CN108774276B - 南方荚蒾果实木脂素提取物及其活性成分和用途 - Google Patents
南方荚蒾果实木脂素提取物及其活性成分和用途 Download PDFInfo
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Abstract
本发明属于中药成分提取剂生物活性技术领域,涉及南方荚蒾果实提取物。本发明公开了一种具有显著的蛋白酪氨酸磷酸酶1B(PTP1B)抑制活性的南方荚蒾果实木脂素提取物及其活性成分和用途。涉及南方荚蒾果实中的木脂素提取物及从其中分离出的4个苯骈二氢呋喃型新木脂素苷类化合物,经体外生物活性测试,实验结果表明这些化合物具有显著的PTP1B抑制活性,因此,可用于制备预防、延缓或治疗糖尿病、肥胖症及其并发症和其他PTP1B介导疾病的药物。
Description
技术领域
本发明属于中药成分提取及生物活性技术领域,具体涉及一种具有PTP1B抑制活性的南方荚蒾果实中木脂素提取物及其活性成分和用途。
背景技术
蛋白酪氨酸磷酸酶1B(PTP1B),是蛋白酪氨酸磷酸酶(protein tyrosinephosphatase,PTP)家族中的重要成员之一,与蛋白酪氨酸激酶(PTK)等共同作用,调节细胞内蛋白酪氨酸磷酸化水平。研究表明,PTP1B能使激活的胰岛素受体及相应的底物蛋白去磷酸化,在胰岛素信号的传导过程中起着重要的负调控作用,导致糖尿病的发生。PTP1B的过量表达还会影响瘦素信号的变化,导致肥胖症的发生。因此PTP1B可视为治疗糖尿病和肥胖症等相关疾病的重要药物靶点。
糖尿病和肥胖症是严重威胁人类身体健康的内分泌紊乱性代谢疾病。糖尿病(Diabetes mellitus)是以高血糖为主要特征,根据糖尿病的发病机制,可分为因胰岛细胞破坏导致胰岛素分泌不足而导致的I型糖尿病(胰岛素依赖型)和主要因胰岛素抵抗而导致的II型糖尿病(非胰岛素依赖性),其中II型糖尿病占90%以上。近年来,越来越多的研究表明通过抑制PTP1B,能提高胰岛素的敏感性,从而降低血糖水平。研究表明,敲除PTP1B基因后,会明显改善肥胖且瘦素抵抗的小鼠的外周胰岛素抵抗和动脉血管功能。因此,寻找安全高效、具有高选择性的PTP1B抑制剂对于糖尿病、肥胖症及其并发症等疾病的预防及治疗具有重要的意义。
南方荚蒾(Viburnum fordiae Hance)为荚蒾属植物,主要分布于安徽、浙江、江西、福建、贵州等地。据《中华本草》记载,其味苦涩、性凉,具有疏风解表、活血散瘀、清热解毒之功效,在民间,常以根、茎、叶和果实入药,用于治疗感冒、发热、过敏性皮炎、湿疹、风湿痹痛等疾病。目前对于南方荚蒾的根、茎和叶的研究较少,其药效作用物质基础尚不明确;同时,其果实的化学成分及生物活性尚未见文献报道。
发明内容
发明目的:针对上述技术问题,本发明提供了一种具有PTP1B抑制活性的南方荚蒾果实中木脂素提取物及其活性成分和用途,从南方荚蒾果实木脂素提取物中分离并鉴定4个新的苯骈二氢呋喃型新木脂素苷,可以用作预防、延缓或治疗糖尿病、肥胖症及其并发症和PTP1B介导的其他疾病的药物、食品或保健品。
技术方案:为了达到上述发明目的,本发明所采用的技术方案如下:
一种具有蛋白酪氨酸磷酸酶1B抑制活性的南方荚蒾果实木脂素提取物,其是由以下步骤制备所得:
(1)以乙醇-水混合溶液为提取剂,对南方荚蒾果实进行回流提取,提取液浓缩,干燥;
(2)将步骤(1)所得提取物溶解于水中,采用有机溶剂进行萃取后,水溶液进行减压浓缩后,获得水溶液浸膏;
(3)将水溶液浸膏溶于水中,上样于大孔吸附树脂柱色谱,依次用水、不同体积百分数的乙醇-水混合溶液梯度洗脱,收集60%至80%乙醇-水混合溶液洗脱物,减压浓缩,将得到的浓缩物溶于水中,上样于MCI GEL柱色谱,依次用水、不同体积百分数的甲醇-水混合溶液梯度洗脱,收集20%至45%甲醇-水混合溶液洗脱物,减压浓缩,即获得所述木脂素提取物。
优选:
步骤(1)中所述乙醇-水混合溶液的体积百分数(乙醇:水)为70%至95%,所述果实为荚蒾属(Viburnum)植物南方荚蒾(Viburnum fordiae Hance)的果实。
步骤(2)中所述有机溶剂为石油醚,正己烷或氯仿。
步骤(3)中所述大孔吸附树脂柱为HPD100、DM130或D101;所述MCI GEL柱色谱柱为MCI GEL CHP20/P120柱色谱。
所述木脂素提取物中的蛋白酪氨酸磷酸酶1B抑制活性成分,包括如下化学结构式所示的4个新的苯骈二氢呋喃型新木脂素苷类化合物:
所述活性成分的制备方法,包括以下步骤:
(1)将所述木脂素提取物溶解,上样于凝胶柱色谱,依次用不同体积百分数的甲醇-水梯度洗脱,收集45%至60%甲醇-水混合溶液洗脱物,减压浓缩,获得流分A-1;
(2)将流分A-1经反相柱色谱进行分离,以不同体积百分数(5%至80%)的甲醇-水溶液为流动相进行梯度洗脱,收集洗脱物,减压浓缩取得流分A-1-1至A-1-9。其中15%至20%的甲醇-水溶液洗脱物为A-1-3,25%至30%的甲醇-水溶液洗脱物为A-1-7、35%至40%的甲醇-水溶液洗脱物为A-1-8;
(3)将流分A-1-3先后经过凝胶柱色谱,甲醇为流动相;制备型高效液相色谱,甲醇-水混合溶剂为流动相,得化合物1;
将流分A-1-7先后经过凝胶柱色谱,甲醇为流动相;制备型高效液相色谱,甲醇-水混合溶剂为流动相,在不同保留时间,得化合物2和化合物3;
将流分A-1-8先后经过凝胶柱色谱,甲醇为流动相;制备型高效液相色谱,甲醇-水混合溶剂为流动相,得化合物4。
优选:
步骤(1)中所述凝胶色谱为Sephadex LH-20凝胶柱。
步骤(2)中所述反相色谱为ODS柱色谱,制备型高效液相色谱所使用的色谱柱为ODS色谱柱。
步骤(3)中所述凝胶柱色谱为Sephadex LH-20凝胶柱,制备型高效液相色谱所用色谱柱为ODS色谱柱,流动相甲醇-水混合溶剂中,甲醇与水的比例为15:85至60:40,优选比例是30:70至45:55。
一种药物组合物,该组合物包含所述木脂素提取物或所述的至少一种新木脂素苷类成分,以及药学和食品学上可接受的载体或赋形剂。
所述药学、食品及保健品可接受的载体或赋形剂选自稀释剂、分散剂、助悬剂、表面活性剂、等渗剂、增稠剂、乳化剂、防腐剂、粘合剂、润滑剂、稳定剂、水合剂、乳化加速剂、缓冲剂、吸收剂、着色剂、香味剂、甜味剂、离子交换剂、脱模剂、涂布剂、矫味剂、和抗氧化剂等。
本发明木脂素提取物或所述的新木脂素苷类化合物在制备预防、延缓或治疗PTP1B介导疾病的药物、食品或保健品中的应用。所述PTP1B介导疾病包括糖尿病、肥胖症及其并发症和其他PTP1B介导的疾病。
本发明的提取分离工艺特点如下:采用一定浓度的乙醇-水混合溶液对南方荚蒾果实进行提取---石油醚脱脂结合大孔树脂HPD100柱色谱和MCI微孔树脂柱色谱富集目标化合物---Sephadex LH-20柱色谱、ODS柱色谱和制备型高效液相进行细化分离。通过这一流程,能够最大可能富集南方荚蒾果实中木脂素类次生代谢产物。
技术效果:相对于现有技术,本发明首次提供了以南方荚蒾果实为原料,富集木脂素、分离纯化并鉴定4个新的苯骈二氢呋喃型新木脂素苷的方法,同时,测试体外PTP1B抑制活性,阐明了其在PTP1B介导的糖尿病或其他疾病的药物、食品或保健品中的应用。
附图说明
图1为本发明化合物1-4的CD谱;
图2为本发明化合物1-4的主要2D NMR相关。
具体实施方式
下面通过具体实施例对本发明所述的技术方案给予进一步详细的说明,但有必要指出以下实施例只用于对发明内容的描述,并不构成对本发明保护范围的限制。
下述制备例中,所涉及主要仪器设备为Bruker AVANCE-600型核磁共振波谱仪(德国);Bruker MaXis超高分辨飞行时间质谱仪(德国),Varian Cary 610/670傅立叶变换红外光谱仪(美国),Varian Cary 5000紫外可见近红外吸收光谱仪(美国),JACSO J-810圆二色光谱仪(日本),Thermo Multiskan GO全波长酶标仪(美国),LC3000型高效液相色谱仪(北京创新通恒);所用填料,MCI微孔树脂(日本三菱公司),Sephadex LH-20(美国GE公司),ODS(日本YMC),液相色谱柱C18(日本YMC),高效硅胶板GF254(中国青岛海洋化工公司);所用药材,南方荚蒾果实采自贵州省贵阳市,并由扬州大学生物科学与技术学院淮虎银教授鉴定为南方荚蒾果实(Viburnum fordiae Hance friuts)。
实施例1:制备南方荚蒾果实木脂素提取物
1.制备南方荚蒾果实粗提物。
(1)取1.0kg干燥的南方荚蒾果实,以体积百分数为95%的乙醇-水混合溶液为提取溶剂,料液比为1:5,回流提取三次,每次3h。合并提取液,减压浓缩即得所述粗提取物。
(2)取1.0kg干燥的南方荚蒾果实,以体积百分数为80%的乙醇-水混合溶液为提取溶剂,料液比为1:5,回流提取三次,每次2h。合并提取液,减压浓缩即得所述粗提取物;
(3)取1.0kg干燥的南方荚蒾果实,以体积百分数为70%的乙醇-水混合溶液为提取溶剂,料液比为1:5,回流提取三次,每次2h。合并提取液,减压浓缩即得所述粗提取物;
2.制备南方荚蒾果实中木脂素提取物。
取步骤1中粗提物,溶于水中,经石油醚萃取三次,水溶液和萃取石油醚的体积比为1:1。水溶液部分,减压浓缩后,水溶解,上样于大孔吸附树脂HPD100柱色谱,依次用水、体积百分数为20%、40%、60%和80%的乙醇-水梯度洗脱,收集60%至80%乙醇-水混合溶液洗脱物,减压浓缩,将此浓缩物溶于水中,上样于MCI GEL柱色谱,依次用水、体积百分数为10%、20%、45%和70%的甲醇-水梯度洗脱,收集20%至45%甲醇-水混合溶液洗脱物,减压浓缩,获得木脂素提取物。
实施例2:制备4个新木脂素苷
1.将获得的木脂素提取物溶于体积百分数为30%的甲醇-水混合溶液中,上样于Sephadex LH-20柱色谱,依次用体积百分数为30%、45%、60%和90%的甲醇-水梯度洗脱,收集45%至60%甲醇-水混合溶液洗脱物,减压浓缩,获得流分A-1。
2.将步骤1获得的流分A-1经ODS柱色谱进行分离,以不同体积百分数(5%至80%)的甲醇-水溶液为流动相进行梯度洗脱,收集洗脱物,减压浓缩取得流分A-1-1至A-1-9。其中15%至20%的甲醇-水溶液洗脱物为A-1-3,25%至30%的甲醇-水溶液洗脱物为A-1-7、35%至40%的甲醇-水溶液洗脱物为A-1-8;
3.将步骤2获得的流分A-1-3先后经过Sephadex LH-20柱色谱,甲醇为流动相;制备型高效液相色谱,甲醇-水(30:70)为流动相,得化合物1(tR=21.9min)。
4.将步骤2获得的流分A-1-7先后经过Sephadex LH-20柱色谱,甲醇为流动相;制备型高效液相色谱,甲醇-水(40:60)为流动相,得化合物2(tR=25.1min),化合物3(tR=22.4min);
5.将步骤2获得的流分A-1-8先后经过Sephadex LH-20柱色谱,甲醇为流动相;制备型高效液相色谱,甲醇-水(45:55)为流动相,得化合物4(tR=23.8min)。
7.根据新木脂素苷类化合物1-4的理化性质和波谱数据鉴定了其结构。经SCIFinder检索,确定1-4是未见报道过的新化合物,分别命名为viburfordoside A、viburfordoside B、viburfordoside C和viburfordoside D。
(1)化合物1的结构鉴定数据如下:
白色无定形粉末(甲醇)。三氯化铁-铁氰化钾反应呈阴性,Molisch反应阳性,酶解检出葡萄糖。CD(MeOH)nm(Δε)216(2.02),221(–4.15),234(–7.38),271(5.60);UV(MeOH)λmax nm(logε)208(4.89),274(4.46);HRESIMS m/z 735.2486[M+Na]+(calcd for C33H44O17Na,735.2471);IR(KBr)vmax 3401,1599,1498,1463,1127,1074,1022,890,636cm-1;1H NMR和13C NMR数据见表1。化合物1的C-7和C-8位反式相对构型由H-7和H-8的偶合常数J=6.6Hz和NOESY谱中H-2/H-6和H-8,H-7和H-9有相关峰确定。其绝对构型7S,8R由CD谱中271nm区域有正康顿效应(Cotton effect)确定。结合HSQC、HMBC、NOESY、1H-1H COSY和HSQC-TOCSY谱1。因此化合物1鉴定为viburfordoside A。
(2)化合物2的结构鉴定数据如下:
白色无定形粉末(甲醇)。三氯化铁-铁氰化钾反应呈阴性,Molisch反应阳性,酸水解检出葡萄糖。CD(MeOH)nm(Δε)217(–6.77),235(4.35),272(–6.79);UV(MeOH)λmax nm(logε)213(4.28),268(3.97);HRESIMS m/z 885.2795[M+Na]+(calcd for C41H50O20Na,885.2788);IR(KBr)vmax 3400,1703,1598,1500,1463,1123,1072,824,765,629cm-1;1H NMR和13C NMR数据见表1。化合物2的C-7和C-8位反式相对构型由H-7和H-8的偶合常数J=6.7Hz和NOESY谱中H-2/H-6和H-8,H-7和H-9有相关峰确定。其绝对构型7R,8S由CD谱中272nm区域有负康顿效应(Cotton effect)确定。结合HSQC、HMBC、NOESY和HSQC-TOCSY谱。因此化合物2鉴定为viburfordoside B。
(3)化合物3的结构鉴定数据如下:
白色无定形粉末(甲醇)。三氯化铁-铁氰化钾反应呈阴性,Molisch反应阳性,酸水解检出葡萄糖。CD(MeOH)nm(Δε)235(8.96),275(–13.39);UV(MeOH)λmax nm(logε)208(5.17),276(4.78);HRESIMS m/z 915.2897[M+Na]+(calcd forC42H52O21Na,915.2893);IR(KBr)vmax 3406,1704,1600,1499,1462,1120,1073,822,765,669cm-1;1H NMR和13C NMR数据见表1。化合物3的C-7和C-8位反式相对构型由H-7和H-8的偶合常数J=6.5Hz和NOESY谱中H-2/H-6和H-8,H-7和H-9有相关峰确定。其绝对构型7R,8S由CD谱中275nm区域有负康顿效应(Cotton effect)确定。结合HSQC、HMBC、NOESY和HSQC-TOCS谱。因此化合物3鉴定为viburfordoside C。
(4)化合物4的结构鉴定数据如下:
白色无定形粉末(甲醇)。三氯化铁-铁氰化钾反应呈阴性,Molisch反应阳性,酸水解检出葡萄糖。CD(MeOH)nm(Δε)224(3.99),231(4.59),277(–12.28),285(–12.64),UV(MeOH)λmax nm(logε)201(5.07),277(4.64);HRESIMS m/z885.2790[M+Na]+(calcd for C41H50O20Na,885.2788);IR(KBr)vmax 3391,1706,1605,1513,1463,1114,1074,1030,863,765,669cm-1;1H NMR和13C NMR数据见表1。化合物4的C-7和C-8位反式相对构型由H-7和H-8的偶合常数J=6.1Hz和NOESY谱中H-2/H-6和H-8,H-7和H-9有相关峰确定。其绝对构型7R,8S由CD谱中277nm和285nm区域有负康顿效应(Cotton effect)确定。结合HMBC和NOESY谱。因此化合物4鉴定为viburfordoside D。
表1.化合物1–4的1H NMR(600MHz)和13C NMR(150MHz)数据归属(溶剂DMSO-d6)
实施例3:蛋白质酪氨酸磷酸酯酶1B(hPTP1B)抑制活性考察
蛋白质酪氨酸磷酸酯酶1B(PTP1B),能水解底物para-Nitrophenyl Phosphate(pNPP)的磷脂键,得到产物pNP在405nm处有强吸收,通过检测405nm处光吸收值,来确定pNP的生成量,以观察酶活性的变化以及化合物对酶活性的抑制情况。
PTP1B抑制剂的体外筛选方法:选择浸膏浓度100μg/mL,木脂素提取物50μg/mL,化合物浓度20μg/mL。取2μL样品溶液加入到反应体系中(50mM 3-吗啉丙磺酸(Mops),pH 7.0,1mM EDTA,2mM DTT,10mM pNPP,2%DMSO,10mM PTP1B),37℃反应30min,测定OD405的变化值,与未加入抑制剂的空白对照比较,对hPTP1B的百分抑制率进行考察。抑制率%=[1-样品组(OD405)/对照组(OD405)]×100%,实验结果见表2。
IC50的测定:IC50即半数抑制浓度,是使酶活性降至原活性一半时的抑制剂浓度。样品溶于DMSO配成合适浓度,2倍稀释,7个稀释度,三次重复。取2μL样品溶液加入到反应体系中(50mM 3-吗啉丙磺酸(Mops),pH 7.0,1mM EDTA,2mM TT,10mMpNPP,2%DMSO,10mMPTP1B)。动态测定波长405nm处的光吸收,时间为3min,其动力学曲线一级反应的斜率作为酶的活性指标,以相对活性对化合物浓度作图,按公式v/v0=100/(1+b×[I]/IC50)拟合得到IC50值,实验结果见表3。
表2.hPTP1B抑制剂的体外初步筛选
表3.测试样品抑制PTP1B的IC50值
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,作出的若干改进和润饰也应视为本发明的保护范围。
Claims (9)
1.一种具有蛋白酪氨酸磷酸酶1B抑制活性的南方荚蒾果实木脂素提取物,其特征在于,所述木脂素提取物是由以下步骤制备所得:
(1)以乙醇-水混合溶液为提取剂,对南方荚蒾果实进行回流提取,提取液浓缩,干燥;
(2)将步骤(1)所得提取物溶解于水中,采用有机溶剂进行萃取后,水溶液进行减压浓缩后,获得水溶液浸膏;
(3)将水溶液浸膏溶于水中,上样于大孔吸附树脂柱色谱,依次用水、不同体积百分数的乙醇-水混合溶液梯度洗脱,收集60%至80%乙醇-水混合溶液洗脱物,减压浓缩,将得到的浓缩物溶于水中,上样于MCI GEL柱色谱,依次用水、不同体积百分数的甲醇-水混合溶液梯度洗脱,收集20%至45%甲醇-水混合溶液洗脱物,减压浓缩,即获得所述木脂素提取物。
2.根据权利要求1所述的木脂素提取物,其特征在于,步骤(1)中所述乙醇-水混合溶液的体积百分数(乙醇:水)为70%至95%,所述果实为荚蒾属(Viburnum)植物南方荚蒾(Viburnum fordiae Hance)的果实。
3.根据权利要求1所述的木脂素提取物,其特征在于,步骤(2)中所述有机溶剂为石油醚、正己烷或氯仿。
4.根据权利要求1所述的木脂素提取物,其特征在于,步骤(3)中所述大孔吸附树脂柱为大孔吸附树脂HPD100、DM130或D101;所述MCI GEL柱为MCI GEL CHP20/P120柱色谱。
6.权利要求5所述活性成分的制备方法,其特征在于,包括以下步骤:
(1)将权利要求1-4任一项所述的木脂素提取物溶解,上样于凝胶柱色谱,依次用不同体积百分数的甲醇-水梯度洗脱,收集45%至60%甲醇-水混合溶液洗脱物,减压浓缩,获得流分A-1;
(2)将流分A-1经反相柱色谱进行分离,以不同体积百分数的甲醇-水溶液为流动相进行梯度洗脱,收集洗脱物,减压浓缩取得流分A-1-1至A-1-9;其中15%至20%的甲醇-水溶液洗脱物为A-1-3,25%至30%的甲醇-水溶液洗脱物为A-1-7,35%至40%的甲醇-水溶液洗脱物为A-1-8;
(3)将流分A-1-7先后经过凝胶柱色谱,甲醇为流动相;制备型高效液相色谱,甲醇-水混合溶剂为流动相,在不同保留时间得化合物1和化合物2;
将流分A-1-8先后经过凝胶柱色谱,甲醇为流动相;制备型高效液相色谱,甲醇-水混合溶剂为流动相,得化合物3。
7.根据权利要求6所述的制备方法,步骤(1)(3)所述凝胶柱色谱为Sephadex LH-20柱色谱;步骤(2)所述的反相柱色谱为ODS柱色谱;步骤(3)所述的制备型高效液相色谱所使用的色谱柱为ODS色谱柱;步骤(3)中所述甲醇-水混合溶剂中,甲醇与水的比例为15:85至60:40。
8.权利要求1所述的木脂素提取物或权利要求5所述的新木脂素苷类化合物在制备预防、延缓或治疗PTP1B介导疾病的药物、食品或保健品中的应用。
9.根据权利要求8所述的应用,其特征在于,所述PTP1B介导疾病为糖尿病、肥胖症或其并发症。
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