CN107176936A - 海藻倍半萜类化合物、其制备方法及用途 - Google Patents
海藻倍半萜类化合物、其制备方法及用途 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/685—Processes comprising at least two steps in series
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
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- C07C37/82—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by solid-liquid treatment; by chemisorption
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/24—Halogenated derivatives
- C07C39/42—Halogenated derivatives containing six-membered aromatic rings and other rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及医药技术领域,具体而言,是指海藻倍半萜类化合物及其制备方法和应用。本发明所述的倍半萜化合物具有如下通式I所示的结构。其制备方法为将海洋红藻冈村凹顶藻经海水冲洗干净后冷冻、剪碎、渗漉提取、并通过多种分离手段得到单体化合物,这类化合物属于天然有机小分子化合物,经体外检测表明具有较明显的抗蛋白酪氨酸磷酸酶1B活性。本发明可以为研制新的抗II型糖尿病药物提供先导化合物,对于开发利用中国海洋生物资源具有重要意义。
Description
技术领域
本发明属于医药技术领域。具体是涉及两种从中国东海海藻中分离得到的化合物及其制备方法和新用途,尤其涉及,其在制备预防和/或治疗II型糖尿病药物中的用途。
背景技术
糖尿病是一种常见病、多发病,已成为现代疾病中的第二杀手,它对人体的危害仅次于癌症,世界卫生组织已将糖尿病列为三大疑难病之一。糖尿病是一组以高血糖为特征的代谢性疾病。高血糖则是由于胰岛素分泌缺陷或其生物作用受损,或两者兼有引起。糖尿病是长期存在的高血糖,导致各种组织,特别是眼、肾、心脏、血管、神经的慢性损害、功能障碍。糖尿病分为I型糖尿病和II型糖尿病。I型糖尿病,原名胰岛素依赖型糖尿病,多发生在儿童和青少年,也可发生于各种年龄,起病比较急剧,体内胰岛素绝对不足,容易发生酮症酸中毒,必须用胰岛素治疗才能获得满意疗效,否则将危及生命。II型糖尿病原名叫成人发病型糖尿病,多在35~40岁之后发病,占糖尿病患者90%以上。II型糖尿病患者体内产生胰岛素的能力并非完全丧失,有的患者体内胰岛素甚至产生过多,但胰岛素的作用效果较差,因此患者体内的胰岛素是一种相对缺乏,可以通过某些口服药物刺激体内胰岛素的分泌。但到后期仍有一些病人需要使用胰岛素治疗。
目前市场上常见的口服降糖药有双胍类、磺脲类、噻唑烷二酮类、苯甲酸衍生物类和α-葡萄糖苷酶抑制剂。PTP1B(蛋白酪氨酸磷酯酶1B)在胰岛素信号转导通路中起着重要的负调控作用。PTP1B抑制剂增强胰岛素的信号响应,已成为治疗II型糖尿病的新靶点。国际上对PTP1B抑制剂的研究不多,主要有以下几类:(1)肽类:含磷酸化酪氨酸残基(pTyr)的肽类:底物与PTP1B有较高的亲和性,但其化学和生物稳定性差;(2)萘醌类(Naphthnoquinone):通过修饰PTPase的活性位点来抑制酶的活性;(3)噻唑烷二酮类(Azolidinediones):通过增加靶器官的胰岛素敏感性来改善血糖的控制,主要包括ciglitazone、troglitazone和rosiglitazone,但由于严重的肝脏毒性,ciglitazone已从市场撤出;(4)苯并[b]萘并[2,3-d]呋喃类(Benzo[b]naphthol[2,3-d]furans)和噻吩类(thiophenes):以苯溴马隆(benzbromarone)(PTP1B抑制剂,IC50=26μM)为先导化合物进行设计合成的系列Benzo[b]naphthol[2,3-d]furans和thiophenes类化合物,在小鼠体内表现出良好的降血糖活性,但要最终成为治疗糖尿病药物还需要克服很多障碍,如电负性高、细胞膜通透性差以及选择专一性差等,以上因素都使这些抑制剂的成药性降低。
对于糖尿病的治疗,目前临床上医生建议采取X+1的服药方式,即在服用降糖药的同时,加一种保肝护肝的药物,这是因为不仅糖尿病本身容易导致肝脏的代谢紊乱,而且长期服用药物也会导致肝脏损伤。在双重压力下,如果不注重保肝治疗,很容易造成脂肪肝、药物性肝炎、肝硬化等严重问题,这不仅带来了用药的繁琐性,更增加了糖尿病病人的经济负担。目前,世界各国共有超过三亿人存在患上糖尿病的风险。对一些高发地区来说,糖尿病造成的经济损失甚至可能大于所谓的“世纪瘟疫艾滋病”。到了2025年,75%的糖尿病患者将集中在发展中国家。中国作为活跃在世界舞台上、人口众多的发展中国家,目前约有5千万糖尿病人,而且有上升的趋势,严重威胁到人类的健康,未来由糖尿病带来的人员和经济损失将不可估计,加之国内目前也尚未有具有自主知识产权的治疗糖尿病的药物,因此,发现具有良好活性的且副作用小的拥有我国自主知识产权的糖尿病药物,仍然是目前的研究热点。
发明内容
本发明的目的是提供海藻倍半萜类化合物及其制备方法和用途。
为实现上述目的,本发明采用的技术方案为:
海藻倍半萜类化合物具有如下所示的通式I所示的结构
其中,
R1为氢或溴;
表示双键或单键,当为单键时,R2为甲基;当为双键时,R2不存在;
R3、R4一起与所在的环基上的碳原子形成呋喃环,或R3为羟基;
当R3、R4一起与所在的环基上的碳原子形成呋喃环时,R5、R6各自为甲基,R7为氢或过氧羟基;
当R3为羟基时,R7为氢,R4、R5、R6同时为甲基,或者R6为甲基,而R4、R5一起与和它们相连的碳原子形成C=CH2,或者R5为甲基,而R4、R6一起形成为亚甲基与和它们相连的碳原子形成三元环。
所述海藻倍半萜类化合物优选为以下五种化合物:
根据本发明的另一方面,提供了所述海藻倍半萜类化合物的制备方法,包括以下步骤:
(1)将冰冻的海洋红藻冈村凹顶藻剪碎,然后用有机溶剂浸泡,合并提取液进行减压浓缩,再用无水乙醚萃取,萃取液浓缩得到无水乙醚浸膏;
(2)将步骤(1)中的无水乙醚浸膏进行硅胶柱层析处理,用有机溶剂进行梯度洗脱,收集洗脱组分;
(3)将收集的洗脱组分再分别经过1次凝胶柱层析和1次或2次硅胶柱层析纯化,即得所述的海藻倍半萜类化合物。
其中,
步骤(1)中所述的有机溶剂可以为丙酮;
步骤(2)中所述的有机溶剂可以是石油醚和二氯甲烷体积比呈梯度的混合溶剂;优选的,所述的有机溶剂为石油醚-二氯甲烷体积比10:0-7:3的混合溶剂,具体可以为石油醚-二氯甲烷体积比依次为10:0、9:1、8:2、7:3的混合溶剂,收集的洗脱组分为收集体积比9:1的部分洗脱组分;
步骤(2)所述硅胶优选为200-300目,可以购买自青岛海洋化工有限公司等;
步骤(3)所述凝胶柱层析可以购买自GE-Healthcare公司;Sephadex LH-20,羟丙基葡聚糖凝胶,17-0090-02,500g。
步骤(3)所述硅胶优选为500-600目,可以购买自青岛海洋化工有限公司。
步骤(3)中,所述的凝胶柱层析洗脱溶剂为体积比2:1:1的石油醚-二氯甲烷-甲醇混合溶剂;
步骤(3)中,所述的两次硅胶柱层析洗脱溶剂分别为石油醚-二氯甲烷体积比9:1和8:2的混合溶剂。
根据本发明的再一方面,提供了所述海藻倍半萜类化合物用于制备预防和/或治疗II型糖尿病的药物的用途。
本发明具有以下优点:
本发明涉及的海洋红藻冈村凹顶藻(Laurenciaokamurai)属于仙菜目(Ceramials),松节藻科(Rhodomelaceae),凹顶藻属(Laurencia)海藻,广泛分布于我国沿海海域,是红藻中最为常见的藻类植物之一。本发明通过海洋红藻冈村凹顶藻经提取、分离、纯化获得的倍半萜类天然化合物属于小分子天然有机化合物,容易制备获得,经实验表明,它们具有显著的抗蛋白酪氨酸磷酸酶1B(PTP1B)活性。不仅可以为研制新的抗II型糖尿病药物提供先导化合物,对于开发利用中国海洋生物资源也具有重要意义。
具体实施方式
下面结合实施例对本发明做进一步阐述。除特殊说明外,本申请采用的试剂、设备及检测方法等均为本领域常规的试剂、设备及方法。
实施例1:
海藻倍半萜类化合物的制备:
(1)将冰冻的海洋红藻冈村凹顶藻剪碎,然后用丙酮浸泡、提取4次,合并提取液进行减压浓缩,再用无水乙醚萃取至上清液接近无色,将萃取液浓缩得到无水乙醚浸膏;
(2)将步骤(1)中的无水乙醚浸膏进行硅胶柱层析(200-300目,青岛海洋化工有限公司)处理,用有机溶剂进行梯度洗脱,收集洗脱组分;
(3)将收集的洗脱组分再分别经过1次凝胶柱层析(GE-Healthcare公司,ephadex LH-20,羟丙基葡聚糖凝胶,17-0090-02,500g)和1次或2次硅胶柱层析纯化(500-600目,青岛海洋化工有限公司),即得化合物1~5。
步骤(2)中,用有机溶剂进行梯度洗脱是使用石油醚-二氯甲烷按体积比10:0-7:3的梯度(具体为10:0、9:1、8:2、7:3)进行洗脱,收集的洗脱组分为体积比为9:1的洗脱部分。
步骤(3)中,所述的两次硅胶柱层析洗脱溶剂分别为石油醚-二氯甲烷体积比9:1和8:2的混合溶剂。
步骤(3)中,所述的凝胶柱层析洗脱溶剂为2:1:1的石油醚-二氯甲烷-甲醇混合溶剂,TLC检测,硫酸-香兰素显色剂显色,化合物1、2、3和5均显示紫色,化合物4显示黄绿色。
薄层层析展开实验中,当展开剂为体积比为2:3的石油醚-二氯甲烷时,Rf值为0.23-0.28处的组分为化合物2,Rf值为0.38-0.43处的组分为化合物1;当展开剂为体积比为3:2的石油醚-二氯甲烷时,Rf值为0.48-0.53处的组分为化合物3,Rf值为0.55-0.60处的组分为化合物5,Rf值为0.62-0.67处的组分为化合物4。
经波普解析,其结构鉴定为如下所示的5个化合物。
化合物1所示结构的理化性质:白色粉末,分子式为C15H19O3Br;核磁共振氢谱数据1H NMR(400MHz,CDCl3):1.21(s),1.36(s),1.41(ddd,J=13.8,13.2,7.2Hz)1.47(s),1.74(dd,J=12.6,7.2Hz),1.92(ddd,J=13.2,12.6,6.6Hz),2.17(dd,J=13.8,6.6Hz)2.31(s),6.59(s),7.17(s)ppm;质谱数据:LREIMS:m/z 326,328.
化合物2所示结构的理化性质:浅黄色油状,分子式为C15H20O3;核磁共振氢谱数据1H NMR(400MHz,CDCl3):1.21(s),1.36(s),1.43(dd,J=13.7,7.1Hz)1.47(s),1.74(dd,J=12.1,7.1Hz),1.91(ddd,J=13.2,12.6,6.6Hz),2.15(dd,J=13.7,6.4Hz)2.29(s),6.53(s),6.69(d7.6),6.94(d 7.6)ppm;质谱数据:LREIMS:m/z 248.
化合物3所示结构的理化性质:白色针晶,分子式为C15H19OBr;核磁共振氢谱数据1H NMR(400MHz,CDCl3):0.56(m,2H),1.15(m),1.26(m),1.34(s),1.40(s),1.65(dd J=12.6,7.2Hz),1.94(m),2.18(ddJ=12.6,5.1Hz),2.31(s),5.24(s),6.61(s),7.60(s)ppm;质谱数据:LREIMS:m/z 294,296.
化合物4所示结构的理化性质:无色油状,分子式为C15H19OBr;核磁共振氢谱数据1H NMR(400MHz,CDCl3):0.90(s),0.99(s),1.03(d,J=6.5Hz),2.07(m),2.11(m),2.34(s),2.53(m),5.35(s),5.77(s),6.84(s),7.19(s)ppm;质谱数据:LREIMS:m/z 294,296.
化合物5所示结构的理化性质:白色针晶,分子式为C15H19OBr;核磁共振氢谱数据1H NMR(400MHz,CDCl3):1.21(d,J=7.0Hz),1.41(m),1.46(s),1.60(ddd J=14.7,9.9,7.2Hz),2.06(m),2.21(ddd J=14.7,9.9,7.2Hz),2.31(s),2.85(m),4.94(d,J=2.1Hz),5.10(d,J=2.1Hz),5.55(s),6.73(s),7.45(s)ppm;质谱数据:LREIMS:m/z 294,296.
NMR测试以CHCl3(δH 7.26ppm;δC 77.0ppm)做内标,仪器为Bruker DRX-400 spectrometer(Bruker Biospin AG,Germany).
实验例2:化合物抑制PTP1B活性测试
1)材料:PTP1B,实验室纯化得到,参考文献Biochim Biophys Acta,2006,1760,1505-1512。
底物:pNPP(对硝基苯磷酸二钠)
2)过程:采用光吸收检测法,在96孔或384孔平底透明微孔板中检测酶活性。底物pNPP经PTP1B水解得到的游离产物在405nm处有很强的光吸收。通过酶标仪监测405nm处光吸收强度的变化,计算得到反应初速度。实验中采用的对照化合物为齐墩果酸。
3)样品处理:样品用DMSO溶解,低温保存,DMSO在最终体系中的浓度控制在不影响检测活性的范围之内。
4)数据处理及结果说明:
初筛选择单浓度条件下,例如20μg/ml,对样品的活性进行测试。对于在一定条件下表现出活性的样品,例如抑制率(%,inhibition)大于50,测试活性剂量依赖关系,即IC50/EC50值,通过样品活性对样品浓度进行非线性拟合得到,计算所用软件为Graphpad Prism4,拟合所使用的模型为S形剂量效应积分模型(sigmoidaldose-response)(varible slope),对于大多数抑制剂筛选模型,将拟合曲线底部和顶部设定为0和100。一般情况下,每个样品在测试中均设置复孔(n≥2),在结果中以标准偏差(Standard Deviation,SD)或者标准误差(Standard Error,SE)表示。每次测试均以齐墩果酸为参照(IC50=1.07±0.18μg/ml)。结果见表1。
表1:化合物的抑制PTP1B的活性数据
化合物名称 | 抑制率(%)(20μg/ml) | IC50(μg/ml) |
化合物1 | 82.92±3.65 | 14.92±2.57 |
化合物2 | 84.87±1.06 | 13.00±2.98 |
化合物3 | 62.32±7.77 | 13.32±2.09 |
化合物4 | 97.88±1.48 | 4.91±0.54 |
化合物5 | 75.72±2.65 | 7.00±0.78 |
根据以上实验说明,这5个化合物对PTP1B有一定的抑制活性,而且这些化合物均来自海洋生物资源,并且在海洋生物资源中比较容易分离得到,这不仅为研发毒副作用小的、拥有中国自主知识产权的新型糖尿病药物提供了可能,还有利于为开发海洋资源、维持生态平衡提供方向。
Claims (7)
1.海藻倍半萜类化合物,其具有如下通式I所示的结构
其中,
R1为氢或溴;
表示双键或单键,当为单键时,R2为甲基;当为双键时,R2不存在;
R3、R4一起与所在的环基上的碳原子形成呋喃环,或R3为羟基;
当R3、R4一起与所在的环基上的碳原子形成呋喃环时,R5、R6各自为甲基,R7为氢或过氧羟基;
当R3为羟基,R7为氢时,R4、R5、R6同时为甲基,或者R6为甲基,而R4、R5一起与和它们相连的碳原子形成C=CH2,或者R5为甲基,而R4、R6一起形成为亚甲基并与和它们相连的碳原子形成三元环。
2.根据权利要求1所述的海藻倍半萜类化合物,其具体选自如下化合物:
3.权利要求1或2所述的海藻倍半萜类化合物的制备方法,其特征在于,包括以下步骤:
(1)将冰冻的海洋红藻冈村凹顶藻剪碎,然后用有机溶剂浸泡,合并提取液进行减压浓缩,再用无水乙醚萃取,萃取液浓缩得到无水乙醚浸膏;
(2)将步骤(1)中的无水乙醚浸膏进行硅胶柱层析处理,用有机溶剂进行梯度洗脱,收集洗脱组分;
(3)将收集的洗脱组分再经过1次凝胶柱层析和1次或2次硅胶柱层析纯化。
4.根据权利要求3所述的制备方法,其特征在于,步骤(1)中所述的有机溶剂为丙酮;步骤(2)中所述的有机溶剂是石油醚和二氯甲烷的混合溶剂。
5.根据权利要求3所述的制备方法,其特征在于,步骤(2)中,所述的有机溶剂为体积比10:0-7:3石油醚-二氯甲烷的混合溶剂,收集的洗脱组分为收集体积比9:1石油醚-二氯甲烷的混合溶剂洗脱时的洗脱组分。
6.权利要求3所述的制备方法,其特征在于,步骤(3)中,所述的凝胶柱层析的洗脱溶剂为体积比2:1:1的石油醚-二氯甲烷-甲醇混合溶剂。
7.如权利要求1或2所述的海藻倍半萜类化合物用于制备预防和/或治疗II型糖尿病的药物的用途。
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