CN110804079B - 一种具有dppiv酶抑制活性的呋喃香豆素及其制备方法 - Google Patents
一种具有dppiv酶抑制活性的呋喃香豆素及其制备方法 Download PDFInfo
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Abstract
本发明提供了一种具有DPPIV酶抑制活性的呋喃香豆素及其制备方法。本发明的呋喃香豆素类化合物6‑β‑D‑葡萄糖基‑6,7‑二羟基‑5‑苯并呋喃丙酸甲酯的结构式如式(Ⅰ)所示，其是从黄皮的果实、根、茎、枝或叶的干品或鲜品中分离获得。经体外药理实验证实，化合物6‑β‑D‑葡萄糖基‑6,7‑二羟基‑5‑苯并呋喃丙酸甲酯对DPPIV酶具有显著的抑制作用，其IC50值为117±8.7μM，说明其具有良好的DPPIV酶抑制活性。所述的呋喃香豆素类化合物6‑β‑D‑葡萄糖基‑6,7‑二羟基‑5‑苯并呋喃丙酸甲酯有望作为先导化合物开发出新型的DPPIV酶抑制剂药物。
Description
技术领域
本发明属于天然药物技术领域，具体涉及一种具有DPPIV酶抑制活性的呋喃香豆素及其制备方法。
背景技术
糖尿病已发展成为继心脑血管病、癌症后的第三大严重的慢性非传染性疾病，是危害现代人类健康的三大杀手之一。2017年全球约有4.25亿人患有糖尿病，其中中国糖尿病确诊人数达1.34亿。庞大的患者人群为个人、家庭和社会带来了沉重的经济负担，糖尿病的预防和治疗已成为全世界面临的最严峻的挑战之一。二肽基肽酶IV(Dipeptidylpeptidase IV,DPPIV)是一种跨膜丝氨酸蛋白酶，在体内多种组织和器官都有分布，其抑制剂能够迅速激活肠促胰岛素、神经肽和细胞因子等内源性物质的生物活性，进而抑制胰高血糖素的释放、降低空腹和餐后血糖，并且还可能改善胰岛素敏感性和胰岛β细胞功能，因此被认为治疗糖尿病的有效靶点之一，目前已上市的DPPIV酶抑制剂有西他列汀(Sitagliptin)、沙格列汀(Saxagliptin)、维达列汀(Vildagliptin)等。
植物和微生物所产生的次生代谢产物是药物发现的重要来源，例如青蒿素、青霉素和紫杉醇等。黄皮(Clausena lansium(Lour.)Skeels)是芸香科黄皮属小乔木，在我国已有1500年栽培历史。黄皮具有很高的药用价值，其果、叶、根、种子均能入药。目前未见有黄皮中具有DPPIV酶抑制活性的香豆素成分的研究报道。
发明内容
本发明的目的是提供一种具有DPPIV酶抑制活性的呋喃香豆素及其制备方法。
本发明所述的新呋喃香豆素类成分6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯，或其药用盐，或其酯化衍生物，其结构如式(Ⅰ)表示：
本发明所述的新呋喃香豆素类成分6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯由本发明人首次从黄皮(Clausena lansium(Lour.)Skeels)植物中分离获得，包括黄皮的果实、根、茎、枝或叶的干品或鲜品。优选，是从黄皮果实各个组织部位的干品或鲜品中分离获得，具体部位可以是果皮、果肉。
本发明提供的新呋喃香豆素类成分6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯，经体外药理实验证实，其对二肽基肽酶IV(DPPIV)具有显著的抑制作用，其半数抑制浓度(IC50值)为117±8.7μM。说明其具有良好的DPPIV酶抑制活性。所述的新呋喃香豆素类成分6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯、或其药用盐、或其酯化衍生物可用于制备DPPIV酶抑制剂药物。
本发明的新呋喃香豆素类成分6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯、或其药用盐、或其酯化衍生物可与制剂或药物允许的赋形剂或载体结合，制备得到具有DPPIV酶抑制活性的可用于治疗糖尿病的药物或药物组合物。该药物或药物组合物可以采用可湿性粉剂、片剂、颗粒剂、胶囊、口服液、滴丸、注射剂、气雾剂等剂型；还可采用现代制药界所公知的控释或缓释剂型或纳米制剂。
因此，本发明还提供了一种DPPIV酶抑制剂药物，其包括上述新呋喃香豆素类成分6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯、或其药用盐，或其酯化衍生物，作为活性成分。
所述的DPPIV酶抑制剂药物还包括制剂或药物允许的赋形剂或载体，如可以采用可湿性粉剂、片剂、颗粒剂、胶囊、口服液、滴丸、注射剂、气雾剂等剂型；还可采用现代制药界所公知的控释或缓释剂型或纳米制剂。
本发明还提供了新呋喃香豆素类成分6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的制备方法，其是从黄皮(Clausena lansium(Lour.)Skeels)植物中分离获得，包括黄皮的果实、根、茎、枝或叶的干品或鲜品。优选，是从黄皮果实各个组织部位的干品或鲜品中分离获得，具体部位可以是果皮和/或果肉。
本发明的新呋喃香豆素类成分6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的制备方法，具体步骤优选为：
将新鲜黄皮果实用体积分数95％的乙醇水溶液进行匀浆后提取，提取液减压浓缩除去有机溶剂后得到混悬液，混悬液用乙酸乙酯和正丁醇依次萃取，正丁醇萃取液经减压浓缩后得到总提取物。总提取物经正相硅胶柱层析，用氯仿/甲醇从体积比100:0至60:40梯度洗脱，收集氯仿/甲醇体积比70:30洗脱的组分F15，组分F15采用Sephadex LH-20柱层析并用甲醇洗脱，收集在1.2～1.6倍柱体积的洗脱流份F15-9，流份F15-9经高效液相分离纯化得到6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯。
本发明采用黄皮果实组织中提取分离强效DPPIV酶抑制剂(药物)，其制备过程条件可控，提取方便，且在采用果实进行提取时可以使植物本身不经破坏而得到长期利用，对环境友好并有潜在好的经济效益，且得到的新呋喃香豆素化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯性质稳定、易存放。其DPPIV酶抑制活性良好，有望作为先导化合物开发出新型的DPPIV酶抑制剂药物，用于治疗糖尿病。
附图说明
图1是化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的1H NMR图谱；
图2是化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的13C NMR图谱；
图3是化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的1H-1H COSY图谱；
图4是化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的HSQC图谱；
图5是化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的HMBC图谱；
图6是化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的HR-EI-MS图谱。
具体实施方式
以下实施例是对本发明的进一步说明，不是对本发明的限制，根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
实施例1：呋喃香豆素类化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的制备
1.1植物来源与鉴定
供提取用植物材料黄皮(Clausena lansium(Lour.)Skeels)的果实样品于2018年8月采自广东省郁南县，由中国科学院华南植物园陈红峰研究员鉴定。
1.2提取与分离
将新鲜无核黄皮果实用体积分数95％的乙醇水溶液进行匀浆后提取，提取液减压浓缩除去有机溶剂后得到混悬液，混悬液用乙酸乙酯和正丁醇依次萃取，正丁醇萃取液经减压浓缩后得到总提取物。总提取物经正相硅胶柱层析，用氯仿/甲醇从体积比100:0至60:40梯度洗脱，收集氯仿/甲醇70:30，v/v洗脱的组分F15，组分F15采用Sephadex LH-20柱层析并用甲醇洗脱，收集在1.2～1.6倍柱体积的洗脱流份F15-9。亚组分F15-9以50％甲醇水溶液(v/v)为流动相，以7mL/min为流速，通过制备HPLC采用Shim-pack PRC-ODS C-18柱(5μm，20×250mm)进一步层析分离纯化得化合物1(化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯，10mg，tR 50min)。
1.3新呋喃香豆素类化合物的结构鉴定
图1是化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的1H NMR图谱；图2是化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的13C NMR图谱；图3是化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的1H-1H COSY图谱；图4是化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的HSQC图谱；图5是化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的HMBC图谱；图6是化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的HR-EI-MS图谱；6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯，无色油状物；
HR-ESI-MS:m/z 397.0811[M-H]-(calcd397.1248,C18H20O10)；1H NMR(CDCl3,600MHz)和13C NMR(CDCl3,150MHz)数据陈列如下表1所示。
表1.化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的NMR数据(inCD3OD)
根据以上紫外、质谱和一维和二维核磁等波谱相关数据的综合分析，解析推导出化合物1的结构式如式(Ⅰ)所示，命名为6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯：
实施例2：呋喃香豆素类化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的DPPIV酶抑制活性检测
1.仪器与材料
二肽基态酶-4(DPPIV)，西他列汀磷酸酯，甘氨酸-脯氨酸-对硝基苯胺，二甲基亚砜(DMSO)均购自sigma，USA。酶标仪为Genois microplate reader(Tecan GENios,Swizerland)。
2.DPPIV酶抑制活性评价
将DPPIV溶解在1mL 100mM的Tris缓冲溶液中(pH＝0.8)，然后稀释50倍配置成DPPIV工作液。样品和西他列汀磷酸酯(阳性对照)均用DMSO溶解。将不同浓度的样品和西他列汀磷酸酯中加入96孔板中，再加入50μL的DPPIV工作液，并将96孔板至于酶标仪中于37℃孵育10min，然后各孔再分别加入50μL 1mM的甘氨酸-脯氨酸-对硝基苯胺和50μL 100mMTris缓冲溶液(pH＝0.8)，将96孔板至于酶标仪中于37℃孵育60min。各孔加入50μL 3％的醋酸溶液终止反应。以DMSO代替样品做空白对照，以样品仅与Tris缓冲液(pH＝0.8)混合为对照来消除样品背景颜色的干扰。反应终止后，于405nm处测吸光值。DPPIV抑制率(％)＝[A405空白-(A405样品-A405背景)]/A405空白×100％
3.实验数据参见表2：
表2.化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的DPPIV酶IC50，μmol/L
4.实验结论：
本实验表明，呋喃香豆素类化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯对二肽基肽酶IV(DPPIV)具有良好的抑制作用，其代表着一种新类型的DPPIV酶抑制活性化合物，将可望能被开发用于制备新型有效的DPPIV酶抑制剂药物，应用潜质广泛，前景看好。
以上仅是本发明的优选实施方式，应当指出的是，上述优选实施方式不应视为对本发明的限制，本发明的保护范围应当以权利要求所限定的范围为准。对于本技术领域的普通技术人员来说，在不脱离本发明的精神和范围内，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (8)
1.呋喃香豆素类化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯或其药用盐，其特征在于，所述的6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的结构如式(Ⅰ)所示：
2.一种权利要求1所述的呋喃香豆素类化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯的制备方法，其特征在于，所述的6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯是从黄皮中分离得到的。
3.根据权利要求2所述的制备方法，其特征在于，具体步骤为：
a.制备总提取物：将黄皮用体积分数95％的乙醇水溶液进行匀浆后提取，提取液减压浓缩除去有机溶剂后得到混悬液，混悬液用乙酸乙酯和正丁醇依次萃取，正丁醇萃取液经减压浓缩后得到总提取物；
b.分离纯化：总提取物经正相硅胶柱层析，用氯仿/甲醇从体积比100:0至60:40梯度洗脱，收集氯仿/甲醇体积比70:30洗脱的组分F15，组分F15采用Sephadex LH-20柱层析并用甲醇洗脱，收集在1.2～1.6倍柱体积的洗脱流份F15-9，流份F15-9经高效液相分离纯化得到6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯。
4.根据权利要求2或3所述的制备方法，其特征在于，所述的黄皮包括黄皮的果实、根、茎、枝或叶的干品或鲜品。
5.根据权利要求4所述的制备方法，其特征在于，所述的黄皮是黄皮果实，包括果实的果肉和/或果皮的干品或鲜品。
6.权利要求1所述的呋喃香豆素类化合物6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯或其药用盐在制备DPPIV酶抑制剂药物中的应用。
7.一种DPPIV酶抑制剂药物，其特征在于，含有有效量的作为活性成分的权利要求1所述的6-β-D-葡萄糖基-6,7-二羟基-5-苯并呋喃丙酸甲酯或其药用盐。
8.根据权利要求7所述的DPPIV酶抑制剂药物，其特征在于，还包括制剂或药物允许的赋形剂或载体。
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