CN114569613B - 蝙蝠葛生物碱类化合物在治疗代谢性疾病中的应用 - Google Patents
蝙蝠葛生物碱类化合物在治疗代谢性疾病中的应用 Download PDFInfo
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Abstract
本发明提供了一种蝙蝠葛生物碱类化合物及其盐在用于治疗和/或预防II型糖尿病或/和高血脂症中的新用途。通过本发明所述的蝙蝠葛生物碱类化合物及其药用盐制备的抑制剂、药物无毒副作用，并且治疗效果显著，具有极大的推广价值。
Description
技术领域
本发明涉及制药领域，具体涉及蝙蝠葛生物碱类化合物在治疗代谢性疾病中的应用。
背景技术
代谢性疾病即因代谢问题引起的疾病，包括代谢障碍和代谢旺盛等原因，主要以肥胖、高血糖、高血脂、高血压、高尿酸、非酒精性脂肪肝病、心脑血管疾病等为代表，是一组复杂的代谢紊乱症候群。随着营养条件和生活方式的改变，过去的十几年里，代谢性疾病的发生率逐渐增加。在当前全球疾病负担80%以上的慢性疾病中，代谢性疾病已占比一半以上，对患者的生命健康造成严重威胁，对其家庭造成极大的心理和经济负担。目前，代谢性疾病的高发病率已经引起卫生组织的重视，其预防与治疗刻不容缓。
近年来，越来越多的证据显示人体菌群与肥胖、糖尿病等人体代谢系统疾病的发生发展密切相关。2017年的相关研究证实了肠道菌群可称为调节和预防肥胖、2型糖尿病等代谢系统疾病的重要治疗路径，肠道微生态与代谢调节密切相关，且肠道微生态参与了二甲双胍等传统降糖药的药效机制。比利时鲁汶大学的研究指出肠道细菌Akkermansia muciniphila可以抑制和持久改善肥胖和糖尿病。美国国家癌症中心的研究指出肠道微生态通过发酵产物（醋酸和乳酸）改善肥胖状态、胰岛素抵抗和脂肪肝的代谢调节路径。芬兰东部大学的研究进一步揭示肠道细菌可能通过代纤维素产生吲哚丙酸，从而达到调节和预防2型糖尿病的效果。发现肠道菌群的新颖作用机制与功能，开发相应靶点，寻找新颖抗代谢性及疾病治疗途径具有重要的科研及社会意义。
近年来，二肽基肽酶-4（DPP-4）抑制剂作为糖尿病治疗的一个新方向吸引了药物化学家的普遍关注。2006年，FDA批准默克公司的西他格利汀上市，是首个上市的DPP-4抑制剂。二肽基肽酶-4（DPP-4）是一种丝氨酸蛋白酶，能迅速裂解和失活GLP-1，GIP等肠促胰岛素。它是一种多功能的蛋白水解酶，应用DPP-4抑制剂能够抑制GLP-1,GIP降解，增强肠促胰岛素和神经肽的活性，降低空腹和餐后葡萄糖浓度及糖化血红蛋白水平，改善胰岛素敏感性和β细胞功能。然而，临床治疗发现目前的DPP-4抑制剂的降糖效果具有一定局限性，同时对体重、血脂的调节作用有限，同时，DPP-4对自身免疫性炎症方面的副作用也逐渐凸显，在一定程度上限制了DPP-4抑制剂的发展与应用。本研究团队工作发现，肠道菌群可以产生与宿主DPP-4功能相同的同源蛋白，可以水解GLP-1并显著影响代谢相关疾病的发生发展，是一种抗代谢性疾病的新颖靶点。
北豆根是一种传统中药，具有清热解毒、止咳和祛痰的功效，临床上用于治疗咽喉肿痛、扁桃体和慢性支气管炎。其中主要成分为一类蝙蝠葛生物碱，研究发现具有自噬抑制功能，可作为缺血再灌注的保护剂。然而，关于蝙蝠葛生物碱在改善代谢性疾病方面的作用并无文献报道。
发明内容
本发明的目的在于填补现有技术的空白，提供一种蝙蝠葛生物碱类化合物在制备治疗和/或预防代谢性疾病的药物中的应用。由本发明的蝙蝠葛生物碱类化合物或其药用盐制备的药物对人体无毒副作用，并且治疗效果显著。为了实现上述技术效果，本发明具体提供如下的技术方案：
本发明的第一方面，提供一种蝙蝠葛生物碱类化合物或其盐在如下（1）至（4）任一项中的应用：
（1）制备治疗和/或预防II型糖尿病的药物组合物；
（2）制备用于降血糖及降血脂的药物组合物；
（3）制备细菌二肽基肽酶4抑制剂；
（4）制备治疗或预防非酒精性脂肪肝的药物组合物。
在一种实施方式中，所述蝙蝠葛生物碱类化合物结构如式（I）所示：其中，R1-R6选自氢、C1-C5的烷基、硝基、氟、氯、溴、酯基、羟基、酰氨基、烷氧基中的任意一种。
在一种优选的实施方案中，所述蝙蝠葛生物碱类化合物的结构如式2-5中任一所示：
本发明的第二个方面，提供一种组合物在如下（1）至（4）任一项中的应用，其特征在于，所述组合物包含至少一种如式2-5中所示的化合物或其盐：
（1）制备治疗和/或预防II型糖尿病的药物组合物；
（2）制备用于降血糖及降血脂的药物组合物；
（3）制备细菌二肽基肽酶4抑制剂；
（4）制备治疗或预防非酒精性脂肪肝的药物组合物。
在一种实施方案中，上述抑制剂或药物为注射液、片剂、粉剂、颗粒剂、丸剂、胶囊、口服液、膏剂、霜剂或喷剂。
在一种实施方案中，上述抑制剂或药物包括一种或以上药学上可接受的辅料。
在一种实施方案中，上述辅料包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂和缓释剂。
在一种实施方案中，上述药物通过口服、胃肠内给药、注射、喷射、物理或化学介导等方法给药，或是被其他物质混合或包裹后给药。
本发明的技术方案相对于现有技术获得了如下有益的技术效果：
本发明首次公开了蝙蝠葛生物碱类化合物及其药用盐具有细菌二肽基肽酶4抑制剂的功能，可有效抑制细菌二肽基肽酶-4的表达，并且在降低血糖和血脂方面具有显著的治疗或预防效果。
附图说明
附图用来提供对本发明的进一步理解，并且构成说明书的一部分，与本发明的实施例一起用于解释本发明，并不构成对本发明的限制。在附图中：
图1 化合物S2-S6的结构图。
具体实施方式
下面结合实施例对本发明做详细描述，但下列实施例不应看作是对本发明范围的限制。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1、蝙蝠葛生物碱类化合物的提取
（1）制备北豆根提取物
将北豆根剪碎，称重5千克。用15 L 95%乙醇-水（体积百分含量）溶液回流提取3次，每次1小时。合并提取液，减压浓缩干燥得到646 g提取物。
进一步将提取物用蒸馏水600ml溶解，用等体积的正己烷萃取三次，弃去有机相。再用等体积乙酸乙酯萃取水相三次，弃去水相，合并乙酸乙酯萃取液。用旋转蒸发仪蒸干乙酸乙酯获得浸膏98 g，记作BDG。
（2）生物碱类化合物的提取
将步骤（1）制备的BDG通过硅胶柱色谱分离，以正己烷:乙酸乙酯体系 (正己烷:乙酸乙酯的体积比为100：1, 20:1, 4:1, 1:1)进行梯度洗脱，每个梯度洗3个保留体积，每个体积 500ml。根据薄层层析色谱行为分析,在正己烷:乙酸乙酯(体积比为100：1)体系得到馏分 BDG-1; 在正己烷:乙酸乙酯(体积比为20:1)中得到馏分BDG-2~4;在正己烷:乙酸乙酯(体积比为4:1)中得到馏分BDG-5~7;在正己烷:乙酸乙酯(体积比为1:1)中得到馏分BDG-8~10;共得到10个馏分，将各馏分冷冻干燥。
通过薄层色谱分析发现BDG-8中生物碱类物质含量较高，因此对该馏分利用 ODS反相硅胶柱进一步分离。用体积百分含量为 10%，20%，30%，40%，50%，70%，90% 的甲醇水溶液依次进行洗脱,每个洗脱体系洗3个保留体积，每个保留体积为 500ml。根据薄层层析色谱行为，照射 254nm 紫外灯判断不同馏分，在体积百分含量为10%的甲醇水溶液中得到馏分 BDG-8-1；在体积百分含量为 20%的甲醇水溶液系统中得到馏分BDG-8-2；在体积百分含量为30%的甲醇水溶液系统中得到馏分BDG-8-3~5；在体积百分含量为 40%的甲醇水溶液系统中得到馏分BDG-8-6~10；在体积百分含量为 50%的甲醇水溶液系统中得到馏分BDG-8-11~15；在体积百分含量为70%，90%的甲醇水溶液系统中得到馏分BDG-8-16；共得到16个子馏分，将各个馏分冷冻干燥。
通过薄层色谱分析发现BDG-8-11中生物碱物质含量较高，因此对BDG-8-11馏分进一步进行HPLC分离。以体积百分含量39%乙腈的酸水(此处的酸水为体积百分含量为 0.01%三氟乙酸的水溶液)溶液为洗脱剂进行 HPLC 制备，流速为 5 ml/min，收集11.1, 13.5,16.9, 20.3, 25.1 min的色谱峰，分别得到五种化合物，记为S2、S3、S4、S5、S6。
上述薄层色谱的条件如下:
薄层板：青岛海洋薄层板公司。薄层条件展开体系：氯仿：甲醇=20：1，2ml；温度25℃；
HPLC 色谱条件如下：以色谱纯的甲醇将样品配制为 10mg/ml 的溶液，上样量为15ul每次，色谱柱为Kromasil 10×250mm C18 半制备柱，柱温为 25℃，210nm波长进行检测。
实施例2、蝙蝠葛生物碱类化合物的结构分析
对制备得到的化合物S2-S6分别进行核磁共振、红外、质谱检测，通过与文献数据比对，确定各化合物的结构分别如图1中式2-式6所示。
其中所使用的核磁共振仪为BrukerMercury-500和BrukerMercury-600兆赫（布鲁克光谱仪器公司），红外色谱仪为Nicolet IS5FT-IR (美国尼高力仪器有限公司)，质谱仪为Bruker APEX III 7.0 T和APEX II FT-ICR (布鲁克光谱仪器公司)。
实施例3、蝙蝠葛生物碱类化合物生物活性验证
准确逐一称取实施例2所制备的S2-S6五种化合物，用DMSO配制成1mM，供活性测试（终浓度范围在1-100μM，配制时溶于少量DMSO后，用蒸馏水稀释至相应浓度，控制DMSO的最终体积分数<0.1%）；配制时溶于少量DMSO后，用蒸馏水稀释至相应浓度，控制DMSO的最终体积分数<0.1%）。
按照细菌二肽基肽酶-4（DPP-4）抑制剂筛选试剂盒中的方法，用细菌DPP4蛋白替换人源DPP4蛋白，对上述化合物S2-S6进行测试（以磷酸西格列汀作为对照药）。
对实验数据进行统计分析，计算各供试样品的IC50值，结果如表1所示。可见，所示化合物均有一定的细菌二肽基肽酶-4抑制活性。
表1 式2-式6的细菌二肽基肽酶-4抑制活性检测结果
实施例4、蝙蝠葛生物碱类化合物对喂食高脂饲料小鼠的血脂影响
材料：准确称取实施例2所制备的S2-6所示的五个化合物，用0.5%CMC-Na配制成10mg/ml溶液，供活性测试。C57小鼠购自北京维通利华实验动物技术有限公司，温度20-24摄氏度，恒湿50-60%，光照12小时（8:00-20:00），隔音，自由摄食、饮水，适应环境一周后进行实验。
方法：雄性C57小鼠20周，体重32-34，8只，作为正常对照组（1）；雄性高脂饲料诱导（HFD）肥胖模型小鼠，6-8周龄C57小鼠给予8周60%高脂饮食饲喂，体重40-45 g，测定空腹血糖，依据血糖值和体重情况平均分组：（2）模型对照组，（3）S2 10 mg/kg，（4）S3 10 mg/kg，(5) S4 10 mg/kg，(6) S5 10 mg/kg，(7) S6 10 mg/kg，每组8只，连续给药5周。模型对照组给予等量的PBS。末次给药后，取血，4摄氏度3000 rpm离心，测定血清总胆固醇TC，低密度脂蛋白LDL-C，甘油三酯TG。
结果如表2-5所示：与对照组和模型组比较，S2-S6化合物都可以显著控制小鼠体重，从第1周起即可降低自由饮食血糖及禁食（4小时）血糖，改善小鼠血脂及肝脏脂肪含量。
表2 化合物式2-6对HFD诱导肥胖小鼠的体重影响
表3 化合物式2-6对HFD诱导肥胖小鼠的血糖影响
表4 化合物式2-6对HFD诱导肥胖小鼠的血脂影响
表5 化合物式2-6对HFD诱导肥胖小鼠的肝脏脂肪含量影响
实施例5、蝙蝠葛生物碱类化合物对非酒精性脂肪性肝病的影响
材料：准确称取实施例2所制备的S2-S6所示的五个化合物，用0.5%CMC-Na配制成10mg/ml溶液，供活性测试。C57小鼠购自北京维通利华实验动物技术有限公司，温度20-24摄氏度，恒湿50-60%，光照12小时（8:00-20:00），隔音，自由摄食、饮水，适应环境一周后进行实验。
雄性SPF级C57小鼠60只，体重22-24 g，购自维通利华实验动物中心。温度20-24摄氏度，恒湿50-60%，光照12小时（8:00-20:00），隔音，自由摄食、饮水，适应环境一周后进行实验。血清总胆固醇TC试剂盒，甘油三酯TG试剂盒，谷丙转氨酶AST试剂盒，谷草转氨酶ALT试剂盒购自南京建成生物工程研究所。
方法：雄性SPF级C57小鼠随机分组：（1）正常组，（2）模型对照组，（3）S2 10 mg/kg，（4）S3 10 mg/kg，(5) S4 10 mg/kg，(6) S5 10 mg/kg，(7) S6 10 mg/kg;每组10只。正常组小鼠标准饲料喂养，其余组小鼠每天喂食蛋氨酸胆碱缺乏饲料（MCD），胆碱缺乏饲料喂养会诱发肝脏细胞变性、肝炎及肝损伤，同时血脂水平升高并诱发胰岛素抵抗，是常用的啮齿类动物脂肪肝的造模方法。
MCD饮食喂养4周后，给药组开始给药，连续4周。正常组和模型对照组给予等量的PBS。给药四周后，麻醉处死小鼠，取肝组织和血。
测定指标：1）肝脏指数。
2）测定血清总胆固醇及甘油三酯含量。
3）测定谷丙转氨酶及谷草转氨酶含量。
实验结果如表6所示：与正常对照组比较，模型组肝指数显著升高，给予S2-S6化合物后能显著降低非酒精性脂肪性肝病小鼠的肝指数。同时模型组的TC、TG均显著升高，提示本模型造成明显的血脂紊乱，与模型组相比，给予式S2-S6化合物后均可降低非酒精性脂肪性肝病小鼠的血脂，同时还能改善肝功能，降低血浆ALT，AST的含量。
表6 化合物式2-6对MCD小鼠肝功能相关指标的影响
实施例6、蝙蝠葛生物碱类化合物的生物安全性验证（小鼠急毒实验）
1实验材料
6-8周龄雄性C57小鼠，20只，体重20-22克，购自北京维通利华实验动物有限公司。
2实验方法
1）化合物的配制
精密称取S2-S6所示的化合物，用0.5% CMC-Na 配制浓度为0.2 g/ml的溶液。
2)动物分组与给药
将小鼠适应性饲养3-5 天后，实验前一天晚6点禁食，自由饮水。实验时，将小鼠按体重随机分组，每组10只，灌胃给药，每10g小鼠体重给0.25 ml，即给药剂量为 5g/kg。对照组灌胃给予0.5% CMC-Na，每10 g小鼠体重0.25 ml。
3）评价指标
给药后观察动物的一般状况，如外观、行为、对刺激的反应、分泌物及排泄物，记录异常现象发生时间。观察有无死亡发生，记录死亡发生时间，尸检，观察有无异常现象。
在急性毒性试验中，灌胃大、小鼠的毒性分级依据LD50分为五级：LD50<1 mg/kg为极毒，LD50在1-50 mg/kg之间为剧毒，LD50在51-500 mg/kg为中等毒，LD50在501-5000 mg/kg之间为低毒，大于5000 mg/kg为实际无毒。
3实验结果
给药后均未发现明显异常现象，第29天后将小鼠脱颈处死，尸检，均未发现明显异常现象。S2-S6所示化合物的LD50均大于5000 mg/kg，且尸检无明显异常，属“实际无毒”。
应理解，在本发明范围内，本发明的上述各技术特征和在下文（如实施例）中具体描述的各技术特征之间都可以相互组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一赘述。
Claims (5)
1.一种蝙蝠葛生物碱类化合物及其盐在制备治疗或预防非酒精性脂肪肝的药物组合物中的应用，其中，所述蝙蝠葛生物碱类化合物结构式如式2、4、5任一所示：
2.一种组合物在制备具有治疗或预防非酒精性脂肪肝的药物组合物中的应用，其特征在于，所述组合物包含如权利要求1中式2、4、5中所示的化合物或其盐。
3.如权利要求1至2中任一所述的应用，其特征在于，所述药物组合物为注射液、片剂、粉剂、颗粒剂、丸剂、胶囊、口服液、膏剂、霜剂或喷剂。
4.如权利要求1至2中任一所述的应用，其特征在于，所述药物组合物包括一种或以上药学上可接受的辅料。
5.如权利要求1至2中任一所述的应用，其特征在于，所述药物组合物通过口服、胃肠内给药、注射、喷射、物理或化学介导方法给药，或是被其他物质混合或包裹后给药。
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