CN107496420A - 环匹阿尼酸类生物碱化合物的用途 - Google Patents
环匹阿尼酸类生物碱化合物的用途 Download PDFInfo
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Abstract
本发明涉及环匹阿尼酸类化合物的制备方法及新用途。将米曲霉进行固体或液体发酵,对发酵产物进行分离纯化,并通过应用质谱、核磁共振波谱、红外光谱等技术及文献对于本发明制备的3个化合物进行表征。本发明还提供了环匹阿尼酸类化合物在制备用于预防和/或治疗神经退行性疾病的药物中的应用。
Description
技术领域
本发明涉及医药技术领域,具体而言,涉及来源于米曲霉的环匹阿尼酸类生物碱化合物在预防和/或治疗神经退行性疾病类药物中的新用途。
背景技术
随着人口老龄化时代的到来,神经退行性疾病呈逐年上升的趋势,呈现出较高的发病率,严重威胁中老年人的生活质量和身体健康。神经退行性疾病是由于神经元和/或其髓鞘的丧失所导致的一类疾病,主要病理特征是神经元脱失和功能异常,可分为急性神经退行性疾病(主要包括脑缺血、脑损伤和癫痫等)和慢性神经退行性疾病(包括阿尔茨海默病、帕金森病、亨廷顿病、肌萎缩性侧索硬化、不同类型脊髓小脑共济失调和Pick病等)。
目前,神经退行性疾病仍无有效的治疗方法,临床上主要采用神经保护剂进行治疗。常用的神经保护剂有谷氨酸拮抗剂、抗炎因子、钙离子通道阻断剂、自由基清除剂、GABA受体拮抗剂、5-羟色胺拮抗剂等,上述药物仅限于缓解症状,且大多数副作用明显。因此,开发有效的神经保护药物成为防治神经退行性疾病的研究热点。
患病率研究显示,美国在2000年的老年痴呆症例数为450万例。年龄每增加5岁,老年痴呆症病人的百分数将上升2倍,也就是说,60岁人群的患病率为1%,而85岁人群的患病率为30%。老年痴呆症是一组病因未明的原发性退行性脑变性疾病,目前公认的发病机制主要有两种:(1).由于淀粉样前蛋白的异常导致蛋白成分漏出细胞膜,导致神经元纤维缠结和细胞死亡,基因位于21号染色体(Arch Gen Psychiatry,2005;62(11):1186-92.)。(2).与载脂蛋白E(APO-E4)的基因有关,APO-E4的增多能对抗APO-E2或APO-E3的功能。APO-E4使神经细胞膜的稳定性降低,导致神经元纤维缠结和细胞死亡。APO-基因纯合子比杂合子患病几率高(Proc.Natl.Acad.Sci.USA,2005;102(4):1211-6)。因此,促进受损神经的修复与再生是目前亟待解决的问题。
发明内容
本发明的目的是提供来源于米曲霉(Aspergillus oryzae)的环匹阿尼酸类生物碱化合物的新用途。
本发明所述环匹阿尼酸类生物碱化合物可用于制备预防和/或治疗神经退行性疾病类药物。
本发明所述的环匹阿尼酸类生物碱化合物具体可为下述1-3中的任意一种:
上述式Ⅰ-Ⅲ药学上可接受的盐、酯及溶剂合物也属于本发明的保护范围。
本发明还提供了所述环匹阿尼酸类生物碱化合物的制备方法,包括以下步骤:
(1)将米曲霉(Aspergillus oryzae)菌种接种到PDA试管琼脂培养基斜面上,进行预培养;预培养的条件为:25摄氏度,避光培养7天(PDA培养基组成:土豆200g,葡萄糖20g,琼脂粉16g,纯净水定容至1L(pH自然))。
(2)待菌丝长满整个斜面后,在无菌条件下将菌丝体转接到液体培养基中进行培养,得到种子培养液;培养的条件为:25摄氏度,避光培养7天。液体培养基:葡萄糖4.0g/L,Malt Extract(麦芽提取物)10.0g/L,Yeast Extract(酵母)4.0g/L,水定容至1L;YeastExtract(酵母提取物)购自Oxoid Ltd.,批号为1074139。
(3)取10毫升种子培养液分别接种到经过灭菌的装有固体培养基的500毫升三角瓶中,接种10瓶,25摄氏度,避光培养40天(固体培养基由80g籼米和120ml水组成)。
(4)发酵结束,将3L有机溶剂加到三角瓶中,常温浸泡提取一周,重复提取3次,合并有机溶剂提取液减压蒸馏干燥,得到80g提取物。
(5)有机溶剂提取物经过硅胶开放柱色谱(青岛海洋化工有限公司200-300目,柱层析硅胶150g;Φ4.5×80cm)分离,正己烷-乙酸乙酯梯度洗脱(100:0,80:1,50:1,30:1,20:1,10:1;v/v),二氯-甲醇混合溶剂梯度洗(100:0,100:1,80:1,50:1,30:1,20:1,10:1,5:1,3:1,2:1;v/v),每个梯度洗脱溶剂5000毫升,每500毫升收集为一个流份。正己烷-乙酸乙酯20:1洗脱的馏分减压浓缩干燥后,反相ODS柱梯度洗脱(甲醇-水:30%,40%,50%,60%,70%,80%,100%)。
(6)40%甲醇-水洗脱的馏分凝胶LH20(二氯-甲醇1:1)得式Ⅰ化合物(化合物1)。
(7)40%甲醇-水洗脱的馏分用甲醇重结晶得到式Ⅱ化合物(化合物2)。
(8)二氯-甲醇50:1洗脱的第二个馏分减压浓缩后,再用HPLC分离(38%乙腈-水,YMC-ODS C18column;5μm;9.4×250mm)得到式Ⅲ化合物(化合物3)。
在如上所述的本发明方法中,本领域技术人员应当理解所述有机溶剂包括多种不溶于水的在室温下是液态的有机溶剂,诸如石油醚、氯仿、乙酸乙酯、丙酮、甲醇等,步骤(4)所述有机溶剂是乙酸乙酯。
本发明提供了利用米曲霉发酵制备化合物1-3,并提供了化合物1-3在制备神经退行性疾病类药物中的应用,与文献报道的其他神经退行性疾病药物相比,具有显著的活性。本发明为研究与开发新的神经退行性疾病类药物提供了候选化合物。
附图说明
图1不同浓度化合物1对未分化PC12细胞轴突生长的作用图。
图2不同浓度化合物1对未分化PC12细胞轴突生长作用的代表性图。
图3不同浓度化合物2对未分化PC12细胞轴突生长的作用图。
图4不同浓度化合物2对未分化PC12细胞轴突生长作用的代表性图。
图5不同浓度化合物3对未分化PC12细胞轴突生长的作用图。
图6不同浓度化合物3对未分化PC12细胞轴突生长作用的代表性图。
具体实施方式
下面用实施例来进一步详述本发明,但本发明的内容并不局限于此。
下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和生物材料,如无特殊说明,均可从商业途径获得。
实施例1米曲霉菌株的培养,化合物的提取分离
(1)菌株活化、培养
将米曲霉菌种接种到PDA试管琼脂培养基斜面上,进行预培养;预培养的条件为:25摄氏度,避光培养7天(PDA培养基组成:土豆200g,葡萄糖20g,琼脂粉16g,纯净水定容至1L(pH自然))。待菌丝长满整个斜面后,在无菌条件下将菌丝体转接到液体培养基中进行培养,得到种子培养液;培养的条件为:25摄氏度,避光培养7天。液体培养基:葡萄糖4.0g/L,Malt Extract(麦芽提取物)10.0g/L,Yeast Extract(酵母)4.0g/L,水定容至1L;YeastExtract(酵母提取物)购自Oxoid Ltd.,批号为1074139。
取10毫升种子培养液分别接种到经过灭菌的装有固体培养基的500毫升三角瓶中,接种10瓶,25摄氏度,避光培养40天(固体培养基由80g籼米和120ml水组成)。
(2)、化合物的提取分离
发酵结束,将3L乙酸乙酯加到三角瓶中,常温浸泡提取一周,重复提取3次,合并乙酸乙酯提取液减压蒸馏干燥,得到80g提取物。乙酸乙酯提取物经过硅胶开放柱色谱(青岛海洋化工有限公司200-300目,柱层析硅胶150g;Φ4.5×80cm)分离,正己烷-乙酸乙酯梯度洗脱(100:0,80:1,50:1,30:1,20:1,10:1;v/v),二氯-甲醇混合溶剂梯度洗(100:0,100:1,80:1,50:1,30:1,20:1,10:1,5:1,3:1,2:1;v/v),每个梯度洗脱溶剂5000毫升,每500毫升收集为一个流份。正己烷-乙酸乙酯20:1洗脱的馏分减压浓缩干燥后,反相ODS柱梯度洗脱(甲醇-水:30%,40%,50%,60%,70%,80%,100%)。40%甲醇-水洗脱的馏分用甲醇重结晶得到式Ⅱ化合物。二氯-甲醇80:1洗脱的第三个馏分减压浓缩后,再用反相ODS柱梯度洗脱(甲醇-水:30%,45%,50%,60%,70%,80%,100%),40%甲醇-水洗脱的馏分凝胶LH20(二氯-甲醇1:1)得式Ⅰ化合物。二氯-甲醇50:1洗脱的第二个馏分减压浓缩后,再用HPLC分离(38%乙腈-水,YMC-ODS C18column;5μm;9.4×250mm)得到式Ⅲ化合物。
化合物的结构:式Ⅰ化合物(化合物1)的结构式为:
式Ⅱ化合物(化合物2)的结构式为:
式Ⅲ化合物(化合物3)的结构式为:
化合物的物理性质:
式Ⅰ化合物:黄色粉末;比旋光度值[α]25D=-94.39(c 0.14CDCl3);CD(c 4.2×10-5M,CDCl3)λmax(△ε)295(-5.2),325(-4.1).HRESIMS m/z 339.1705[M+H]+;依据化合物的理化性质、氢谱、碳谱数据,并与参考文献数值比对(Tetrahedron 26(1970)5239-5246),确定该化合物的结构与Bissecodehydrocyclopiazinic acid相同。
式Ⅱ化合物:淡黄色粉末;HRESIMS m/z 367.1229[M+H]+;依据化合物的理化性质、氢谱、碳谱数据,并与参考文献数值比对(Heterocycles 7(2014)1662-1669),确定该化合物的结构与Speradine E相同。
式Ⅲ化合物:淡黄色粉末;比旋光度值依据化合物的理化性质、氢谱、碳谱数据,并与参考文献数值比对(Tetrahedron 71(2015)3522e3527),确定该化合物的结构与Speradine D相同。
表1.NMR数据
实施例2.
式Ⅰ化合物的促进未分化PC12细胞突促生长作用
(1)实验原理:未分化PC12细胞在神经生长因子作用下可使感觉神经元和交感神经元增大,加快有丝***,使神经细胞数目增加并诱导神经纤维定向生长。它还能增加神经元存活数量,刺激神经元胞体和树突发育,增加神经纤维在支配靶区的密度,对受损伤的神经元有保护作用。本实验基于以上原理观察化合物是否具有类神经生长因子作用并促进未分化PC12细胞突促生长。
(2)实验方法:所有化合物均用100%DMSO溶解至10-2M。未分化PC12细胞经消化后,悬于含5%胎生牛血清(Gibco)、10%马血清(Gibco)的DMEM培养液(Gibco)中。以8×104cells/ml的密度将未分化PC12细胞接种于12孔培养板上,接种体积为1ml/孔,置于含5%CO2的37℃恒温培养箱内培养。未分化PC12细胞培养24小时后,将各组的培养液均换成无血清的DMEM培养液。在给药组和阳性对照组中分别加入相应浓度的待测化合物和40ng/ml NGF(Upstate)、正常对照组加入培养液,孵育48小时。孵育48小时后,在显微镜下观察突触生长的情况并拍摄生长状态图像。
(3)实验结果:化合物1-3在25、50、100μM对未分化PC12细胞具有潜在的促进突促突触生长作用。(图1—图6)
实施例3.
式Ⅰ-Ⅲ化合物对受损PC12细胞的修复作用
细胞培养:PC12细胞株用含10%胎牛血清,100U/ml青霉素,100U/ml链霉素的DMEM培养基接种于培养瓶中,CO2细胞培养箱的培养条件为37℃,5%CO2浓度,饱和湿度,待细胞长至80%左右开始传代或接种。倒置显微镜观察细胞生长状况,实验时取对数生长期细胞进行实验。
药物处理及分组:细胞共分为5组,无血清培养基接种12h后进行药物干预。①正常对照组:正常PC12细胞;②模型组:400μmol/L的H2O2造模液100μl/孔,作用4h;③化合物组:400μmol/L的H2O2+0.1μM化合物。作用24h后,每孔加入10μLCCK8细胞凋亡检测液,4h后于450nm下测定吸光度。
Claims (8)
1.一种环匹阿尼酸类生物碱化合物在制备预防和/或治疗神经退行性疾病药物中的用途。
2.根据权利要求1所述的用途,其特征在于:所述的神经退行性疾病包括血管性痴呆、血管性认知障碍、老年痴呆症、记忆力减退、脑组织退行性病变症候群或胆碱能神经退行性病变。
3.根据权利要求1所述环匹阿尼酸类生物碱化合物,其特征在于:所述的化合物为式Ⅰ
化合物、式Ⅱ化合物、式Ⅲ化合物;
所述的式Ⅰ化合物的结构式为:
所述的式Ⅱ化合物的结构式为:
所述的式Ⅲ化合物的结构式为:
4.一种健康食品组合物,其特征在于,包括式Ⅰ、式Ⅱ、式Ⅲ的一种或/和几种化合物。
5.根据权利要求4所述的健康食品组合物,其特征在于,其剂型包括片剂、胶囊、口服液、颗粒剂。
6.一种药物组合物,其特征在于,包括式Ⅰ、式Ⅱ、式Ⅲ的一种或/和几种化合物。
7.根据权利要求6所述的药物组合物,其特征在于,其剂型包括片剂、胶囊、口服液、乳剂、注射剂、混悬剂、酊剂、颗粒剂、气雾剂。
8.权利要求1所述环匹阿尼酸类生物碱化合物的制备方法,其特征在于,包括以下步骤:
(1)将米曲霉菌种接种到PDA试管琼脂培养基斜面上,进行预培养;
(2)待菌丝长满整个斜面后,在无菌条件下将菌丝体转接到液体培养基中进行培养,得到种子培养液;
(3)取种子培养液分别接种到经过灭菌的装有固体培养基的瓶中,接种,25摄氏度,避光培养40天;
(4)发酵结束,将有机溶剂加到瓶中,常温浸泡提取一周,重复提取3次,合并有机溶剂提取液减压蒸馏干燥,得到提取物;
(5)有机溶剂提取物经过硅胶开放柱色谱分离,正己烷-乙酸乙酯梯度洗脱(100:0,80:1,50:1,30:1,20:1,10:1;v/v),二氯-甲醇混合溶剂梯度洗(100:0,100:1,80:1,50:1,30:1,20:1,10:1,5:1,3:1,2:1;v/v),每个梯度洗脱溶剂5000毫升,每500毫升收集为一个流份;正己烷-乙酸乙酯20:1洗脱的馏分减压浓缩干燥后,反相ODS柱梯度洗脱(甲醇-水:30%,40%,50%,60%,70%,80%,100%);
(6)40%甲醇-水洗脱的馏分凝胶LH20(二氯-甲醇1:1)得式Ⅰ化合物(化合物1);
(7)40%甲醇-水洗脱的馏分用甲醇重结晶得到式Ⅱ化合物(化合物2);
(8)二氯-甲醇50:1洗脱的第二个馏分减压浓缩后,再用HPLC分离(38%乙腈-水,YMC-ODS C18 column;5μm;9.4×250mm)得到式Ⅲ化合物(化合物3)。
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CN114409661A (zh) * | 2022-01-27 | 2022-04-29 | 云南中烟工业有限责任公司 | 一种吲哚生物碱类化合物及其制备方法与应用 |
CN114409660A (zh) * | 2022-01-27 | 2022-04-29 | 云南中烟工业有限责任公司 | 一种cpa型吲哚生物碱类化合物及其制备方法与用途 |
CN114409661B (zh) * | 2022-01-27 | 2023-02-28 | 云南中烟工业有限责任公司 | 一种吲哚生物碱类化合物及其制备方法与应用 |
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