CN111747881B - 两种具有α-葡萄糖苷酶抑制作用的异戊烯基取代吲哚生物碱及其制备方法和应用 - Google Patents
两种具有α-葡萄糖苷酶抑制作用的异戊烯基取代吲哚生物碱及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供了两种异戊烯基取代吲哚生物碱类化合物,其结构式如图1所示。上述异戊烯基吲哚生物碱类化合物从菊科药用植物款冬(Tussilago farfara L.)的花蕾中通过溶剂提取、萃取、柱层析、高效液相色谱等方法分离得到。上述异戊烯基吲哚生物碱类化合物具有良好的α‑葡萄糖苷酶抑制活性,因此可制成具有降血糖作用的α‑葡萄糖苷酶抑制剂,用于制备预防和/或治疗糖尿病、肥胖症及其并发症的组合物、药物、保健品。
Description
技术领域
本发明属于天然药物化学领域,具体涉及两个异戊烯基取代吲哚生物碱及其在制备α-葡萄糖苷酶抑制剂和制备预防或治疗糖尿病、肥胖症及其并发症的组合物、药物、保健品中的应用。
背景技术
糖尿病是一种代谢性疾病,是由于胰岛素分泌绝对不足或相对不足引起糖、脂肪、蛋白质三大代谢紊乱,体内多种营养物质不能被正常利用所致。其主要症状是血糖、尿糖升高及糖耐量降低,并逐步表现出多饮、多食、多尿体重减轻等症状。糖尿病在临床上的分型有I型糖尿病(胰岛素依赖型糖尿病)和II型糖尿病(非胰岛素依赖型糖尿病)两种,其中II型糖尿病约占糖尿病的90%以上。α-葡萄糖苷酶抑制剂可以延缓肠道碳水化合物吸收,被认为是控制II型糖尿病的理想途径。因此,从药用植物中发现α-葡萄糖苷酶抑制剂对于II型糖尿病的预防或治疗具有重要意义。
发明内容
为了进一步发掘中药款冬花的药用价值,本发明提供一种从款冬花中提取的异戊烯基取代吲哚生物碱类化合物,具有α-葡萄糖苷酶抑制活性。
本发明的另一目的是提供一种上述异戊烯基吲哚类生物碱类化合物的制备方法。
本发明的再一目的是提供一种上述异戊烯基吲哚类生物碱类化合物在治疗II型糖尿病方面的应用。
为实现上述目的,本发明采用如下技术方案。
两种异戊烯基吲哚生物碱类化合物,其结构式如图1所示。
上述异戊烯基吲哚生物碱类化合物的制备方法,包括以下步骤:
(1)款冬干燥花蕾(款冬花),粉碎后用乙醇浸提,浸提液浓缩得到粗浸膏;
(2)粗浸膏悬浮于水中,然后用乙酸乙酯萃取,将乙酸乙酯萃取相浓缩得到乙酸乙酯萃取物;
(3)将乙酸乙酯萃取物过D101大孔树脂柱层析,依次用30%、50%、80%和95%v/v的乙醇-水洗脱,得到4个组分A~D;
(4)将组分C过正相硅胶柱层析,依次用20:1、15:1、10:1、5:1、2:1、1:1、1:2v/v的石油醚-乙酸乙酯洗脱,得到组分C1~C14;
(5)将组分C13过正相硅胶柱层析,依次用15:1、10:1、5:1、2:1、1:1、1:2v/v的石油醚-乙酸乙酯洗脱,得到组分C13-1~C13-12;
(6)将组分C13-11过正相硅胶柱层析,依次用5:1、2:1、1:1、1:2v/v的石油醚-丙酮洗脱,得到组分C13-11-1~C13-11-2;
(7)将组分C13-11-1经YMC-Pack ODS-A色谱柱,用88%v/v的乙腈水溶液等度洗脱,检测波长为210和254nm,收集保留时间14.0min的组分,除去溶剂得到化合物1;
(8)将组分C13-12过Sephadex LH-20凝胶柱层析,用纯甲醇洗脱,得到组分C13-12-1~C13-12-9;
(9)将组分C13-12-9经YMC-Pack ODS-A色谱柱,用93%v/v的甲醇水溶液等度洗脱,检测波长为210和254nm,收集保留时间13.2min的组分,除去溶剂得到化合物2。
步骤(1)中,款冬花与乙醇的料液比为1:2.5(w/v)。
步骤(1)中,所述款冬花粉碎至粒度直径小于3mm。
步骤(1)中,所述浸提次数为3次,每次时间为7天。
步骤(1)中,浓缩为原体积的1/50~1/70。
步骤(2)中,所述粗浸膏重量与水的体积比为1:1~2。
步骤(2)中,所述乙酸乙酯与水的体积比为1:1。
步骤(2)中,所述乙酸乙酯萃取次数为3~5次。
步骤(6)和(9)中,流速3.0mL/min。
本发明提供一种含有步骤(1)中提取物,或图1所示化合物的α-葡萄糖苷酶抑制药物。所述具有α-葡萄糖苷酶抑制作用药物还包括医学上可接受的辅料。所述具有α-葡萄糖苷酶抑制作用药物还可以包括其他有效成分,以增强抑制α-葡萄糖苷酶或降低血糖的效果。
本发明具有以下优点:本发明的异戊烯取代吲哚生物碱类化合物可以通过款冬花提取分离获得,具有α-葡萄糖苷酶抑制活性,在制备α-葡萄糖苷酶抑制剂方面具有应用潜力。
附图说明
图1是化合物1和2的结构式;
图2是图1所示化合物1和2的氢谱和碳谱数据;
图3是图1所示化合物1的高分辨质谱;
图4是图1所示化合物1的氢谱;
图5是图1所示化合物1的碳谱;
图6是图1所示化合物1的二维COSY谱;
图7是图1所示化合物1的二维HSQC谱;
图8是图1所示化合物1的二维HMBC谱;
图9是图1所示化合物2的高分辨质谱;
图10是图1所示化合物2的氢谱;
图11是图1所示化合物2的碳谱;
图12是图1所示化合物2的二维COSY谱;
图13是图1所示化合物2的二维HSQC谱;
图14是图1所示化合物2的二维HMBC谱;
图15为图1所示化合物2的(S)-Mosher酯衍生物2a的氢谱;
图16为图1所示化合物2的(R)-Mosher酯衍生物2b的氢谱;
图17为图1所示化合物2的Marfey分析方法产物的HPLC对比图。
下面结合实施例和附图对本发明做进一步说明,但本发明不受下述实施例的限制。
实施例1化合物1和2的制备。
30kg款冬干燥花蕾(款冬花),粉碎至粒度直径小于3mm,用95%的乙醇浸泡提取3次,每次25L,每次7天。将乙醇提取液合并,减压浓缩得到粗浸膏3.0kg;
粗浸膏悬浮于3.5L的水中,然后用乙酸乙酯萃取五次,每次4.0L。合并乙酸乙酯萃取相,减压浓缩得到乙酸乙酯萃取物1.0kg;
将该萃取物进行D101大孔树脂柱层析,用乙醇-水(v/v,30%、50%、80%和95%)洗脱,依次得到4个组分A~D;
组分C(300g)经正相硅胶柱层析,用石油醚-乙酸乙酯(v/v,20:1、15:1、10:1、5:1、2:1、1:1、1:2)洗脱,根据薄层层析分析洗脱液成分,收集得到组分C1-C14;
组分C13正相硅胶柱层析,用石油醚-乙酸乙酯(v/v,15:1、10:1、5:1、2:1、1:1、1:2)洗脱,得到12个组分C13-1和C13-12;
组分C13-11过正相硅胶柱层析,依次用5:1、2:1、1:1、1:2v/v的石油醚-丙酮洗脱,得到组分C13-11-1~C13-11-2;
组分C13-12过Sephadex LH-20凝胶柱层析,用纯甲醇洗脱,得到组分C13-12-1~C13-12-9;
组分C13-11-1经制备液相色谱纯化(色谱柱:YMC-Pack ODS-A,10×250mm,流速:3.0mL/min,检测波长为210和254nm),用乙腈-水(v/v,88%)等度洗脱,收集保留时间14.0min的组分,除去溶剂得到化合物1新成分纯品1.0mg。
组分C13-12-9经制备液相色谱纯化(色谱柱:YMC-Pack ODS-A,10×250mm,流速:3.0mL/min,检测波长为210和254nm),用甲醇-水(v/v,93%)等度洗脱,收集保留时间13.2min的组分,除去溶剂得到化合物2新成分纯品4.8mg。
款冬花提取新成分的物理性质:化合物1,白色无定形粉末,易溶于甲醇、二甲亚砜和氯仿,不溶于水。化合物2,白色无定形粉末,易溶于甲醇、二甲亚砜和氯仿,不溶于水;比旋光度[α]D 25–17.7(c 0.4,CHCl3);圆二色性ECD(c 0.05,MeOH)λ(△ε)211(-2.01),237(+0.51),335(-0.32)nm。
实施例2化合物1的结构鉴定。
对分离获得的化合物1进行高分辨质谱(HR-ESIMS)、1H NMR、13C NMR、2D 1H-1HCOSY、HSQC、HMBC分析(图3-图8),确定了化合物1的结构。
实施例3化合物2的结构鉴定。
对分离获得的化合物2进行高分辨质谱(HR-ESIMS)、1H NMR、13C NMR、2D 1H-1HCOSY、HSQC、HMBC分析(图9-图14),确定了化合物2的平面结构;通过Mosher法分别制备了其(S)-Mosher酯2a和(R)-Mosher酯2b(图15-图16),并根据氢谱化学位移差值确定了连羟基手性碳的绝对构型;通过Marfey分析法(图17)确定了分子中丙氨酸片段的绝对构型。
实施例4图1所示化合物2的Mosher酯衍生物的制备。
称取1.0mg图1所示化合物2溶于0.5mL无水吡啶中,往溶液中加入Mosher试剂10μL(R)-2-甲氧基-2-三氟甲基苯乙酰氯和1.0mg DMAP(作为催化剂),于室温反应9小时。将溶剂减压蒸干后,将粗品采用高效液相半制备得到化合物2a;将Mosher试剂换为(S)-2-甲氧基-2-三氟甲基苯乙酰氯,相同的方法得到化合物2b。
实施例5图1所示化合物2的Marfey反应分析。
将化合物2(0.5mg)溶于6.0N 1.0mL的HCl于密封小瓶中,并在115℃下加热17h。将反应混合物减压干燥,重新悬浮于100μL水中,然后通过添加20μL 1.0M的NaHCO3与100μLFDAA(1%)反应,并保持在40℃下1h。冷却后,将溶液添加20μL 2.0N的HCl,蒸发至干燥并溶解于甲醇中。用同样的方法得到了标准D-和L-丙氨酸的FDAA衍生物。在安捷伦SB-C18柱(5.0μm,4.6×150mm)上进行高效液相色谱分析进行比对。
提取成分化合物1和2的氢谱(600MHz,CDCl3)和碳谱(150MHz,CDCl3)数据如图2所示。
实施例6图1所示化合物1和2的α-葡萄糖苷酶抑制活性。
用磷酸缓冲液(0.1mol/L,pH=6.9)配置PNPG(对-硝基苯基-β-D-葡萄糖苷)溶液(0.4mmol/L)备用;用磷酸缓冲液(0.1mol/L pH=6.9)配置冻干酶粉(酶活力为16U/mL)溶液(0.2U/mL)备用;实验分为实验组、空白组和对照组,将2.0μL含有不同浓度样品的DMSO溶液与25μL 0.2U/mL的酶溶液、98μL PBS缓冲液加入到96孔板中混匀,37℃孵育20min;然后加入25.0μL 0.4mM PNPG,37℃孵育15min;最后加入50.0μL 0.2M Na2CO3终止反应。酶标仪405nm处测试其吸光度,计算抑制率和IC50。
实验结果显示,图1所示化合物1和2具有很好的α-葡萄糖苷酶抑制活性,IC50值分别为105±4.7和35.2±3.2μM,远远优于阳性对照阿卡波糖(IC50=503±1.5μM)。
Claims (9)
2.一种如权利要求1所述的异戊烯基吲哚类生物碱的制备方法,其特征在于,包括以下步骤:
(1)款冬干燥花蕾,粉碎后用乙醇浸提,浸提液浓缩得到粗浸膏;
(2)粗浸膏悬浮于水中,然后用乙酸乙酯萃取,将乙酸乙酯萃取相浓缩得到乙酸乙酯萃取物;
(3)将乙酸乙酯萃取物过D101大孔树脂柱层析,依次用30%、50%、80%和95%v/v的乙醇-水洗脱,得到4个组分A~D;
(4)将组分C过正相硅胶柱层析,依次用20:1、15:1、10:1、7:1、5:1、2:1、1:1、1:2v/v的石油醚-乙酸乙酯洗脱,得到组分C1~C13;
(5)将组分C13过正相硅胶柱层析,依次用15:1、10:1、5:1、2:1、1:1、1:2v/v的石油醚-乙酸乙酯洗脱,得到组分C13-1~C13-12;
(6)将组分C13-11过正相硅胶柱层析,依次用5:1、3:1、2:1、1:1、1:2v/v的石油醚-丙酮洗脱,得到组分C13-11-1~C13-11-2;
(7)将组分C13-11-1经YMC-Pack ODS-A色谱柱,用88%v/v的乙腈水溶液等度洗脱,检测波长为210和254nm,收集保留时间14.0min的组分,除去溶剂得到化合物1;
(8)将组分C13-12过Sephadex LH-20凝胶柱层析,用纯甲醇洗脱,得到组分C13-12-1~C13-12-9;
(9)将组分C13-12-9经YMC-Pack ODS-A色谱柱,用93%v/v的甲醇水溶液等度洗脱,检测波长为210和254nm,收集保留时间13.2min的组分,除去溶剂得到化合物2。
3.根据权利要求2所述的制备方法,其特征在于,步骤(1)中,款冬花药材重量与乙醇的体积比例为1:2.5,w/v。
4.根据权利要求2所述的制备方法,其特征在于,步骤(1)中,所述款冬花粉碎至粒度直径小于3mm。
5.根据权利要求2所述的制备方法,其特征在于,步骤(1)中,所述浸提次数为3次,每次时间为7天。
6.根据权利要求2所述的制备方法,其特征在于,步骤(1)中,浓缩为原体积的1/50~1/70。
7.根据权利要求2所述的制备方法,其特征在于,步骤(2)中,所述粗浸膏与水的体积比为1:1~2。
8.根据权利要求2所述的制备方法,其特征在于,步骤(2)中,所述乙酸乙酯与水的体积比为1:2;所述乙酸乙酯萃取次数为3-5次。
9.一种如权利要求1所述的异戊烯基取代吲哚生物碱类化合物在制备α-葡萄糖苷酶抑制剂方面的应用。
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