CN115025077B - 鼠尾草酸的衍生物的制备方法及其应用 - Google Patents
鼠尾草酸的衍生物的制备方法及其应用 Download PDFInfo
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Abstract
本申请公开一种鼠尾草酸的衍生物的制备方法及其应用,通过从迷迭香提取物中制备高纯度鼠尾草酸,并对鼠尾草酸进行结构修饰得到衍生物,将其应用于血压调节。鼠尾草酸的衍生物能够与AT1R结合,通过阻断AT1R介导的G蛋白信号通路下游信号从而降低血压。本发明扩大了鼠尾草酸的应用范围,具有操作简单,高效,产品获取率高等优点,在医学与食品工程领域有广阔的应用前景。
Description
技术领域
本申请涉及一种生物医药技术领域,具体鼠尾草酸的衍生物的制备方法及其应用。
背景技术
高血压是一个全球性的公共卫生问题,是心脏病、脑卒中、脑血栓等心脑血管疾病最重要的危险因素,影响着全球10亿人的健康。因此,预防和治疗高血压成为全球医务界面临的一项艰巨任务。
AT1R是血压调节系统(Renin-angiotensin system, RAS)中的关键作用靶点。目前,以AT1R为靶点的降血压药物(angiotensin Ⅱ receptor blockers, ARB)与其他降血压药物相比有更高的安全性,长期用药对心肾功能有较好的保护作用,已成为高血糖和心律失常高血压患者的首选药物。至2005年,该类药物已成为占据全球降血压药物市场43%的第一大类药物。目前已报道的ARB均为化学合成药物。但是,近年来接连发生的由于致癌物亚硝胺残留引发的ARB召回事件为化学合成ARB的广泛使用带来了更多的安全隐患。因此,以AT1R为作用靶点筛选天然ARB将有助于解决化学合成ARB类降血压药物存在的潜在安全问题,为非药物干预调节血压提供新的思路,具有广阔的市场应用前景。
发明内容
本申请旨在克服现有技术的不足,开发安全的食源性降血压产品,提供一种鼠尾草酸的衍生物的制备方法及其应用。
为实现上述目的,本发明技术方案如下:
第一方面,提供鼠尾草酸的衍生物作为唯一活性成分在制备治疗高血压的药物中的应用,其中,所述鼠尾草酸的衍生物作为AT1R拮抗剂影响血压调节系统;所述鼠尾草酸的衍生物的结构式为以下任意一个:
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优选地,所述鼠尾草酸的衍生物的制备方法,包括:
在三口瓶中加入鼠尾草酸,然后加入无水乙醇作溶剂,混合均匀后,再滴加催化量的浓硫酸,加热至回流条件下反应,TLC监测反应,直至原料反应完全,处理反应,取下反应体系冷却至室温,减压脱溶,然后加入水,用乙酸乙酯萃取三次,有机层用无水硫酸钠干燥,旋干,得到白色固体、浅黄色固体状的鼠尾草酸衍生物。
第二方面,提供鼠尾草酸及其衍生物在制备降血压制剂中的应用。具体地,所述鼠尾草酸作为AT1R拮抗剂影响血压调节系统。优选地,所述降血压制剂包括药物制剂或食品制剂。可选择地,所述鼠尾草酸结构式如式Ⅰ所示:,式Ⅰ。进一步地,所述鼠尾草酸的衍生物通过对鼠尾草酸进行以下至少一种化学修饰获得:邻二酚羟基酯化、乙酰化、羰基化、糖基化、生物素化、荧光基团修饰和聚乙二醇PEG修饰。可选择地,所述鼠尾草酸的衍生物的结构式如式Ⅱ:/>,式Ⅱ;其中,R1可为甲基、羟甲基、羧基、酯基等,R2、R3分别可为氢或烷基。
第三方面,提供一种鼠尾草酸的制备方法,所述方法包含以下步骤;(1)将迷迭香脂溶性提取物充分溶解于正己烷中,获得有机相溶液;(2)用碱性水溶液萃取所述有机相溶液,获得水相溶液;(3)将所述水相溶液调至酸性之后,收集沉淀;(4)将所述沉淀溶解于有机溶剂中,形成过饱和溶液,低温结晶获得鼠尾草酸结晶。可选择地,步骤(1)中,所述迷迭香脂溶性提取物与正己烷的固液比为1:10 ~100。可选择地,步骤(2)中,所述碱性水溶液为氨水、NaOH水溶液或NaHCO3水溶液。进一步可选择地,步骤(3)中,选用HCl、CH3COOH或H3PO4调节酸碱度,调节后的pH范围为1~4。进一步可选择地,步骤(4)中,所述有机溶剂为正己烷、环己烷或乙酸乙酯。可选择地,所述步骤(1)中,所述迷迭香脂溶性提取物的制备步骤如下:采用干燥的迷迭香的茎和叶作为原材料,采用乙醇水作为提取溶剂浸泡所述原材料成为固液混合物;采用层析柱将所述固液混合物洗脱出混合提取液;采用旋转蒸发法分离所述混合提取液中的水溶性成分和脂溶性成分;对所述脂溶性成进行脱色和干燥后,获得迷迭香脂溶性提取物。
与现有技术相比,本发明的有益效果为:
本申请提供的鼠尾草酸的制备方法条件温和,工艺简单,成本低,得率高,能够有效防止鼠尾草酸在制备过程中的降解,适合于大规模工业化生产。
同时,本申请提供了鼠尾草酸及其衍生物在调节血压方面的应用。ARB是继ACEI之后的一类新型抗高血压药,是以血管紧张素Ⅱ受体1(Ang Ⅱ type one receptor, AT1R)为靶点,通过阻断Ang Ⅱ与AT1R的结合,起到降压和保护靶器官的作用。以AT1R为作用靶点筛选天然ARB,将有助于解决化学合成ARB类降血压药物存在的潜在安全问题,为非药物干预调节血压提供新的思路。
本申请通过活性筛选证实,迷迭香中的主要活性成分鼠尾草酸及其衍生物通过与AT1R结合,能够有效阻断与AT1R结合的Gq蛋白聚合物的解离及信号通路下游Ca2+的释放,具有潜在的降血压功效。由此,鼠尾草酸及其衍生物可用于食源性降血压产品的主要添加剂。
附图说明
图1为通过本申请鼠尾草酸制备方法制得的鼠尾草酸HPLC检测图;
图2为通过本申请鼠尾草酸制备方法制得的鼠尾草酸样品;
图3为本申请中使用的BRET技术原理示意图;
图4 为通过BRET技术检测本申请方法制得的鼠尾草酸对细胞内Cq蛋白聚合物的解离结果图;
图5为天然多肽(A)、迷迭香酸/鼠尾草酸(B)和通过本申请制备方法制得的不同浓度鼠尾草酸(C)对细胞内Ca2+释放的抑制作用。
具体实施方式
以下结合附图和具体实施方式对本申请作进一步详细描述。
下文自始至终相同或类似的名词表示相同或类似的物质或具有相同或类似功能的物质。下述实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的材料、试剂等,如无特殊说明,为可从商业途径得到的试剂和材料。
迷迭香是唇形科、迷迭香属植物。除了是一种广泛使用的香料外,迷迭香还具有很强的抗氧化活性。作为唯一列入目录的植物源性抗氧化剂,迷迭香提取物以其高效、广谱、耐热、安全等优良性能,在食品工业和一些相关行业的应用范围越来越宽,有望成为化学合成抗氧化剂的理想替代品。
鼠尾草酸外观为无色至淡黄色粉末晶体,易溶于油脂而不溶于水,主要存在于迷迭香、三叶鼠尾草、南欧丹参等植物中,是这些植物中主要的天然抗氧化成分,鼠尾草酸和迷迭香酸是迷迭香的主要功能成分,我国食品安全国家标准分别将鼠尾草酸和迷迭香酸作为指标物质评价迷迭香脂溶性抗氧化剂(鼠尾草酸含量≥10%)和水溶性抗氧化剂(迷迭香酸含量≥5%)的质量。
实施例1:鼠尾草酸的制备方法
一种可能的实施方式中,从迷迭香提取物中制备鼠尾草酸的方法,具体包含以下内容:
1)将迷迭香脂溶性提取物按固液比1∶50溶解于正己烷中;
2)待充分溶解后用等体积的2% NaHCO3萃取正己烷溶液,收集下层萃取相;
3)用0.5mol/L HCL将收集的下层萃取相调节至pH3,4℃静置4h,收集沉淀;
4)将沉淀溶解于环己烷中,配成鼠尾草酸过饱和溶液,低温过夜结晶,获得类黄色或浅黄色,纯度为98%的鼠尾草酸制品(图2);
另一种可供选择的实施方式是:从迷迭香提取物中制备鼠尾草酸的方法,具体包含以下内容:
1)将迷迭香脂溶性提取物按固液比1∶10溶解于正己烷中;
2)待充分溶解后用等体积的1% NaHCO3萃取正己烷溶液,收集下层萃取相;
3)用0.5mol/L HCL将收集的下层萃取相调节至PH3,4℃静置4h,收集沉淀;
4)将沉淀溶解于环己烷中,配成鼠尾草酸过饱和溶液,低温过夜结晶,得白色鼠尾草酸产品,纯度为85%。
另一种可供选择的实施方式是:从迷迭香提取物中制备鼠尾草酸的方法,具体包含以下内容:
1)将迷迭香脂溶性提取物按固液比1∶100溶解于正己烷中;
2)待充分溶解后用等体积的3% NaHCO3萃取正己烷溶液,收集下层萃取相;
3)用1mol/L HCL将收集的下层萃取相调节至PH3,4℃静置4h,收集沉淀;
4)将沉淀溶解于环己烷中,配成鼠尾草酸过饱和溶液,低温过夜结晶,得类黄色或黄色鼠尾草酸产品,纯度为89%。
通过此方法获取的化合物的颜色、外形、晶体与鼠尾草酸标准品一致,并且通过HPLC分析,此化合物与鼠尾草酸标准品一致(图1).
实施例2:鼠尾草酸衍生物的制备
在50ml三口瓶中加入实施例1中鼠尾草酸,然后加入无水乙醇作溶剂,混合均匀后,在滴加催化量的浓硫酸,加热至回流条件下反应,TLC监测反应,直至原料反应完全,处理反应,取下反应体系冷却至室温,减压脱溶,然后加入水,用乙酸乙酯萃取三次,有机层用无水硫酸钠干燥,旋干,得到白色固体、浅黄色固体状的鼠尾草酸衍生物,收率:95%。
本申请通过对鼠尾草酸样品进行酯化、酰胺化等结构修饰方式获取鼠尾草酸衍生物,使用高效液相色谱法跟踪反应结果,最终产品经核磁共振氢谱确定结构。
表 1鼠尾草酸衍生物
实施例3:鼠尾草酸及其衍生物的降压效果
一、利用SHR大鼠模型检验鼠尾草酸对AT1R的拮抗作用及体内降血压效果
1.采用12周龄清洁级雄性SHR(自发性高血压大鼠,血压收缩压大于150mmHg)大鼠20只,体重约280-320 g;
2.随机分成4组,分别为模型组、低剂量组(1 mg/kg·d)、中剂量组(5 mg/kg·d)和高剂量组(10 mg/kg·d),每组5只;
3.采用SHR年龄、性别相匹配的同源WKY(正常血压大鼠)5只,体重约300-380 g;
4.将大鼠置于清洁、恒温环境中,每天白天(采用人工照明)与夜间各12h分笼饲养,喂食普通饲料,自由取水,动物室内温度18~25 ℃,相对湿度40~70%。
5.实验进行28天后,对小鼠进行脊髓脱臼处死,而后进行剖检,取各组血液和心肌样本;
6.用大鼠AngⅡ和AT1R ELISA试剂盒测定血液和心肌中AngⅡ和AT1R的含量;
7.利用Werstern-blot技术检测AT1R下游ERK的磷酸化水平。
所有动物在饲养7天后开始实验。模型组和WKY组正常饲养,给药组每日通过静脉注射不同剂量的鼠尾草酸。实验进行28天,分别每4天利用无创血压计测量大鼠血压和心率变化,并记录下来。
结果显示,模型组与WKY组在实验过程中血压物任何变化,模型组持续处于高血压状态,WKY组的血压持续处于正常状态,而实验组大鼠血压持续下降;其中高剂量组尤为明显,其次为中剂量组,再次为低剂量组。
高剂量组在第一次检测时即出现实验鼠血压下降的情况,后续检测中血压持续下降,在第四次检测时实验鼠的体内血压趋近于WKY组,明显低于模型组,在后续检测中,实验组大鼠血压下降平缓,与WKY组大鼠血压持平。
中剂量组在第二次检测时出现血压下降情况,第四次检测时出现明显血压下降情况,在第六次检测时,中剂量组大鼠的血压趋近于WKY组,明显低于模型组,在后续检测中,实验组大鼠血压下降平缓。
低剂量组在第三次检测时出现血压下降情况,后续检测中,实验组大鼠血压持续下降,第七次检测时,血压仍高于WKY组,但明显低于模型组。
表 2鼠尾草酸对体内血压的影响
“+”表示在鼠尾草酸的影响下,大鼠体内血压下降情况,随着下降强度的增加,“+”也随之增加;“/”表示大鼠体内血压没有变化。
二、BRET技术检测Gq的解离情况
BRET技术的显著优势是能够在活细胞中,实时检测蛋白质与蛋白质之间的相互作用(图3)。
通过在Gα蛋白上融合表达Rluc蛋白,在Gγ2蛋白上融合表达YFP蛋白,构建得到了Gq蛋白BRET传感器。采用脂质体转染方法在HEK293细胞中共转染AT1R和Gq蛋白BRET传感器质粒。将培养好的孔板细胞吸取DMEM培养基后加入150μl/孔PBS,在细胞恒温培养箱中饥饿处理1h。吸取PBS后补加30μl/孔PBS和10μl/孔Coelenterazine h使用液,充分混匀后加入10μl不同浓度鼠尾草酸,置于多功能酶标仪中,检测530 nm和480 nm处的发光值,530 nm和480 nm的发光比率即为BRET比率(图四)。
结果显示,鼠尾草酸和降血压药Losartan都可以有效抑制Gq蛋白聚合物的解离,迷迭香酸对Gq的解离没有显著的抑制作用。以上实验证明,鼠尾草酸能够通过抑制AngII对AT1R的激活作用抑制G蛋白信号通路中Gq蛋白聚合物的解离,鼠尾草酸能够拮抗AT1R介导的G蛋白信号通路。
三、鼠尾草酸对细胞内Ca2+ 释放的抑制作用
在确定鼠尾草酸能够抑制Ang Ⅱ与AT1R结合的基础上,检测其对细胞内Ca2+浓度的的影响,具体实验步骤如下:
(一)细胞铺板,使用多聚鸟氨酸包被测钙用的96孔板,将AT1R细胞系细胞消化,离心,重悬,均匀分入96孔板中,置于细胞培养箱中过夜培养;
(二)第二天将96孔板中培养液吸出,加入Ca2+荧光探针Fluo-4,避光放于培养箱中孵育1h;
(三)配制3种不同浓度的多肽,待Fluo-4孵育时间结束,在96孔板中分别加入FLEXbuffer和不同浓度的多肽,避光置于培养箱中预孵育30min;
(四)向体系中加入AT1R激动剂AngII,使用FLIPR检测钙流信号的变化。
结果如图5所示,酵母多肽、辣木多肽和鳄鱼肉多肽均不能有效抑制AT1R下游Ca2+在细胞内的释放(图5A);而在迷迭香的两个活性物质中,迷迭香酸对细胞内Ca2+的释放没有显著影响,而鼠尾草酸能够显著抑制细胞内Ca2+的释放,且抑制效果高于同样浓度的ARB降血压药Losartan(图5B)。通过不同浓度鼠尾草酸对Ca2+的释放的影响的实验证实,鼠尾草酸对Ca2+的释放的抑制作用呈浓度依赖性(图5C),当鼠尾草酸浓度越大,抑制效果也即越明显。以上实验初步证实,鼠尾草酸及其衍生物有较好的AT1R的拮抗作用。
通过表3可以看出,鼠尾草酸衍生物对AT1R具有较好的拮抗作用,通过结合Gq蛋白聚合物对蛋白解离产生影响,以及影响钙流信号变化,对细胞内Ca2+产生抑制作用。
表3鼠尾草酸衍生物实验结果
“+”表示一般影响,“++”表示明显影响,“+++”表示强烈影响
实施例4:鼠尾草酸及其衍生物可作为食源性降血压产品添加剂
本申请鼠尾草酸及其衍生物可作为食品添加剂制备成液体饮料、袋茶包、浸膏、散剂、丸剂、颗粒/粉末剂、胶囊、片剂、丸剂等。为使上述剂型得以实现,需在制备过程中加入食品和药物制剂中可以使用的辅料:如填充剂、崩解剂、润滑剂、助悬剂、粘合剂、甜味剂、矫味剂、防腐剂等。
综上所述,本申请鼠尾草酸的制备方法及其应用,通过从迷迭香提取物中制备高纯度鼠尾草酸与鼠尾草酸衍生物,并将其应用于制备降血压制剂中。所述制备方法包含将迷迭香提取物溶于正己烷中,通过萃取、pH沉淀、低温结晶等方式获取高纯度的鼠尾草酸,并对其进行结构修饰得到鼠尾草酸衍生物。所述将鼠尾草酸及其衍生物应用于制备降血压制剂中的降血压制剂包括药物制剂或食品制剂。鼠尾草酸及其衍生物能够与AT1R结合,通过阻断AT1R介导的G蛋白信号通路下游信号从而降低血压。上述实施例为本申请较佳的实施方式,但并不仅仅受上述实施例的限制,其他的任何未背离本申请的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,均包含在本申请的保护范围之内。
Claims (2)
1.鼠尾草酸的衍生物作为唯一活性成分在制备治疗高血压的药物中的应用,其特征在于,所述鼠尾草酸的衍生物作为AT1R拮抗剂影响血压调节系统;所述鼠尾草酸的衍生物的结构式为以下任意一个:
;
;
。
2.如权利要求1所述的应用,其特征在于,所述鼠尾草酸的衍生物的制备方法,包括:
在三口瓶中加入鼠尾草酸,然后加入无水乙醇作溶剂,混合均匀后,再滴加催化量的浓硫酸,加热至回流条件下反应,TLC监测反应,直至原料反应完全,处理反应,取下反应体系冷却至室温,减压脱溶,然后加入水,用乙酸乙酯萃取三次,有机层用无水硫酸钠干燥,旋干,得到白色固体、浅黄色固体状的鼠尾草酸衍生物。
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