CN114886890A - 大鱼藤树酸的制备方法及降血糖应用 - Google Patents
大鱼藤树酸的制备方法及降血糖应用 Download PDFInfo
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Abstract
本发明公开了大鱼藤树酸的制备方法及降血糖应用。发明人通过实验发现大鱼藤树酸具有抑制α‑葡萄糖苷酶活性的作用，体外降血糖功效良好。本发明首次发现并确定大鱼藤树酸的新生物活性——降血糖活性，因此，大鱼藤树酸在降血糖方面具有较高的医药应用价值。发明人还发现，大鱼藤树酸与阿卡波糖联合应用具有协同增效的作用，使得降血糖活性更佳，两者联用抑制α‑葡萄糖苷酶活性高于二者单独使用，抑制率提高了32.37％。综上，本发明将为天然活性成分大鱼藤树酸的研发提供实验依据和理论基础，也为从传统中药中开发出降糖药物提供新药源，同时为开发出新的具有改善糖尿病的产品奠定了基础。
Description
技术领域
本发明属于药品及保健品技术领域，尤其涉及一种大鱼藤树酸的制备方法及降血糖应用。
背景技术
随着经济的快速发展，人们工作压力较大，饮食不规律和久坐不动的生活方式成为当前全球流行的生存方式，使得人们身体的健康亮起红灯。糖尿病(DM)目前是十大死亡原因之一和世界上最贵的危害人类健康的疾病，而且已有愈发严重的趋势。根据2019年公布的最新统计结果显示,全世界成年的DM患者高达4.63亿，约有9.3％的人患DM，而中国和印度等东南亚国家发病率较高。DM是人体内一种慢性、非传染性、多系统的代谢性疾病，其发病率极高、增长速度快、覆盖面广。
现阶段临床上治疗2型糖尿病(T2DM)的药物比较多，如α-葡萄糖苷酶抑制剂、双胍类药物、噻唑烷二酮类药物、磺酰脲类药物等，它们可以较好的控制血糖，但同时存在低血糖、体重增加、胃肠道反应和心血管损伤等不良反应。因此，研发降糖效果好、不良反应少且使用方便的降糖药物显得尤为迫切。
大鱼藤树酸(robustic acid)是从壮药毛果鱼藤的藤茎中提取、分离得到的一种吡喃香豆素类化合物，其分子式为C22H20O6，相对分子质量(MW)为380，主要分布于豆科植物中。目前，针对大鱼藤树酸的生物活性开展的研究较少，现有研究发现，大鱼藤树酸具有抗氧化、抗肿瘤以及抗凝血等生理药理活性。
发明内容
本发明要解决的技术问题是提供一种大鱼藤树酸的制备方法及降血糖应用，为深入发掘大鱼藤树酸的医药用途提供了新的思路，为研发新型降糖药物提供了新的药源。
为解决上述技术问题，本发明采用以下技术方案：
大鱼藤树酸在制备降血糖药物、保健品或食品方面的应用。
根降血糖药物为糖尿病治疗药物或代谢综合症治疗药物。
糖尿病治疗药物为α-葡萄糖苷酶抑制剂。
降血糖组合物，包括大鱼藤树酸。
上述降血糖组合物，还包括阿卡波糖。
大鱼藤树酸和阿卡波糖的重量比为1:1。
上述降血糖组合物在制备降血糖药物、保健品或食品方面的应用。
大鱼藤树酸的制备方法，包括以下步骤：
(1)粉碎：将毛果鱼藤藤茎研磨成粉末；
(2)提取：取毛果鱼藤粉末加入95％乙醇，回流提取3次，每次2h，合并提取液，过滤，浓缩，得到毛果鱼藤提取浸膏；
(3)粗分：将毛果鱼藤提取浸膏依次用石油醚、三氯甲烷和正丁醇进行萃取，得石油醚部位提取物、三氯甲烷部位提取物和正丁醇部位提取物；
(4)纯化：取三氯甲烷部位提取物进行色谱分离。
步骤(4)中色谱分离按以下操作进行：采用体积比为100:0-0:100的石油醚：乙酸乙酯进行梯度洗脱，得到流分Fr1-11，将流分Fr3再次进行硅胶柱色谱分离，采用体积比为5:0-5:4的石油醚：乙酸乙酯进行梯度洗脱，得到组分Fr3-C，对组分Fr3-C采用葡聚糖凝胶色谱法进行分离、纯化，即得。
流分Fr3是体积比为9:1的石油醚：乙酸乙酯洗脱的流分；组分Fr3-C是体积比为5:2的石油醚：乙酸乙酯洗脱的流分；葡聚糖凝胶色谱法采用体积比1:1的甲醇：二氯甲烷进行洗脱。
为充分利用中草药和天然药物的生物活性，寻找到适合DM患者安全、高效、方便的降糖药物，发明人从壮药毛果鱼藤的提取物中分离出单体化合物-大鱼藤树酸。通过实验发现大鱼藤树酸具有抑制α-葡萄糖苷酶活性的作用，体外降血糖功效良好。本发明首次发现并确定大鱼藤树酸的新生物活性——降血糖活性，因此，大鱼藤树酸在降血糖方面具有较高的医药应用价值。发明人还发现，大鱼藤树酸与阿卡波糖联合应用具有协同增效的作用，使得降血糖活性更佳，两者联用抑制α-葡萄糖苷酶活性高于二者单独使用，抑制率提高了32.37％。综上，本发明将为天然活性成分大鱼藤树酸的研发提供实验依据和理论基础，也为从传统中药中开发出降糖药物提供新药源，同时为开发出新的具有改善糖尿病的产品奠定了基础。
附图说明
图1是大鱼藤树酸的1H NMR谱。
图2是大鱼藤树酸的13C NMR谱。
具体实施方式
为充分说明本发明如何实施，以下通过具体实施例作进一步说明。
一、大鱼藤树酸的制备
1.1制备工艺
(1)粉碎：将毛果鱼藤藤茎在阴凉处晾干后，研磨成粉末。
(2)提取：取毛果鱼藤粉末样品(5kg)加入95％乙醇(5L)，回流提取3次，每次2h，合并提取液，过滤，浓缩，得到毛果鱼藤提取浸膏(730.3g)。
(3)粗分：将毛果鱼藤提取浸膏依次用石油醚、三氯甲烷和正丁醇进行萃取，得石油醚部位提取物、三氯甲烷部位提取物(329.1g)和正丁醇部位提取物。
(4)纯化：取三氯甲烷部位提取物进行硅胶柱色谱分离，采用不同比例的石油醚：乙酸乙酯(100:0-0:100，v/v)进行梯度洗脱，得到流分1-11(Fr1-11)，将流分Fr3(35.9g，石油醚：乙酸乙酯＝9:1，(v/v)流分)再次进行硅胶柱色谱分离，采用不同比例的石油醚：乙酸乙酯(5:0-5:4，v/v)进行梯度洗脱，得到组分Fr3-C(石油醚：乙酸乙酯＝5:2，v/v)，对组分Fr3-C通过葡聚糖凝胶(Sephadex LH-20)柱(直径3cm,长1.2m)进一步分离纯化，洗脱液用甲醇和二氯甲烷(甲醇:二氯甲烷＝1:1)，流速为0.1mL/min，收集流分，浓缩，得目标产物。
1.2结构确认
制备所得产物的1H NMR和13C NMR图分别如图1和图2所示，结构表征数据如下：
1H NMR(400MHz,CDCl3)δ：9.93(1H,s,4-OH),7.47(2H,d,J＝8.7Hz,H-2',6'),6.96(2H,d,J＝8.7Hz,H-3',5'),6.64(1H,s,H-8),6.50(1H,d,J＝10.0Hz,H-4"),5.77(1H,d,J＝10Hz,H-3"),3.99(3H,s,5-OCH),3.84(3H,s,4-OCH3),1.48(6H,s,2"-CH3×2)。
13C NMR(126MHz,CDCl3)δ：160.26(C-2),159.12(C-4'),157.32(C-7),154.00(C-5),152.31(C-9),131.93(C-4"),131.58(C-6'),123.50(C-1),115.24(C-3"),113.76(C-3),110.85(C-8),104.14(C-10),101.91(C-3),64.56(5-OCH3),55.44(4'-OCH3),28.15(2"-CH3)。
根据以上数据推断所得化合物为大鱼藤树酸，其分子式为C22H20O6，相对分子质量(MW)为380，结构式为：
二、大鱼藤树酸与阿卡波糖联合应用对α-葡萄糖苷酶活性抑制作用的研究
(1)实验溶液的配制
0.2U/mLα-葡萄糖苷酶溶液：取5μL提前配制好的400U/mLα-葡萄糖苷酶溶液，加入9995μL提前配制好的0.1mol/L PBS溶液，混合均匀备用。
2.5mmol/L PNPG(4-硝基苯基-β-D-吡喃半乳糖苷)溶液：准确称取7.53mg PNPG，加入10mL PBS溶液溶解完全，放入-20℃冰箱避光保存。
不同浓度的阿卡波糖的配置：准确称取1.937mg阿卡波糖，加入2mL DMSO溶解，配制成1.5mmol/L阿卡波糖(终浓度为100μmol/L)，使用时再进行对半稀释，稀释四个浓度，终浓度分别为50μmol/L、25μmol/L、12.5μmol/L、6.25μmol/L。
不同浓度的大鱼藤树酸：准确称取1.2mg大鱼藤树酸，加入2mL DMSO溶解，配制成1.5mmol/L大鱼藤树酸(终浓度为100μmol/L)，使用时再进行对半稀释，稀释四个浓度，终浓度分别为50μmol/L、25μmol/L、12.5μmol/L、6.25μmol/L。
大鱼藤树酸联合阿卡波糖：取1.5mmol/L阿卡波糖与1.5mmol/L大鱼藤树酸各50μL，混合均匀，配制成终浓度为100μmol/L，使用时再进行对半稀释，稀释四个浓度，终浓度分别为50μmol/L、25μmol/L、12.5μmol/L、6.25μmol/L。
(2)实验方法
采用体外抑制α-葡萄糖苷酶活性实验，以PNPG为底物，通过与α-葡萄糖苷酶反应水解转化为葡萄糖和对硝基酚(PNP)，从而测出PNP的最大吸收值。测定大鱼藤树酸及阳性药阿卡波糖对α-葡萄糖苷酶活性的抑制作用，对照实验组、对照空白组和样品实验组分别加入100μL的α-葡萄糖苷酶于96孔板中，对照组加入10μL的DMSO，样品组加入10μL不同浓度的样品溶液，混合均匀放入37℃水浴放置15min后，实验组加入40μL的2.5mmol/L PNPG溶液，空白组加入40μL的PBS缓冲液，混合均匀，放入37℃水浴放置15min后，405nm处测定吸光度值。每组浓度的样品做三个平行实验，将各组吸光度代入下列公式，计算出α-葡萄糖苷酶抑制率，并计算IC50值。
α-葡萄糖苷酶抑制率＝(OD对照实验-(OD样品实验-OD样品空白))/(OD对照实验-OD对照空白)×100％
(3)数据处理
采用SPSS 21.0统计学软件进行数据统计，多组间比较使用单因素方差分析(ANOVA)，根据实验数据求其半数抑制浓度IC50，实验结果以
表示。
(4)实验结果与分析
大鱼藤树酸及阿卡波糖对α-葡萄糖苷酶的抑制作用如表1所示。
表1大鱼藤树酸及其与对阿卡波糖联合应用对α-葡萄糖苷酶活性的抑制作用
由表1可知，大鱼藤树酸和阿卡波糖均可使α-葡萄糖苷酶活性降低，大鱼藤树酸对α-葡萄糖苷酶的抑制作用随着大鱼藤树酸浓度的提高而显著增强，在浓度为100μmol/L时，大鱼藤树酸对α-葡萄糖苷酶的抑制率为62.81％，随着大鱼藤树酸的浓度降低，其对α-葡萄糖苷酶的抑制率逐渐下降，呈现剂量依赖性。虽然大鱼藤树酸对α-葡萄糖苷酶的抑制作用不及阿卡波糖，但将大鱼藤树酸和阿卡波糖按1:1联合应用，即大鱼藤树酸和阿卡波糖的终浓度各为50μmol/L时，其对α-葡萄糖苷酶的抑制率高达95.18％，优于单用50μmol/L阿卡波糖及单用50μmol/L大鱼藤树酸时对α-葡萄糖苷酶的抑制率。在大鱼藤树酸+阿卡波糖浓度各为3.125μmol/L时，其对α-葡萄糖苷酶的抑制率达到86.57％，相当于6.25μmol/L阿卡波糖的α-葡萄糖苷酶的抑制率，显示了大鱼藤树酸与阿卡波糖联合应用可以显著提高抑制α-葡萄糖苷酶的活性，达到协同增效的作用。
上述结果表明，大鱼藤树酸与阿卡波糖具有协同抑制α-葡萄糖苷酶活性的作用，具有良好的降血糖，
综上，大鱼藤树酸具有抑制α-葡萄糖苷酶活性、降低血糖的作用；大鱼藤树酸与阿卡波糖联合应用，可以显著提高抑制α-葡萄糖苷酶的活性，达到协同增效的作用，对降血糖有良好效果，可改善糖尿病病症。因此，可将大鱼藤树酸单独或联合阿卡波糖用于进一步研究相关降血糖药物、保健品或食品。
Claims (10)
1.大鱼藤树酸在制备降血糖药物、保健品或食品方面的应用。
2.根据权利要求1所述的应用，其特征在于：所述降血糖药物为糖尿病治疗药物或代谢综合症治疗药物。
3.根据权利要求1所述的应用，其特征在于：所述糖尿病治疗药物为α-葡萄糖苷酶抑制剂。
4.一种降血糖组合物，其特征在于包括大鱼藤树酸。
5.根据权利要求4所述的降血糖组合物，其特征在于还包括阿卡波糖。
6.根据权利要求5所述的降血糖组合物，其特征在于：所述大鱼藤树酸和阿卡波糖的重量比为1:1。
7.权利要求4至6所述降血糖组合物在制备降血糖药物、保健品或食品方面的应用。
8.一种大鱼藤树酸的制备方法，其特征在于包括以下步骤：
(1)粉碎：将毛果鱼藤藤茎研磨成粉末；
(2)提取：取毛果鱼藤粉末加入95％乙醇，回流提取3次，每次2h，合并提取液，过滤，浓缩，得到毛果鱼藤提取浸膏；
(3)粗分：将毛果鱼藤提取浸膏依次用石油醚、三氯甲烷和正丁醇进行萃取，得石油醚部位提取物、三氯甲烷部位提取物和正丁醇部位提取物；
(4)纯化：取三氯甲烷部位提取物进行色谱分离。
9.根据权利要求8所述的大鱼藤树酸的制备方法，其特征在于步骤(4)中所述色谱分离按以下操作进行：采用体积比为100:0-0:100的石油醚：乙酸乙酯进行梯度洗脱，得到流分Fr1-11，将流分Fr3再次进行硅胶柱色谱分离，采用体积比为5:0-5:4的石油醚：乙酸乙酯进行梯度洗脱，得到组分Fr3-C，对组分Fr3-C采用葡聚糖凝胶色谱法进行分离、纯化，即得。
10.根据权利要求9所述的大鱼藤树酸的制备方法，其特征在于：所述流分Fr3是体积比为9:1的石油醚：乙酸乙酯洗脱的流分；所述组分Fr3-C是体积比为5:2的石油醚：乙酸乙酯洗脱的流分；所述葡聚糖凝胶色谱法采用体积比1:1的甲醇：二氯甲烷进行洗脱。
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