后细胞因子平均含量)/模型组细胞因子平均含量]×100%
2.3CCK-8法检测化合物对小鼠原代腹腔巨噬细胞活力的影响
将培养贴壁后的PMs进行如下处理:Control组,加入等体积的完全培养基;化合物组(化合物1、2、3、4),加入终浓度为50μmol/L的化合物,继续培养4h。弃上清,避光环境下,将CCK-8:DMEM=1:10进行配制,混匀,每孔加入100μL,另加入不含细胞及药物的CCK-8液3孔,继续孵育1h,立即测定OD450吸光值。
细胞存活率=[(化合物组吸光度值-CCK-8液吸光度平均值)/(Control组吸光度平均值-CCK-8液吸光度平均值)]×100%
2.4统计分析处理:
所有实验结果采用GraphPad Prism 8.0.2软件进行统计学分析,所有数值以均数±标准差(x±s)表示,采用单因素方差分析、双尾无配对学生t检验进行统计学分析并作图。#,p>0.05,无统计学二差异;*,p<0.05,有统计学差异;**,p<0.01,有显著统计学差异;***,p<0.001,有非常显示统计学差异。
3.实验结果
抗炎活性测试结果表明,化合物1、2、3、4对炎症细胞因子TNF-α均有较好的抑制作用,具有抗炎活性。
实验结果分别见表1(1-1、1-2)及图1。
表1-1化合物1可抑制LPS诱导的小鼠腹腔巨噬细胞释放TNF-α
***p<0.001vs Control;**p<0.05vs LPS50。
表1-2化合物2-4可抑制LPS诱导的小鼠腹腔巨噬细胞释放TNF-α
***p<0.001vs Control;**p<0.01vs LPS50;*p<0.05vs LPS50。
从图1的细胞活力检测结果显示,所示化合物1、化合物2、化合物3和化合物4在浓度为50μM时对小鼠原代腹腔巨噬细胞的生长没有毒性作用。
由以上实验可知,本发明提出的式Ⅰ、式Ⅱ、式Ⅲ和式Ⅳ化合物对脂多糖诱导的小鼠原代腹腔巨噬细胞炎症细胞因子有较好的抑制作用,具有一定抗炎活性,为抗炎药物的研发提供新的选择。
申请文件中,compound 1、compound 2、compound 3、compound 4分别指化合物1、化合物2、化合物3和化合物4。
以上所述的仅是本发明的实施例,方案中公知的具体结构及特性等常识在此未作过多描述。应当指出,对于本领域的技术人员来说,在不脱离本发明结构的前提下,还可以作出若干变形和改进,这些也应该视为本发明的保护范围,这些都不会影响本发明实施的效果和专利的实用性。本申请要求的保护范围应当以其权利要求的内容为准,说明书中的具体实施方式等记载可以用于解释权利要求的内容。
Claims (8)
1. 一种吉玛烷型倍半萜类化合物的制备方法,所述吉玛烷型倍半萜类化合物的的化学结构式如式Ⅰ、式 Ⅱ、式Ⅲ或式Ⅳ所示,如下:
、/>;
、/>;其特征在于:制备过程包括以下步骤:
步骤1:取宽叶缬草根并粉碎,采用95 %工业乙醇或甲醇在室温下对粉碎后的宽叶缬草根浸提3~5次,每次3天,回收醇浓缩得到浸膏;
步骤2:将步骤1所得浸膏用水混溶成浑浊物,经过乙酸乙酯等体积萃取、经旋转蒸发仪浓缩得乙酸乙酯层浸膏;
步骤3:将步骤2所得乙酸乙酯层浸膏经过硅胶柱层析,采用石油醚与乙酸乙酯体积比为60:1、20:1、10:1、8:2、7:3、1:1比例的洗脱剂梯度洗脱,每个梯度400份,运用硅胶薄层色谱技术对不同洗脱馏分进行检测,具有相同的薄层色谱结果的馏分进行合并,得到4个馏分:Fr.1、Fr.2、Fr.3和 Fr.4;
步骤4:(1)将步骤3中Fr.3进行硅胶柱层析,采用石油醚与丙酮体积比为100:1~1:1比例的洗脱剂梯度洗脱,运用硅胶薄层色谱技术对不同洗脱馏分进行检测,具有相同的薄层色谱结果的馏分进行合并,被分为6个亚馏分:Fr.3a、Fr.3b、Fr.3c、Fr.3d、Fr.3e和Fr.3f;Fr.3c进行硅胶柱层析,氯仿与乙酸乙酯体积比为100:1~100:10比例的洗脱剂梯度洗脱,得到化合物1;Fr.3e经甲醇的Sephadex LH-20凝胶柱层析和经半制备高效液相色谱,甲醇与水比例为80:20,得到化合物2;
(2)将步骤3中Fr.4进行硅胶柱层析,采用石油醚与丙酮体积比为100:1~1:1比例的洗脱剂梯度洗脱,运用硅胶薄层色谱技术对不同洗脱馏分进行检测,具有相同的薄层色谱结果的馏分进行合并,被分为5个亚馏分:Fr.4a、Fr.4b、Fr.4c、Fr.4d和Fr.4e;Fr.4b进行硅胶柱层析,氯仿与乙酸乙酯体积比为100:1~100:10比例的洗脱剂梯度洗脱,得到化合物3,Fr.4c经甲醇的Sephadex LH-20凝胶柱层析和经半制备高效液相色谱,甲醇与水比例为80:20,得到化合物4。
2. 一种吉玛烷型倍半萜类化合物的应用,其特征在于:吉玛烷型倍半萜类化合物或其光学异构体、外消旋体或其药学上可接受的盐在制备抗炎药物中的应用,所述吉玛烷型倍半萜类化合物的化学结构式如式Ⅰ、式 Ⅱ、式Ⅲ或式Ⅳ所示,如下:
、/>;
、/>。
3.根据权利要求2所述的一种吉玛烷型倍半萜类化合物的应用,其特征在于:所述药学上可接受的盐包括盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
4.根据权利要求2或3所述的一种吉玛烷型倍半萜类化合物的应用,其特征在于:所述抗炎药物的剂型为液体制剂、固体制剂、半固体制剂或气体制剂。
5.根据权利要求4所述的一种吉玛烷型倍半萜类化合物的应用,其特征在于:所述液体制剂为注射剂、溶液剂、混悬剂、糖浆剂或洗剂。
6.根据权利要求4所述的一种吉玛烷型倍半萜类化合物的应用,其特征在于:所述固体制剂为片剂、颗粒剂、散剂或胶囊剂。
7.根据权利要求4所述的一种吉玛烷型倍半萜类化合物的应用,其特征在于:所述半固体制剂为软膏剂或栓剂。
8.根据权利要求4所述的一种吉玛烷型倍半萜类化合物的应用,其特征在于:所述气体制剂为气雾剂或喷雾剂。
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