CN116473953A - 咖啡酸甘油酯类化合物在制备药物或功能食品中的应用 - Google Patents
咖啡酸甘油酯类化合物在制备药物或功能食品中的应用 Download PDFInfo
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- CN116473953A CN116473953A CN202210045231.9A CN202210045231A CN116473953A CN 116473953 A CN116473953 A CN 116473953A CN 202210045231 A CN202210045231 A CN 202210045231A CN 116473953 A CN116473953 A CN 116473953A
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- caffeic acid
- acid glyceride
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- diabetes
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Abstract
本发明提供了式Ⅰ所示咖啡酸甘油酯类化合物或其药学上可接受的盐、酯、溶剂合物在制备降血糖、预防和/或治疗糖尿病或糖尿病并发症药物或功能食品中的应用,或在制备α‑葡萄糖苷酶活性抑制剂中的应用,或在制备抗氧化产品中的应用。本发明还提供了一种药物组合物,包含式Ⅰ所示化合物和药学上可接受的药用辅料,用作药物制剂,所述药物为降血糖、治疗糖尿病、预防和/或治疗糖尿病并发症,或抗氧化药物。在式Ⅰ中R选自H、OH或OCH3中的任意一种。
Description
技术领域
本发明涉及医药或保健品应用领域,具体涉及咖啡酸甘油酯类化合物在制备药物或功能食品中的应用,尤其涉及一种咖啡酸甘油酯类化合物在降血糖、预防或治疗糖尿病、糖尿病并发症药物或功能食品中的应用、或制备α-葡萄糖苷酶抑制剂或抗氧化产品中的应用。
背景技术
糖尿病是一种以高血糖为特征的综合性代谢性疾病,主要分为1型糖尿病和2型糖尿病。随着现代生活水平提高、人口老龄化以及肥胖发生率的增加,糖尿病在全球范围内持续高发的态势。糖尿病的持续高血糖与长期代谢紊乱等可导致全身组织器官,特别是心脑血管、眼、肾及神经系统的损害及其功能障碍和衰竭,是心脑血管疾病、肿瘤和新冠等重大疾病的高危因素。目前,临床上使用的抗糖尿病降血糖药物主要有胰岛素类,二甲双胍类,α-葡萄糖苷酶抑制剂类(如阿卡波糖和伏格列波糖等),GLP-1受体激动剂类(如利拉鲁肽等),DPP-4抑制剂类(如西格列汀等),促胰岛素分泌剂磺脲类(如格列美脲等)以及胰岛素增敏类(如双胍类及噻唑烷二酮类)等。但这些药物仍然存在给药不方便、不能稳定控制血糖水平或副作用较大(如肝肾毒性、浮肿以及严重胃肠道反应)等问题。因此,新型降血糖药物或功能食品的的研发依然是抗糖尿病治疗领域的研究热点。
α-葡萄糖苷酶属于低聚糖水解酶类,其抑制剂通过竞争性抑制小肠上皮绒毛膜上的糖苷酶的作用来减少糖类的降解,延缓糖类的消化和吸收,从而有效地降低糖尿病人餐后血糖浓度的峰值,达到控制血糖的目的。α-葡萄糖苷酶抑制剂(如阿卡波糖等)为临床广泛应用的一类口服降糖药物,可广泛用于1型及2型糖尿病人的血糖控制。但目前临床上使用较广的阿卡波糖等α-葡萄糖苷酶抑制剂具有易导致患者腹胀、腹泻和腹痛等胃肠道功能紊乱以及肝损伤等副作用。因此,研发更加安全有效的新型α-葡萄糖苷酶抑制剂具有重要的意义。
发明内容
针对现有技术问题,本发明的目的在于提供咖啡酸甘油酯类化合物在制备药物或功能食品中的应用。
为达到此发明目的,本发明采用以下技术方案:
第一方面,本发明提供式Ⅰ所示咖啡酸甘油酯类化合物或其药学上可接受的盐、酯、溶剂合物在制备降血糖、预防和/或治疗糖尿病或糖尿病并发症药物或功能食品中的应用:
在式Ⅰ中R选自H、OH或OCH3中的任意一种。
优选地,所述降血糖为降低1型糖尿病或2型糖尿病的高血糖,所述糖尿病并发症为氧化应激引起的并发症。
优选地,所述药物或功能食品具有抑制α-葡萄糖苷酶活性和抗氧作用。
优选地,所述咖啡酸甘油酯类化合物为式Ⅱ—式Ⅲ中的任一种或两种以任意比例组合:
式Ⅱ英文名为:1,3-O-dicaffeoylglycerol,式Ⅲ英文名为:1-O-p-coumaroyl-3-O-caffeoylglycerol,可从药食两用植物香茅草中分离得到,具有较高的安全性。
优选地,式Ⅱ和式Ⅲ化合物组合的摩尔比为9~1:1~9。
优选地,所述药物或功能食品还包含药学或食品上可接受的辅料,包括载体、稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、包衣材料、着色剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂中的任意一种或至少两种的组合;
优选地,所述药物剂型为片剂、胶囊剂、注射剂、颗粒剂或口服液体剂;
优选地,所述咖啡酸甘油酯类化合物每天的使用剂量按体重计算为0.01~100mg/kg。
本发明意外地发现,式Ⅰ所示咖啡酸甘油酯类化合物或其药学上可接受的盐、酯、溶剂合物可抑制α-葡萄糖苷酶活性,且具有抗氧化活性,可应用于降血糖,糖尿病,或糖尿病并发症的预防和治疗。本发明人通过α-葡萄糖苷酶抑制剂活性和DPPH自由基清除实验研究,发现化合物1,3-O-dicaffeoylglycerol和1-O-p-coumaroyl-3-O-caffeoylglycerol具有抑制α-葡萄糖苷酶活性,其IC50值分别为5.4585±0.2475和11.4475±1.8225μmol/L,两者组合后可显著提高其活性,且具有临床药物阿卡波糖所不具备的强抗氧化活性,其清除DPPH自由基的IC50值分别为8.818±1.117和14.810±1.830μmol/L,在降血糖的同时,可对氧化应激引起的糖尿病并发症具有很好的治疗和预防作用。
第二方面,本发明提供式Ⅰ所示咖啡酸甘油酯类化合物或其药学上可接受的盐、酯、溶剂合物或其组合物在制备α-葡萄糖苷酶活性抑制剂中的应用:
在式Ⅰ中R选自H、OH或OCH3中的任意一种。
第三方面,本发明提供式Ⅰ所示咖啡酸甘油酯类化合物或其药学上可接受的盐、酯、溶剂合物在制备抗氧化产品中的应用:
在式Ⅰ中R选自H、OH或OCH3中的任意一种。
第四方面,本发明提供一种药物组合物,包含式Ⅰ所示咖啡酸甘油酯类化合物或其药学上可接受的盐、酯、溶剂合物中的一种或几种和药学上可接受的辅料,用作药物制剂,所述药物为降血糖药物、治疗或预防糖尿病药物、预防或治疗糖尿病并发症药物、α-葡萄糖苷酶活性抑制剂或抗氧化药物:
在式Ⅰ中R选自H、OH或OCH3中的任意一种。
优选地,按组合物的总重量计,含有0.001-99wt%的所述咖啡酸甘油酯类化合物或其药学上可接受的盐、酯、溶剂合物;
优选地,所述咖啡酸甘油酯类化合物每天的使用剂量按体重计算为0.01~100mg/kg。
优选地,所述药学上可接受的辅料,包括载体、稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、包衣材料、着色剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂中的任意一种或至少两种的组合,如黏合剂和稀释剂的组合、崩解剂和填充剂的组合、崩解剂、填充剂和润滑剂的组合等,其他任意的组合方式便不在此一一赘述。
优选地,所述药物制剂为片剂、胶囊剂、注射剂、颗粒剂或口服液体剂。本发明所述咖啡酸甘油酯类化合物或其药学上可接受的盐、酯、溶剂合物,还可以与其他药物联用实现更好的降血糖效果。
在本发明中,所述药物的给药途径可以根据实际需要选择口服给药、舌下给药、静脉注射、肌肉注射或皮下注射的任意一种方式。优选口服给药或静脉注射。
本发明意外地发现,式Ⅰ所示咖啡酸甘油酯类化合物或其药学上可接受的盐、酯、溶剂合物可抑制α-葡萄糖苷酶活性,且具有很好的抗氧化活性,可用于降低血糖,即可用于制备降血糖药物或功能食品,尤其适用于制备预防或治疗糖尿病或糖尿病并发症药物,可降低1型糖尿病或2型糖尿病的高血糖,且可发挥抗氧化作用,清除体内氧化自由基,预防或降低氧化应激引起的各种症状,对衰老相关疾病有益。尤其是化合物1,3-O-dicaffeoylglycerol(1)和1-O-p-coumaroy-l-3-O-caffeoylglycerol(2),其抑制α-葡萄糖苷酶活性的IC50值分别为5.4585±0.2475和11.4475±1.8225μmol/L,两种化合物组合后可显著提高其活性(化合物(1):(2)摩尔比为9:1、5:5和1:9时的IC50值分别为2.405±0.191、3.098±0.201和3.378±0.301μmol/L)。清除DPPH自由基的IC50值分别为8.818±1.117和14.810±1.830μmol/L,具有临床药物阿卡波糖所不具备的强抗氧化活性,由此,将可望使1,3-O-dicaffeoylg lycerol或1-O-p-coumaroyl-3-O-caffeoylglycerol,或其任意比例组合物,应用于临床降血糖、糖尿病或糖尿病并发症、抗氧化等药物或功能食品中,其活性高,可大幅降低临床用药剂量,减轻病人的用药负担,且可降低或预防糖尿病氧化应激导致的并发症,并且其广泛存在于香茅草等中草药中,毒副作用小,具有较高的安全性。
具体实施方式:
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。各实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。
除非另有说明,本说明书中使用的全部专业术语和科学用语的含义均与本发明所属技术领域的技术人员一般理解的含义相同。但如有冲突,以包含定义的本说明书为准。
其中化合物1,3-O-dicaffeoylglycero(1)和1-O-p-coumaroyl-3-O-caffeoylglycerol(2)为中国科学院西双版纳热带植物园张玉梅实验室自制样品。
α-葡萄糖苷酶、对硝基苯基-β-D-吡喃半乳糖苷、抗坏血酸和阿卡波糖都购自Sigma公司。
实施例1
1,3-O-dicaffeoylglycerol(1)和1-O-p-coumaroyl-3-O-caffeoylglycerol(2)的制备
香茅草120kg,晒干粉碎后用工业乙醇冷浸提取3次(7天,7天,7天)。减压浓缩提取液,得到8.1kg乙醇总浸膏。乙醇浸膏用热水搅拌溶解,冷却后依次用石油醚、乙酸乙酯、正丁醇各萃取4次。减压浓缩回收溶剂后,得到石油醚浸膏2.43kg,乙酸乙酯浸膏1.12kg、正丁醇部位浸膏1.34kg和水相浸膏。将各个萃取物部分用薄层色谱、硅胶柱色谱、SephadexLH-20柱色谱、HPLC等方法进行分离纯化,
乙酸乙酯部分以硅胶柱分离,以氯仿-甲醇(30:1,15:1,9:1,4:1,2:1,0:1)梯度洗脱,得到12个组分B1-B12;B5经反复硅胶柱层析,Sephadex LH-20和重结晶纯化,得到化合物1,3-O-dicaffeoylglycerol(1)(6.3g);B10经反复硅胶柱层析和Sephadex LH-20纯化,得到化合物1-O-p-coumaroyl-3-O-caffeoylglycerol(2)(5.1g)。
质谱和核磁检测分析,进行结构确证:1,3-O-dicaffeoylglycerol(1)和1-O-p-coumaroyl-3-O-caffeoylglycerol(2)的波谱数据如下:1,3-O-dicaffeoylglycerol(1),pale yellow solid,C21H20O9,EI-MS:m/z 439[M+Na]+.1H-NMR(C5D5N5,800MHz)δ:7.97(2H,d,J=15.8Hz,H-7,3′),7.57(2H,d,J=1.4Hz,H-9,5′),7.21(2H,d,J=8.1Hz,H-12,8′),7.12(2H,dd,J=8.1,1.7Hz,H-13,9′),6.58(2H,d,J=15.8Hz,H-6,2′).13C-NMR(C5D5N5,200MHz)δ:66.6(C-1),68.3(C-2),66.6(C-3),167.8(C-5),115.0(C-6),146.5(C-7),127.2(C-8),116.2(C-9),150.5(C-10),146.5(C-11),117.0(C-12),122.5(C-13),167.5(C-1′),115.0(C-2′),146.5(C-3′),127.2(C-4′),115.9(C-5′),150.5(C-6′),146.5(C-7′),117.0(C-8′),122.5(C-9′).
1-O-p-coumaroyl-3-O-caffeoylglycerol(2),white solid,C21H20O8,EI-MS:m/z423[M+Na]+.1H-NMR(CD3COCD3,600MHz)δ:7.66(1H,d,J=16.0Hz,H-7),7.59(1H,d,J=16.0Hz,H-3′),7.58(2H,d,J=8.6Hz,H-5′,9′),7.06(1H,dd,J=8.2,1.9Hz,H-9′),6.89(2H,d,J=8.6Hz,H-10,12),6.87(1H,d,J=8.2Hz,H-8′),6.39(1H,d,J=15.9Hz,H-6),6.32(1H,d,J=15.9Hz,H-2′),4.27(4H,m,H-1,3),4.19(1H,dd,J=10.5,5.2Hz,H-2).13C-NMR(CD3COCD3,150MHz)δ:66.4(C-1),68.7(C-2),66.4(C-3),167.7(C-5),115.7(C-6),146.7(C-7),127.4(C-8),131.4(C-9),116.8(C-10),161.0(C-11),116.8(C-12),131.4(C-13),167.8(C-1′),115.6(C-2′),146.1(C-3′),128.0(C-4′),115.3(C-5′),149.2(C-6′),146.5(C-7′),116.4(C-8′),122.7(C-9′).
实施例2
1,3-O-dicaffeoylglycerol(1)和1-O-p-coumaroyl-3-O-caffeoylglycerol(2)及其组合物对α-葡萄糖苷酶抑制活性评价
实验原理:
α-葡萄糖苷酶属于低聚糖水解酶类,其抑制剂通过竞争性抑制小肠上皮绒毛膜上的糖苷酶的作用来减少糖类的降解,延缓糖类的消化和吸收,从而有效地降低糖尿病人餐后血糖浓度的峰值,达到控制血糖的目的。α-葡萄糖苷酶抑制剂(如阿卡波糖等)目前已成为临床上广泛应用的一类口服降糖药物。
α-葡萄糖苷酶抑制剂活性筛选可通过酶与其底物对硝基苯基-β-D-吡喃半乳糖苷(PNPG,麦芽糖类似物)的体外酶促反应来检测。α-葡萄糖苷酶加入酶反应的底物后,底物被酶催化分解为对硝基苯酚(PNP)和葡萄糖。PNP是一种有色物质,在400nm左右有最大吸收,可通过酶标仪来测定,根据OD值算出样品的抑制活性。
实验方法:
1,3-O-dicaffeoylglycerol(1)和1-O-p-coumaroyl-3-O-caffeoylglycerol(2)样品溶液:用DMSO溶液配成4mmol/L溶液,再稀释为浓度为0.4、0.2、0.1、0.05、0.025mmol/L溶液。
1,3-O-dicaffeoylglycerol(1)和1-O-p-coumaroyl-3-O-caffeoylglycerol(2)组合物样品溶液:按(1):(2)摩尔比为9:1、5:5和1:9,用DMSO溶液配成4mmol/L溶液,再稀释为浓度为0.4、0.2、0.1、0.05、0.025mmol/L溶液。
阿卡波糖(阳性对照):用DMSO溶液配成2mmol/L溶液,再稀释为浓度为0.2、0.1、0.05、0.025、0.0125mmol/L溶液。
分别将10μL不同浓度(1)、(2)、(1)和(2)不同摩尔比的组合物样品溶液或阳性对照品溶液与50μL浓度为0.1U/ml的酶溶液、100μL浓度为50mmol/L,pH7.0的磷酸盐缓冲液、40μL浓度为5mmol/L的底物顺序加入96孔酶标板,充分混匀,设置两孔重复。同时设置不含药物的空白对照(加入同量的DMSO溶液)。37℃孵育50min,酶标仪(型号Thermo MultiskanFC)测定405nm处的OD值,计算得出α-葡萄糖苷酶活性的抑制率,抑制率计算公式如下:
其中A0为空白对照组OD值,A1为样品组OD值。
依据抑制率,按照Reed&Muench法计算出IC50值。
实验结果见表1,结果显示,1,3-O-dicaffeoylglycerol(1)和1-O-p-coumaroyl-3-O-caffeoylglycerol(2)具有显著的α-葡萄糖苷酶抑制活性,其IC50值分别为5.4585±0.2475和11.4475±1.8225μmol/L,且化合物(1):(2)摩尔比为9:1、5:5和1:9时的IC50值分别为2.405±0.191、3.098±0.201和3.378±0.301μmol/L,即化合物(1)与(2)的任意比例组合物的活性均优于任意化合物(1)或(2)单体的活性。
表1.化合物(1)、(2)及其组合物对α-葡萄糖苷酶的抑制活性
实施例3
1,3-O-dicaffeoylglycerol(1)和1-O-p-coumaroyl-3-O-caffeoylglycerol(2)的抗氧化活性评价
DPPH·是一种中文名为1,1-二苯基-2-三硝基苯肼的稳定自由基。在其分子中,与三硝基苯基相连的是一个带有不成对电子的氮,该物质具有氧化性。依据抑制50%DPPH·活性时的样品浓度(IC50)值,并以L-抗坏血酸作为阳性对照参照成分。
用无水甲醇将DPPH·溶液的配制成0.1mM,并将分离出的样品用DMSO配置成所需浓度梯度。在避光条件下,先在96孔板内加180μl DPPH溶液,样品组再加入20μl样品溶液,对照组加入20μl DMSO溶液。在室温25℃下遮光反应30分钟,之后用酶标仪测517nm吸光度值。
实验结果见表2,结果显示,1,3-O-dicaffeoylglycerol(1)和1-O-p-coumaroyl-3-O-caffeoylglycerol(2)具有显著的抗氧化活性,其IC50值分别为8.818±1.117和14.810±1.830μmol/L,活性强于阳性对照抗坏血酸。由此可见,化合物1,3-O-dicaffeoylglycerol(1)或1-O-p-coumaroyl-3-O-caffeoylglycerol(2),兼具α-葡萄糖苷酶抑制活性和抗氧化活性,在降血糖的同时,可对抗氧化应激,在降血糖、糖尿病或糖尿病并发症、抗氧化等药物中具有广泛的应用前景。
表2.化合物(1)和(2)的抗氧化活性
实施例4
片剂:将1g化合物1,3-O-dicaffeoylglycerol(1)或1-O-p-coumaroyl-3-O-caffeoylglycerol(2)与0.6g乳糖和0.5g淀粉混合,用水均匀湿润、把湿润后的混合物过筛并干燥,再过筛,加入0.1g硬脂酸镁,混匀、压片,压制成20片,片重:110mg,含量:50mg/片。
实施例5
胶囊剂:将1g化合物1,3-O-dicaffeoylglycerol(1)或1-O-p-coumaroyl-3-O-caffeoylglycerol(2)与.0.5g乳糖和0.1g硬脂酸镁混合均匀,过筛,均匀混合,把得到的混合物装入20颗硬明胶胶囊,囊重:80mg,含量:50mg/粒。
实施例6
口服安瓿剂:将1g化合物1,3-O-dicaffeoylglycerol(1)或1-O-p-coumaroyl-3-O-caffeoylglycerol(2)加入制备口服液所用常规添加剂及纯净水,定容至0.1L,在无菌条件下装入20只安瓿瓶中,每瓶5ml,含量:50mg/瓶。
实施例7
颗粒剂:将1g化合物1,3-O-dicaffeoylglycerol(1)或1-O-p-coumaroyl-3-O-caffeoylglycerol(2)与1g乳糖和0.6g淀粉混合均匀,用水均匀湿润、把湿润后的混合物过筛并干燥,再过筛,然后将混合物制成颗粒装袋20袋,每袋重130mg,含量为50mg/袋。
以上所述,仅是本申请的几个实施例,并非对本申请做任何形式的限制,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
Claims (10)
1.式Ⅰ所示咖啡酸甘油酯类化合物或其药学上可接受的盐、酯、溶剂合物在制备降血糖、预防和/或治疗糖尿病或糖尿病并发症药物或功能食品中的应用:
在式Ⅰ中R选自H、OH或OCH3中的任意一种。
2.如权利要求1所述应用,其特征在于,所述降血糖为降低1型糖尿病或2型糖尿病的高血糖,所述糖尿病并发症为氧化应激引起的并发症。
3.如权利要求1所述应用,其特征在于,所述药物或功能食品具有抑制α-葡萄糖苷酶活性和抗氧作用。
4.如权利要求1至3所述应用,其特征在于,所述咖啡酸甘油酯类化合物为式Ⅱ—式Ⅲ中的任一种或两种以任意比例组合:
5.如权利要求1至3所述应用,其特征在于,所述药物或功能食品还包含药学或食品上可接受的辅料,包括载体、稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、包衣材料、着色剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂中的任意一种或至少两种的组合;
优选地,所述药物剂型为片剂、胶囊剂、注射剂、颗粒剂或口服液体剂;
优选地,所述咖啡酸甘油酯类化合物每天的使用剂量按体重计算为0.01~100mg/kg。
6.式Ⅰ所示咖啡酸甘油酯类化合物或其药学上可接受的盐、酯、溶剂合物在制备α-葡萄糖苷酶活性抑制剂中的应用:
在式Ⅰ中R选自H、OH或OCH3中的任意一种。
7.式Ⅰ所示咖啡酸甘油酯类化合物或其药学上可接受的盐、酯、溶剂合物在制备抗氧化产品中的应用:
在式Ⅰ中R选自H、OH、或OCH3中的任意一种。
8.一种药物组合物,包含式Ⅰ所示咖啡酸甘油酯类化合物或其药学上可接受的盐、酯、溶剂合物中的一种或几种和药学上可接受的辅料,用作药物制剂,所述药物为降血糖药物、治疗或预防糖尿病药物、预防和/或治疗糖尿病并发症药物、α-葡萄糖苷酶活性抑制剂或抗氧化药物:
在式Ⅰ中R选自H、OH或OCH3中的任意一种。
9.如权利要求8所述组合物,其特征在于,按组合物的总重量计,含有0.001-99wt%的所述咖啡酸甘油酯类化合物或其药学上可接受的盐、酯、溶剂合物;
优选地,所述咖啡酸甘油酯类化合物每天的使用剂量按体重计算为0.01~100mg/kg。
10.如权利要求8所述组合物,其特征在于,所述药物制剂为片剂、胶囊剂、注射剂、颗粒剂或口服液体剂。
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