CN115353536B - 白英中分离的萜类化合物及其制备方法和应用 - Google Patents
白英中分离的萜类化合物及其制备方法和应用 Download PDFInfo
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Abstract
白英中分离的萜类化合物及其制备方法和应用,属于医药技术领域,涉及从茄科茄属植物白英(Solanum lyratum Thunb.)中提取分离的4个萜类化合物,以及所述化合物在制备神经保护活性的医药新用途。本发明制备方法简单易行,重现性比较好,纯度较高。获得的化合物具有良好的神经保护活性作用。
Description
技术领域
本发明属于医药技术领域,具体涉及植物白英中制备萜类化合物的方法及这类化合物在抗神经炎症方面的应用。
背景技术
白英:白英[Solanum lyratum Thunb.]又名山甜菜,属于茄科草质藤本植物。白英主要分布在我国甘肃、陕西,山西、河南、山东、江苏等地。其具有悠久的入药历史,白英性平、微苦,归肝、肾经。具有清热解毒、利湿消肿的功效,临床上常用于治疗风热感冒、黄疸型肝炎、胆囊炎、风湿性关节炎及各类癌症。药理学研究表明白英提取物及其单体成分具有抗肿瘤、抗氧化、抗炎、抗过敏等作用。
随着全球人口老龄化的进程,神经退行性疾病的发病率一直在增加。以阿尔茨海默病和帕金森病为代表的神经退行性疾病是以进行性和不可逆的神经元细胞变性为特征。以往的研究表明,神经退行性疾病是由线粒体DNA突变、氧化应激损伤、兴奋性毒素和免疫相关炎症引起的,其中氧化应激起重要作用。当产生含有过量的活性氧的H2O2时,就会发生氧化应激。而氧化应激可导致神经元细胞损伤。因此,H2O2诱导的神经元样细胞损伤,例如人类神经母细胞瘤SH-SY5Y细胞,被用作研究各种化合物在神经退行性疾病中的神经保护作用的模型。具有神经保护活性的化合物可以减少活性氧的产生,延缓神经退行性疾病的进程,对于治疗神经退行性疾病有着很好的前景。
发明内容
本发明的首要目的是提供4种从茄科茄属植物白英[Solanum lyratum Thunb.]中分离得到的萜类化合物,结构如下所示:
本发明的制备技术方案包括如下步骤:
取干燥的白英全草以乙醇提取,合并提取液浓缩得浸膏,浸膏分别采用乙酸乙酯和正丁醇萃取,正丁醇萃取所得组分经硅胶柱色谱,以二氯甲烷-甲醇系统100:0-0:100进行等度梯度洗脱,共收集到2个馏分Fr.1~Fr.2;
馏分Fr.2经正相硅胶柱,以二氯甲烷-甲醇系统30:1-3:1进行梯度洗脱,得到2个组分Fr.2.1和Fr.2.2;利用HP-20柱色谱将Fr.2.1组分以乙醇-水系统10:90-90:10进行梯度洗脱,得3个组分Fr.2.1.1~Fr.2.1.3;
所得组分Fr 2.1.1经ODS柱色谱以乙醇-水系统20:80-80:20在TLC分析的基础上得到2个亚组分Fr.A~Fr.B;
在制备性反相高效液相色谱上使用乙腈-水31:69(v/v)的流动相来分离Fr.B得到化合物1-4。
上述制备方法,其中:
所述乙醇为浓度为70%-80%的工业乙醇,所述提取为回流提取,提取2-3次,每次2-3小时。
所述白英为茄科茄属植物白英[Solanum lyratum Thunb.]。
所得化合物经过系统结构鉴定结果如下:
利用多种波谱技术及计算ECD对化合物1-4的结构鉴定(附图1-31)。
Solanoid F(1):无色油状(甲醇);HRESIMS给出准分子离子峰m/z 433.1894[M+Na]+(calcd for C21H30O8Na,433.1833),确定该化合物的分子量为410,分子式为C21H30O8,计算不饱和度为7。
1H NMR(600MHz,DMSO-d6)和13C NMR(150MHz,DMSO-d6)谱,低场区给出如下信息:δH6.69(1H,s,H-10),6.69(1H,s,H-8),δC 155.2(C-9),137.2(C-7),137.2(C-11),129.6(C-6),116.0(C-8),116.0(C-10)提示为一组对称的四取代芳环波谱信号。在高场区,δH 2.69(1H,dd,J=14.0,2.8Hz,H-5a),2.56(1H,overlap,H-5b),2.56(1H,overlap,H-2a),2.18(1H,d,J=16.8,7.7Hz,H-2b),δC 34.0(C-2),27.4(C-5)提示为两组磁不等价的亚甲基波谱信号;δH 2.39(1H,m,H-3),δC45.1(C-3)提示为一组次甲基波谱信号;δH 2.25(3H,s,H3-12),2.25(3H,s,H3-13),1.48(3H,s,H3-14),1.36(3H,s,H3-15),δC 26.5(C-14),21.3(C-15),20.2(C-12),20.2(C-13)提示为四组甲基波谱信号;δH 4.78(1H,d,J=7.7Hz,H-1′),δC100.5(C-1′)提示为一个单糖单元上的波谱信号。除此之外,还有一个五元内酯环的羰基碳信号δC 175.1(C-1)和一组连氧季碳的碳信号δC 86.4(C-4)。
在HMBC谱中,可以观察到H2-2与C-1,C-3,C-4存在相关,H-3与C-1,C-2,C-4,C-14,C-15存在相关,H3-14与C-3,C-4,C-15存在相关,H3-15与C-3,C-4,C-14存在相关,说明该结构存在一个连有偕二甲基的五元内酯环。此外,H-3与C-6有相关,H2-2与C-5有相关,H2-5与C-6,C-7,C-11存在相关,说明五元内酯环与芳香环是通过C-5位的亚甲基连接的。H3-12与C-6,C-9,C-10存在相关,H3-13与C-6,C-8,C-9存在相关,说明两个甲基分别连接在C-11位和C-7位。除此之外,H-1′与C-9存在相关,且C-9的化学位移值明显向低场偏移,由此推测化合物的C-9位成苷。综上,结合HSQC谱,HMBC谱以及1H-1H COSY谱确定化合物1的平面结构。
根据糖端基质子的耦合常数J=7.7Hz,可以确定糖端基碳的相对构型为β构型。为了进一步确定糖基的绝对构型,进行柱前衍生化实验,通过酸水解获取糖的单体后,使用L-半胱氨酸甲酯盐酸盐和异硫酸氰酯对糖单体进行衍生化,对萃取后的衍生化产物进行HPLC液相分析,通过与标准糖衍生化产物的保留时间进行比较,从而判定化合物1的糖基的绝对构型是D-型葡萄糖。其中,分析时乙腈与水的比例为20:80,流速0.8mL/min,标准D型和L型葡萄糖衍生化产物的保留时间分别为16.53min和15.18min,化合物1的糖基衍生化产物的保留时间为16.66min。
该化合物的绝对构型是通过计算ECD确定的,化合物1与计算的3R构型吻合度较高,因此确定化合物1的绝对构型为3R。
化合物1的1H(600MHz)与13C(150MHz)NMR数据(DMSO-d6)
Solanoid G(2):无色黄色油状;UV(MeOH)λmax(logε)275(2.52),204(3.80)nm;HRESIMS给出准分子离子峰m/z 433.1831[M+Na]+(calcd forC21H30O8Na,433.1833),结合1H和13C NMR数据,推测其分子式为C21H30O8,计算不饱和度为7。
1H NMR(600MHz,DMSO-d6)谱中,在低场区,δH 6.93(1H,d,J=8.4Hz,H-10),6.86(1H,d,J=8.4Hz,H-9)提示为一个四元取代苯环的氢信号。在高场区,δH 2.75(1H,dd,J=13.8,2.7Hz,H-5a),2.65(1H,m,H-5b),2.58(1H,m,H-2a),2.17(1H,overlap,H-2b)提示为两组磁不等同的亚甲基氢信号;δH 2.39(1H,m,H-3)提示为一个次甲基氢信号;δH 2.23(3H,s,H3-12),2.18(3H,s,H3-13),1.50(3H,s,H3-14),1.39(3H,s,H3-15)提示为四个甲基氢信号。此外,δH 4.70(1H,d,J=7.2Hz,H-1′)提示化合物2存在一个单糖单元,其余氢信号则为糖上的连氧次甲基信号和连氧亚甲基信号。
13C NMR(150MHz,DMSO-d6)谱中,提示存在21个碳信号,包括苷元中芳香环上的6个碳信号δC 154.0(C-8),137.1(C-6),129.1(C-11),128.1(C-10),125.4(C-7),112.9(C-9),2个亚甲基碳信号δC 33.9(C-2),28.3(C-5),1个次甲基碳信号δC 45.0(C-3),1个连氧季碳的碳信号δC 86.4(C-4),4个甲基碳信号δC 26.5(C-14),21.4(C-15),19.6(C-12),12.3(C-13)以及1个酯羰基碳信号δC 175.0(C-1)。除此之外,还观察到C-1′位的端基碳信号(δC101.2)。
在HMBC谱中,可以观察到H2-2与C-1,C-3,C-4存在相关,H-3与C-1,C-2,C-4,C-14,C-15存在相关,H3-14与C-3,C-4,C-15存在相关,H3-15与C-3,C-4,C-14存在相关,说明该结构存在一个连有偕二甲基的五元内酯环。此外,H-3与C-6有相关,H2-2与C-5有相关,H2-5与C-6,C-7,C-11存在相关,说明五元内酯环与芳香环是通过C-5位的亚甲基连接的。H3-12与C-6,C-10,C-11存在相关,H3-13与C-6,C-7,C-8存在相关,说明两个甲基分别连接在C-11位和C-7位。除此之外,H-1′与C-8存在相关,且C-8的化学位移值明显向低场偏移,由此推测化合物的C-8位成苷。
根据糖端基质子的耦合常数J=7.2Hz,可以确定糖端基碳的相对构型为β构型。为了进一步确定糖基的绝对构型,进行柱前衍生化实验,方法同化合物1一致,标准D型和L型葡萄糖衍生化产物的保留时间分别为16.53min和15.11min,2的糖基衍生化产物的保留时间为16.07min。从而判定化合物2的糖基的绝对构型是D-型葡萄糖。
化合物2的绝对构型采用计算ECD的方法,化合物2的实测ECD与3S构型的计算ECD吻合度较高,所以确定化合物2的绝对构型为3S。
化合物2的1H(600MHz)与13C(150MHz)NMR数据(DMSO-d6)
Solanoid H(3):黄色油状;UV(MeOH)λmax(logε)282(2.94),209(3.75)nm;HRESIMS给出准分子离子峰m/z 487.3057[M+Na]+(calcd forC15H20O4Na,287.1254),结合1H和13C NMR数据,推测其分子式为C15H20O4,计算不饱和度为6。
1H NMR(600MHz,DMSO-d6)和13C NMR(150MHz,DMSO-d6)谱提示:在低场区,δH 6.70(1H,d,J=2.2Hz,H-8),6.47(1H,d,J=2.2Hz,H-10),δC 155.1(C-9),141.6(C-7),137.1(C-11),125.3(C-6),115.9(C-10),112.8(C-8)为一组四元取代苯环的波谱信号。在较高场区给出了一组连氧sp2杂化亚甲基波谱信号δH 4.43(2H,t,J=5.3Hz,H-13),δC 61.0(C-13)。在高场区给出两组磁不等价的亚甲基波谱信号δH 2.66(1H,dd,J=14.0,2.6Hz,H-5a),2.55(1H,m,H-2a),2.52(1H,m,H-5b),2.14(1H,dd,J=16.8,7.6Hz,H-2b),δC 34.0(C-10),26.3(C-13);一组次甲基波谱信号δH 2.38(1H,m,H-3),δC 45.4(C-3)。此外,还给出三组甲基波谱信号δH 2.20(3H,s,H-12),1.47(3H,s,H-14),1.34(3H,s,H-15),δC 26.5(C-14),21.4(C-15),19.9(C-12)以及一个连氧季碳碳信号δC 86.4(C-4)。结合不饱和度,提示化合物3存在一个丁内酯片段。
HMBC谱中,H-8与C-6,C-10,C-13存在,H-10与C-6,C-8,C-10存在相关,H-12与C-6,C-10存在相关,H-13与C-6,C-8存在相关,以上信息提示了C-7位连接了羟甲基片段,C-11位连接了甲基片段,C-9位连接了羟基片段。H-14与C-3,C-4,C-15存在相关,H-15与C-3,C-4,C-14存在相关,提示了谐二甲基连接在C-4位上。H-2与C-1,C-4,C-5存在相关,H-3与C-6存在相关,H-5与C-2,C-4,C-7,C-11存在相关,确证化合物3存在一个丁内酯片段,且通过C-5位与芳香环的C-6位直接相连。由此确定了化合物平面结构。
化合物3的绝对构型通过计算ECD确定的,化合物实测ECD曲线与计算的3S构型的ECD曲线能够较好的吻合,因此确定化合物的绝对构型为3S。
化合物3的1H(600MHz)与13C(150MHz)NMR数据(DMSO-d6)
Solanoid B(4):白色不定形粉末;HRESIMS给出m/z245.1178[M-H]-(calcd for C15H17O2,245.1183),结合1H NMR和13C NMR数据确定化合物分子式为C15H18O2,计算不饱和度为7。
1H NMR(600MHz,CDCl3)谱中,在芳香区,δH 7.02(2H,overlap)提示结构中存在一个四取代的苯环,δH 6.26(1H,d,J=3.3Hz),5.63(1H,d,J=3.3Hz)为末端双键氢信号,δH4.16(1H,m),2.83(1H,m)为两组次甲基氢信号,δH 3.22(1H,dd,J=16.1,4.9Hz),2.63(1H,dd,J=16.1,11.7Hz),3.33(1H,dd,J=15.2,5.3Hz),2.87(1H,m)为两组磁不等同的亚甲基信号,δH 2.26(3H,s),2.27(3H,s)为两组甲基信号。13C NMR(150MHz,CDCl3)谱显示其有15个碳信号,提示化合物为倍半萜。δC 170.8为一羰基碳信号,δC 132.0,128.3(×2),133.0,134.8,135.5为苯环上碳信号,δC 139.3,119.1为末端双键碳信号,δC 44.5,79.8为两个次甲基碳信号,δC 29.0,33.0为两个亚甲基碳信号,δC 20.0(×2)为两个甲基。
在HMBC谱中,观察到H3-14和C-1,C-2,C-10有相关,H3-15和C-3,C-5有相关,确定了两个甲基的取代位置(Fig.2-56)。H-6和C-4,C-8有相关,H-8和C-6有相关,H-9和C-1,C-7,C-8,C-10有相关(Fig.2-57),以及1H-1H COSY中,H2-6/H-7/H-8/H2-9的相关,提示结构中存在一个苯骈六元环的结构。另外,H-6和C-11有相关,H-7和C-8,C-11有相关,H2-13和C-7,C-11,C-12有相关,并且根据C-8位的化学位移值,提示C-7位存在丙烯酸基团,而C-8位存在一个羟基。根据以上相关信息建立了化合物4的平面结构,为桉叶烷型倍半萜。
化合物的相对构型是通过NOESY实验并结合相关氢之间的偶合常数确定下来的。在NOESY谱中,H-8与H-6b存在较强相关,提示这两个质子处于同侧。接下来借助H-6b的偶合常数来对C-7和C-8位的相对构型加以判断。在氢谱中,H-6b的偶合常数分别为16.1Hz和11.7Hz,其中16.1Hz是同碳之间的偕偶偶合常数,而11.7Hz是与H-7的偶合,偶合常数较大,提示这两个质子在六元环系统中都处于直立键,因此可以确定化合物的相对构型。
该化合物的绝对构型是通过比较实验ECD与计算ECD的方法确定的,计算的7R,8S构型与实测的ECD的图谱吻合度较高,故确定该化合物的绝对构型为7R,8S。
化合物4的1H(600MHz)与13C(150MHz)NMR数据(CDCl3)
一种药物组合物,包含所述4个萜类化合物和药学上可接受的载体和赋形剂。
所述4个萜类化合物或所述药物组合物在制备神经保护药物中的应用。
一种白英提取物,包含所述4个萜类化合物,应用于制备神经保护药物中。
对本发明所述4个新化合物的神经保护活性进行了考察,其中在H2O2诱导的SH-SY5Y细胞模型中,MTT分析表明化合物1、3显着降低了H2O2诱导的SH-SY5Y细胞损伤。特别是,化合物3表现出与Trolox相当的神经保护活性。因此本发明所述的萜类化合物具有进一步开发神经保护类药物的前景。
本发明的优点在于,所述的化合物都为新化合物,结构新颖,且均为立体构型确定的光学纯化合物,同时神经保护活性强,具有进一步开发的价值。
附图说明
图1化合物1的UV谱;
图2化合物1的HR-ESIMS谱;
图3化合物1的1H-NMR谱(600MHz,DMSO-d6);
图4化合物1的13C-NMR谱(150MHz,DMSO-d6);
图5化合物1的HSQC谱(600MHz,DMSO-d6);
图6化合物1的HMBC谱(600MHz,DMSO-d6);
图7化合物1的1H-1H COSY谱(600MHz,DMSO-d6);
图8化合物2的UV谱;
图9化合物2的HR-ESIMS谱;
图10化合物2的1H-NMR谱(600MHz,DMSO-d6);
图11化合物2的13C-NMR谱(150MHz,DMSO-d6);
图12化合物2的HSQC谱(600MHz,DMSO-d6);
图13化合物2的HMBC谱(600MHz,DMSO-d6);
图14化合物2的1H-1H COSY谱(600MHz,DMSO-d6);
图15化合物3的UV谱;
图16化合物3的HR-ESIMS谱;
图17化合物3的1H-NMR谱(600MHz,DMSO-d6);
图18化合物3的13C-NMR谱(150MHz,DMSO-d6);
图19化合物3的HSQC谱(600MHz,DMSO-d6);
图20化合物3的HMBC谱(600MHz,DMSO-d6);
图21化合物3的1H-1H COSY谱(600MHz,DMSO-d6);
图22化合物4的UV谱;
图23化合物4的HR-ESIMS谱;
图24化合物4的1H-NMR谱(600MHz,CDCl3);
图25化合物4的13C-NMR谱(150MHz,CDCl3);
图26化合物4的HSQC谱(600MHz,CDCl3);
图27化合物4的HMBC谱(600MHz,CDCl3);
图28化合物4的1H-1H COSY谱(600MHz,CDCl3);
图29化合物4的NOESY谱(600MHz,CDCl3);
图30化合物1-4的ECD谱;
图31经酸水解和柱前衍生的化合物1、2和D-Glu的HPLC分析图;
图32化合物1-4对H2O2处理的SH-SY5Y细胞的神经保护作用。
具体实施方式
下面所列实施例有助于本领域技术人员更好地理解本发明,但不以任何方式限制本发明。
实施例1
萜类化合物1-4的制备:
取干燥的白英全草(40kg)以80%工业乙醇回流提取3次,每次2小时,合并提取液浓缩得浸膏(2.5kg),浸膏分别采用18L乙酸乙酯和20L正丁醇萃取,正丁醇萃取所得组分(1114.0g)经硅胶柱色谱,以二氯甲烷-甲醇系统100:0-0:100进行等度梯度洗脱,共收集到2个馏分Fr.1~Fr.2。
馏分Fr.2(229.6g)经正相硅胶柱,以二氯-甲醇系统30:1-3:1进行梯度洗脱,得2个组分Fr.2.1和Fr.2.2。利用HP-20柱色谱将Fr.2.1(110.0g)组分以乙醇-水系统10:90-90:10进行梯度洗脱,得3个组分Fr.2.1.1~Fr.2.1.3。
所得组分Fr 2.1.1(25.0g)经ODS柱色谱以乙醇-水系统20:80-80:20在TLC分析的基础上得到两个亚组分Fr.A~Fr.B。
在制备性反相高效液相色谱上使用乙腈-水31:69(v/v)的流动相来分离Fr.B(11.0g)得到化合物1(tR 21.2min;5.0mg),2(tR 25.0min;3.1mg),3(tR 32.0min;2.0mg)和化合物4(tR 35.2min;2.4mg)。
实施例2
所述萜类化合物1-4的抗神经炎症的活性考察。
将计数后的SH-SY5Y细胞以5.5×103个/孔的细胞密度接种到96孔培养板上,静置于周围温度为37℃的培养箱中,待过夜细胞贴壁后,给药组加入不同浓度(12.5μM,25μM,50μM)的受试样品(化合物1-4),于恒温培养箱中与培养液孵育1小时。对照组(以水溶维生素E作为阳性对照药)和模型组加入与受试样品体积一致的空白培养基,并于恒温培养箱中欲孵育1小时。随后,模型组及给药组分别加入H2O2于恒温培养箱中孵育4小时,使细胞损伤率达50%。实验重复三次,且一次设置三个复孔。每个孔分别加入20μL的MTT溶液以及150μL的DMSO,使其完全溶解形成在490nm下有吸收度的甲瓒结晶,再使用酶标仪检测吸光度值。
存活率(%)=[A490(给药组)-A490(对照组)]/[A490(对照组)-A490(模型组)]×100%
结果如图32所示,在给药浓度为25μM、12.5μM、50μM的条件下,化合物1、3-4显示良好的神经保护活性。在给药浓度为50μM,化合物2体现出良好的神经保护活性,化合物3体现出强于Trolox的神经保护活性。
Claims (9)
1.一种白英中分离的萜类化合物,其特征在于,其为如下所示化合物:
2.根据权利要求1所述白英中分离的萜类化合物,其特征在于,由茄科茄属植物白英(Solanum lyratum Thunb.)中分离得到。
3.一种权利要求1或2所述白英中分离的萜类化合物的制备方法,其特征在于,包括如下步骤:
取干燥的白英全草以乙醇提取,合并提取液浓缩得浸膏,浸膏分别采用乙酸乙酯和正丁醇萃取,正丁醇萃取所得组分经硅胶柱色谱,以二氯甲烷-甲醇系统100:0-0:100进行等度梯度洗脱,共收集到2个馏分Fr.1~Fr.2;
馏分Fr.2经正相硅胶柱,以二氯甲烷-甲醇系统30:1-3:1进行梯度洗脱,得2个组分Fr.2.1和Fr.2.2;利用HP-20柱色谱将Fr.2.1组分以乙醇-水系统10:90-90:10进行梯度洗脱,得3个组分Fr.2.1.1~Fr.2.1.3;
所得组分Fr 2.1.1经ODS柱色谱以乙醇-水系统20:80-80:20在TLC分析的基础上得到2个亚组分Fr.A~Fr.B;
在制备性反相高效液相色谱上使用乙腈-水31:69的流动相来分离Fr.B得到化合物3。
4.根据权利要求3所述白英中分离的萜类化合物的制备方法,其特征在于,所述乙醇为浓度为70%-80%的工业乙醇,所述提取为回流提取,提取2-3次,每次2-3小时。
5.根据权利要求3所述白英中分离的萜类化合物的制备方法,其特征在于,所述白英为茄科茄属植物白英[Solanum lyratum Thunb.]。
6.一种药物组合物,其特征在于,包含权利要求1或2所述白英中分离的萜类化合物和药学上可接受的载体和赋形剂。
7.权利要求1或2所述白英中分离的萜类化合物在制备神经保护药物中的应用。
8.权利要求6所述药物组合物在制备神经保护药物中的应用。
9.一种白英提取物,其特征在于,包含权利要求1或2所述白英中分离的萜类化合物,应用于制备神经保护药物中。
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