CN117050139A - 一类甘草中的化合物及其药物组合物和应用 - Google Patents
一类甘草中的化合物及其药物组合物和应用 Download PDFInfo
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- CN117050139A CN117050139A CN202210490734.7A CN202210490734A CN117050139A CN 117050139 A CN117050139 A CN 117050139A CN 202210490734 A CN202210490734 A CN 202210490734A CN 117050139 A CN117050139 A CN 117050139A
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- acid
- compound
- oxidative stress
- pharmaceutically acceptable
- licorice
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- 235000011477 liquorice Nutrition 0.000 title abstract description 9
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- 208000014674 injury Diseases 0.000 claims abstract description 20
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Abstract
本发明属于医药领域,涉及一类甘草中的化合物及其药物组合物和应用,具体为一类甘草中结构新颖的环肽化合物及其制备方法以及该类化合物在制备抗氧化应激损伤药物中的应用。经药理学实验证明,该类化合物可以明显抑制钴离子催化过氧化氢后ROS的产生,对过氧化氢诱导的肝细胞氧化应激损伤亦具有明显的保护作用,可用于制备成抗氧化应激损伤疾病的药物。
Description
技术领域
本发明属于医药领域,具体涉及一类从中药甘草中分离得到的化合物及其药物组合物在抗氧化应激损伤中的应用。
背景技术
氧化应激(oxidative stress)是指机体氧化与抗氧化作用失衡的一种状态,通常伴随有活性氧(ROS)和活性氮(RNS)的生成急剧增加,引起细胞膜脂质、蛋白质和核酸的氧化损伤。常见的ROS包括超氧阴离子(·O2-)、羟自由基(·OH)和过氧化氢(H2O2)等;RNS包括一氧化氮(·NO)、二氧化氮(·NO2)和过氧化亚硝酸盐(·ONOO-)等。越来越多的研究证实:ROS和RNS的过度积累不仅直接加速了机体的衰老过程,还参与高血脂、动脉粥样硬化、急性心肌梗死、2型糖尿病、慢性阻塞性肺病和肿瘤等多种慢性疾病的发病。因此,抑制ROS和RNS的产生或者加速其清除的药物极具临床应用价值。
目前研究的抗氧化应激损伤的药物一般分为自由基终止剂和还原剂两大类。常见的自由基终止剂有没食子酸以及天然存在的生育酚等,这类物质在提供质子以后,可以形成稳定的共振结构而阻断氧化过程。还原剂主要是由是通过试剂本身的氧化还原反应来抑制氧化。如抗坏血酸,B族维生素等。除此之外,金属离子螯合剂,单旋态氧抑制剂等都有一定的抗氧化损伤作用。但是,由于分子结构的差别,不同的抗氧化剂的组织细胞分布也不尽相同,其针对不同氧化损伤疾病的治疗效果也不一致,其临床应用存在较大的局限性。因此,开发抗氧化靶点明确、代谢特征好、副作用小的新型抗氧化损伤药物成为当前药物研发的重点。
甘草(Glycyrrhiza uralensis)为豆科(Leguminosae)甘草属(GlycyrrhizaLinn.)植物,药用部位为干燥根及其根茎。甘草性味甘、平,有解毒、祛痰、止痛、解痉之功效。目前对甘草的药效物质基础研究已经比较深入,它的主要活性成分为三萜类成分(甘草酸、甘草次酸等)和黄酮类成分(甘草宁等),药理活性包括抗病毒作用、降糖作用、抗炎作用、抗氧化、胆碱能作用和抗肿瘤作用等。
发明内容
申请者研究发现,从甘草中分离得到了一类结构新颖的化合物——GlycnsisitinA~C,化学结构如下,
经药理学实验证明化合物Glycnsisitin A、Glycnsisitin B和Glycnsisitin C均能够显著降低反应体系中钴离子催化过氧化氢产生的羟基自由基的水平,抑制自由基对荧光素二钠的氧化过程,其中以Glycnsisitin A效果最优。此外,细胞生物学实验证明化合物Glycnsisitin A~C均能够显著抑制由过氧化氢诱导的肝脏细胞损伤,显著提升细胞活率,其中以Glycnsisitin A效果最优。目前,尚未见有将这类化合物用于治疗氧化应激损伤的研究报道、制备方法和专利文献。
本发明解决的技术问题是提供一类从中药甘草中分离提取的化合物的制备方法及其在制备抗氧化应激损伤药物中的应用。
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一类化合物或其药学上可接受的盐,其特征在于,该类化合物的结构如下:
上述的药学上可接受的盐选自化合物和有机酸包括甲酸、乙酸、乙二酸、丙酸、丙二酸、丁酸、丁二酸、戊酸、戊二酸、己酸、己二酸、庚酸、庚二酸、柠檬酸、抗坏血酸、苯甲酸、水杨酸、咖啡酸、琥珀酸、亚油酸,所属的无机酸包括硅酸、磷酸、硫酸、碳酸、硝酸、亚硫酸、亚磷酸、次碘酸、次氯酸、次溴酸、焦磷酸、三磷酸、硫代硫酸、氢碘酸;有机碱包括甲胺、乙胺、二乙胺、三乙胺、丙胺、丁胺、辛胺、己二胺、乙二胺、丙二胺、丁二胺、苯甲胺、苯乙胺、邻苯二甲胺、对苯二甲胺;无机碱包括氢氧化钠、氢氧化钾、氢氧化钙、碳酸钠,碳酸钾,碳酸氢钠、碳酸氢钾。
本发明所述的化合物Glycnsisitin A,Glycnsisitin B,Glycnsisitin C分别是从甘草中分离提取得到的,该类化合物基本骨架结构新颖,未有文献和专利报道该类型化合物。
本发明技术方案的第二方面是提供第一方面所述化合物的制备方法,其制备方法如下:甘草药材80%乙醇回流提取,浓缩后浸膏通过大孔树脂柱层析、凝胶柱层析及制备型HPLC分离纯化,得到上述化合物Glycnsisitin A~C,经UV、IR、NMR、MS及X-射线单晶衍射等谱学手段分析鉴定其结构,为一类双环杂环肽类化合物,目前未有该类物质报道。
本发明技术方案的第三方面提供了一种药物组合物,所述的药物组合物包括本发明第一方面所述化合物或其药学上可接受的盐和药学上可接受的载体或赋形剂。所述的药物组合物的剂型包括片剂、胶囊剂、丸剂、颗粒剂、口服液或混悬剂。
本发明技术方案的第四方面是提供本发明第一方面所述化合物在制备抗氧化应激损伤药物中的应用。所述的氧化应激损伤以大量ROS和RNS产生为特征的细胞组织损伤,且普遍存在于高血脂、动脉粥样硬化、急性心肌梗死、2型糖尿病、慢性阻塞性肺病和肿瘤等疾病。
有益技术效果:
1、本发明的一类甘草新化合物具有明显的抗氧化应激损伤的作用。其一,对钴离子催化过氧化氢产生的自由基有明显的抑制作用;其二,具有显著的抗肝细胞氧化应激损伤作用。
2、本发明的一类甘草新化合物结构新颖,未有文献报道,具有进一步开发成抗氧化应激损伤药物的潜力。
附图说明
图1为Glycnsisitin A,Glycnsisitin B,Glycnsisitin C对于钴离子催化过氧化氢产生自由基的抑制作用,荧光信号的衰减速率代表自由基的氧化效率。
图2为Glycnsisitin A,Glycnsisitin B,Glycnsisitin C对过氧化氢诱导的肝细胞损伤保护作用。
具体实施方式
下面的实施例及药理活性实验用于进一步说明本发明,但这并不意味着对本发明的任何限制。
无水溶剂为市售分析纯试剂经Pure Solv.溶剂纯化系统除水制备,其它试剂均为市售分析纯。
实验中所使用的化合物若无特别说明,均购买自Sigma公司。
实施例中所述的PBS,指浓度为0.1M,pH值为7.2的磷酸盐缓冲液。
实施例中所述的室温为本领域常规的室温,较佳地为15~30℃。
实验结果用均值±标准误表示,经参数或者非参数方差检验,经比较p<0.05被认为有显著性差异,p<0.01被认为有极其显著性差异。若无特别说明,#为模型组和正常组比较的结果,*为模型+化合物处理组与模型组比较的结果。
实施例1甘草中单体化合物Glycnsisitin A~C的制备及鉴定
甘草(Glycyrrhiza uralensis)药材(130kg)粉碎后,经80%乙醇回流提取2次。提取液合并,经减压浓缩后,补加水混匀后4℃条件下静置,可见下层有沉淀析出,沉淀弃去,保留上清液,减压浓缩后得甘草水沉浓缩液。
甘草水沉浓缩液进行大孔树脂HP-20柱层析分离,以乙醇-水梯度洗脱(0→95%),共得到6个部位:水部位(弃去),15%乙醇部位(Fr.1),30%乙醇部位(Fr.2),45%乙醇部位(Fr.3),60%乙醇部位(Fr.4),95%乙醇部位(Fr.5)。其中Fr.2,Fr.3和Fr.4合并后进行凝胶LH-20柱层析分离,根据HPLC分析结果追踪甘草肽类化合物在流分中的分布及含量,将所有含有甘草肽的流分合并。
结合HPLC分析结果,对富含甘草肽的样品进行中压柱层析分离,以CH3OH-H2O(15%→45%)为洗脱剂进行梯度洗脱,进一步经HPLC制备,液相条件为:(1)色谱柱:YMC ODS-AC18(250mm×30mm,5μm);(2)流动相:CH3CN-H2O(21:89,含0.1%CH3COOH);(3)流速:7.0mL/min;(4)柱温:25℃;(5)检测波长:280nm。制备得化合物Glycnsisitin A,Glycnsisitin B,Glycnsisitin C。
上述新化合物的波谱信息及核磁信号归属如下:
Glycnsisitin A:白色无定形粉末,UV(MeOH)λmax 203,223,280;IR(KBr)νmax 3302,2956,1659,1513,1447,1268,1237,1048,826cm-1;1HNMR[600MHz,CD3OD/D2O(4:1)]δH:见表1;13C NMR[150MHz,CD3OD/D2O(4:1)]δC:见表2;HRFABMSm/z 967.41913[M+H]+(calcd for C49H59O13N8,967.41961).
Glycnsisitin B:白色无定形粉末;UV(MeOH)λmax 203,226,282;IR(KBr)νmax 3303,2966,1660,1512,1446,1266,1223,1118,824cm-1;1HNMR[600MHz,CD3OD/D2O(4:1)]δH:见表1;13C NMR[150MHz,CD3OD/D2O(4:1)]δC:见表2;HRFABMSm/z 983.41394[M+H]+(calcd for C49H59O14N8,983.41452).
Glycnsisitin C:白色无定形粉末;UV(MeOH)λmax 203,224,279;IR(KBr)νmax 3315,2963,1660,1513,1447,1263,1237,1050,829cm-1;1HNMR[600MHz,CD3OD/D2O(4:1)]δH:见表1;13C NMR[150MHz,CD3OD/D2O(4:1)]δC:见表2;HRFABMSm/z 983.41492[M+H]+(calcd for C49H59O14N8,983.41452).
表1化合物Glycnsisitin A-C的1H NMR{δH[int.mult,J(Hz)]}数据[600MHz,溶剂:CD3OD/D2O(4:1)]
表2化合物Glycnsisitin A-C的13C NMR数据[150MHz,溶剂:CD3OD/D2O(4:1)]
实验例1化合物Glycnsisitin A~C对钴离子催化过氧化氢产生ROS的抑制作用
按照如下方式配制实验所需溶液,
溶液A:将荧光素二钠溶解于磷酸盐缓冲液当中,配制成67nM的工作液。
溶液B:将15.7mg四水氟氯化钴和20mg吡啶甲酸溶解在10ml蒸馏水中,制得钴溶液。
溶液C:将30%H2O2溶液用蒸馏水稀释,得到1.1M过氧化氢溶液。
在避光96孔板中按照180μl A溶液,5μl B溶液,5μl C溶液,10μl DMSO或者受试药物的体积加入反应试剂,分别在第0、10、20、30、40分钟测定与于激发波长495nm,发射波长515nm下的荧光强度值。
结果见表3和附图1,钴离子可以催化过氧化氢产生大量的自由基,可以迅速的氧化荧光素使其荧光淬灭,40分钟内的荧光强度折线下面积降低至29.76%。Glycnsisitin A~C均能够明显抑制荧光素的淬灭,尤其以Glycnsisitin A效果最优。
表3化合物Glycnsisitin A-C对钴离子催化过氧化氢产生ROS的抑制作用
实验例2化合物Glycnsisitin A~C对过氧化氢诱导的肝细胞氧化应激损伤的保护作用
小鼠肝细胞AML12(购自武汉普诺赛公司)在含有10%胎牛血清(FBS)和1%青霉素-链霉素(10,000U/ml)的F12K培养基于5%的CO2,37℃培养箱中培养。传代时以4000个/孔的密度接种于96孔板,过夜贴壁后,按照实验分组给予相应的化合物处理,12小时后加入过氧化氢(终浓度0.5mM),24小时后,加入10%CCK8试剂,37℃培养箱孵育2小时后,在酶标仪上检测450nm处的OD值,每组6个复孔。
细胞存活率=[(As-Ab)/(Ac-Ab)]×100%
As:实验孔(含有细胞的培养基、CCK8,含待测物质)
Ac:对照孔(含有细胞的培养基、CCK8,不含待测物质)
Ab:空白孔(不含细胞的培养基、CCK8,不含待测物质)
结果见表4和附图2,过氧化氢对AML12肝细胞具有明显的损伤作用,使细胞存活率降至36.97%,Glycnsisitin A~C均可明显增加过氧化氢处理的AML-12肝实质细胞的存活率,尤其以Glycnsisitin A效果最优。
表4化合物Glycnsisitin A-C对过氧化氢诱导肝细胞损伤保护作用
由实施例2-3中结果可知,在钴离子催化过氧化氢产生ROS的模型中,Glycnsisitin A~C能显著抑制ROS的产生,增加荧光素的稳定性,证明其具有良好的抗氧化损伤活性。在过氧化氢诱导的肝细胞损伤模型中,Glycnsisitin A~C可明显增加过氧化氢处理的AML-12肝细胞的存活率。上述结果提示Glycnsisitin A~C该类化合物具有良好的抗氧化损伤活性,有潜力开发成为治疗氧化损伤相关疾病的新型药物。
Claims (11)
1.一类化合物或其药学上可接受的盐,其特征在于,该类化合物的结构如下:
。
2.根据权利要求1的化合物或其药学上可接受的盐,其特征在于,所述的药学上可接受的盐选自化合物和有机酸或无机酸、有机碱或无机碱成的盐。
3.根据权利要求2的化合物或其药学上可接受的盐,其特征在于,所述的有机酸包括甲酸、乙酸、乙二酸、丙酸、丙二酸、丁酸、丁二酸、戊酸、戊二酸、己酸、己二酸、庚酸、庚二酸、柠檬酸、抗坏血酸、苯甲酸、水杨酸、咖啡酸、琥珀酸、亚油酸,所属的无机酸包括硅酸、磷酸、硫酸、碳酸、硝酸、亚硫酸、亚磷酸、次碘酸、次氯酸、次溴酸、焦磷酸、三磷酸、硫代硫酸、氢碘酸,有机碱包括甲胺、乙胺、二乙胺、三乙胺、丙胺、丁胺、辛胺、己二胺、乙二胺、丙二胺、丁二胺、苯甲胺、苯乙胺、邻苯二甲胺、对苯二甲胺,所述的无机碱包括氢氧化钠、氢氧化钾、氢氧化钙、碳酸钠,碳酸钾,碳酸氢钠、碳酸氢钾。
4.权利要求1的化合物的制备方法,其特征在于,所述的制备方法如下:甘草药材80%乙醇回流提取,浓缩后浸膏通过大孔树脂柱层析、凝胶柱层析及制备型HPLC分离纯化,得到权利要求1中所述化合物Glycnsisitin A~C。
5.根据权利要求4的化合物的制备方法,其特征在于,所选的甘草药材,其特征在于,包括以下甘草类型:甘草(Glycyrrhiza uralensis Fisch.)、胀果甘草(Glycyrrhizainflata Bat.)或光果甘草(Glycyrrhiza glabra L.)。
6.一种药物组合物,其特征在于,所述的药物组合物包括权利要求1-3任一项的化合物或其药学上可接受的盐和药学上可接受的载体或赋形剂。
7.根据权利要求6的药物组合物,其特征在于,所述的药物组合物的剂型包括片剂、胶囊剂、丸剂、颗粒剂、口服液或混悬剂。
8.权利要求1-3任一项所述的化合物在制备抗氧化应激损伤药物中的应用。
9.如权利要求8所述的应用,其特征在于,所述的氧化应激损伤由细胞内ROS或RNS诱发。
10.如权利要求8所述的应用,其特征在于,所述的氧化应激损伤是由以大量ROS和RNS产生为特征的细胞组织损伤。
11.如权利要求8所述的应用,其特征在于,所述的氧化应激损伤存在于高血脂、动脉粥样硬化、急性心肌梗死、2型糖尿病、慢性阻塞性肺病和肿瘤疾病中。
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